scholarly journals Signaling Pathways in Proton and Non-proton ASIC1a Activation

2021 ◽  
Vol 15 ◽  
Author(s):  
Libia Catalina Salinas Castellanos ◽  
Osvaldo Daniel Uchitel ◽  
Carina Weissmann
Keyword(s):  
Signaling Pathways ◽  
Sodium Influx ◽  
Downstream Signaling ◽  
Pathological Conditions ◽  
Acid Sensing Ion Channels ◽  
Sustained Effect ◽  
Pathological Mechanism ◽  
Large Extracellular Loop ◽  
Downstream Signaling Pathway

Acid-sensing ion channels (ASICs) regulate synaptic activities and play important roles in neurodegenerative diseases as well as pain conditions. Classically, ASICs are described as transiently activated by a reduced pH, followed by desensitization; the activation allows sodium influx, and in the case of ASIC1a-composed channels, also calcium to some degree. Several factors are emerging and extensively analyzed as modulators, activating, inhibiting, and potentiating specific channel subunits. However, the signaling pathways triggered by channel activation are only starting to be revealed.The channel has been recently shown to be activated through a mechanism other than proton-mediated. Indeed, the large extracellular loop of these channels opens the possibility that other non-proton ligands might exist. One such molecule discovered was a toxin present in the Texas coral snake venom. The finding was associated with the activation of the channel at neutral pH via the toxin and causing intense and unremitting pain.By using different pharmacological tools, we analyzed the downstream signaling pathway triggered either by the proton and non-proton activation for human, mouse, and rat ASIC1a-composed channels in in vitro models. We show that for all species analyzed, the non-protonic mode of activation determines the activation of the ERK signaling cascade at a higher level and duration compared to the proton mode.This study adds to the growing evidence of the important role ASIC1a channels play in different physiological and pathological conditions and also hints at a possible pathological mechanism for a sustained effect.

scholarly journals Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Sareshma Sudhesh Dev ◽  
Syafiq Asnawi Zainal Abidin ◽  
Reyhaneh Farghadani ◽  
Iekhsan Othman ◽  
Rakesh Naidu
Keyword(s):  
Signaling Pathways ◽  
Cancer Progression ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Surface Proteins ◽  
Downstream Signaling ◽  
Anti Cancer ◽  
Rtk Inhibitors

Receptor tyrosine kinases (RTKs) are transmembrane cell-surface proteins that act as signal transducers. They regulate essential cellular processes like proliferation, apoptosis, differentiation and metabolism. RTK alteration occurs in a broad spectrum of cancers, emphasising its crucial role in cancer progression and as a suitable therapeutic target. The use of small molecule RTK inhibitors however, has been crippled by the emergence of resistance, highlighting the need for a pleiotropic anti-cancer agent that can replace or be used in combination with existing pharmacological agents to enhance treatment efficacy. Curcumin is an attractive therapeutic agent mainly due to its potent anti-cancer effects, extensive range of targets and minimal toxicity. Out of the numerous documented targets of curcumin, RTKs appear to be one of the main nodes of curcumin-mediated inhibition. Many studies have found that curcumin influences RTK activation and their downstream signaling pathways resulting in increased apoptosis, decreased proliferation and decreased migration in cancer both in vitro and in vivo. This review focused on how curcumin exhibits anti-cancer effects through inhibition of RTKs and downstream signaling pathways like the MAPK, PI3K/Akt, JAK/STAT, and NF-κB pathways. Combination studies of curcumin and RTK inhibitors were also analysed with emphasis on their common molecular targets.

CIP4 Targeted to Recruit GTP-Cdc42 Involving in Invadopodia Formation Through NF-κB Signaling Pathway Promotes Invasion and Metastasis of Colorectal Cancer

2021 ◽  
Author(s):  
Zhiyan Hu ◽  
Jiaxian Zhu ◽  
Yidan Ma ◽  
Ting Long ◽  
Lingfang Gao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathway ◽  
Tumor Metastasis ◽  
Migration And Invasion ◽  
Downstream Signaling ◽  
And Function ◽  
Downstream Signaling Pathway ◽  
Invadopodia Formation

