Abstract 169: Activation of the Phosphoinositide 3-Kinase/Akt Pathway is Responsible for Cardioprotection Induced by Modulation of TLR2

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Chuanfu Li ◽  
Fang Hua ◽  
Tuanzhu Ha ◽  
Jing Ma ◽  
Jim Kelley ◽  
...  
Keyword(s):  
Ischemic Injury ◽  
Akt Signaling ◽  
Toll Like Receptor ◽  
Akt Signaling Pathway ◽  
Wild Type ◽  
Tlr2 Ligand ◽  
Toll Like Receptor 2 ◽  
Phosphoinositide 3 Kinase ◽  
Dependent Mechanism

Activation of the phosphoinositide-3 kinase/Akt (PI3K/Akt) signaling pathway protects cells from ischemic injury. We have reported that the immune modulator, glucan, rapidly induces cardioprotection. Dectin-1 is a specific receptor for glucan and Toll-like receptor 2 (TLR2) is required for transmitting the signal from Dectin-1 into cells. However, the role of modulation of TLR2 in cardioprotection has not been investigated. We hypothesized that modulation of TLR2 will induce cardioprotection through a PI3K/Akt-dependent mechanism. To evaluate our hypothesis, we examined the effect of modulation of TLR2 on myocardial ischemic injury. TLR2 knockout (KO) (n=8) and wild type mice (n=8) were treated with glucan (1 mg/25g) or peptidoglycan (PDG, 75 μg/25g), a specific TLR2 ligand, one hr before the hearts were subjected to ischemia (1 hr)/reperfusion (4 hrs). Untreated mice (n=8) were also subjected to I/R. Myocardial infarction was determined by TTC staining. Infarct size was significantly reduced in glucan (11.6 ± 2.38% vs 36.1 ± 3.48%, p<0.01) and PDG (10.5 ± 3.03% vs 30.1 ± 7.59%, p<0.01) treated mice vs untreated mice. The levels of phospho-Akt (0.80 ± 0.10 vs 0.45 ± 0.09) and phospho-GSK3β (0.66 ± 0.14 vs 0.33 ± 0.10) were significantly increased in the myocardium of glucan treated mice compared with untreated mice. However, both glucan and PDG-induced cardioprotection were completely abolished in TLR2 KO mice. To investigate whether PI3K/Akt signaling is involved in cardioprotection induced by modulation of TLR2, we administered glucan (1 mg/25g) or PDG (75 μg/25g) to kdAkt (kinase deficient Akt) transgenic mice (n=8) one hr before myocardial I/R. Both glucan and PDG-induced cardioprotection were completely abolished in kdAkt mice. The results suggest that modulation of TLR2, either directly or indirectly, will induce cardioprotection through a PI3K/Akt dependent mechanism and that there is a critical link between TLR2 and PI3K/Akt signaling during myocardial I/R.

scholarly journals Toll-Like Receptor 2 is Involved in Abnormal Pregnancy in Mice Infected with Toxoplasma gondii During Late Pregnancy

2021 ◽  
Vol 12 ◽  
Author(s):  
Rina Ikeda ◽  
Nanako Ushio ◽  
Ahmed M. Abdou ◽  
Hidefumi Furuoka ◽  
Yoshifumi Nishikawa
Keyword(s):  
Toxoplasma Gondii ◽  
Premature Birth ◽  
Disease Onset ◽  
Congenital Toxoplasmosis ◽  
Late Pregnancy ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Abnormal Pregnancy ◽  
Toll Like Receptor 2

Infection with Toxoplasma gondii during pregnancy causes failure of pregnancy maintenance, resulting in fetal death, abortion, stillbirth, or premature birth, but the mechanism of disease onset remains unclear. Although Toll-like receptor 2 (TLR2) is expressed on antigen-presenting cells and trophoblasts, the role of TLR2 in T. gondii infection during pregnancy is unknown. In this study, we investigated the role of TLR2 in congenital toxoplasmosis using TLR2-deficient (TLR2−/−) mice. T. gondii infection on gestational day 12.5 (Gd12.5) induced more abnormal pregnancy, including premature birth and stillbirth, in wild-type mice than in TLR2−/− mice. Multiple calcifications were observed in the placentas of the infected wild-type mice. At Gd18.5 (6days postinfection), the parasite numbers in the placenta and uterus and the histological changes did not differ significantly between the wild-type and TLR2−/− mice. However, T. gondii infection reduced the mRNA expression of interleukin-12p40 (IL-12p40) and increased IL-4 and IL-10 mRNAs in the placentas of the wild-type mice. In contrast, the placentas of the TLR2−/− mice showed no changes in the expression of these cytokines, including IL-6 and tumor necrosis factor α, in response to T. gondii infection. Serum interferon-γ levels were significantly lower in the infected TLR2−/− mice than in the infected wild-type mice on Gd18.5. Thus, the TLR2−/− mice were less susceptible to the induction of immune responses by T. gondii infection during late pregnancy. Therefore, TLR2 signaling may play a role in the development of disease states during pregnancy, specifically placental hypofunction.

scholarly journals An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2

2017 ◽  
Author(s):  
Rachel E. Miller ◽  
Richard J. Miller ◽  
Shingo Ishihara ◽  
Phuong B. Tran ◽  
Suzanne B. Golub ◽  
...  
Keyword(s):  
Joint Pain ◽  
Enzymatic Degradation ◽  
Joint Damage ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Nociceptive Neurons ◽  
Predominant Symptom ◽  
Osteoarthritis Pain ◽  
Toll Like Receptor 2

