scholarly journals Brain Tissue-Derived Extracellular Vesicle Mediated Therapy in the Neonatal Ischemic Brain

2022 ◽  
Vol 23 (2) ◽  
pp. 620
Author(s):  
Nam Phuong Nguyen ◽  
Hawley Helmbrecht ◽  
Ziming Ye ◽  
Tolulope Adebayo ◽  
Najma Hashi ◽  
...  
Keyword(s):  
Time Window ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Brain Slices ◽  
Neurological Injury ◽  
Inflammatory Factors ◽  
Dependent Manner ◽  
Therapeutic Dosage ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory

Hypoxic-Ischemic Encephalopathy (HIE) in the brain is the leading cause of morbidity and mortality in neonates and can lead to irreparable tissue damage and cognition. Thus, investigating key mediators of the HI response to identify points of therapeutic intervention has significant clinical potential. Brain repair after HI requires highly coordinated injury responses mediated by cell-derived extracellular vesicles (EVs). Studies show that stem cell-derived EVs attenuate the injury response in ischemic models by releasing neuroprotective, neurogenic, and anti-inflammatory factors. In contrast to 2D cell cultures, we successfully isolated and characterized EVs from whole brain rat tissue (BEV) to study the therapeutic potential of endogenous EVs. We showed that BEVs decrease cytotoxicity in an ex vivo oxygen glucose deprivation (OGD) brain slice model of HI in a dose- and time-dependent manner. The minimum therapeutic dosage was determined to be 25 μg BEVs with a therapeutic application time window of 4–24 h post-injury. At this therapeutic dosage, BEV treatment increased anti-inflammatory cytokine expression. The morphology of microglia was also observed to shift from an amoeboid, inflammatory phenotype to a restorative, anti-inflammatory phenotype between 24–48 h of BEV exposure after OGD injury, indicating a shift in phenotype following BEV treatment. These results demonstrate the use of OWH brain slices to facilitate understanding of BEV activity and therapeutic potential in complex brain pathologies for treating neurological injury in neonates.

Ulinastatin Activated The ERK5/Mer Signaling Pathway To Promote Macrophage Efferocytosis And Ameliorate Lung Inflammation

2021 ◽  
Author(s):  
Jinju Li ◽  
Rongge Shao ◽  
Qiuwen Xie ◽  
XueKe Du
Keyword(s):  
Lung Injury ◽  
Signaling Pathway ◽  
Lung Inflammation ◽  
Raw264.7 Cells ◽  
Inflammatory Factors ◽  
Inflammatory Factor ◽  
Dependent Manner ◽  
Anti Inflammatory

Abstract Purpose:Ulinastatin (UTI) is an endogenous protease inhibitor with potent anti-inflammatory, antioxidant and organ protective effects. The inhibitor has been reported to ameliorate inflammatory lung injury but precise mechanisms remain unclear. Methods: An in vivo model of lung injury has been constructed by intratracheal infusion of lipopolysaccharide (LPS). The number of neutrophils and the phagocytosis of apoptotic neutrophils were observed by Diff- Quick method. Lung injury was observed by HE staining .BALF cells were counted by hemocytometer and concentrations of protein plus inflammatory factors were measured with a BCA test kit. During in vitro experiments, RAW264.7 cells were pretreated with UTI (1000 and 5000U/ mL), stained with CellTrackerTM Green B0DIPYTM and HL60 cells added with UV-induced apoptosis and PKH26 Red staining. The expression of ERK5\Mer related proteins was detected by western blot and immunofluorescence.Results: An in vivo model of lung injury has been constructed by intratracheal infusion of lipopolysaccharide (LPS). UTI treatment enhanced the phagocytotic effect of mouse alveolar macrophages on neutrophils, alleviated lung lesions, decreased the pro-inflammatory factor and total protein content of BALF and increased levels of anti-inflammatory factors. in vitro experiments ，UTI enhanced the phagocytosis of apoptotic bodies by RAW264.7 cells in a dose-dependent manner. Increased expression levels of ERK5 and Mer by UTI were shown by Western blotting and immunofluorescence.Conclusions: UTI mediated the activation of the ERK5/Mer signaling pathway, enhanced phagocytosis of neutrophils by macrophages and improved lung inflammation. The current study indicates potential new clinical approaches for accelerating the recovery from lung inflammation.

