scholarly journals A potential role for Galectin-3 inhibitors in the treatment of COVID-19

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9392 ◽  
Author(s):  
John L. Caniglia ◽  
Maheedhara R. Guda ◽  
Swapna Asuthkar ◽  
Andrew J. Tsung ◽  
Kiran K. Velpula
Keyword(s):  
Disease Process ◽  
Standard Of Care ◽  
Host Cells ◽  
World Health ◽  
Necrosis Factor Alpha ◽  
Viral Attachment ◽  
Tnf Α ◽  
Galectin 3

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the causative agent of coronavirus disease 2019 (COVID-19), has been declared a global pandemic by the World Health Organization. With no standard of care for the treatment of COVID-19, there is an urgent need to identify therapies that may be effective in treatment. Recent evidence has implicated the development of cytokine release syndrome as the major cause of fatality in COVID-19 patients, with elevated levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) observed in patients. Galectin-3 (Gal-3) is an animal lectin that has been implicated in the disease process of a variety of inflammatory conditions. Inhibitors of the small molecule Gal-3 have been shown to reduce the levels of both IL-6 and TNF-α in vitro and have shown anti-inflammatory effects in vivo. Additionally, a key domain in the spike protein of β-coronaviridae, a genus which includes SARS-CoV2, is nearly identical in morphology to human Gal-3. These spike proteins are critical for the virus’ entry into host cells. Here we provide a systematic review of the available literature and an impetus for further research on the use of Gal-3 inhibitors in the treatment of COVID-19. Further, we propose a dual mechanism by which Gal-3 inhibition may be beneficial in the treatment of COVID-19, both suppressing the host inflammatory response and impeding viral attachment to host cells.

scholarly journals Strain-Dependent Activation of Monocytes and Inflammatory Macrophages by Lipopolysaccharide ofPorphyromonas gingivalis

1998 ◽  
Vol 66 (6) ◽  
pp. 2736-2742 ◽  
Author(s):  
Lior Shapira ◽  
Catherine Champagne ◽  
Thomas E. Van Dyke ◽  
Salomon Amar
Keyword(s):  
Inflammatory Response ◽  
Biological Activities ◽  
Periodontal Diseases ◽  
Host Cells ◽  
Necrosis Factor Alpha ◽  
Proinflammatory Mediators ◽  
Tnf Α ◽  
Strain Dependent

ABSTRACT Porphyromonas gingivalis is one of the pathogens associated with periodontal diseases, and its lipopolysaccharide (LPS) has been suggested as a possible virulence factor, acting by stimulation of host cells to secrete proinflammatory mediators. However, recent studies have shown that P. gingivalis LPS inhibited some components of the inflammatory response. The present study was designed to test the hypothesis that there are strain-dependent variations in the ability of P. gingivalisLPS to elicit the host inflammatory response. By using LPS preparations from two strains of P. gingivalis, W50 and A7346, the responses of mouse macrophages and human monocytes were evaluated by measuring the secretion of nitric oxide (NO) and tumor necrosis factor alpha (TNF-α). Both direct and indirect (priming) effects were investigated. LPS from Salmonella typhosa was used as a reference LPS. P. gingivalis A7436 LPS induced lower secreted levels of NO from the tested cells than S. typhosaLPS but induced similar levels of TNF-α. In contrast, LPS fromP. gingivalis W50 did not induce NO or TNF-α secretion. Preincubation of macrophages with LPS from S. typhosa orP. gingivalis A7436 prior to stimulation with S. typhosa LPS upregulated NO secretion and downregulated TNF-α secretion, while preincubation with P. gingivalis W50 LPS enhanced both TNF-α and NO secretory responses. These results demonstrate that LPSs derived from different strains of P. gingivalis vary in their biological activities in vitro. The findings may have an impact on our understanding of the range ofP. gingivalis virulence in vivo.

