Importance of PLC-Dependent PI3K/AKT and AMPK Signaling in RANTES/CCR5 Mediated Macrophage Chemotaxis

Chien, Hung-Che; Chan, Pei Chi; Tu, Chuan Chou; Day, Yuan Ji; Hung, Li-Man; Juan, Chi Chang; Tian, Yu; Hsieh, Po Shiuan

doi:10.4077/cjp.2018.bag584

Cited by 18 publications

(16 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Glucose uptake was determined, as previously reported [ 41 ]. Briefly, C2C12 myotubes attached to the plate were incubated in 1 mL of media buffer supplemented with 138 mM NaCl, 1.85 mM CaCl2 1.3 mM MgSO4, 4.8 mM KCl, 50 mM HEPES pH 7.4 and 0.2% (W/V) BSA for 2 h. Then, 250 mL of 2-deoxy-H 3 -glucose (1 mCi/mL) was added to the well, and the cells were incubated for 15 min.…”

Section: Methodsmentioning

confidence: 99%

PPARδ and FOXO1 Mediate Palmitate-Induced Inhibition of Muscle Pyruvate Dehydrogenase Complex and CHO Oxidation, Events Reversed by Electrical Pulse Stimulation

Chien

Greenhaff

Constantin‐Teodosiu

2020

IJMS

Self Cite

View full text Add to dashboard Cite

The mechanisms behind the reduction in muscle pyruvate dehydrogenase complex (PDC)-controlled carbohydrate (CHO) oxidation during chronic high-fat dietary intake are poorly understood, as is the basis of CHO oxidation restoration during muscle contraction. C2C12 myotubes were treated with (300 μM) palmitate or without (control) for 16 h in the presence and absence of electrical pulse stimulation (EPS, 11.5 V, 1 Hz, 2 ms). Compared to control, palmitate reduced cell glucose uptake (p < 0.05), PDC activity (p < 0.01), acetylcarnitine accumulation (p < 0.05) and glucose-derived mitochondrial ATP production (p < 0.01) and increased pyruvate dehydrogenase kinase isoform 4 (PDK4) (p < 0.01), peroxisome proliferator-activated receptor alpha (PPARα) (p < 0.01) and peroxisome proliferator-activated receptor delta (PPARδ) (p < 0.01) proteins, and reduced the whole-cell p-FOXO1/t-FOXO1 (Forkhead Box O1) ratio (p < 0.01). EPS rescued palmitate-induced inhibition of CHO oxidation, reflected by increased glucose uptake (p < 0.01), PDC activity (p < 0.01) and glucose-derived mitochondrial ATP production (p < 0.01) compared to palmitate alone. EPS was also associated with less PDK4 (p < 0.01) and PPARδ (p < 0.01) proteins, and lower nuclear p-FOXO1/t-FOXO1 ratio normalised to the cytoplasmic ratio, but with no changes in PPARα protein. Collectively, these data suggest PPARδ, and FOXO1 transcription factors increased PDK4 protein in the presence of palmitate, which limited PDC activity and flux, and blunted CHO oxidation and glucose uptake. Conversely, EPS rescued these metabolic events by modulating the same transcription factors.

show abstract

Section: Methodsmentioning

confidence: 99%

PPARδ and FOXO1 Mediate Palmitate-Induced Inhibition of Muscle Pyruvate Dehydrogenase Complex and CHO Oxidation, Events Reversed by Electrical Pulse Stimulation

Chien

Greenhaff

Constantin‐Teodosiu

2020

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…The chemokine ligand 5 (CCL5) also known as RANTES (regulated upon activation, normal T cell expressed, and secreted) is the natural ligand for CCR5 ( Chien et al., 2018 ), whereas the CXC-chemokine ligand 12 (CXCL12), also known as SDF-1 (stromal cell-derived factor 1) is the natural ligand for CXCR4 ( Smith et al., 2017 ). Inhibition of either CCR5 or CXCR4 leads HIV to shift to a more virulent dual-tropic strain.…”

Section: Introductionmentioning

confidence: 99%

Discovery of HIV entry inhibitors via a hybrid CXCR4 and CCR5 receptor pharmacophore‐based virtual screening approach