scholarly journals Matrine reduces cigarette smoke-induced airway neutrophilic inflammation by enhancing neutrophil apoptosis

2019 ◽  
Vol 133 (4) ◽  
pp. 551-564 ◽  
Author(s):  
Xuhua Yu ◽  
Huei Jiunn Seow ◽  
Hao Wang ◽  
Desiree Anthony ◽  
Steven Bozinovski ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Lung Inflammation ◽  
Therapeutic Potential ◽  
Proteolytic Enzymes ◽  
Ex Vivo ◽  
Lavage Fluid ◽  
Airflow Limitation ◽  
Chronic Obstructive ◽  
Neutrophilic Inflammation ◽  
Anti Inflammatory

AbstractChronic Obstructive Pulmonary Disease (COPD) is a major incurable global health burden and will become the third largest cause of death in the world by 2030. It is well established that an exaggerated inflammatory and oxidative stress response to cigarette smoke (CS) leads to, emphysema, small airway fibrosis, mucus hypersecretion, and progressive airflow limitation. Current treatments have limited efficacy in inhibiting chronic inflammation and consequently do not reverse the pathology that initiates and drives the long-term progression of disease. In particular, there are no effective therapeutics that target neutrophilic inflammation in COPD, which is known to cause tissue damage by degranulation of a suite of proteolytic enzymes including neutrophil elastase (NE). Matrine, an alkaloid compound extracted from Sophora flavescens Ait, has well known anti-inflammatory activity. Therefore, the aim of the present study was to investigate whether matrine could inhibit CS-induced lung inflammation in mice. Matrine significantly reduced CS-induced bronchoalveolar lavage fluid (BALF) neutrophilia and NE activity in mice. The reduction in BALF neutrophils in CS-exposed mice by matrine was not due to reductions in pro-neutrophil cytokines/chemokines, but rather matrine’s ability to cause apoptosis of neutrophils, which we demonstrated ex vivo. Thus, our data suggest that matrine has anti-inflammatory actions that could be of therapeutic potential in treating CS-induced lung inflammation observed in COPD.

scholarly journals Immunomodulation of Murine Chronic DSS-Induced Colitis by Tuftsin–Phosphorylcholine

2019 ◽  
Vol 9 (1) ◽  
pp. 65
Author(s):  
Dana Ben-Ami Shor ◽  
Jordan Lachnish ◽  
Tomer Bashi ◽  
Shani Dahan ◽  
Asaf Shemer ◽  
...  
Keyword(s):  
Murine Model ◽  
Lupus Erythematosus ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Activity Index ◽  
Clinical Manifestations ◽  
Host Immune System ◽  
Chronic Colitis ◽  
Mesenteric Lymph Nodes ◽  
Anti Inflammatory

Helminths or their products can immunomodulate the host immune system, and this phenomenon may be applied as the basis of new anti-inflammatory treatments. Previously, we have shown the efficacy of tuftsin–phosphorylcholine (TPC), based on a helminth product, in four animal models of autoimmune diseases: arthritis, colitis, systemic lupus erythematosus, and experimental autoimmune encephalomyelitis. We demonstrated that TPC reduced inflammatory process ex vivo in peripheral blood lymphocytes (PBLs) and in biopsies from giant-cell arteritis. In the present study, we assessed the therapeutic potential of TPC treatment on a chronic colitis murine model. C57BL/6 mice with chronic colitis were treated with TPC after the third cycle of 2% dextran sodium sulfate (DSS). Oral TPC treatment resulted in amelioration of the colitis clinical manifestations exemplified by reduced disease activity index (DAI) score, expansion of mesenteric lymph nodes (MLN) T regulatory cells (shown by Fluorescence Activated Cell Sorting (FACS)), significant reduction in the expression of pro-inflammatory cytokines (IL-1β, IL17, IL-6, TNFα), and elevation in the expression of anti-inflammatory cytokine IL-10 (shown by RT-PCR). This study demonstrated the potential immunomodulatory effects of oral administration of TPC in a chronic colitis murine model. Further clinical trials are needed in order to evaluate this novel approach for the treatment of patients with inflammatory bowel disease.