scholarly journals Micrococcus luteus Teichuronic Acids Activate Human and Murine Monocytic Cells in a CD14- and Toll-Like Receptor 4-Dependent Manner

2001 ◽  
Vol 69 (4) ◽  
pp. 2025-2030 ◽  
Author(s):  
Shuhua Yang ◽  
Shunji Sugawara ◽  
Toshihiko Monodane ◽  
Masahiro Nishijima ◽  
Yoshiyuki Adachi ◽  
...  
Keyword(s):  
Lipid A ◽  
Micrococcus Luteus ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Monocytic Cells ◽  
Tnf Α

ABSTRACT Teichuronic acid (TUA), a component of the cell walls of the gram-positive organism Micrococcus luteus (formerlyMicrococcus lysodeikticus), induced inflammatory cytokines in C3H/HeN mice but not in lipopolysaccharide (LPS)-resistant C3H/HeJ mice that have a defect in the Toll-like receptor 4 (TLR4) gene, both in vivo and in vitro, similarly to LPS (T. Monodane, Y. Kawabata, S. Yang, S. Hase, and H. Takada, J. Med. Microbiol. 50:4–12, 2001). In this study, we found that purified TUA (p-TUA) induced tumor necrosis factor alpha (TNF-α) in murine monocytic J774.1 cells but not in mutant LR-9 cells expressing membrane CD14 at a lower level than the parent J774.1 cells. The TNF-α-inducing activity of p-TUA in J774.1 cells was completely inhibited by anti-mouse CD14 monoclonal antibody (MAb). p-TUA also induced interleukin-8 (IL-8) in human monocytic THP-1 cells differentiated to macrophage-like cells expressing CD14. Anti-human CD14 MAb, anti-human TLR4 MAb, and synthetic lipid A precursor IVA, an LPS antagonist, almost completely inhibited the IL-8-inducing ability of p-TUA, as well as LPS, in the differentiated THP-1 cells. Reduced p-TUA did not exhibit any activities in J774.1 or THP-1 cells. These findings strongly suggested that M. luteus TUA activates murine and human monocytic cells in a CD14- and TLR4-dependent manner, similar to LPS.

scholarly journals Metabolic Profiling of Buddleia indica Leaves using LC/MS and Evidence of their Antioxidant and Hepatoprotective Activity Using Different In Vitro and In Vivo Experimental Models

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 412
Author(s):  
Fadia S. Youssef ◽  
Mohamed L. Ashour ◽  
Hesham A. El-Beshbishy ◽  
Abdel Nasser B. Singab ◽  
Michael Wink
Keyword(s):  
Antioxidant Properties ◽  
Lipid Peroxide ◽  
Hepatoprotective Activity ◽  
Experimental Models ◽  
Ionization Mass ◽  
Necrosis Factor Alpha ◽  
Stress Markers ◽  
Tnf Α

LC-ESI-MS (Liquid Chromatography coupled with Electrospray Ionization Mass Spectrometry profiling of a methanol extract from Buddleia indica (BIM) leaves revealed 12 main peaks in which verbascoside and buddlenoid B represent the major compounds. The antioxidant and hepatoprotective activities of BIM were investigated using different in vitro and in vivo experimental models. BIM exhibited substantial in vitro antioxidant properties in DPPH· and HepG2 assays. Regarding CCl4 (carbon tetrachloride) induced hepatotoxicity in a rat model, oxidative stress markers became significantly ameliorated after oral administration of BIM. Lipid peroxide levels showed a 51.85% decline relative to CCl4-treated rats. Super oxide dismutase (SOD), total antioxidant status (TAS), and catalase (CAT) revealed a marked increase by 132.48%, 187.18%, and 114.94% relative to the CCl4 group. In a tamoxifen-induced hepatotoxicity model, BIM showed a considerable alleviation in liver stress markers manifested by a 46.06% and 40% decline in ALT (Alanine Transaminase) and AST (Aspartate Transaminase) respectively. Thiobarbituric acid reactive substances (TBARS) were reduced by 28.57% and the tumor necrosis factor alpha (TNF-α) level by 50%. A virtual screening of major secondary metabolites of BIM to TNF-alpha employing the C-docker protocol showed that gmelinoside H caused the most potent TNF- α inhibition as indicated from their high fitting scores. Thus, BIM exhibited a potent hepatoprotective activity owing to its richness in antioxidant metabolites.

