Pirfenidone Alleviates Features of Well-Established Chronic Pancreatitis in Mouse Models

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S74-S74
Author(s):  
E Palathingal Bava ◽  
M Tarique ◽  
S Iyer ◽  
P Sahay ◽  
R Dawra ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Chronic Pancreatitis ◽  
Mouse Models ◽  
Inflammatory Cytokines ◽  
Weight Ratio ◽  
Stellate Cells ◽  
M2 Macrophage ◽  
Mrna Levels ◽  
Pancreatic Atrophy

Abstract Introduction/Objective Chronic pancreatitis (CP) is a fibro-inflammatory disease of pancreas with no targeted therapy and is considered irreversible. Antifibrotic agent pirfenidone is FDA approved for idiopathic pulmonary fibrosis. However, exact molecular mechanism of its action is not clear. The aim of this study was to evaluate pirfenidone as a therapeutic agent for CP. Methods Caerulein-CP was induced in C57BL/6 mice by caerulein injections (50ug/kgx7, i.p., hourly x twice weekly x10 weeks). At 11 weeks, animals were randomized and assigned to either saline or pirfenidone group (400 mg/kg/d by oral gavage for 5 weeks). Mice were euthanized at 17 weeks. L-arginine induced CP was induced by i.p. injections of L-arginine (4.5g/kg x2 hourly, once a week x 4) and treatment was started after 5 weeks of start. Mice were sacrificed at early time-points after starting treatment. Single-cell suspension of pancreata were used for flow- cytometry. Pancreatic atrophy, histology, fibrosis and cytokine mRNA profile were evaluated. In vitro studies were done on stellate cells. Results The treated caerulein-CP mice had improvement in pancreas/mouse weight ratio, (7.03±0.41 vs. 4.75±0.28; p<0.0001). Histology scores and fibrosis markers were reduced. Pancreatic atrophy and histology scores showed significant improvement by day 14 of treatment in L-arginine CP. Flow cytometry showed that by day 7 of treatment there was significant reduction in macrophage infiltration (1.09 ± 0.18 % vs 3.26 ± 0.4 %; p<0.001) and pro-fibrotic M2 macrophage markers [IL-4 (1.5 ± 0.1 % vs 2.8 ± 0.2%; p=0.007)], while M1 marker (MHC II) did not change. mRNA levels of pro-inflammatory and pro-fibrotic cytokines decreased, and of anti-inflammatory cytokines increased. In vitro study on stellate cells showed reduction in mRNA levels of pro-fibrotic and pro-inflammatory cytokines as well as fibrosis markers in treatment group. Conclusion Pirfenidone ameliorates well-established CP in mouse models by altering immune cells.

scholarly journals Complement Component 5 Mediates Development of Fibrosis, via Activation of Stellate Cells, in 2 Mouse Models of Chronic Pancreatitis

2015 ◽  
Vol 149 (3) ◽  
pp. 765-776.e10 ◽  
Author(s):  
Matthias Sendler ◽  
Georg Beyer ◽  
Ujjwal M. Mahajan ◽  
Vivien Kauschke ◽  
Sandrina Maertin ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Mouse Models ◽  
Stellate Cells ◽  
Complement Component

scholarly journals Thyroxine Affects Lipopolysaccharide-Induced Macrophage Differentiation and Myocardial Cell Apoptosis via the NF-κB p65 Pathway Both In Vitro and In Vivo

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Shan Zhu ◽  
Yuan Wang ◽  
Hongtao Liu ◽  
Wen Wei ◽  
Yi Tu ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cardiac Dysfunction ◽  
Cell Apoptosis ◽  
Cardiac Injury ◽  
Myocardial Cell ◽  
M2 Macrophage ◽  
Mrna Levels ◽  
Cytokine Mrna ◽  
M1 Macrophage

