miR-30a-3p participates in the development of asthma by targeting CCR3

AbstractThis study aimed to investigate the role and relevant mechanism of miR-30a-3p action in asthma. The results of this study revealed that the expression levels of miR-30a-3p were significantly decreased in the peripheral blood of asthmatic patients. In addition, we found that the CC chemokine receptor (CCR3) was a target of miR-30a-3p. Subsequently, an asthma mouse model was established using ovalbumin (OVA). The results showed that the expression of miR-30a-3p and CCR3 was downregulated and upregulated, respectively, in the peripheral blood of asthmatic mice. Enzyme-linked immunosorbent assay (ELISA) in asthmatic mouse serum demonstrated that miR-30a-3p mimic treatment significantly decreased the secretion of OVA-specific IgE, eotaxin-1, interleukin (IL)-5, and IL-4. These results suggested that miR-30a-3p inhibited CCR3 signaling pathway and relieved the inflammatory response against asthma in vivo. Eosinophils have also been implicated in the asthmatic inflammatory response. Therefore, the in vitro effects of miR-30a-3p on eosinophil activity were determined. Findings suggested that miR-30a-3p mimic significantly reduced eosinophil viability and migration and induced apoptosis. In addition, CCR3 and eotaxin-1 downregulation were observed. The aforementioned results were significantly reversed following CCR3 overexpression. This study suggested that miR-30a-3p was involved in asthma by regulating eosinophil activity and targeting CCR3.

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In vivo priming of platelet-activating factor-induced eosinophil chemotaxis in allergic asthmatic individuals

Blood ◽

10.1182/blood.v79.7.1836.1836 ◽

1992 ◽

Vol 79 (7) ◽

pp. 1836-1841 ◽

Cited By ~ 65

Author(s):

RA Warringa ◽

HJ Mengelers ◽

PH Kuijper ◽

JA Raaijmakers ◽

PL Bruijnzeel ◽

...

Keyword(s):

Peripheral Blood ◽

Platelet Activating Factor ◽

Chemotactic Response ◽

Healthy Individuals ◽

Gm Csf ◽

Asthmatic Patients ◽

Allergic Asthmatic ◽

Eosinophil Chemotaxis

Abstract The cytokines granulocyte-macrophage colony-stimulating factor (GM- CSF), interleukin (IL)-3, and IL-5 are important modulators of eosinophilia and eosinophil function. Eosinophil chemotaxis is known to be particularly sensitive for cytokine priming. In the present study, we compared chemotactic responses of eosinophils derived from peripheral blood of allergic asthmatics to responses of eosinophils from peripheral blood of healthy individuals. Eosinophils from allergic asthmatics exhibited a markedly increased sensitivity in their chemotactic response toward platelet-activating factor (PAF) compared with eosinophils from normal donors. In contrast, C5a-induced eosinophil chemotaxis between both groups was similar. This in vivo- primed phenotype could be mimicked in vitro, by preincubating eosinophils from peripheral blood of healthy individuals with picomolar concentrations of either GM-CSF, IL-3, or IL-5. The chemotactic response of eosinophils derived from the circulation of allergic asthmatic patients toward GM-CSF was significantly lower compared with the response of eosinophils of healthy individuals. Our data strongly suggest that release of cytokines may be an important in vivo priming mechanism for eosinophils in the circulation of allergic asthmatic patients. Such an in vivo priming can subsequently result in selective upregulation and downregulation of chemotactic responses toward various chemoattractants release in the lung tissue.

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Synergistic antitumor effect of 5-fluorouracil with the novel LSD1 inhibitor ZY0511 in colorectal cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920937428 ◽

2020 ◽

Vol 12 ◽

pp. 175883592093742

Author(s):