scholarly journals Modulation of Endotoxin- and Enterotoxin-Induced Cytokine Release by In Vivo Treatment with β-(1,6)-Branched β-(1,3)-Glucan

1999 ◽  
Vol 67 (1) ◽  
pp. 244-252 ◽  
Author(s):  
Jindrich Soltys ◽  
Mark T. Quinn
Keyword(s):  
Proinflammatory Cytokines ◽  
Necrosis Factor Alpha ◽  
Enhanced Production ◽  
Tnf Α ◽  
Host Mortality ◽  
Toxic Shock Syndrome Toxin ◽  
Stimulation Of ◽  
In Cells

ABSTRACT Leukocytes activated by endotoxin or enterotoxins release proinflammatory cytokines, thereby contributing to the cascade of events leading to septic shock. In the present studies, we analyzed the effects of in vivo administration of a soluble immunomodulator, β-(1,6)-branched β-(1,3)-glucan (soluble β-glucan), on toxin-stimulated cytokine production in monocytes and lymphocytes isolated from treated mice. In vitro stimulation of lymphocytes isolated from soluble β-glucan-treated mice with lipopolysaccharide (LPS) resulted in enhanced production of interleukin-6 (IL-6) and suppressed production of tumor necrosis factor alpha (TNF-α), while stimulation of these cells with staphylococcal enterotoxin B (SEB) or toxic shock syndrome toxin 1 (TSST-1) resulted in enhanced production of gamma interferon (IFN-γ) and suppressed production of IL-2 and TNF-α compared to that in cells isolated from untreated mice. In vitro stimulation of monocytes isolated from soluble β-glucan-treated mice with LPS also resulted in suppressed TNF-α production, while stimulation of these cells with SEB or TSST-1 resulted in suppressed IL-6 and TNF-α production compared to that in cells isolated from untreated mice. Thus, the overall cytokine pattern of leukocytes from soluble β-glucan-treated mice reflects suppressed production of proinflammatory cytokines, especially TNF-α. Taken together, our results suggest that treatment with soluble β-glucan can modulate the induction cytokines during sepsis, resulting in an overall decrease in host mortality.

scholarly journals Mechanisms Involved in the Pathogenesis of Sepsis Are Not Necessarily Reflected by In Vitro Cell Activation Studies

1998 ◽  
Vol 66 (11) ◽  
pp. 5372-5378 ◽  
Author(s):  
Claudia R. Amura ◽  
R. Silverstein ◽  
D. C. Morrison
Keyword(s):  
Cell Activation ◽  
Endotoxic Shock ◽  
Peritoneal Macrophages ◽  
In Vitro Studies ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
In Vitro Systems ◽  
A Cell

ABSTRACT It is thought that lipopolysaccharide (LPS) from gram-negative bacteria contributes significantly to the pathogenesis of septic shock. In vitro studies to address the mechanisms involved in this process have often investigated human monocytes or mouse macrophages, since these cells produce many of the mediators found in septic patients. Targeting of these mediators, especially tumor necrosis factor alpha (TNF-α), has been pursued as a means of reducing mortality in sepsis. Two experimental approaches were designed to test the assumption that in vitro studies with macrophages accurately predict in vivo mechanisms of LPS pathogenesis. In the first approach, advantage was taken of the fact that on consecutive days after injection of thioglycolate into mice, increased numbers of macrophages could be harvested from the peritoneum. These cells manifested markedly enhanced levels of in vitro TNF-α, interleukin 6 (IL-6), and nitric oxide production in response to LPS. In d-galactosamine-sensitized mice, however, thioglycolate treatment significantly decreased mortality due to LPS, as well as levels of circulating TNF-α and IL-6. Anti-TNF-α treatment confirmed this cytokine’s role in the observed lethality. In a second experimental approach, we compared the mouse macrophage-stimulating potencies of different LPS preparations with their lethalities to mice. In these studies, the in vitro macrophage-stimulating profiles presented by rough-LPS and smooth-LPS preparations were the reverse of their relative lethal potencies in vivo. In conclusion, peritoneal macrophages appear not to be the major cells responsible for the overall host response during endotoxic shock. These findings underscore the importance of verifying the correlation of in vivo systems with in vitro systems when attributing specific functions to a cell type.