Background. Numerous studies have demonstrated that the inflammatory response is involved in the progression of lipopolysaccharide- (LPS-) induced myocardial cell apoptosis. Accumulating evidence has shown that thyroxine participates in diseases by downregulating the inflammatory response. This study aimed at investigating whether thyroxine alleviates LPS-induced myocardial cell apoptosis. Methods. Bone marrow-derived macrophages (Mø) were treated with LPS and thyroxine, and Mø differentiation and Mø-related cytokine expression were measured. The effect of Mø differentiation on mouse cardiomyocyte (MCM) apoptosis was also detected in vitro. In addition, C57BL/6 mice underwent thyroidectomy and were treated with LPS 35 days later; subsequently, Mø differentiation and myocardial cell apoptosis in hearts were analyzed. To determine whether the nuclear factor-kappa B (NF-κB) p65 pathway mediates the effect of thyroxine on Mø differentiation and myocardial cell apoptosis, the specific NF-κB p65 pathway inhibitor JSH-23 was administered to mice that underwent a thyroidectomy. Results. Levothyroxine treatment significantly reduced the activation of the NF-κB p65 pathway, decreased M1 macrophage (Mø1) differentiation and Mø1-related cytokine mRNA levels in LPS-treated Mø, and increased M2 macrophage (Mø2) differentiation and Mø2-related cytokine mRNA expression. The protective effects of levothyroxine on MCM apoptosis mediated by LPS-treated Mø were alleviated by JSH-23. In mice, thyroidectomy aggravated LPS-induced cardiac injury and cardiac dysfunction, further promoted NF-κB p65 activation, and increased cardiac Mø1 expression and myocardial cell apoptosis but decreased cardiac Mø2 expression. JSH-23 treatment significantly ameliorated the thyroidectomy-induced increases in myocardial cell apoptosis and Mø differentiation. Conclusions. Thyroxine alleviated the Mø1/Mø2 imbalance, reduced the inflammatory response, decreased myocardial cell apoptosis, and protected against cardiac injury and cardiac dysfunction in LPS-treated mice. Thyroxine may be a novel therapeutic strategy to prevent and treat LPS-induced cardiac injury.

scholarly journals B7-H4 Inhibits the Development of Primary Sjögren’s Syndrome by Regulating Treg Differentiation in NOD/Ltj Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Xu Zheng ◽  
Qikai Wang ◽  
Xiang Yuan ◽  
Yingbo Zhou ◽  
Hui Chu ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Salivary Gland ◽  
T Cell ◽  
Salivary Glands ◽  
Inflammatory Cytokines ◽  
Mrna Levels ◽  
Lymphocyte Infiltration ◽  
Flow Cytometry Analysis ◽  
Treg Differentiation

Background. This study is aimed at exploring the role of B7-H4 in the pathogenesis of primary Sjögren’s syndrome (pSS) in NOD/Ltj mouse. Methods. B7-H4 expression in salivary glands was examined by IHC, and lymphocyte infiltration was showed by H&E. Next, anti-B7-H4 mAb or immunoglobulin isotype was injected into NOD/Ltj mice. Cytokine levels were measured by quantitative RT-PCR, and immunoglobulins were measured by ELISA. T cell subsets were analyzed by flow cytometry. Last, we treated NOD/Ltj mice with B7-H4Ig and control Ig. CD4+Foxp3+ T cells were assessed by immunohistochemistry. Two-tailed Student’s t-tests were used to detect the statistical difference in various measures between the two groups. Results. B7-H4 expression was remarkably reduced in salivary glands of NOD/Ltj mice at 15 weeks compared with the NOD/Ltj mice at 8 weeks. Anti-B7-H4 mAb treatment increased lymphocyte infiltration in salivary glands. Inflammatory cytokines including IL-12, IL-18, IL-1α, TNF-α, IFN-α, and BAFF were upregulated markedly in anti-B7-H4 mAb-treated mice compared to IgG isotype-treated mice. Flow cytometry analysis showed that anti-B7-H4 mAb-treated mice had lower levels of CD4+Foxp3+/CD4+ T cells in spleen. Moreover, Foxp3 mRNA levels of salivary glands were diminished in anti-B7-H4 mAb-treated mice. Flow cytometry analysis showed that anti-B7-H4 mAb inhibited CD4+Foxp3+/CD4+ T cell production, while B7-H4Ig would promote naïve CD4+ T into Treg differentiation. Administration with B7-H4Ig displayed significantly decreased lymphocyte infiltration in salivary glands and low levels of total IgM and IgG in serum. Analysis of inflammatory cytokines in salivary glands after B7-H4Ig treatment revealed that the mRNA levels of IL-12, IL-6, IL-18, IL-1α, TNF-α, and IFN-α were significantly downregulated in B7-H4Ig-treated mice compared to control Ig treatment. B7-H4Ig-treated mice had significantly higher levels of CD4+Foxp3+/CD4+ T cells in spleen. IHC in salivary gland revealed that CD4+Foxp3+ T cells of B7-H4Ig treatment mouse were more than control Ig treatment. Conclusions. Our findings implicate that B7-H4 has a protective role for salivary gland epithelial cells (SGECs) and therapeutic potential in the treatment of pSS.