Abstract Background CIP4 (Cdc42-interacting protein 4), a member of the F-BAR family which plays an important role in regulating cell membrane and actin, has been reported to interact with Cdc42 and closely associated with tumor invadopodia formation. However, the specific mechanism of the interaction between CIP4 and Cdc42 as well as the downstream signaling pathway in response in colorectal cancer (CRC) remains unknown, which is worth exploring for its impact on tumor infiltration and metastasis. Methods Immunohistochemistry and western blot analyses were performed to detect the expression of CIP4 and Cdc42. Their relationship with CRC clinicopathological characteristics was further analyzed. Wound-healing, transwell migration and invasion assays tested the effect of CIP4 on cells migration and invasion ability in vitro, and the orthotopic xenograft colorectal cancer mouse mode evaluated the tumor metastasis in vivo. The invadopodia formation and function were assessed by immunofluorescence, scanning electron microscopy (SEM) and matrix degradation assay. The interaction between CIP4 and Cdc42 was confirmed by co-immunoprecipitation (co-IP) and GST-Pull down assays. Immunofluorescence was used to observed the colocalization of CIP4, GTP-Cdc42 and invadopodia. The related downstream signaling pathway was investigated by western blot and immunofluorescence. Results CIP4 expression was significantly higher in human colorectal cancer tissues and correlated with the CRC infiltrating depth and metastasis as well as the lower survival rate in patients. In cultured CRC cells, knockdown of CIP4 inhibited cell migration and invasion ability in vitro and the tumor metastasis in vivo, while overexpression of CIP4 confirmed the opposite situation by promoting invadopodia formation and matrix degradation ability. In addition, we identified GTP-Cdc42 as a directly interactive protein of CIP4, which was upregulated and recruited by CIP4 to participate in this process. Furthermore, activated NF-κB signaling pathway was found in CIP4 overexpression CRC cells contributing to invadopodia formation while inhibition of either CIP4 or Cdc42 led to suppression of NF-κB pathway resulted in decrease quantity of invadopodia. Conclusion Our findings suggested that CIP4 targets to recruit GTP-Cdc42 and directly combines with it to accelerate invadopodia formation and function by activating NF-κB signaling pathway, thus promoting CRC infiltration and metastasis.

scholarly journals Metformin alleviates the calcification of aortic valve interstitial cells through activating the PI3K/AKT pathway in an AMPK dependent way

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Qiao En ◽  
Huang Zeping ◽  
Wang Yuetang ◽  
Wang Xu ◽  
Wang Wei
Keyword(s):  
Aortic Valve ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Interstitial Cells ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Aortic Valves ◽  
Valve Interstitial Cells ◽  
Pathological Mechanism

Abstract Background Calcific aortic valve disease (CAVD) is the most prevalent valvular disease worldwide. However, no effective treatment could delay or prevent the progression of the disease due to the poor understanding of its pathological mechanism. Many studies showed that metformin exerted beneficial effects on multiple cardiovascular diseases by mediating multiple proteins such as AMPK, NF-κB, and AKT. This study aims to verify whether metformin can inhibit aortic calcification through the PI3K/AKT signaling pathway. Methods We first analyzed four microarray datasets to screen differentially expressed genes (DEGs) and signaling pathways related to CAVD. Then aortic valve samples were used to verify selected genes and pathways through immunohistochemistry (IHC) and western blot (WB) assays. Aortic valve interstitial cells (AVICs) were isolated from non-calcific aortic valves and then cultured with phosphate medium (PM) with or without metformin to verify whether metformin can inhibit the osteogenic differentiation and calcification of AVICs. Finally, we used inhibitors and siRNA targeting AMPK, NF-κB, and AKT to study the mechanism of metformin. Results We screened 227 DEGs; NF-κB and PI3K/AKT signaling pathways were implicated in the pathological mechanism of CAVD. IHC and WB experiments showed decreased AMPK and AKT and increased Bax in calcific aortic valves. PM treatment significantly reduced AMPK and PI3K/AKT signaling pathways, promoted Bax/Bcl2 ratio, and induced AVICs calcification. Metformin treatment ameliorated AVICs calcification and apoptosis by activating the PI3K/AKT signaling pathway. AMPK activation and NF-κB inhibition could inhibit AVICs calcification induced by PM treatment; however, AMPK and AKT inhibition reversed the protective effect of metformin. Conclusions This study, for the first time, demonstrates that metformin can inhibit AVICs in vitro calcification by activating the PI3K/AKT signaling pathway; this suggests that metformin may provide a potential target for the treatment of CAVD. And the PI3K/AKT signaling pathway emerges as an important regulatory axis in the pathological mechanism of CAVD.

