scholarly journals Enhanced Suppression of Immune Cells In Vitro by MSC Overexpressing FasL

2020 ◽  
Vol 22 (1) ◽  
pp. 348
Author(s):  
Ana-Maria Vacaru ◽  
Madalina Dumitrescu ◽  
Andrei Mircea Vacaru ◽  
Ioana Madalina Fenyo ◽  
Radu Ionita ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Immunomodulatory Activity ◽  
Proof Of Concept ◽  
Differentiation Potential ◽  
Adenoviral Transduction ◽  
Characteristic Features ◽  
Set Up ◽  
The Impact

Mesenchymal stromal cells (MSC) display several mechanisms of action that may be harnessed for therapeutic purposes. One of their most attractive features is their immunomodulatory activity that has been extensively characterized both in vitro and in vivo. While this activity has proven to be very efficient, it is transient. We aimed to enhance it by transforming MSC to overexpress a first apoptosis signal (Fas) ligand (FasL). In this study, our goal was to induce FasL overexpression through adenoviral transduction in MSC to improve their immunomodulatory activity. We characterized the impact of FasL overexpression on the morphology, proliferation, viability, phenotype, multilineage differentiation potential and immunomodulation of MSC. Moreover, we determined their suppressive properties in mixed reactions with A20 cells, as well as with stimulated splenocytes. Our findings demonstrate that FasL-overexpressing MSC exhibit improved immunosuppressive properties, while maintaining their MSC-characteristic features. In conclusion, we establish, in a proof-of-concept set-up, that FasL-overexpressing MSC represent good candidates for therapeutic intervention targeted at autoimmune disorders.

scholarly journals Ferulic acid attenuates microglia-mediated neuroinflammation in retinal degeneration

2020 ◽  
Author(s):  
Xiaowei Sun ◽  
Peng Sun ◽  
Limei Liu ◽  
Pengfei Jiang ◽  
YUANBIN LI
Keyword(s):  
Ferulic Acid ◽  
Retinal Degeneration ◽  
Microglia Activation ◽  
Immunofluorescent Staining ◽  
Inflammatory Factors ◽  
Immunomodulatory Activity ◽  
Ccl2 Expression ◽  
The Impact

Abstract Background : To explore the impact of Ferulic acid (FA) on microglia-mediated neuroinflammation as well as associated retinal degeneration by using a rd10 mouse model as a means. Methods : Rd10 mice received different concentrations of FA treatment every day from postnatal day (P)4 to P24. At P25, mice visual function were detected by electroretinogram, then retinae were collected for further investigation. Retinal microglia activation state and relevant cytokines were evaluated by qPCR, Western blot and immunofluorescent staining. The retinal structure was assessed by HE Staining. Results :50mg/kg FA supplement exhibited optimal protection against retinal degeneration, with treated mice exhibiting more photoreceptor nuclei as well as significant wave amplitude amplification in electroretinograms. FA suppressed microglia activation both in vivo and in vitro , inhibited pro-inflammatory factors Tnfα, IL1β, Ccl2 expression in rd10 retinae. Furthermore, FA suppressed the activation of STAT1 and subsequently IRF8 expression, potentially highlighting a role for these pathways in FA-mediated immunomodulatory activity. Conclusions : Attenuating neuroinflammation by FA may be beneficial to retard retinal degeneration.

Effect of L-Carnitine on Human Immunodeficiency Virus-1 Infection-Associated Apoptosis: A Pilot Study

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3817-3824 ◽  
Author(s):  
Sonia Moretti ◽  
Edoardo Alesse ◽  
Luisa Di Marzio ◽  
Francesca Zazzeroni ◽  
Barbara Ruggeri ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Fas Ligand ◽  
Cd4 Counts ◽  
Immunodeficiency Virus ◽  
The Impact ◽  
Ceramide Production ◽  
Hiv 1