scholarly journals Growth Arrest-Specific 6 Enhances the Suppressive Function of CD4+CD25+Regulatory T Cells Mainly through Axl Receptor

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Guang-ju Zhao ◽  
Jia-yi Zheng ◽  
Jia-lan Bian ◽  
Long-wang Chen ◽  
Ning Dong ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Regulatory T Cells ◽  
Growth Arrest ◽  
Mrna Levels ◽  
Suppressive Function ◽  
Naturally Occurring ◽  
Tam Receptors

Background.Growth arrest-specific (Gas) 6 is one of the endogenous ligands of TAM receptors (Tyro3, Axl, and Mertk), and its role as an immune modulator has been recently emphasized. Naturally occurring CD4+CD25+regulatory T cells (Tregs) are essential for the active suppression of autoimmunity. The present study was designed to investigate whether Tregs express TAM receptors and the potential role of Gas6-TAM signal in regulating the suppressive function of Tregs.Methods.The protein and mRNA levels of TAM receptors were determined by using Western blot, immunofluorescence, flow cytometry, and RT-PCR. Then, TAM receptors were silenced using targeted siRNA or blocked with specific antibody. The suppressive function of Tregs was assessed by using a CFSE-based T cell proliferation assay. Flow cytometry was used to determine the expression of Foxp3 and CTLA4 whereas cytokines secretion levels were measured by ELISA assay.Results.Tregs express both Axl and Mertk receptors. Gas6 increases the suppressive function of Tregs in vitro and in mice. Both Foxp3 and CTLA-4 expression on Tregs are enhanced after Gas6 stimulation. Gas6 enhances the suppressive activity of Tregs mainly through Axl receptor.Conclusion. Gas6 has a direct effect on the functions of CD4+CD25+Tregs mainly through its interaction with Axl receptor.

scholarly journals Synaptic Plasticity of Human Umbilical Cord Mesenchymal Stem Cell Differentiating into Neuron-like Cells In Vitro Induced by Edaravone

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Yunpeng Shi ◽  
Chengrui Nan ◽  
Zhongjie Yan ◽  
Liqiang Liu ◽  
Jingjing Zhou ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Umbilical Cord ◽  
Neuron Specific Enolase ◽  
Control Group ◽  
Human Umbilical Cord ◽  
Mrna Levels ◽  
Neuronal Markers ◽  
Hla Dr ◽  
Umbilical Cord Tissue

Objective. The human umbilical cord mesenchymal stem cells (hUMSCs) are characterized with the potential ability to differentiate to several types of cells. Edaravone has been demonstrated to prevent the hUMSCs from the oxidative damage, especially its ability in antioxidative stress. We hypothesized that Edaravone induces the hUMSCs into the neuron-like cells. Methods. The hUMSCs were obtained from the human umbilical cord tissue. The differentiation of hUMSCs was induced by Edaravone with three different doses: 0.65 mg/ml, 1.31 mg/ml, and 2.62 mg/ml. Flow cytometry was used to detect the cell markers. Protein and mRNA levels of nestin, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP) were detected by Western blot and RT-PCR. The expression of synaptophysin (SYN), growth-associated protein 43 (GAP43), and postsynaptic density 95 (PSD95) was detected by Real-Time PCR. Results. As long as the prolongation of the culture, the hUMSCs displayed with the long strips or long fusiform to fat and then characterized with the radial helix growth. By using flow cytometry, the cultured hUMSCs at the 3rd, 5th, and 10th passages were expressed with CD73, CD90, and CD105 but not CD11b, CD19, CD34, CD45, and HLA-DR. Most of the hUMSCs cultured with Edaravone exhibited typical nerve-immediately characters including the cell body contraction, increased refraction, and protruding one or more elongated protrusions, which were not found in the control group without addition of Edaravone. NSE, nestin, and GFAP were positive in these neuron-like cells. Edaravone dose-dependently increased expression levels of NSE, nestin, and GFAP. After replacement of maintenance fluid, neuron-like cells continued to be cultured for five days. These neuron-like cells were positive for SYN, PSD95, and GAP43. Conclusion. Edaravone can dose-dependently induce hUMSCs to differentiate into neuron-like cells that expressed the neuronal markers including NSE, nestin, and GFAP and synaptic makers such as SYN, PSD95, and GAP43.