scholarly journals Characterization of the Plasmacytoid Dendritic Cell Response to Transmitted/Founder and Nontransmitted Variants of HIV-1

2018 ◽  
Vol 92 (19) ◽  
Author(s):  
Jordan Ari Schwartz ◽  
Hongliang Zhang ◽  
Zachary Ende ◽  
Martin J. Deymier ◽  
Terry Lee ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Plasmacytoid Dendritic Cell ◽  
Female Genital Tract ◽  
Enzyme Linked Immunosorbent Assay ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
The Impact ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection often arises from a single transmitted/founder (TF) viral variant among a large pool of viruses in the quasispecies in the transmitting partner. TF variants are typically nondominant in blood and genital secretions, indicating that they have unique traits. The plasmacytoid dendritic cell (pDC) is the primary alpha interferon (IFN-α)-producing cell in response to viral infections and is rapidly recruited to the female genital tract upon exposure to HIV-1. The impact of pDCs on transmission is unknown. We investigated whether evasion of pDC responses is a trait of TF viruses. pDCs from healthy donors were stimulated in vitro with a panel of 20 HIV-1 variants, consisting of one TF variant and three nontransmitted (NT) variants each from five transmission-linked donor pairs, and secretion of IFN-α and tumor necrosis factor alpha (TNF-α) was measured by enzyme-linked immunosorbent assay (ELISA). No significant differences in cytokine secretion in response to TF and NT viruses were observed, despite a trend toward enhanced IFN-α and TNF-α production in response to TF viruses. NT viruses demonstrated polarization toward production of either IFN-α or TNF-α, indicating possible dysregulation. Also, for NT viruses, IFN-α secretion was associated with increased resistance of the virus to inactivation by IFN-α in vitro, suggesting in vivo evolution. Thus, TF viruses do not appear to preferentially subvert pDC activation compared to that with nontransmitted HIV-1 variants. pDCs may, however, contribute to the in vivo evolution of HIV-1. IMPORTANCE The plasmacytoid dendritic cell (pDC) is the first cell type recruited to the site of HIV-1 exposure; however, its contribution to the viral bottleneck in HIV-1 transmission has not been explored previously. We hypothesized that transmitted/founder viruses are able to avoid the pDC response. In this study, we used previously established donor pair-linked transmitted/founder and nontransmitted (or chronic) variants of HIV-1 to stimulate pDCs. Transmitted/founder HIV-1, instead of suppressing pDC responses, induced IFN-α and TNF-α secretion to levels comparable to those induced by viruses from the transmitting partner. We noted several unique traits of chronic viruses, including polarization between IFN-α and TNF-α production as well as a strong relationship between IFN-α secretion and the resistance of the virus to neutralization. These data rule out the possibility that TF viruses preferentially suppress pDCs in comparison to the pDC response to nontransmitted HIV variants. pDCs may, however, be important drivers of viral evolution in vivo.

scholarly journals Borrelia burgdorferiSpirochetes Induce Mast Cell Activation and Cytokine Release

1999 ◽  
Vol 67 (3) ◽  
pp. 1107-1115 ◽  
Author(s):  
Jeffrey Talkington ◽  
Steven P. Nickell
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Cell Types ◽  
Host Cells ◽  
Mast Cell Activation ◽  
Cytokine Release ◽  
Necrosis Factor Alpha ◽  
Tnf Α