Abstract The Fas/Fas ligand system is involved in uncontrolled apoptosis, which ultimately leads to the loss of T lymphocytes in human immunodeficiency virus (HIV)-infected individuals. The signal transduced by Fas receptor involves the activation of an acidic sphingomyelinase, sphingomyelin breakdown, and ceramide production. Our recent reports have shown that L-carnitine inhibits Fas-induced apoptosis and ceramide production both in vitro and in vivo. The aim of this study was to study, in a preliminary fashion, the impact of long-term L-carnitine administration on CD4 and CD8 absolute counts, rate, and apoptosis in HIV-1–infected subjects. The generation of cell-associated ceramide and HIV-1 viremia was also investigated. Eleven, asymptomatic, HIV-1–infected subjects, who refused any antiretroviral treatment despite experiencing a progressive decline of CD4 counts, were treated with daily infusions of L-carnitine (6 g) for 4 months. Immunologic and virologic measures and safety were monitored at the start of the treatment and then on days 15, 30, 90, and 150. L-carnitine therapy resulted in an increase of absolute CD4 counts, which was statistically significant on day 90 and 150 (P = .010 and P = .019, respectively). A positive, not significant trend was also observed even in the change in absolute counts of CD8 lymphocytes. L-carnitine therapy also led to a drop in the frequency of apoptotic CD4 and CD8 lymphocytes. This reduction occurred gradually, but changes in actual values between each time point and baseline were strongly significant (P = .001 at the end of the study compared with the baseline). A strong reduction (P = .001) in cell-associated ceramide levels was found at the end of the study. In general, HIV-1 viremia increased slightly. No toxicity related to L-carnitine therapy was observed and dose reductions were not necessary. In HIV-1–infected subjects, long-term infusions of L-carnitine produced substantial increases in the rate and absolute counts of CD4 and, to a lesser degree, of CD8 lymphocytes. This was paralleled by a reduced frequency of apoptotic cells of both subgroups and a decline in the levels of ceramide. No clinically relevant change of HIV-1 viremia was observed.

scholarly journals Ferulic acid attenuates microglia-mediated neuroinflammation in retinal degeneration

2020 ◽  
Author(s):  
Xiaowei Sun ◽  
Peng Sun ◽  
Limei Liu ◽  
Pengfei Jiang ◽  
YUANBIN LI
Keyword(s):  
Ferulic Acid ◽  
Retinal Degeneration ◽  
Microglial Activation ◽  
Inflammatory Factors ◽  
Immunomodulatory Activity ◽  
Retinal Structure ◽  
The Impact ◽  
Optimal Protection

Abstract Background: Retinal degeneration is often accompanied by microglia-mediated neuroinflammation. Ferulic acid (FA), an active ingredient of traditional Chinese medicines (TCMs), has been reported to have anti-inflammatory effects. This study explores the impact of FA on microglia-mediated neuroinflammation and associated retinal degeneration in rd10 mice. Methods: Rd10 mice received different concentrations of FA every day from postnatal day (P)4 to P24. On P25, the visual function of the mice was evaluated by electroretinogram, and retinae were collected for further investigation. Microglial activation and the expression of relevant cytokines in the retina were evaluated by qPCR, western blotting and immunofluorescence staining. Retinal structure was assessed by haematoxylin and eosin (HE) staining.Results: Supplementation with 50 mg/kg FA provided optimal protection against retinal degeneration, with treated mice exhibiting more photoreceptor nuclei as well as greater wave amplitude amplification on electroretinogram than untreated mice. FA suppressed microglial activation both in vivo and in vitro, and inhibited the expression of pro-inflammatory factors Tnfα, IL1β, and Ccl2 in the retinae of rd10 mice. Furthermore, FA suppressed the activation of STAT1 and subsequently inhibited IRF8 expression, potentially highlighting a role for these pathways in FA-mediated immunomodulatory activity. Conclusions: Attenuation of neuroinflammation by FA may be beneficial for retarding retinal degeneration.

scholarly journals Ferulic acid attenuates microglia-mediated neuroinflammation in retinal degeneration

2020 ◽  
Author(s):  
Xiaowei Sun ◽  
Peng Sun ◽  
Limei Liu ◽  
Pengfei Jiang ◽  
YUANBIN LI
Keyword(s):  
Ferulic Acid ◽  
Retinal Degeneration ◽  
Microglia Activation ◽  
Immunofluorescent Staining ◽  
Inflammatory Factors ◽  
Immunomodulatory Activity ◽  
Ccl2 Expression ◽  
The Impact

