scholarly journals Increasing phagocytosis of microglia through targeting CD33 with liposomes displaying glycan ligands

2021 ◽  
Author(s):  
Abhishek Bhattacherjee ◽  
Gour Daskhan ◽  
Arjun Bains ◽  
Adrianne E.S. Watson ◽  
Ghazaleh Eskandari-Sedighi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Intracellular Signaling ◽  
Opposite Effect ◽  
Microglial Cell ◽  
Cell Function ◽  
Dependent Manner ◽  
Intracerebroventricular Injection ◽  
Binding Properties ◽  
Binding Ability ◽  
Monocytic Cells

CD33 is an immunomodulatory receptor expressed on microglia and genetically linked to Alzheimer's disease (AD) susceptibility. While antibodies targeting CD33 have entered clinical trials to treat neurodegeneration, it is unknown whether the glycan-binding properties of CD33 can be exploited to modulate microglia. Here, we use liposomes that multivalently display glycan ligands of CD33 (CD33L liposomes) to engage CD33. We find that CD33L liposomes increase phagocytosis of cultured monocytic cells and microglia in a CD33-dependent manner. Enhanced phagocytosis strongly correlates with loss of CD33 from the cell surface and internalization of liposomes. Increased phagocytosis by treatment with CD33L liposomes is dependent on a key intracellular signaling motif on CD33 as well as the glycan-binding ability of CD33. These effects are specific to trans engagement of CD33 by CD33L liposomes, as cis engagement through insertion of lipid-linked CD33L into cells produces the opposite effect on phagocytosis. Moreover, intracerebroventricular injection of CD33L liposomes in mice enhances phagocytosis of microglia in a CD33-dependent manner. These results demonstrate that multivalent engagement of CD33 with glycan ligands can modulate microglial cell function.

Molecular Characterization of the Cannabinoid-Mediated Migration of Monocytes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3878-3878
Author(s):  
In-Woo Park ◽  
Appakkudal R. Anand ◽  
Jerome E. Groopman
Keyword(s):  
Intracellular Signaling ◽  
Cannabinoid Receptors ◽  
Rho Kinase ◽  
Surface Expression ◽  
Dependent Manner ◽  
Monocytic Differentiation ◽  
Monocytic Cells ◽  
Potent Inducer ◽  
Monocyte Migration ◽  
Enhanced Secretion

Abstract 2-Arachidonoylglycerol (2-AG), an endogenous ligand for the cannabinoid receptors CB1 and CB2, functions as a chemokine for monocyte migration. However, the molecular mechanism of its chemotactic effects is not clear. We found, consistent with previous data, that 2-AG induces the migration of differentiated but not undifferentiated monocytic cells in a dose-dependent manner. We first asked whether the expression of cannabinoid receptors changed during monocytic differentiation. Treatment with 1,25-(OH)2vitamin D3, a potent inducer of monocyte differentiation, or with 2-AG did not alter the surface expression of the CB1 and CB2 receptors, indicating that signaling downstream of receptor ligation accounted for the observed effect on monocyte migration. In addition, treatment of differentiated monocytic cells with inhibitors for adenyl cyclase and rho kinase blocked the 2-AG-mediated migration, directly implicating these signaling molecules in monocyte motility. Upon eliminating the concentration gradient of 2-AG, the motility of the cells from the upper to lower compartment was sharply reduced, but not completely abrogated. This suggested that the chemotactic effect may not fully explain the observed change in cell migration. Of note, treatment of monocytes with 2-AG resulted in an enhanced secretion of the chemokines MCP-1 and IL-8. Moreover, exposure of the cells to 2-AG inhibited their migration towards MCP-1, while exposure to MCP-1 did not alter migration toward 2-AG. Taken together, our findings demonstrate that intracellular signaling cascades as well as induction of chemokine secretion contribute to the cannabinoid-mediated migration of monocytes.

scholarly journals Growth Promotion or Osmotic Stress Response: How SNF1-Related Protein Kinase 2 (SnRK2) Kinases Are Activated and Manage Intracellular Signaling in Plants

Plants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1443
Author(s):  
Yoshiaki Kamiyama ◽  
Sotaro Katagiri ◽  
Taishi Umezawa
Keyword(s):  
Protein Kinase ◽  
Plant Growth ◽  
Osmotic Stress ◽  
Protein Function ◽  
Intracellular Signaling ◽  
Growth Promotion ◽  
Research Field ◽  
Dependent Manner ◽  
Related Protein ◽  
Wide Range