scholarly journals Pharmacological Modulation of Ubiquitin-Proteasome Pathways in Oncogenic Signaling

2021 ◽  
Vol 22 (21) ◽  
pp. 11971
Author(s):  
Anmol Sharma ◽  
Heena Khan ◽  
Thakur Gurjeet Singh ◽  
Amarjot Kaur Grewal ◽  
Agnieszka Najda ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Cell Cycle Control ◽  
In Vivo Studies ◽  
Oncogenic Signaling ◽  
Aberrant Expression ◽  
Downstream Signaling ◽  
Ubiquitin Proteasome ◽  
Progressive Growth

The ubiquitin-proteasome pathway (UPP) is involved in regulating several biological functions, including cell cycle control, apoptosis, DNA damage response, and apoptosis. It is widely known for its role in degrading abnormal protein substrates and maintaining physiological body functions via ubiquitinating enzymes (E1, E2, E3) and the proteasome. Therefore, aberrant expression in these enzymes results in an altered biological process, including transduction signaling for cell death and survival, resulting in cancer. In this review, an overview of profuse enzymes involved as a pro-oncogenic or progressive growth factor in tumors with their downstream signaling pathways has been discussed. A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on modulation of ubiquitin-proteasome pathways in oncogenic signaling. Various in vitro, in vivo studies demonstrating the involvement of ubiquitin-proteasome systems in varied types of cancers and the downstream signaling pathways involved are also discussed in the current review. Several inhibitors of E1, E2, E3, deubiquitinase enzymes and proteasome have been applied for treating cancer. Some of these drugs have exhibited successful outcomes in in vivo studies on different cancer types, so clinical trials are going on for these inhibitors. This review mainly focuses on certain ubiquitin-proteasome enzymes involved in developing cancers and certain enzymes that can be targeted to treat cancer.

scholarly journals Inhibition of cAMP/PKA/CREB Signaling Axis Improves Fibroblast Plasticity for Direct Cardiac Reprogramming

2021 ◽  
Author(s):  
Emre Bektik ◽  
Yu Sun ◽  
Adrienne Dennis ◽  
Phraew Sakon ◽  
Dandan Yang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Primary Cell Culture ◽  
Myofibroblast Differentiation ◽  
Camp Concentration ◽  
Cultured Fibroblasts ◽  
Downstream Signaling ◽  
Upstream Regulator ◽  
Reprogramming Efficiency ◽  
Signaling Axis

Direct cardiac reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a promising approach but remains a challenging technology of regenerative medicine for damaged myocardium. Efforts have been focused on improving the efficiency by understanding fundamental mechanisms. One of the major challenges is that the plasticity of cultured fibroblast varies batch to batch with unknown mechanisms. Here, we noticed that a portion of in vitro cultured fibroblasts have been activated to differentiate into myofibroblasts, marked by the expression of αSMA, even in the primary cell culture of tissues. Both forskolin, which activates adenylyl cyclase and increases cAMP concentration, and TGFbeta inhibitor SB431542 can efficiently suppress myofibroblast differentiation of cultured fibroblasts. However, SB431542 improved but forskolin blocked iCM reprogramming of fibroblasts that were infected with retroviruses of Gata4, Mef2c and Tbx5 (GMT). Moreover, inhibitors of cAMP downstream signaling pathways, PKA or CREB-CBP, significantly improved the efficiency of iCM reprogramming. Consistently, inhibition of p38/MAPK, another upstream regulator of CREB-CBP, also improved reprogramming efficiency. We then investigated if inhibition of these signaling pathways in primary cultured fibroblast could improve their plasticity for reprogramming, and found that preconditioning of cultured fibroblasts with CREB-CBP inhibitor significantly improved the cellular plasticity of fibroblasts to be reprogrammed, yielding ~2-fold amount of reprogrammed iCMs compared to that of untreated control cells. In conclusion, suppression of cAMP/PKA/CREB signaling axis improves fibroblast plasticity for direct cardiac reprogramming.