Cytokine-Mediated Inflammatory Pathways Promote Clonal Evolution and Disease Progression in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1688-1688 ◽  
Author(s):  
Christopher O. Eden ◽  
David K. Edwards ◽  
Christopher A. Eide ◽  
Elie Traer ◽  
Jeffrey W. Tyner ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Disease Progression ◽  
Inflammatory Cytokines ◽  
Clonal Expansion ◽  
Wild Type ◽  
Cd34 Cells ◽  
Clonogenic Potential

Abstract Background: Inflammatory cytokines secreted in the bone marrow microenvironment play important roles in modulating cell survival, proliferation, differentiation, and immune responses in cancer. Perhaps not surprisingly, there is also an association between chronic inflammation and tumor progression. We recently used an ex vivo functional screen of 94 cytokines to show that the pro-inflammatory cytokines IL1α and IL1β promoted the expansion of AML progenitors in 70% (40/60) of primary samples. We therefore hypothesized that inflammatory cytokines are crucial to clonal expansion and disease progression in AML and that therapeutic targeting of these pathways may circumvent disease heterogeneity. Here we provide in vitro and in vivo evidence that IL1-mediated signaling elicits profound expansion of leukemia progenitors in AML patients harboring various genetic mutations and promotes in vivo clonal expansion and disease progression in a murine AML model. Further, these effects are reversed by targeting IL1 signaling. Methods: We validated the role of IL1 signaling using a shRNA approach and in murine competitive repopulation and bone marrow transplantation models. We evaluated the influence of these cytokines on inflammatory markers using immunoblotting, flow cytometry, and Luminex assays, and assessed strategies to target these pathways using small-molecule inhibitors. Results: IL1 stimulation promoted a 3- to 20-fold increase in growth, survival, and clonogenic potential of AML CD34+ cells, while paradoxically suppressing growth of healthy CD34+ cells. To identify the influence of IL1 on in vivo clonal expansion of healthy and leukemic progenitors simultaneously, we established an in vivo murine competitive repopulation study utilizing TET2-null mice. IL1 treatment promoted clonal expansion of TET2-null myeloid cells over wild-type cells during 6 weeks of IL1β treatment. Consistent with this, both flow cytometry analysis and blood differential counts showed an increased percentage of granulocytes and reduced percentage of lymphocytes in IL1-treated mice. In this model, TET2-null monocytes have greater expression of IL1 than wild-type cells, suggesting IL1 promotes clonal growth of TET2-mutated early leukemic progenitors. Similarly, IL1β and IL1 receptors (IL1R1 and IL1RAP) were overexpressed in IL1-sensitive AML bone marrow and peripheral blood samples compared to nonsensitive AML samples and normal samples. Intracellular FACS showed that the majority of IL1β was secreted by monocytes and to some extent by myeloid progenitors. Accordingly, IL1-sensitive AML samples exhibited trends towards monocytic and myelomonocytic clinical features. Reduced survival of AML cells after monocyte depletion was rescued by IL1 treatment, suggesting that IL1 mediates paracrine regulation of AML cell growth. Silencing of the IL1 receptor, IL1R1, reduced the clonogenic potential of AML primary samples and oncogene (AML1-ETO9a, NRASG12D, and MLL-ENL)-transduced mouse bone marrow. In a murine bone marrow transplantation model, recipients of IL1R1-/- marrow transduced with AML1-ETO9a/NRASG12D survived significantly longer than did recipients of wild-type marrow. We also found that IL1β increased phosphorylation of p38MAPK and MK2, as well as secretion of multiple downstream inflammatory cytokines (IL6, IL8, MCP1, MIP1α, and MIP1β) from CD34+ progenitors, in IL1-sensitive AML samples compared to IL1-nonsensitive progenitors. Conversely, treating AML cells with p38MAPK inhibitors such as doramapimod andralimetinib reduced the growth of AML cells by decreasing p38MAPK and MK2 phosphorylation and reducing secretion of inflammatory cytokines from AML progenitors. Clinical and demographic analyses suggest that AML patients are dependent on IL1 signaling irrespective of mutation status and clinical features. Targeting this unifying mechanism of IL1-mediated clonal expansion may thus have application across heterogeneous AML subtypes. Conclusion: We demonstrate that IL1 promotes in vitro and in vivo clonal expansion of leukemic cells and promotes disease progression in AML. As IL1 signaling is active across heterogeneous disease subtypes, AML patients may therefore benefit from drugs targeting IL1/p38MAPK signaling because of their potential to inhibit AML while enhancing normal hematopoiesis, a significant clinical advantage over traditional chemotherapy. Disclosures Agarwal: CTI BioPharma Corp: Research Funding.