Wen Peng ◽

Huaqing Zhang ◽

Shisheng Tan ◽

Yan Li ◽

Yang Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Antitumor Effect ◽

Underlying Mechanism ◽

Synergistic Antitumor Effect ◽

Anticancer Effects ◽

Potential Marker ◽

And Migration ◽

Induced Apoptosis

Background: Lysine-specific histone demethylase 1 (LSD1) is a potential target of cancer therapy. In the present study, we aimed to investigate the combined antitumor activity of a novel LSD1 inhibitor (ZY0511) with 5-fluorouracil (5-FU) and elucidate the underlying mechanism in colorectal cancer (CRC). Methods: We evaluated LSD1 expression in CRC tissues from patients who received 5-FU treatment. The synergistic antitumor effect of 5-FU with ZY0511 against human CRC cells was detected both in vitro and in vivo. The underlying mechanism was explored based on mRNA sequencing (mRNA-seq) technology. Results: Overexpression of LSD1 was observed in human CRC tissues, and correlated with CRC development and 5-FU resistance. ZY0511, a novel LSD1 inhibitor, effectively inhibited CRC cells proliferation, both in vitro and in vivo. Notably, the combination of ZY0511 and 5-FU synergistically reduced CRC cells viability and migration in vitro. It also suppressed Wnt/β-catenin signaling and DNA synthesis pathways, which finally induced apoptosis of CRC cells. In addition, the combination of ZY0511 with 5-FU significantly reduced CRC xenograft tumor growth, along with lung and liver metastases in vivo. Conclusions: Our findings identify LSD1 as a potential marker for 5-FU resistance in CRC. ZY0511 is a promising candidate for CRC therapy as it potentiates 5-FU anticancer effects, thereby providing a new combinatorial strategy for treating CRC.

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Interleukin-4 (IL-4) enhances and soluble interleukin-4 receptor (sIL-4R) inhibits histamine release from peripheral blood basophils and mast cellsin vitroandin vivo

Mediators of Inflammation ◽

10.1080/09629359791802 ◽

1997 ◽

Vol 6 (2) ◽

pp. 111-118 ◽

Cited By ~ 5

Author(s):

B. Niggemann ◽

T. Zuberbier ◽

U. Herz ◽

K. Enssle ◽

U. Wahn ◽

...

Keyword(s):

Mast Cells ◽

Histamine Release ◽

Peripheral Blood ◽

Specific Ige ◽

Interleukin 4 ◽

Effector Cells ◽

Antibody Titres ◽

Interleukin 4 Receptor

The aim of the study was to analyse the effect of interleukin-4 (IL-4) on allergen and anti-IgE mediated histamine release from basophils and human skin mast cells and to assess whether soluble recombinant interleukin-4 receptor (sIL4R) can inhibit these effects. Anti-IgE stimulated histamine release from peripheral blood basophils and mast cells of atopic donors was enhanced after preincubation with IL-4, whereas after preincubation with sIL-4R it was inhibited. These effects were even more pronounced when samples were stimulated with a clinically relevant allergen. In IL-4 preincubated skin mast cells, there was a similar enhancement of anti-IgE stimulated histamine release, which could again be inhibited by sIL-4R. The effects of IL-4 and sIL4R were dose- and time-dependent. Mice sensitized to ovalbumin and treated with soluble recombinant murine sIL-4R showed significantly reduced immediate-type cutaneous hypersensitivity responses compared with untreated mice. Thesein vivoeffects were IgE independent, since there were no significant differences in total and allergen specific IgE/IgG1 antibody titres between treated and untreated mice. This indicates that IL4 exerts priming effects on histamine release by effector cells of the allergic response and that these effects are potently antagonized by soluble IL-4R bothin vitroandin vivo.

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In vivo priming of platelet-activating factor-induced eosinophil chemotaxis in allergic asthmatic individuals

Blood ◽

10.1182/blood.v79.7.1836.bloodjournal7971836 ◽

1992 ◽

Vol 79 (7) ◽

pp. 1836-1841 ◽

Cited By ~ 2

Author(s):

RA Warringa ◽

HJ Mengelers ◽

PH Kuijper ◽

JA Raaijmakers ◽

PL Bruijnzeel ◽

...

Keyword(s):