scholarly journals The antihelminthic moxidectin enhances tonic GABA currents in rodent hippocampal pyramidal neurons

2018 ◽  
Vol 119 (5) ◽  
pp. 1693-1698
Author(s):  
Jay Spampanato ◽  
Anne Gibson ◽  
F. Edward Dudek
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Gaba Receptors ◽  
Pyramidal Neurons ◽  
Ex Vivo ◽  
Companion Animals ◽  
Brain Slices ◽  
Dependent Manner ◽  
Hippocampal Pyramidal Neurons ◽  
Mammalian Central Nervous System

Macrocyclic lactones (MLs) are commonly used treatments for parasitic worm and insect infections in humans, livestock, and companion animals. MLs target the invertebrate glutamate-activated chloride channel that is not present in vertebrates. MLs are not entirely inert in vertebrates, though; they have been reported to have activity in heterologous expression systems consisting of ligand-gated ion channels that are present in the mammalian central nervous system (CNS). However, these compounds are typically not able to reach significant concentrations in the CNS because of the activity of the blood-brain barrier P-glycoprotein extrusion system. Despite this, these compounds are able to reach low levels in the CNS that may be useful in the design of novel “designer” ligand-receptor systems that can be used to directly investigate neuronal control of behavior in mammals and have potential for use in treating human neurological diseases. To determine whether MLs might affect neurons in intact brains, we investigated the activity of the ML moxidectin (MOX) at native GABA receptors. Specifically, we recorded tonic and phasic miniature inhibitory postsynaptic currents (mIPSCs) in ex vivo brain slices. Our data show that MOX potentiated tonic GABA currents in a dose-dependent manner but had no concomitant effects on phasic GABA currents (i.e., MOX had no effect on the amplitude, frequency, or decay kinetics of mIPSCs). These studies indicate that behavioral experiments that implement a ML-based novel ligand-receptor system should take care to control for potential effects of the ML on native tonic GABA receptors.NEW & NOTEWORTHY We have identified a novel mechanism of action in the mammalian central nervous system for the antihelminthic moxidectin, commonly prescribed to animals worldwide and currently being evaluated for use in humans. Specifically, moxidectin applied to rodent brain slices selectively enhanced the tonic GABA conductance of hippocampal pyramidal neurons.

scholarly journals Evaluations and Mechanistic Interrogation of Natural Products Isolated From Paeonia suffruticosa for the Treatment of Inflammatory Bowel Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Kun-Chang Wu ◽  
Der-Yen Lee ◽  
Jeh-Ting Hsu ◽  
Chi-Fang Cheng ◽  
Joung-Liang Lan ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Therapeutic Potential ◽  
Ethyl Acetate Fraction ◽  
Root Bark ◽  
Dependent Manner ◽  
Paeonia Suffruticosa ◽  
Inflammatory Bowel ◽  
Anti Inflammatory ◽  
The Impact

Mu Dan Pi (MDP), a traditional Chinese medicine derived from the root bark of Paeonia suffruticosa Andrews, is used to treat autoimmune diseases due to its anti-inflammatory properties. However, the impact of MDP on inflammatory bowel disease (IBD) and its principal active compounds that contribute to the anti-inflammatory properties are uncertain. Thus, this study systemically evaluated the anti-inflammatory effects of fractionated MDP, which has therapeutic potential for IBD. MDP fractions were prepared by multistep fractionation, among which the ethyl acetate-fraction MDP5 exhibited the highest potency, with anti-inflammatory activity screened by the Toll-like receptor (TLR)-2 agonist, Pam3CSK4, in a cell-based model. MDP5 (at 50 μg/ml, p < 0.001) significantly inhibited nuclear factor kappa-B (NF-κB) reporters triggered by Pam3CSK4, without significant cell toxicity. Moreover, MDP5 (at 10 μg/ml) alleviated proinflammatory signaling triggered by Pam3CSK4 in a dose-dependent manner and reduced downstream IL-6 and TNF-α production (p < 0.001) in primary macrophages. MDP5 also mitigated weight loss, clinical inflammation, colonic infiltration of immune cells and cytokine production in a murine colitis model. Index compounds including paeoniflorin derivatives (ranging from 0.1 to 3.4%), gallic acid (1.8%), and 1,2,3,4,6-penta-O-galloyl-β-D-glucose (1.1%) in MDP5 fractions were identified by LC-MS/MS and could be used as anti-inflammatory markers for MDP preparation. Collectively, these data suggest that MDP5 is a promising treatment for IBD patients.