Effects of Compressive Loading on Human Synovium-derived Cells

2007 ◽  
Vol 86 (8) ◽  
pp. 786-791 ◽  
Author(s):  
Y. Muroi ◽  
K. Kakudo ◽  
K. Nakata
Keyword(s):  
Protein Expression ◽  
Temporomandibular Joint ◽  
Inflammatory Cytokines ◽  
Apoptotic Cell ◽  
Compressive Loading ◽  
Cell Number ◽  
Joint Disease ◽  
Mrna Levels ◽  
Dna Amount

Compressive stress may be involved in temporomandibular joint (TMJ) synovitis, but its mechanism has not been fully elucidated. We hypothesized that mechanical stress to the synovial cells of the TMJ potentially causes degenerative changes in temporomandibular joint disease. We examined the effect of cyclic compressive loading on three-dimensionally engineered constructs using human TMJ synovium-derived cells in vitro. Human TMJ synovium-derived cells were cultured onto collagen scaffolds, resulting in three-dimensional constructs. Cyclic compression loading was applied to the constructs by means of a custom-designed apparatus. DNA amount, apoptotic cells, and mRNA levels for inflammatory cytokines were analyzed. The protein expression and activity of MMPs were examined. DNA amount or apoptotic cell number was unchanged by loading. MMP-2, -3, and IL-8 mRNA expression was up-regulated by the compression, and both MMP-1 and -3 protein expression and MMP-2 activity were detected. Thus, compression of human TMJ synovium-derived cells appears to modulate inflammatory cytokines.

scholarly journals Secretome of senescent hepatoma cells modulate macrophage polarization and neutrophil extracellular traps formation

2021 ◽  
Author(s):  
Bijoya Sen ◽  
Savera Aggarwal ◽  
Rhisita Nath ◽  
Rashi Sehgal ◽  
Archana Rastogi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Flow Cytometry ◽  
Macrophage Polarization ◽  
Hepatoma Cells ◽  
Senescent Cell ◽  
Neutrophil Extracellular Trap ◽  
M2 Macrophage ◽  
Vitro Assay ◽  
Huh7 Cells