Reversible phosphorylation is a major mechanism for regulating protein function and controls a wide range of cellular functions including responses to external stimuli. The plant-specific SNF1-related protein kinase 2s (SnRK2s) function as central regulators of plant growth and development, as well as tolerance to multiple abiotic stresses. Although the activity of SnRK2s is tightly regulated in a phytohormone abscisic acid (ABA)-dependent manner, recent investigations have revealed that SnRK2s can be activated by group B Raf-like protein kinases independently of ABA. Furthermore, evidence is accumulating that SnRK2s modulate plant growth through regulation of target of rapamycin (TOR) signaling. Here, we summarize recent advances in knowledge of how SnRK2s mediate plant growth and osmotic stress signaling and discuss future challenges in this research field.

scholarly journals PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects

2021 ◽  
Vol 22 (7) ◽  
pp. 3464
Author(s):  
Rosalin Mishra ◽  
Hima Patel ◽  
Samar Alanazi ◽  
Mary Kate Kilroy ◽  
Joan T. Garrett
Keyword(s):  
Clinical Trials ◽  
Intracellular Signaling ◽  
Pi3k Pathway ◽  
Combination Therapies ◽  
Intracellular Signaling Pathway ◽  
Pi3k Inhibitors ◽  
Promising Therapeutic Target ◽  
Cancer Cell Survival ◽  
Current Therapies ◽  
Cancer Types

The phospatidylinositol-3 kinase (PI3K) pathway is a crucial intracellular signaling pathway which is mutated or amplified in a wide variety of cancers including breast, gastric, ovarian, colorectal, prostate, glioblastoma and endometrial cancers. PI3K signaling plays an important role in cancer cell survival, angiogenesis and metastasis, making it a promising therapeutic target. There are several ongoing and completed clinical trials involving PI3K inhibitors (pan, isoform-specific and dual PI3K/mTOR) with the goal to find efficient PI3K inhibitors that could overcome resistance to current therapies. This review focuses on the current landscape of various PI3K inhibitors either as monotherapy or in combination therapies and the treatment outcomes involved in various phases of clinical trials in different cancer types. There is a discussion of the drug-related toxicities, challenges associated with these PI3K inhibitors and the adverse events leading to treatment failure. In addition, novel PI3K drugs that have potential to be translated in the clinic are highlighted.

scholarly journals Glucolipotoxicity and GLP-1 secretion

2021 ◽  
Vol 9 (1) ◽  
pp. e001905
Author(s):  
Jung-Hee Hong ◽  
Dae-Hee Kim ◽  
Moon-Kyu Lee
Keyword(s):  
Glucose Transporter ◽  
Cell Function ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Gene Expressions ◽  
Simultaneous Treatment ◽  
L Cells ◽  
Triglyceride Accumulation

IntroductionThe concept of glucolipotoxicity refers to the combined, deleterious effects of elevated glucose and/or fatty acid levels.Research design and methodsTo investigate the effects of chronic glucolipotoxicity on glucagon-like peptide-1-(7-36) amide (GLP-1) secretion, we generated glucolipotoxic conditions in human NCI-H716 enteroendocrine cells using either 5 or 25 mM glucose with or without 500 µM palmitate for 72 hours. For in vivo study, we have established a chronic nutrient infusion model in the rat. Serial blood samples were collected for 2 hours after the consumption of a mixed meal to evaluate insulin sensitivity and β-cell function.ResultsChronic glucolipotoxic conditions decreased GLP-1 secretion and the expressions of pCREB, pGSK3β, β-catenin, and TCF7L2 in NCI-H716 cells. Glucolipotoxicity conditions reduced glucose transporter expression, glucose uptake, and nicotinamide-adenine dinucleotide phosphate (NADPH) levels in L-cells, and increased triglyceride accumulation. In contrast, PPARα and ATP levels were reduced, which correlated well with decreased levels of SUR1 and Kir6.2, cAMP contents and expressions of pCAMK2, EPAC and PKA. We also observed an increase in reactive oxygen species production, UCP2 expression and Complex I activity. Simultaneous treatment with insulin restored the GLP-1 secretion. Glucolipotoxic conditions decreased insulin secretion in a time-dependent manner in INS-1 cells, which was recovered with exendin-4 cotreatment. Glucose and SMOFlipid infusion for 6 hours decreased GLP-1 secretion and proglucagon mRNA levels as well as impaired the glucose tolerance, insulin and C-peptide secretion in rats.ConclusionThese results provide evidence for the first time that glucolipotoxicity could affect GLP-1 secretion through changes in glucose and lipid metabolism, gene expressions, and proglucagon biosynthesis and suggest the interrelationship between glucolipotoxicities of L-cells and β-cells which develops earlier than that of L-cells.