scholarly journals Ex-vivo mucolytic and anti-inflammatory activity of BromAc in tracheal aspirates from COVID-19

2021 ◽  
Author(s):  
Jordana Grazziela A. Coelho dos Reis ◽  
Geovane Marques Ferreira ◽  
Alice Aparecida Lourenco ◽  
Agata Lopes Ribeiro ◽  
Camila Pacheco da Silveira Martins da Mata ◽  
...  
Keyword(s):  
Critically Ill ◽  
Ex Vivo ◽  
Tracheal Aspirate ◽  
Inflammatory Activity ◽  
Dependent Manner ◽  
Cytokine Storm ◽  
Next Of Kin ◽  
Anti Inflammatory ◽  
Inflammatory Effect ◽  
Tracheal Aspirates

COVID-19 is a lethal disease caused by the pandemic SARS-CoV-2, which continues to be a public health threat. COVID-19 is principally a respiratory disease and is often associated with sputum retention, for which there are limited therapeutic options. In this regard, we evaluated the use of BromAc, a combination of Bromelain and Acetylcysteine (NAC). Both drugs present mucolytic effect and have been studied to treat COVID-19. Therefore, we sought to examine the mucolytic, antiviral, and anti-inflammatory effect of BromAc in tracheal aspirate samples from critically ill COVID-19 patients requiring mechanical ventilation. Method: Tracheal aspirate samples from COVID-19 patients were collected following next of kin consent and mucolysis, rheometry and cytokine storm analysis was performed. Results: BromAc displayed a robust mucolytic effect in a dose dependent manner. BromAc showed anti-inflammatory activity, reducing the action of cytokine storm, chemokines including MIP-1alpha, CXCL8, MIP-1b, MCP-1 and IP-10, and regulatory cytokines IL-5, IL-10, IL-13 IL-1RA and total reduction for IL-9 compared to NAC alone and control. BromAc acted on IL-6, demonstrating a reduction in G-CSF and VEGF-D at concentrations of 125 and 250ug. Conclusion: These results indicate robust mucolytic and anti-inflammatory effect of BromAc in tracheal aspirates from critically ill COVID-19 patients, indicating its potential as a therapeutic strategy to COVID-19.

scholarly journals Triptolide Attenuates Neuropathic Pain by Regulating Microglia Polarization through the CCL2/CCR2 Axis

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Xubin Bao ◽  
Cai Chen ◽  
Liyong Yuan
Keyword(s):  
Neuropathic Pain ◽  
Fluorescence Intensity ◽  
Quantitative Polymerase Chain Reaction ◽  
Inflammatory Factors ◽  
Dependent Manner ◽  
Arginase 1 ◽  
M2 Polarization ◽  
Anti Inflammatory ◽  
Factor Α ◽  
In Cells