Abstract Background: To use a rd10 mouse model as a means of exploring the impact of Ferulic acid(FA) on microglia-mediated neuroinflammation as well as associated retinal degeneration. Methods: Rd10 mice received different concentrations of FA treatment every day from postnatal day (P)4 to P24. At P25, mice visual function were detected by electroretinogram, then retinae were collected for further investigation. Retinal microglia activation state and relevant cytokines were evaluated by qPCR, Western blot and immunofluorescent staining. The retinal structure was assessed by HE Staining. Results:50mg/Kg FA supplement exhibited optimal protection against retinal degeneration, with treated mice exhibiting more photoreceptor nuclei as well as significant wave amplitude amplification in electroretinograms. FA suppressed microglia activation both in vivo and in vitro, inhibited pro-inflammatory factors Tnfα, IL1β, Ccl2 expression in rd10 retinae. Furthermore, FA suppressed the activation of STAT1 and subsequently IRF8 expression, potentially highlighting a role for these pathways in FA-mediated immunomodulatory activity. Conclusions: Attenuating neuroinflammation by FA may be beneficial to retard retinal degeneration.

scholarly journals A New Human Blood–Retinal Barrier Model Based on Endothelial Cells, Pericytes, and Astrocytes

2020 ◽  
Vol 21 (5) ◽  
pp. 1636 ◽  
Author(s):  
Claudia G. Fresta ◽  
Annamaria Fidilio ◽  
Giuseppe Caruso ◽  
Filippo Caraci ◽  
Frank J. Giblin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Diabetic Retinopathy ◽  
High Glucose ◽  
Potential Effect ◽  
Blood Retinal Barrier ◽  
Retinal Astrocytes ◽  
Set Up ◽  
The Impact

Blood–retinal barrier (BRB) dysfunction represents one of the most significant changes occurring during diabetic retinopathy. We set up a high-reproducible human-based in vitro BRB model using retinal pericytes, retinal astrocytes, and retinal endothelial cells in order to replicate the human in vivo environment with the same numerical ratio and layer order. Our findings showed that high glucose exposure elicited BRB breakdown, enhanced permeability, and reduced the levels of junction proteins such as ZO-1 and VE-cadherin. Furthermore, an increased expression of pro-inflammatory mediators (IL-1β, IL-6) and oxidative stress-related enzymes (iNOS, Nox2) along with an increased production of reactive oxygen species were observed in our triple co-culture paradigm. Finally, we found an activation of immune response-regulating signaling pathways (Nrf2 and HO-1). In conclusion, the present model mimics the closest human in vivo milieu, providing a valuable tool to study the impact of high glucose in the retina and to develop novel molecules with potential effect on diabetic retinopathy.

scholarly journals Mesenchymal Stromal Cell-Derived Extracellular Vesicles – Silver Linings for Cartilage Regeneration?

2020 ◽  
Vol 8 ◽  
Author(s):  
Andrea De Luna ◽  
Alexander Otahal ◽  
Stefan Nehrer
Keyword(s):  
Extracellular Vesicles ◽  
Treatment Options ◽  
Cartilage Regeneration ◽  
Bioactive Molecules ◽  
Paracrine Factors ◽  
Differentiation Potential ◽  
Vast Number ◽  
The Impact

As the world’s population is aging, the incidence of the degenerative disease Osteoarthritis (OA) is increasing. Current treatment options of OA focus on the alleviation of the symptoms including pain and inflammation rather than on restoration of the articular cartilage. Cell-based therapies including the application of mesenchymal stromal cells (MSCs) have been a promising tool for cartilage regeneration approaches. Due to their immunomodulatory properties, their differentiation potential into cells of the mesodermal lineage as well as the plurality of sources from which they can be isolated, MSCs have been applied in a vast number of studies focusing on the establishment of new treatment options for Osteoarthritis. Despite promising outcomes in vitro and in vivo, applications of MSCs are connected with teratoma formation, limited lifespan of differentiated cells as well as rejection of the cells after transplantation, highlighting the need for new cell free approaches harboring the beneficial properties of MSCs. It has been demonstrated that the regenerative potential of MSCs is mediated by the release of paracrine factors rather than by differentiation into cells of the desired tissue. Besides soluble factors, extracellular vesicles are the major component of a cell’s secretome. They represent novel mechanisms by which (pathogenic) signals can be communicated between cell types as they deliver bioactive molecules (nucleic acids, proteins, lipids) from the cell of origin to the target cell leading to specific biological processes upon uptake. This review will give an overview about extracellular vesicles including general characteristics, isolation methods and characterization approaches. Furthermore, the role of MSC-derived extracellular vesicles in in vitro and in vivo studies for cartilage regeneration will be summarized with special focus on transported miRNA which either favored the progression of OA or protected the cartilage from degradation. In addition, studies will be reviewed investigating the impact of MSC-derived extracellular vesicles on inflammatory arthritis. As extracellular vesicles are present in all body fluids, their application as potential biomarkers for OA will also be discussed in this review. Finally, studies exploring the combination of MSC-derived extracellular vesicles with biomaterials for tissue engineering approaches are summarized.