scholarly journals Effect of memantine, an anti-Alzheimer’s drug, on rodent microglial cells in vitro

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Toru Murakawa-Hirachi ◽  
Yoshito Mizoguchi ◽  
Masahiro Ohgidani ◽  
Yoshinori Haraguchi ◽  
Akira Monji
Keyword(s):  
Neuronal Death ◽  
Phagocytic Activity ◽  
Microglial Cell ◽  
Cell Function ◽  
Microglial Cells ◽  
Phagocytosis Assay ◽  
Intracellular Ca ◽  
Β Amyloid ◽  
The Brain

AbstractThe pathophysiology of Alzheimer’s disease (AD) is related to neuroinflammatory responses mediated by microglia. Memantine, an antagonist of N-methyl-d-aspartate (NMDA) receptors used as an anti-Alzheimer’s drug, protects from neuronal death accompanied by suppression of proliferation and activation of microglial cells in animal models of AD. However, it remains to be tested whether memantine can directly affect microglial cell function. In this study, we examined whether pretreatment with memantine affects intracellular NO and Ca2+ mobilization using DAF-2 and Fura-2 imaging, respectively, and tested the effects of memantine on phagocytic activity by human β-Amyloid (1–42) phagocytosis assay in rodent microglial cells. Pretreatment with memantine did not affect production of NO or intracellular Ca2+ elevation induced by TNF in rodent microglial cells. Pretreatment with memantine also did not affect the mRNA expression of pro-inflammatory (TNF, IL-1β, IL-6 and CD45) or anti-inflammatory (IL-10, TGF-β and arginase) phenotypes in rodent microglial cells. In addition, pretreatment with memantine did not affect the amount of human β-Amyloid (1–42) phagocytosed by rodent microglial cells. Moreover, we observed that pretreatment with memantine did not affect 11 major proteins, which mainly function in the phagocytosis and degradation of β-Amyloid (1–42), including TREM2, DAP12 and neprilysin in rodent microglial cells. To the best of our knowledge, this is the first report to suggest that memantine does not directly modulate intracellular NO and Ca2+ mobilization or phagocytic activity in rodent microglial cells. Considering the neuroinflammation hypothesis of AD, the results might be important to understand the effect of memantine in the brain.

Amacrine and ganglion cell contributions to the electroretinogram in amphibian retina

2001 ◽  
Vol 18 (1) ◽  
pp. 147-156 ◽  
Author(s):  
GAUTAM AWATRAMANI ◽  
JUE WANG ◽  
MALCOLM M. SLAUGHTER
Keyword(s):  
Contrast Agents ◽  
Ganglion Cell ◽  
Neuronal Activity ◽  
Opposite Effect ◽  
Cell Function ◽  
Ganglion Cells ◽  
Field Potential ◽  
Tiger Salamander ◽  
Third Order ◽  
Light Responses

The neuronal generators of the b- and d-waves of the electroretinogram (ERG) were investigated in the tiger salamander retina to determine if amacrine and ganglion cells contribute to this field potential. Several agents were used that affect third-order neurons, such as tetrodotoxin, baclofen, and NMDA agonists and antagonists. Baclofen, an agent that enhances light responses in third-order neurons, increased the d-wave and reduced the b-wave. In contrast, agents that decrease light responses in third-order neurons had the opposite effect of enhancing the b-wave and depressing the d-wave. The effect on the d-wave was particularly pronounced. The results indicate that third-order neuronal activity influences b- and d-waves of the ERG. The opposing actions suggest that the b-wave to d-wave ratio might serve as an measure of ganglion cell function.

scholarly journals Effects of Extra Virgin Olive Oil Polyphenols on Beta-Cell Function and Survival

Plants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 286
Author(s):  
Nicola Marrano ◽  
Rosaria Spagnuolo ◽  
Giuseppina Biondi ◽  
Angelo Cignarelli ◽  
Sebastio Perrini ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Olive Oil ◽  
Beta Cells ◽  
Intracellular Signaling ◽  
Beta Cell Function ◽  
Cell Function ◽  
Virgin Olive Oil ◽  
Extra Virgin Olive Oil ◽  
Insulin Biosynthesis