ABSTRACT The Lyme disease spirochete, Borrelia burgdorferi, is introduced into human hosts via tick bites. Among the cell types present in the skin which may initially contact spirochetes are mast cells. Since spirochetes are known to activate a variety of cell types in vitro, we tested whether B. burgdorferi spirochetes could activate mast cells. We report here that freshly isolated rat peritoneal mast cells or mouse MC/9 mast cells cultured in vitro with live or freeze-thawed B. burgdorferi spirochetes undergo low but detectable degranulation, as measured by [5-3H] hydroxytryptamine release, and they synthesize and secrete the proinflammatory cytokine tumor necrosis factor alpha (TNF-α). In contrast to findings in previous studies, where B. burgdorferi-associated activity was shown to be dependent upon protein lipidation, mast cell TNF-α release was not induced by either lipidated or unlipidated recombinant OspA. This activity was additionally shown to be protease sensitive and surface expressed. Finally, comparisons of TNF-α-inducing activity in known low-, intermediate-, and high-passage B. burgdorferi B31 isolates demonstrated passage-dependent loss of activity, indicating that the activity is probably plasmid encoded. These findings document the presence in low-passage B. burgdorferi spirochetes of a novel lipidation-independent activity capable of inducing cytokine release from host cells.

scholarly journals EXTH-29. GALECTIN-3 AS A POTENTIAL THERAPEUTIC TARGET IN RECURRENT ATYPICAL AND MALIGNANT MENINGIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi88-vi88
Author(s):  
Arabinda Das ◽  
Jaime Martinez Santos ◽  
Indira Kanginakudru ◽  
Daniel G McDonald ◽  
Libby Kosnik Infinger ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Survival Rates ◽  
Laboratory Data ◽  
Standard Of Care ◽  
Potential Therapeutic Target ◽  
Protein Levels ◽  
Signaling Transduction Pathway ◽  
Galectin 3

Abstract Atypical and malignant meningiomas are rare tumors that unlike WHO I meningiomas are characteristically more aggressive in nature and are associated with higher recurrence risks of recurrence. In fact despite aggressive treatment of malignant meningiomas, the average 5-year survival rates are in the range of 30% to 60%. Still the standard of care for atypical and malignant meningiomas (AM and MM) has yet to be established. Our laboratory data demonstrated that galectin-3 (Gal-3), a multifunctional β-galactoside-binding protein, is highly expressed in AM and MM as compared to normal tissue. However, the biological functions of Gal-3 in meningioma cells are not fully understood. To address this, we used either small interfering RNA (siRNA) to knock down Gal-3 expression or Gal-3 inhibitor, TD139 to suppress Gal-3 expression in in vitro cell culture model. Silencing or inhibiting of Gal-3 expression significantly decreased the protein levels of urokinase-type plasminogen activator receptor (uPAR) as well as uPAR’s downstream signaling transduction pathway, including phosphorylation of AKT. In both cases, we found that silencing of Gal-3 or inhibiting Gal-3 expression decreased the proliferative activity, and migratory potential of AM and MM cells. Furthermore, we demonstrated that TD139 inhibits MM growth in an in vivo xenograft MM model. Taken together, our results suggest that Gal-3 modulates uPAR expression and that Gal-3 may be a potential therapeutic target for the treatment of atypical and malignant meningiomas.

scholarly journals Suppression of Murine Endotoxin Response by E5531, a Novel Synthetic Lipid A Antagonist

1998 ◽  
Vol 42 (11) ◽  
pp. 2824-2829 ◽  
Author(s):  
Seiichi Kobayashi ◽  
Tsutomu Kawata ◽  
Akifumi Kimura ◽  
Kaname Miyamoto ◽  
Koichi Katayama ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Lipid A ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
In Vivo Models ◽  
Lps Challenge ◽  
Tnf Α