Peripheral Blood ◽

Platelet Activating Factor ◽

Chemotactic Response ◽

Healthy Individuals ◽

Gm Csf ◽

Asthmatic Patients ◽

Allergic Asthmatic ◽

Eosinophil Chemotaxis

The cytokines granulocyte-macrophage colony-stimulating factor (GM- CSF), interleukin (IL)-3, and IL-5 are important modulators of eosinophilia and eosinophil function. Eosinophil chemotaxis is known to be particularly sensitive for cytokine priming. In the present study, we compared chemotactic responses of eosinophils derived from peripheral blood of allergic asthmatics to responses of eosinophils from peripheral blood of healthy individuals. Eosinophils from allergic asthmatics exhibited a markedly increased sensitivity in their chemotactic response toward platelet-activating factor (PAF) compared with eosinophils from normal donors. In contrast, C5a-induced eosinophil chemotaxis between both groups was similar. This in vivo- primed phenotype could be mimicked in vitro, by preincubating eosinophils from peripheral blood of healthy individuals with picomolar concentrations of either GM-CSF, IL-3, or IL-5. The chemotactic response of eosinophils derived from the circulation of allergic asthmatic patients toward GM-CSF was significantly lower compared with the response of eosinophils of healthy individuals. Our data strongly suggest that release of cytokines may be an important in vivo priming mechanism for eosinophils in the circulation of allergic asthmatic patients. Such an in vivo priming can subsequently result in selective upregulation and downregulation of chemotactic responses toward various chemoattractants release in the lung tissue.

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Tryptanthrin exerts anti-breast cancer effects both in vitro and in vivo through modulating the inflammatory tumor microenvironment

Acta Pharmaceutica ◽

10.2478/acph-2021-0020 ◽

2021 ◽

Vol 71 (2) ◽

pp. 245-266

Author(s):

Qingfang Zeng ◽

Cairong Luo ◽

Junlae Cho ◽

Donna Lai ◽

Xiangchun Shen ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Colony Formation ◽

Migration And Invasion ◽

Mouse Serum ◽

Enzyme Linked Immunosorbent Assay ◽

Tumor Tissues ◽

Mcf 7

AbstractTryptanthrin is an indole quinazoline alkaloid from the indigo-bearing plants, such as Isatis indigotica Fort. Typically, this natural compound shows a variety of pharmacological activities such as antitumor, antibacterial, anti-inflammatory and antioxidant effects. This study was conducted to assess the antitumor activity of tryptanthrin in breast cancer models both in vitro and in vivo, and to explore the important role of the inflammatory tumor microenvironment (TME) in the antitumor effects of tryptanthrin. Human breast adenocarcinoma MCF-7 cells were used to assess the antitumor effect of tryptanthrin in vitro. MTT assay and colony formation assay were carried out to monitor the antiproliferative effect of tryptanthrin (1.56~50.0 μmol L−1) on inhibiting the proliferation and colony formation of MCF-7 cells, respectively. The migration and invasion of MCF-7 cells were evaluated by wound healing assay and Transwell chamber assay, respectively. Moreover, the 4T1 murine breast cancer model was established to examine the pharmacological activity of tryptanthrin, and three groups with different doses of tryptanthrin (25, 50 and 100 mg kg−1) were set in study. Additionally, tumor volumes and organ coefficients were measured and calculated. After two weeks of tryptanthrin treatment, samples from serum, tumor tissue and different organs from tumor-bearing mice were collected, and the enzyme-linked immunosorbent assay (ELISA) was performed to assess the regulation of inflammatory molecules in mouse serum. Additionally, pathological examinations of tumor tissues and organs from mice were evaluated through hematoxylin and eosin (H&E) staining. The expression of inflammatory proteins in tumor tissues was measured by immunohistochemistry (IHC) and Western blotting. Tryptanthrin inhibited the proliferation, migration and invasion of MCF-7 cells, up-regulated the protein level of E-cadherin, and down-regulated those of MMP-2 and Snail, as suggested by the MCF-7 cell experiment. According to the results from in vivo experiment, tryptanthrin was effective in inhibiting tumor growth, and it showed favorable safety without inducing the fluctuations of body mass and organ coefficient (p > 0.05). In addition, tryptanthrin also suppressed the expression levels of NOS1, COX-2 and NF-κB in mouse tumor tissues, and regulated those of IL-2, IL-10 and TNF-α in the serum of tumor cells-transplanted mice. Tryptanthrin exerted its anti-breast cancer activities through modulating the inflammatory TME both in vitro and in vivo.

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Adipose-derived exosomes protect the pulmonary endothelial barrier in ventilator-induced lung injury by inhibiting the TRPV4/Ca2+ signaling pathway

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00255.2019 ◽

2020 ◽

Vol 318 (4) ◽

pp. L723-L741 ◽

Cited By ~ 6

Author(s):

Qian Yu ◽

Daoxin Wang ◽

Xiaoting Wen ◽

Xumao Tang ◽

Di Qi ◽

...