Mirza

Saadabadi

Vanmeert

et al. 2020

European Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

Chemokine receptors are key regulators of cell migration in terms of immunity and inflammation. Among these, CCR5 and CXCR4 play pivotal roles in cancer metastasis and HIV-1 transmission and infection. They act as essential co-receptors for HIV and furnish a route to the cell entry. In particular, inhibition of either CCR5 or CXCR4 leads very often the virus to shift to a more virulent dual-tropic strain. Therefore, dual receptor inhibition might improve the therapeutic strategies against HIV. In this study, we aimed to discover selective CCR5, CXCR4, and dual CCR5/CXCR4 antagonists using both receptor- and ligand-based computational methods. We employed this approach to fully incorporate the interaction attributes of the binding pocket together with molecular dynamics (MD) simulations and binding free energy calculations. The best hits were evaluated for their anti-HIV-1 activity against CXCR4- and CCR5-specific NL4.3 and BaL strains. Moreover, the Ca 2+ mobilization assay was used to evaluate their antagonistic activity. From the 27 tested compounds, three were identified as inhibitors: compounds 27 (CCR5), 6 (CXCR4) and 3 (dual) with IC 50 values ranging from 10.64 to 64.56 μM. The binding mode analysis suggests that the active compounds form a salt bridge with the glutamates and π-stacking interactions with the aromatic side chains binding site residues of the respective co-receptor. The presented hierarchical virtual screening approach provides essential aspects in identifying potential antagonists in terms of selectivity against a specific co-receptor. The compounds having multiple heterocyclic nitrogen atoms proved to be relatively more specific towards CXCR4 inhibition as compared to CCR5. The identified compounds serve as a starting point for further development of HIV entry inhibitors through synthesis and quantitative structure-activity relationship studies.

show abstract

“…Further, while not specific to CCR5, studies have suggested that the release of G βγ , rather than G αi is essential for chemotaxis mediated by G αi -coupled receptors [ 195 , 229 ]. Both the PLCβ and PI3K signaling cascades mediate the chemotactic response to CCR5 binding by activating a number of Ser/Thr protein kinases, particularly members of the PAK and FAK families, in macrophages [ 230 , 242 , 273 , 276 ] and T-lymphocytes [ 213 , 214 , 276 ]. Signaling via the PLCβ signaling cascade also activates MAPKs [ 221 , 267 ], which is associated with the production of inflammatory mediators [ 31 , 267 , 277 ] and chemotactic responses [ 223 , 278 , 279 ].…”

Section: Chemokine Receptorsmentioning

confidence: 99%

Co-receptor signaling in the pathogenesis of neuroHIV

et al. 2021

View full text Add to dashboard Cite

The HIV co-receptors, CCR5 and CXCR4, are necessary for HIV entry into target cells, interacting with the HIV envelope protein, gp120, to initiate several signaling cascades thought to be important to the entry process. Co-receptor signaling may also promote the development of neuroHIV by contributing to both persistent neuroinflammation and indirect neurotoxicity. But despite the critical importance of CXCR4 and CCR5 signaling to HIV pathogenesis, there is only one therapeutic (the CCR5 inhibitor Maraviroc) that targets these receptors. Moreover, our understanding of co-receptor signaling in the specific context of neuroHIV is relatively poor. Research into co-receptor signaling has largely stalled in the past decade, possibly owing to the complexity of the signaling cascades and functions mediated by these receptors. Examining the many signaling pathways triggered by co-receptor activation has been challenging due to the lack of specific molecular tools targeting many of the proteins involved in these pathways and the wide array of model systems used across these experiments. Studies examining the impact of co-receptor signaling on HIV neuropathogenesis often show activation of multiple overlapping pathways by similar stimuli, leading to contradictory data on the effects of co-receptor activation. To address this, we will broadly review HIV infection and neuropathogenesis, examine different co-receptor mediated signaling pathways and functions, then discuss the HIV mediated signaling and the differences between activation induced by HIV and cognate ligands. We will assess the specific effects of co-receptor activation on neuropathogenesis, focusing on neuroinflammation. We will also explore how the use of substances of abuse, which are highly prevalent in people living with HIV, can exacerbate the neuropathogenic effects of co-receptor signaling. Finally, we will discuss the current state of therapeutics targeting co-receptors, highlighting challenges the field has faced and areas in which research into co-receptor signaling would yield the most therapeutic benefit in the context of HIV infection. This discussion will provide a comprehensive overview of what is known and what remains to be explored in regard to co-receptor signaling and HIV infection, and will emphasize the potential value of HIV co-receptors as a target for future therapeutic development.

show abstract

Importance of PLC-Dependent PI3K/AKT and AMPK Signaling in RANTES/CCR5 Mediated Macrophage Chemotaxis

Cited by 18 publications

References 37 publications

PPARδ and FOXO1 Mediate Palmitate-Induced Inhibition of Muscle Pyruvate Dehydrogenase Complex and CHO Oxidation, Events Reversed by Electrical Pulse Stimulation

PPARδ and FOXO1 Mediate Palmitate-Induced Inhibition of Muscle Pyruvate Dehydrogenase Complex and CHO Oxidation, Events Reversed by Electrical Pulse Stimulation

Discovery of HIV entry inhibitors via a hybrid CXCR4 and CCR5 receptor pharmacophore‐based virtual screening approach

Co-receptor signaling in the pathogenesis of neuroHIV

Contact Info

Product

Resources

About