AbstractPain is the predominant symptom of osteoarthritis, but the connection between joint damage and the genesis of pain is not well understood. Loss of articular cartilage is a hallmark of osteoarthritis, and it occurs through enzymatic degradation of aggrecan by ADAMTS-4/5-mediated cleavage in the interglobular domain (E373-374 A). Further cleavage by MMPs (N341-342 F) releases a 32-amino-acid aggrecan fragment (32-mer). We investigated the role of this 32-mer in driving joint pain. We demonstrated that the 32-mer excites dorsal root ganglion (DRG) nociceptive neurons, both in culture and in intact explants. Treatment of cultured sensory neurons with the 32-mer induced them to express the pro-algesic chemokine, MCP-1/CCL2. These effects were mediated through Toll-like receptor (TLR)2, which we demonstrated was expressed by nociceptive neurons. In addition, intra-articular injection of the 32-mer provoked knee hyperalgesia in wild-type but not Tlr2 null mice. Blocking the production or action of the 32-mer in transgenic mice prevented the development of knee hyperalgesia in a murine model of osteoarthritis. These findings suggest that the aggrecan 32-mer fragment directly activates TLR2 on joint nociceptors and is an important mediator of the development of osteoarthritis-associated joint pain.

Biological role of AKT, and regulation of AKT signaling pathway by thymoquinone: perspectives in cancer therapeutics

2020 ◽  
Vol 20 ◽  
Author(s):  
Md. Junaid ◽  
Yeasmin Akter ◽  
Syeda Samira Afrose ◽  
Mousumi Tania ◽  
Md. Asaduzzaman Khan
Keyword(s):  
Clinical Trials ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Inhibitory Effect ◽  
Akt Signaling ◽  
Review Article ◽  
Therapeutic Drug ◽  
Akt Signaling Pathway ◽  
Anti Cancer

Background: AKT/PKB is an important enzyme with numerous biological functions, and its overexpression is related to the carcinogenesis. AKT stimulates different signaling pathways that are downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase, hence functions as an important target for anti-cancer drugs. Objective: In this review article, we have interpreted the role of AKT signaling pathways in cancer and natural inhibitory effect of Thymoquinone (TQ) in AKT and its possible mechanism. Method: We have collected the updated information and data on AKT, their role in cancer and inhibitory effect of TQ in AKT signaling pathway from google scholar, PubMed, Web of Science, Elsevier, Scopus and many more. Results: There are many drugs already developed, which can target AKT, but very few among them have passed clinical trials. TQ is a natural compound, mainly found in black cumin, which has been found to have potential anti-cancer activities. TQ targets numerous signaling pathways, including AKT, in different cancers. In fact, many studies revealed that AKT is one of the major targets of TQ. The preclinical success of TQ suggests its clinical studies on cancer. Conclusion: This review article summarizes the role of AKT in carcinogenesis, its potent inhibitors in clinical trials, and how TQ acts as an inhibitor of AKT and TQ’s future as a cancer therapeutic drug.

Role of Akt signaling pathway regulation in the speckled mousebird (Colius striatus) during torpor displays tissue specific responses

2020 ◽  
Vol 75 ◽  
pp. 109763
Author(s):  
Stuart R. Green ◽  
Rasha Al-Attar ◽  
Andrew E. McKechnie ◽  
Samantha Naidoo ◽  
Kenneth B. Storey
Keyword(s):  
Signaling Pathway ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Tissue Specific ◽  
Pathway Regulation

scholarly journals Akt isoforms differentially regulate neutrophil functions

Blood ◽  
2010 ◽  
Vol 115 (21) ◽  
pp. 4237-4246 ◽  
Author(s):  
Jia Chen ◽  
Haiyang Tang ◽  
Nissim Hay ◽  
Jingsong Xu ◽  
Richard D. Ye
Keyword(s):  
Kinase Inhibitor ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Leading Edge ◽  
Neutrophil Activation ◽  
Enzyme Release ◽  
Wild Type ◽  
Akt Isoforms ◽  
Phosphoinositide 3 Kinase ◽  
O2 Production

In neutrophils, the phosphoinositide 3-kinase/Akt signaling cascade is involved in migration, degranulation, and O2− production. However, it is unclear whether the Akt kinase isoforms have distinct functions in neutrophil activation. Here we report functional differences between the 2 major Akt isoforms in neutrophil activation on the basis of studies in which we used individual Akt1 and Akt2 knockout mice. Akt2−/− neutrophils exhibited decreased cell migration, granule enzyme release, and O2− production compared with wild-type and Akt1−/− neutrophils. Surprisingly, Akt2 deficiency and pharmacologic inhibition of Akt also abrogated phorbol ester-induced O2− production, which was unaffected by treatment with the phosphoinositide 3-kinase inhibitor LY294002. The decreased O2− production in Akt2−/− neutrophils was accompanied by reduced p47phox phosphorylation and its membrane translocation, suggesting that Akt2 is important for the assembly of phagocyte nicotinamide adenine dinucleotide phosphate oxidase. In wild-type neutrophils, Akt2 but not Akt1 translocated to plasma membrane upon chemoattractant stimulation and to the leading edge in polarized neutrophils. In the absence of Akt2, chemoattractant-induced Akt protein phosphorylation was significantly reduced. These results demonstrate a predominant role of Akt2 in regulating neutrophil functions and provide evidence for differential activation of the 2 Akt isoforms in neutrophils.

scholarly journals Key Role of CD36 in Toll-Like Receptor 2 Signaling in Cerebral Ischemia

Stroke ◽  
2010 ◽  
Vol 41 (5) ◽  
pp. 898-904 ◽  
Author(s):  
Takato Abe ◽  
Munehisa Shimamura ◽  
Katherine Jackman ◽  
Hitomi Kurinami ◽  
Josef Anrather ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Toll Like Receptor ◽  
Toll Like Receptor 2
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