scholarly journals Effect of L-Carnitine on Human Immunodeficiency Virus-1 Infection-Associated Apoptosis: A Pilot Study

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3817-3824
Author(s):  
Sonia Moretti ◽  
Edoardo Alesse ◽  
Luisa Di Marzio ◽  
Francesca Zazzeroni ◽  
Barbara Ruggeri ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Fas Ligand ◽  
Cd4 Counts ◽  
Immunodeficiency Virus ◽  
The Impact ◽  
Ceramide Production ◽  
Hiv 1

The Fas/Fas ligand system is involved in uncontrolled apoptosis, which ultimately leads to the loss of T lymphocytes in human immunodeficiency virus (HIV)-infected individuals. The signal transduced by Fas receptor involves the activation of an acidic sphingomyelinase, sphingomyelin breakdown, and ceramide production. Our recent reports have shown that L-carnitine inhibits Fas-induced apoptosis and ceramide production both in vitro and in vivo. The aim of this study was to study, in a preliminary fashion, the impact of long-term L-carnitine administration on CD4 and CD8 absolute counts, rate, and apoptosis in HIV-1–infected subjects. The generation of cell-associated ceramide and HIV-1 viremia was also investigated. Eleven, asymptomatic, HIV-1–infected subjects, who refused any antiretroviral treatment despite experiencing a progressive decline of CD4 counts, were treated with daily infusions of L-carnitine (6 g) for 4 months. Immunologic and virologic measures and safety were monitored at the start of the treatment and then on days 15, 30, 90, and 150. L-carnitine therapy resulted in an increase of absolute CD4 counts, which was statistically significant on day 90 and 150 (P = .010 and P = .019, respectively). A positive, not significant trend was also observed even in the change in absolute counts of CD8 lymphocytes. L-carnitine therapy also led to a drop in the frequency of apoptotic CD4 and CD8 lymphocytes. This reduction occurred gradually, but changes in actual values between each time point and baseline were strongly significant (P = .001 at the end of the study compared with the baseline). A strong reduction (P = .001) in cell-associated ceramide levels was found at the end of the study. In general, HIV-1 viremia increased slightly. No toxicity related to L-carnitine therapy was observed and dose reductions were not necessary. In HIV-1–infected subjects, long-term infusions of L-carnitine produced substantial increases in the rate and absolute counts of CD4 and, to a lesser degree, of CD8 lymphocytes. This was paralleled by a reduced frequency of apoptotic cells of both subgroups and a decline in the levels of ceramide. No clinically relevant change of HIV-1 viremia was observed.

scholarly journals Ferulic acid attenuates microglia-mediated neuroinflammation in retinal degeneration

2020 ◽  
Author(s):  
Xiaowei Sun ◽  
Peng Sun ◽  
Limei Liu ◽  
Pengfei Jiang ◽  
YUANBIN LI
Keyword(s):  
Ferulic Acid ◽  
Retinal Degeneration ◽  
Microglial Activation ◽  
Inflammatory Factors ◽  
Immunomodulatory Activity ◽  
Retinal Structure ◽  
The Impact ◽  
Optimal Protection

Abstract Background: Retinal degeneration is often accompanied by microglia-mediated neuroinflammation. Ferulic acid (FA), an active ingredient of traditional Chinese medicines (TCMs), has been reported to have anti-inflammatory effects. This study explores the impact of FA on microglia-mediated neuroinflammation and associated retinal degeneration in rd10 mice.Methods: Rd10 mice received different concentrations of FA every day from postnatal day (P)4 to P24. On P25, the visual function of the mice was evaluated by electroretinogram, and retinae were collected for further investigation. Microglial activation and the expression of relevant cytokines in the retina were evaluated by qPCR, western blotting and immunofluorescence staining. Retinal structure was assessed by haematoxylin and eosin(HE) staining. Results: supplementation with 50 mg/kg FA provided optimal protection against retinal degeneration, with treated mice exhibiting more photoreceptor nuclei as well as greater wave amplitude amplification on electroretinogram than untreated mice. FA suppressed microglial activation both in vivo and in vitro, and inhibited the expression of pro-inflammatory factors Tnfα, IL1β, and Ccl2 in the retinae of rd10 mice. Furthermore, FA suppressed the activation of STAT1 and subsequently inhibited IRF8 expression, potentially highlighting a role for these pathways in FA-mediated immunomodulatory activity. Conclusions: Attenuation of neuroinflammation by FA may be beneficial for retarding retinal degeneration.