Keyword(s):

Lung Injury ◽

Inflammatory Response ◽

Transient Receptor Potential ◽

Inflammatory Responses ◽

Endothelial Barrier ◽

Mouse Serum ◽

Transient Receptor Potential Vanilloid ◽

Ventilator Induced Lung Injury

Mechanical ventilation (MV) is the main supportive treatment of acute respiratory distress syndrome (ARDS), but it may lead to ventilator-induced lung injury (VILI). Large epidemiological studies have found that obesity was associated with lower mortality in mechanically ventilated patients with acute lung injury, which is known as “obesity paradox.” However, the effects of obesity on VILI are unknown. In the present study, wild-type mice were fed a high-fat diet (HFD) and ventilated with high tidal volume to investigate the effects of obesity on VILI in vivo, and pulmonary microvascular endothelial cells (PMVECs) were subjected to 18% cyclic stretching (CS) to further investigate its underlying mechanism in vitro. We found that HFD protects mice from VILI by alleviating the pulmonary endothelial barrier injury and inflammatory responses in mice. Adipose-derived exosomes can regulate distant tissues as novel adipokines, providing a new mechanism for cell-cell interactions. We extracted three adipose-derived exosomes, including HFD mouse serum exosome (S-Exo), adipose tissue exosome (AT-Exo), and adipose-derived stem cell exosome (ADSC-Exo), and further explored their effects on MV or 18% CS-induced VILI in vivo and in vitro. Administration of three exosomes protected against VILI by suppressing pulmonary endothelial barrier hyperpermeability, repairing the expression of adherens junctions, and alleviating inflammatory response in vivo and in vitro, accompanied by transient receptor potential vanilloid 4 (TRPV4)/Ca2+ pathway inhibition. Collectively, these data indicated that HFD-induced obesity plays a protective role in VILI by alleviating the pulmonary endothelial barrier injury and inflammatory response via adipose-derived exosomes, at least partially, through inhibiting the TRPV4/Ca2+ pathway.

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Nivalenol induced apoptosis in human peripheral blood lymphocytes in vitro and mouse peripheral blood lymphocytes in vivo

JSM Mycotoxins ◽

10.2520/myco1975.1997.45_33 ◽

1997 ◽

Vol 1997 (45) ◽

pp. 33-37 ◽

Cited By ~ 3

Author(s):

Naoto YOSHINO ◽

Mari TAKIZAWA ◽

Hiroki OKUMURA ◽

Tomomi IHARA ◽

Masao SUGAMATA ◽

...

Keyword(s):

Peripheral Blood ◽

Human Peripheral Blood ◽

Peripheral Blood Lymphocytes ◽

Blood Lymphocytes ◽

Human Peripheral Blood Lymphocytes ◽

Induced Apoptosis

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Knockdown of Kremen2 Inhibits Tumor Growth and Migration in Gastric Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.534095 ◽

2021 ◽

Vol 10 ◽

Author(s):

Beibei Chen ◽

Sai-Qi Wang ◽

Jinxi Huang ◽

Weifeng Xu ◽

Huifang Lv ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Xenograft Model ◽

Gastric Cancer Cells ◽

And Migration ◽

Induced Apoptosis ◽

Gastric Cancer Patients

Kremen2 (Krm2) plays an important role in embryonic development, bone formation, and tumorigenesis as a crucial regulator of classical Wnt/β-catenin signaling pathway. However, the role of Krm2 in gastric cancer is not clear. The aim of this study was to explore the regulatory role of Krm2 in the tumorigenesis and metastasis of gastric cancer. It was demonstrated that, compared to para-cancerous tissues, Krm2 was significantly up-regulated in gastric cancer tissues and was positively correlated with the pathological grade of gastric cancer patients. Given that Krm2 is abundantly expressed in most tested gastric cancer cell lines, Krm2 knockdown cell models were established and further used to construct mice xenograft model. After knocking down Krm2, both the cell survival in vitro and tumorigenesis in vivo of gastric cancer cells were inhibited. At the same time, knockdown of Krm2 induced apoptosis, cell cycle arrest at G2/M phase and repression of migration in gastric cancer cells in vitro. Mechanistically, we found that knockdown of Krm2 suppressed PI3K/Akt pathway. Therefore, we revealed the novel role and the molecular mechanism of Krm2 in promoting the tumorigenesis and metastasis in gastric cancer. Krm2 can be a potent candidate for designing of targeted therapy.