Triptolide (T10) is a common anti-inflammatory and analgesic drug. However, the activation of microglia and elimination of the corresponding inflammatory response are new targets for the treatment of neuropathic pain. Chemokine CCL (CCL2) is a key mediator for activating microglia. In this study, the effects of triptolide on the activation and polarization of microglia cells and CCL2 and its corresponding receptor, chemokine receptor 2 (CCR2), were mainly discussed. Microglia were stimulated with 1 μg/mL lipopolysaccharide (LPS) and pretreated with 10, 20, and 40 nM T10 and CCR2 antagonist (RS102895), respectively. The quantitative polymerase chain reaction (QPCR) and western blot results showed that T10 could obviously inhibit the upregulation of CCL2 and CCR2 induced by LPS stimulation in microglia cells, inhibit the fluorescence intensity of glial fibrillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS) antibody immunostaining in cells, and upregulate the fluorescence intensity of arginase 1 antibody in cells. The expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) was inhibited in a dose-dependent manner. RS102895 can significantly reverse the activation and M2 polarization of microglia pretreated with 40 nM T10 and weaken the anti-inflammatory effect of T10. The addition of CCL2 did not extremely affect the function of RS102895. T10 may inhibit microglia activation and M1 polarization by inhibiting the expression of CCL2 and CCR2, promoting M2 polarization, reducing the level of inflammatory factors in cells, and exerting its analgesic effect, which is worthy of clinical promotion as a drug for neuropathic pain.

scholarly journals Non-Genetic Reprogramming of Monocytes via Microparticle Phagocytosis for Sustained Modulation of Macrophage Phenotype

2019 ◽  
Author(s):  
Kathryn L. Wofford ◽  
Bhavani S. Singh ◽  
D. Kacy Cullen ◽  
Kara L. Spiller
Keyword(s):  
Cell Therapy ◽  
Inflammatory Factors ◽  
Macrophage Phenotype ◽  
Vast Number ◽  
Inflammatory Drug ◽  
Rapid Acquisition ◽  
Therapy Strategy ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory ◽  
Over Time

ABSTRACTMonocyte-derived macrophages orchestrate tissue regeneration by homing to sites of injury, phagocytosing pathological debris, and stimulating other cell types to repair the tissue. Accordingly, monocytes have been investigated as a translational and potent source for cell therapy, but their utility has been hampered by their rapid acquisition of a pro-inflammatory phenotype in response to the inflammatory injury microenvironment. To overcome this problem, we designed a cell therapy strategy where we collect and exogenously reprogram monocytes by intracellularly loading the cells with biodegradable microparticles containing an anti-inflammatory drug in order to modulate and maintain an anti-inflammatory phenotype over time. To test this concept, poly(lactic-co-glycolic) acid microparticles were loaded with the anti-inflammatory drug dexamethasone (Dex) and administered to primary human monocytes for four hours to facilitate phagocytic uptake. After removal of non-phagocytosed microparticles, microparticle-loaded monocytes differentiated into macrophages and stored the microparticles intracellularly for several weeks in vitro, releasing drug into the extracellular environment over time. Cells loaded with intracellular Dex microparticles showed decreased expression and secretion of inflammatory factors even in the presence of pro-inflammatory stimuli up to 7 days after microparticle uptake compared to untreated cells or cells loaded with blank microparticles. This study represents a new strategy for long-term maintenance of anti-inflammatory macrophage phenotype using a translational monocyte-based cell therapy strategy without the use of genetic modification. Because of the ubiquitous nature of monocyte-derived macrophage involvement in pathology and regeneration, this strategy holds potential as a treatment for a vast number of diseases and disorders.

The EGFR-Inhibitor Erlotinib Induces Apoptosis in Neoplastic Cells of Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML), an Effect Determined by the Expression Level of Nucleophosmin (NPM).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 856-856
Author(s):  
Simone Boehrer ◽  
Lionel Ades ◽  
Claire Fabre ◽  
Pierre Fenaux ◽  
Guido Kroemer
Keyword(s):  
Cell Lines ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Myeloid Cell ◽  
Expression Level ◽  
Apoptotic Cells ◽  
Dependent Manner ◽  
Egfr Inhibitor ◽  
Down Regulation