scholarly journals “Bowel on the Bench”: Proof of Concept of a Three-Stage, In Vitro Fermentation Model of the Equine Large Intestine

2019 ◽  
Vol 86 (1) ◽  
Author(s):  
J. Leng ◽  
G. Walton ◽  
J. Swann ◽  
A. Darby ◽  
R. La Ragione ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Intestinal Microbiota ◽  
Ex Vivo ◽  
Cost Effective ◽  
Chain Fatty Acid ◽  
Proof Of Concept ◽  
Bacterial Function ◽  
The Impact

ABSTRACT The intestinal microbiota of the horse, an animal of huge economic and social importance worldwide, is essential to the health of the animal. Understanding the intestinal ecosystem and its dynamic interaction with diet and dietary supplements currently requires the use of experimental animals, with consequent welfare and financial constraints. Here, we describe the development and assessment, using multiple analytical platforms, of a three-vessel, continuous-flow, in vitro model of the equine hindgut. After inoculation of the model with fresh horse feces, the bacterial communities established in each vessel had a taxonomic distribution similar to that of the source animal. Short-chain fatty acid (SCFA) and branched-chain fatty acid (BCFA) production within the model at steady state was consistent with the expected bacterial function, although higher concentrations of some SCFA/BCFA relative to those in the ex vivo gut content were apparent. We demonstrate the intermodel repeatability and the ability of the model to capture some aspects of individual variation in bacterial community profiles. The findings of this proof-of-concept study, including recognition of the limitions of the model, support its future development as a tool for investigating the impact of disease, nutrition, dietary supplementation, and medication on the equine intestinal microbiota. IMPORTANCE The equine gut model that we have developed and describe has the potential to facilitate the exploration of how the equine gut microbiota is affected by diet, disease, and medication. It is a convenient, cost-effective, and welfare-friendly alternative to in vivo research models.

scholarly journals Ferulic acid attenuates microglia-mediated neuroinflammation in retinal degeneration

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiaowei Sun ◽  
Peng Sun ◽  
Limei Liu ◽  
Pengfei Jiang ◽  
Yuanbin Li
Keyword(s):  
Ferulic Acid ◽  
Retinal Degeneration ◽  
Microglial Activation ◽  
Inflammatory Factors ◽  
Immunomodulatory Activity ◽  
Retinal Structure ◽  
The Impact ◽  
Optimal Protection

Abstract Background Retinal degeneration is often accompanied by microglia-mediated neuroinflammation. Ferulic acid (FA), an active ingredient of traditional Chinese medicines (TCMs), has been reported to have anti-inflammatory effects. This study explores the impact of FA on microglia-mediated neuroinflammation and associated retinal degeneration in rd10 mice. Methods Rd10 mice received different concentrations of FA every day from postnatal day (P)4 to P24. On P25, the visual function of the mice was evaluated by electroretinogram, and retinae were collected for further investigation. Microglial activation and the expression of relevant cytokines in the retina were evaluated by qPCR, western blotting and immunofluorescence staining. Retinal structure was assessed by haematoxylin and eosin (HE) staining. Results Supplementation with 50 mg/kg FA provided optimal protection against retinal degeneration, with treated mice exhibiting more photoreceptor nuclei as well as greater wave amplitude amplification on electroretinogram than untreated mice. FA suppressed microglial activation both in vivo and in vitro, and inhibited the expression of pro-inflammatory factors Tnfα, IL1β, and Ccl2 in the retinae of rd10 mice. Furthermore, FA suppressed the activation of STAT1 and subsequently inhibited IRF8 expression, potentially highlighting a role for these pathways in FA-mediated immunomodulatory activity. Conclusions Attenuation of neuroinflammation by FA may be beneficial for retarding retinal degeneration.

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