AbstractPresence of dysfunctional senescent hepatocyte is a hallmark feature of cirrhosis. We now report the presence of senescent hepatocytes (p21 and p53 positive) in vicinity of infiltrated immune cells in hepatocellular carcinoma. Hence, we checked if senescent cells can alter fate of macrophage polarization and neutrophil extracellular trap (NETs) formation. Using an in vitro assay, senescence was induced in hepatoma cells (HepG2 and Huh7 cells) by doxorubicin treatment and senescent cell showed secretory phenotype with strong expression of cytokines (IL1β, IL6, IL8 and IL13) as evaluated by Flow cytometry. The senescent secretome from hepatoma cells induced macrophage differentiation predominantly with M2 markers (CD80, CD86) while that of non-senescent cell induced M1 phenotype (CD163, CD206) as analysed by flow cytometry. Human hepatocellular carcinoma harbouring senescent hepatocytes showed presence of M2 macrophages, while M1 macrophages were predominant in non-tumorous region. Additionally, the senescent secretome from Huh7 cells (p53mut) enhanced the NETs formation, while HepG2 (p53+/+) secretome had an inhibitory affect In conclusion, the “pro-inflammatory” senescent secretome drives non-inflammatory type M2 macrophage polarization and modulate neutrophil traps thereby modulating the microenvironment towards tumor promotion. Targeting senescent hepatocyte secretome appears a promising therapeutic target in liver cancer in future.Abstract FigureWork Highlight (Diagrammatic Representation).

scholarly journals Increased Circulating Proplatelets and Elevated Plasma TPO Levels: A Novel Pathological Mechanism of Cerebral Infarction

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-9
Author(s):  
Mo Yang ◽  
Liang Li ◽  
Lixia Zhou ◽  
Hua Zhang ◽  
Liuming Yang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cerebral Infarction ◽  
Inflammatory Cytokines ◽  
Fluorescence Microscope ◽  
The Body ◽  
Control Group ◽  
Elevated Plasma ◽  
Platelet Production ◽  
Pathological Mechanism

Background: Platelets are produced by megakaryocytes and are primarily regulated by thrombopoietin (TPO). In the conditions of inflammation or stress, increased 5-HT and other inflammatory cytokines may affect liver and bone marrow to increase TPO and platelet production (Yang et al., Stem Cells, 2007; 2014). Mature megakaryocytes are fragmented in pulmonary circulation to generate more platelet intermediate proplatelets, then entered the circulation. We hypothesized that in patients with cerebral infarction, the secretion of inflammatory cytokines increases under stress or inflammatory conditions, increasing circulating TPO levels, followed by an increase in platelet production, and an increase in the number of platelet intermediate proplatelets. At the same time, platelets also have varying degrees of activation. Therefore, the increase in the number of proplatelets in the circulation and the increase in TPO levels may be the new pathological mechanism of cerebral infarction. Methods: The plasma levels of TPO were detected by ELISA. The in vivo proplatelets from patients were stained with CD41-FITC, which was further confirmed under a fluorescence microscope and flow cytometry. The in vitro proplatelets were observed in a culture system by CD41-FITC staining under a fluorescence microscope and flow cytometry detection. Results: Our clinical data demonstrated that patients with acute inflammation states, plasma TPO levels were significantly higher compared with healthy subjects (181.1 ± 35.38 vs 96.1 ± 9.7 pg/ml, p<0.001, n=65), which may act as an acute response protein to protect the body. We also detected 20 patients with cerebral infarction and 20 normal controls and found that the plasma TPO levels of cerebral infarction patients (186.2±12.5 pg/ml) was significantly higher than that of the control group (122.3±10.2 pg/ml). The number of platelets in patients with cerebral infarction (222.11±8.55 ×109/L, n=20) was slightly higher than that in the control group (206.55±8.83 ×109/L, n=20). More importantly, we found more large platelets or proplatelets in the circulating blood of patients with cerebral infarction, which was significantly different from the control group (n=8). Furthermore, in vitro study confirmed that in 200 megakaryocytes (MKs), (18±2.5)% of MKs producing proplatelets in the TPO group (100 ng/ml), and in 5-HT group (100 nM), (15±3.2)% of MKs producing proplatelets, while the control group was only (7±3.2)% (n=5). At the same time, the effects of TPO and 5-HT were interfered by the corresponding receptor blockers, confirming that their effects were mediated by its receptors. The study further confirmed that both TPO and 5-HT affect the cytoskeleton by activating p-ERK1/2, reorganizing F-actin to generate proplatelets, and its role was blocked by PD98059. Conclusions: The study demonstrated that increased numbers of proplatelets in circulation and elevated plasma TPO levels may be novel pathological mechanisms of cerebral infarction Disclosures No relevant conflicts of interest to declare.

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