Extra virgin olive oil (EVOO) is a major component of the Mediterranean diet and is appreciated worldwide because of its nutritional benefits in metabolic diseases, including type 2 diabetes (T2D). EVOO contains significant amounts of secondary metabolites, such as phenolic compounds (PCs), that may positively influence the metabolic status. In this study, we investigated for the first time the effects of several PCs on beta-cell function and survival. To this aim, INS-1E cells were exposed to 10 μM of the main EVOO PCs for up to 24 h. Under these conditions, survival, insulin biosynthesis, glucose-stimulated insulin secretion (GSIS), and intracellular signaling activation (protein kinase B (AKT) and cAMP response element-binding protein (CREB)) were evaluated. Hydroxytyrosol, tyrosol, and apigenin augmented beta-cell proliferation and insulin biosynthesis, and apigenin and luteolin enhanced the GSIS. Conversely, vanillic acid and vanillin were pro-apoptotic for beta-cells, even if they increased the GSIS. In addition, oleuropein, p-coumaric, ferulic and sinapic acids significantly worsened the GSIS. Finally, a mixture of hydroxytyrosol, tyrosol, and apigenin promoted the GSIS in human pancreatic islets. Apigenin was the most effective compound and was also able to activate beneficial intracellular signaling. In conclusion, this study shows that hydroxytyrosol, tyrosol, and apigenin foster beta-cells’ health, suggesting that EVOO or supplements enriched with these compounds may improve insulin secretion and promote glycemic control in T2D patients.

scholarly journals A biomimetic assay platform for the interrogation of antigen-dependent anti-tumor T-cell function

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jeremy To ◽  
Doug Quackenbush ◽  
Emily Rowell ◽  
Lilin Li ◽  
Connor Reed ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Cell Activity ◽  
Cytotoxic T Cell ◽  
Dependent Manner ◽  
Cyclin Dependent Kinase ◽  
Histocompatibility Complex ◽  
T Cell Function ◽  
Cytolytic Granule ◽  
Screening Platform

AbstractOvercoming tumor-mediated immunosuppression and enhancing cytotoxic T-cell activity within the tumor microenvironment are two central goals of immuno-oncology (IO) drug discovery initiatives. However, exploratory assays involving immune components are often plagued by low-throughput and poor clinical relevance. Here we present an innovative ultra-high-content assay platform for interrogating T-cell-mediated killing of 3D multicellular tumor spheroids. Employing this assay platform in a chemical genomics screen of 1800 annotated compounds enabled identification of small molecule perturbagens capable of enhancing cytotoxic CD8+ T-cell activity in an antigen-dependent manner. Specifically, cyclin-dependent kinase (CDK) and bromodomain (BRD) protein inhibitors were shown to significantly augment anti-tumor T-cell function by increasing cytolytic granule and type II interferon secretion in T-cells in addition to upregulating major histocompatibility complex (MHC) expression and antigen presentation in tumor cells. The described biotechnology screening platform yields multi-parametric, clinically-relevant data and can be employed kinetically for the discovery of first-in-class IO therapeutic agents.

Phosphatidylinositol 3-kinase mediates integrin-dependent NF-(κ)B and MAPK activation through separate signaling pathways

2001 ◽  
Vol 114 (8) ◽  
pp. 1579-1589 ◽  
Author(s):  
M. Reyes-Reyes ◽  
N. Mora ◽  
A. Zentella ◽  
C. Rosales
Keyword(s):  
Signaling Pathways ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Small Gtpase ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Dependent Manner ◽  
Monocytic Leukemia ◽  
Monocytic Cells ◽  
Mapk Activation

Integrin-mediated signals play an important but poorly understood role in regulating many leukocyte functions. In monocytes and monocytic leukemia cells, (β)1 integrin-mediated adhesion results in a strong induction of immediate-early genes that are important in inflammation. To investigate the signaling pathways from integrins in monocytic cells, THP-1 cells were stimulated via (β)1 integrins by binding to fibronectin and by crosslinking the integrins with specific monoclonal antibodies. The involvement of MAPK and PI 3-K on nuclear factor (κ)B (NF-(κ)B) activation was then analyzed. We found that integrins activated both NF-(κ)B and MAPK in a PI 3-K-dependent manner, as wortmannin and LY294002 blocked these responses. However, the specific MEK inhibitor PD98059 did not prevent integrin-mediated NF-(κ)B activation. In contrast, a dominant negative mutant of Rac completely prevented NF-(κ)B activation, but it did not affect MAPK activation. These results indicate that integrin signaling to NF-(κ)B is not mediated by the MAPK pathway, but rather by the small GTPase Rac. In addition, a dominant negative form of Ρ augmented NF-(κ)B activation and blocked MAPK activation, implying that these two pathways are in competition with each other. These data suggest that integrins activate different signaling pathways in monocytic cells. One uses PI 3-K and Rac to activate NF-(κ)B, while the other uses PI 3-K, MEK, and MAPK to activate other nuclear factors, such as Elk-1.

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