Abstract Background: the epidermal-growth-factor-receptor (EGFR)-inhibitor erlotinib was rationally designed to antagonize the deregulated EGFR-activity in solid tumors. Abundant studies in these entities not only demonstrated clinical efficacy, but also a favorable toxicity profile. In particular the absence of hematopoietic toxicity prompted us to investigate the therapeutic potential of erlotinib in MDS and AML cells. Methods: We incubated ex vivo cells from patients with MDS (n=4, 2 lower risk and 2 higher risk) and AML (n=6, de novo: 3; post MDS: 3), as well as a broad spectrum of myeloid cell lines (P39, KG-1, HL-60, MV4-11, MOLM-13) with increasing dosages of erlotinib (1μM to 10μM). As controls (n=4) we used non-malignant CD34 + bone marrow cells. Before incubation, all ex vivo cells underwent CD34 + selection. Serial FACS-analyses of parameters determining apoptosis (DIOC/PI and AnnexinV/PI) were carried out over a maximum of 6 days. Results: We found that erlotinib was able to induce a considerable degree of apoptosis in MDS and AML cells. Although there was a high interindividual difference in sensitivity towards erlotinib, “responders” treated with 10μM erlotinib showed an increase of apoptotic cells between 20–30% after 72h, which reached a maximum of 60% on day 6. This apoptosis-inducing effect was achieved in a dose-dependent manner and not restricted to a specific entity. Noteworthy, erlotinib exhibited no toxicity towards non-neoplastic progenitor cells. Evaluating the molecular mechanisms determining sensitivity we showed that the apoptosis-inducing effect of erlotinib critically depended on the expression level of NPM. Thus erlotinib-resistant myeloid cell lines (i.e. P39) exhibited a higher epression of NPM than sensitive cell lines (i.e. KG-1). In addition, down-regulation of NPM by small-interfering RNA not only increased the apoptosis-inducing effect of erlotinib in sensitive cells, but moreover established sensitivity in otherwise erlotinib-resistant cells. Accordingly, siRNA-induced down-regulation of NPM in P39 cells elevated the percentage of apoptotic cells upon treatment with 10μM erlotinib by about 30% as compared to mock-transfected controls. Conclusion, we showed an off-target effect of erlotinib, as evidenced by its ability to induce apoptosis in EGFR-negative cells. Of particular interest is the observation that erlotinib induced apoptosis exclusively in neoplastic myeloid cells while sparing non-malignant progenitors. To the best of our knowledge, this is the first report providing evidence for the therapeutic potential of erlotinib in MDS and AML.

scholarly journals Anti-inflammatory and antinociceptive activities of methanolic extract from red seaweed Dichotomaria obtusata

2013 ◽  
Vol 49 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Neivys García Delgado ◽  
Ana Iris Frías Vázquez ◽  
Hiran Cabrera Sánchez ◽  
Roberto Menéndez Soto del Valle ◽  
Yusvel Sierra Gómez ◽  
...  
Keyword(s):  
Phospholipase A2 ◽  
Methanolic Extract ◽  
Therapeutic Potential ◽  
Intraperitoneal Administration ◽  
Moderate Activity ◽  
Dependent Manner ◽  
Ear Edema ◽  
Antinociceptive Effects ◽  
Anti Inflammatory ◽  
Phospholipase A2 Activity

The aim of the present work was to investigate the anti-inflammatory and antinociceptive effects of methanolic extract from D. obtusata using classic models in mice (croton oil-induced ear edema and acetic acid-induced writhing) and a phospholipase A2 activity test. Qualitative analysis of the chemical composition of seaweed was also determined by extraction with solvents of increasing polarity and precipitation and color tests. Results of qualitative chemical study showed the presence of lactonic and phenolic compounds, reduced carbohydrates, other sugars, flavonoids, fatty compounds, triterpenes and steroids. The extract inhibited mouse ear edema in a dose-dependent manner with an efficacy higher than 90% and a mean effective dose of 4.87µg/ear, while intraperitoneal administration presented a moderate activity. The extract did not inhibit phospholipase A2 activity. In the writhing test, the intraperitoneal administration of the extract showed a strong antinociceptive activity (80.2%), while the oral route showed a lower efficacy. In conclusion, this study demonstrated the anti-inflammatory and antinociceptive effects of methanol extract of D. obtusata in experimental models, suggesting its therapeutic potential in the treatment of peripheral painful and/or inflammatory pathologies.

Sign in / Sign up

Export Citation Format

Share Document