ABSTRACT As a consequence of blood-borne bacterial sepsis, endotoxin or lipopolysaccharide (LPS) from the cell walls of gram-negative bacteria can trigger an acute inflammatory response, leading to a series of pathological events and often resulting in death. To block this inflammatory response to endotoxin, a novel lipid A analogue, E5531, was designed and synthesized as an LPS antagonist, and its biological properties were examined in vitro and in vivo. In murine peritoneal macrophages, E5531 inhibited the release of tumor necrosis factor alpha (TNF-α) by Escherichia coli LPS with a 50% inhibitory concentration (IC50) of 2.2 nM, while E5531 elicited no significant increases in TNF-α on its own. In support of a mechanism consistent with antagonism of binding to a cell surface receptor for LPS, E5531 inhibited equilibrium binding of radioiodinated LPS ([125I]2-(r-azidosalicylamido)-1, 3′-dithiopropionate-LPS) to mouse macrophages with an IC50 of 0.50 μM. E5531 inhibited LPS-induced increases in TNF-α in vivo when it was coinjected with LPS into C57BL/6 mice primed with Mycobacterium bovis bacillus Calmette-Guérin (BCG). In this model, the efficacy of E5531 was inversely correlated to the LPS challenge dose, consistent with a competitive antagonist-like mechanism of action. Blockade of the inflammatory response by E5531 could further be demonstrated in other in vivo models: E5531 protected BCG-primed mice from LPS-induced lethality in a dose-dependent manner and suppressed LPS-induced hepatic injury in Propionibacterium acnes-primed or galactosamine-sensitized mice. These results argue that the novel synthetic lipid A analogue E5531 can antagonize the action of LPS in in vitro and suppress the pathological effects of LPS in vivo in mice.

scholarly journals Differential Regulation of DAP12 and Molecules Associated with DAP12 during Host Responses to Mycobacterial Infection

2004 ◽  
Vol 72 (5) ◽  
pp. 2477-2483 ◽  
Author(s):  
Naoko Aoki ◽  
Anna Zganiacz ◽  
Peter Margetts ◽  
Zhou Xing
Keyword(s):  
Mycobacterial Infection ◽  
Host Responses ◽  
Necrosis Factor Alpha ◽  
Lung Macrophage ◽  
Tnf Α ◽  
Kinetic Expression ◽  
Ifn Γ

ABSTRACT DAP12 and its associating molecules MDL-1, TREM-1, and TREM-2 are the recently identified immune regulatory molecules, expressed primarily on myeloid cells including monocytes/macrophages, dendritic cells, NK cells, and neutrophils. However, little is known about the regulation of their expression during host antimicrobial responses. We have investigated the effect of pulmonary mycobacterial infection and type 1 cytokines on the expression of these molecules both in vivo and in vitro. While DAP12 was constitutively expressed at high levels in the lungs, the MDL-1, TREM-1, and TREM-2 molecules were inducible during mycobacterial infection. Their kinetic expression was correlated with that of the type 1 cytokines tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ). In primary lung macrophage cultures, high constitutive levels of DAP12 and TREM-2 were not modulated by mycobacterial or type 1 cytokine exposure. In contrast, expression of both MDL-1 and TREM-1 was markedly induced by mycobacterial infection and such induction was inhibited by concurrent exposure to IFN-γ. On mycobacterial infection of TNF-α−/− and IFN-γ−/− mice in vivo or their lung macrophages in vitro, TNF-α was found to be critical for mycobacterially induced MDL-1, but not TREM-1, expression whereas IFN-γ negatively regulated mycobacterially induced MDL-1 and TREM-1 expression. Our findings thus suggest that DAP12 and its associating molecules are differentially regulated by mycobacterial infection and type 1 cytokines and that MDL-1- and TREM-1-triggered DAP12 signaling may play an important role in antimicrobial type 1 immunity.

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