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Could Arachidonic Acid-Derived Pro-Resolving Mediators Be a New Therapeutic Strategy for Asthma Therapy?

Frontiers in Immunology ◽

10.3389/fimmu.2020.580598 ◽

2020 ◽

Vol 11 ◽

Author(s):

Daniella Bianchi Reis Insuela ◽

Maximiliano Ruben Ferrero ◽

Diego de Sá Coutinho ◽

Marco Aurélio Martins ◽

Vinicius Frias Carvalho

Keyword(s):

Arachidonic Acid ◽

Inflammatory Response ◽

Lung Inflammation ◽

Clinical Investigation ◽

Inflammatory Cells ◽

Airway Epithelial ◽

Asthmatic Patients ◽

Beneficial Effects

Asthma represents one of the leading chronic diseases worldwide and causes a high global burden of death and disability. In asthmatic patients, the exacerbation and chronification of the inflammatory response are often related to a failure in the resolution phase of inflammation. We reviewed the role of the main arachidonic acid (AA) specialized pro-resolving mediators (SPMs) in the resolution of chronic lung inflammation of asthmatics. AA is metabolized by two classes of enzymes, cyclooxygenases (COX), which produce prostaglandins (PGs) and thromboxanes, and lypoxygenases (LOX), which form leukotrienes and lipoxins (LXs). In asthma, two primary pro-resolving derived mediators from COXs are PGE2 and the cyclopentenone prostaglandin15-Deoxy-Delta-12,14-PGJ2 (15d-PGJ2) while from LOXs are the LXA4 and LXB4. In different models of asthma, PGE2, 15d-PGJ2, and LXs reduced lung inflammation and remodeling. Furthermore, these SPMs inhibited chemotaxis and function of several inflammatory cells involved in asthma pathogenesis, such as eosinophils, and presented an antiremodeling effect in airway epithelial, smooth muscle cells and fibroblasts in vitro. In addition, PGE2, 15d-PGJ2, and LXs are all able to induce macrophage reprogramming to an alternative M2 pro-resolving phenotype in vitro and in vivo. Although PGE2 and LXA4 showed some beneficial effects in asthmatic patients, there are limitations to their clinical use, since PGE2 caused side effects, while LXA4 presented low stability. Therefore, despite the strong evidence that these AA-derived SPMs induce resolution of both inflammatory response and tissue remodeling in asthma, safer and more stable analogs must be developed for further clinical investigation of their application in asthma treatment.

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The novel role of circular RNA ST3GAL6 on blocking gastric cancer malignant behaviors through autophagy regulated by the FOXP2/MET/mTOR axis

10.21203/rs.3.rs-402505/v3 ◽

2021 ◽

Author(s):

Penghui Xu ◽

Xing Zhang ◽

Jiacheng Cao ◽

Jing Yang ◽

Zetian Chen ◽

...

Keyword(s):

Gastric Cancer ◽

Circular Rna ◽

Circular Rnas ◽

The Novel ◽

Transcriptional Inhibition ◽

And Migration ◽

Induced Apoptosis

Abstract Gastric cancer (GC) ranks third in motality among all cancers worldwide. Circular RNAs (circRNAs) play essential roles in the malignant progression and metastasis of gastric cancer. As a transcription factor, FOXP2 is involved in the progression of many tumours. However, the regulation and association between circRNAs and FOXP2 remain to be discovered. In our study, CircST3GAL6 was significantly depressed in GC tissues and cells. circST3GAL6 overexpression inhibited the proliferation, invasion and metastasis of GC cells in vitro and in vivo. Importantly, circST3GAL6 overexpression induced apoptosis and promote autophagy in GC cells. Furthermore, we found that circST3GAL6 sponged miR-300 and subsequently regulated FOXP2. We further revealed that FOXP2 suppressed the activation of the Met/AKT/mTOR axis, a classic pathway that regulates autophagy-mediated proliferation and migration. In summary, our ﬁndings revealed that circST3GAL6 functions as a tumour suppressor through the miR-300/FOXP2 axis in GC, regulates apoptosis and autophagy through FOXP2-mediated transcriptional inhibition of the MET axis and may be a biomarker for GC treatment.

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