scholarly journals Warfarin Treatment Alters Gas6 and Protein S Activity and Their Downstream Signaling Pathways in Brain, and Stimulates Microglial Activity (P24-002-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Guylaine Ferland ◽  
Pierre Allaire ◽  
Bouchra Ouliass
Keyword(s):  
Signaling Pathways ◽  
Tyrosine Kinases ◽  
Protein S ◽  
Convincing Evidence ◽  
Bdnf Expression ◽  
Behavioral Impairment ◽  
Downstream Signaling ◽  
Funding Sources ◽  
Male Wistar Rats

Abstract Objectives There is now convincing evidence that vitamin K (VK) has important actions in the nervous system and cognition. Two VK-dependent proteins are closely linked to the brain namely Gas6 and protein S (PS). Functionally, both proteins are ligands for receptors of tyrosine kinases Tyro3, Axl, and Mer. In vitro, Gas6 and PS have been shown to possess pro-survival activity towards neurons and glia through stimulation of the extracellular signal-regulated (ERK) and serine-threonine (Akt) kinases pathways. In a previous study, targeted depletion of VK in brain induced by warfarin (W) treatment, a VK antagonist, resulted in cognitive and behavioral impairment. In the present study, we aimed to characterize the role of Gas6 and PS and their signaling pathways in W-treated rats fed or not with supplemental menaquinone-4 (MK-4), the principal K vitamer in brain. Methods Male Wistar rats (n = 5–7/gp) were randomly allocated to a AIN-93 based diet containing 750 mcg phylloquinone (K1)/kg/d supplemented with 100 mg MK-4/kg/d (MK-4) or not (N). After one week, rats were administered 14 mg W/kg/d (in drinking water) and subcutaneous K1 (94 mg/kg), 3X/wk, for 9 wks. [Subcutaneous K1 treatment is required to maintain the coagulation function]. A control gp (C) treated with normal water and injected with saline was also included. Gas6, PS, pAkt, pERK as well as brain-derived neurotrophic factor (BDNF) and microglial CD11b/c protein, were assessed in hippocampus (HPP), frontal cortex (FC) and striatum (STR), three regions involved in cognition, by immunoblotting. Group difference were tested by one-way ANOVA. Results Impact of W treatment was particularly marked in HPP, rats from N group showing decreased Gas6, PS and ERK activity as well as decreased BDNF expression, compared to C gp. Further, rats from N group presented increased expression of CD11bc, a marker of inflammation (all P < 0.05). Supplementing the diet with MK-4 normalized PS activity and BDNF and CD11bc expression in HPP, Gas6 and pERK in CF, and pAkt in STR (all P < 0.05). Conclusions Results indicate that W treatment as used in the present study alters Gas6 and PS activity and their downstream signaling pathways, and stimulates microglial activity. Supplementing the diet with large amounts of MK-4 normalized much of the phenotype. Funding Sources Study funded by CIHR.

scholarly journals Inhibition of CREB-CBP Signaling Improves Fibroblast Plasticity for Direct Cardiac Reprogramming

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1572
Author(s):  
Emre Bektik ◽  
Yu Sun ◽  
Adrienne T. Dennis ◽  
Phraew Sakon ◽  
Dandan Yang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Cell Cultures ◽  
Myofibroblast Differentiation ◽  
Heart Regeneration ◽  
Cultured Fibroblasts ◽  
Downstream Signaling ◽  
Upstream Regulator ◽  
Reprogramming Efficiency ◽  
Camp Levels

Direct cardiac reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a promising approach but remains a challenge in heart regeneration. Efforts have focused on improving the efficiency by understanding fundamental mechanisms. One major challenge is that the plasticity of cultured fibroblast varies batch to batch with unknown mechanisms. Here, we noticed a portion of in vitro cultured fibroblasts have been activated to differentiate into myofibroblasts, marked by the expression of αSMA, even in primary cell cultures. Both forskolin, which increases cAMP levels, and TGFβ inhibitor SB431542 can efficiently suppress myofibroblast differentiation of cultured fibroblasts. However, SB431542 improved but forskolin blocked iCM reprogramming of fibroblasts that were infected with retroviruses of Gata4, Mef2c, and Tbx5 (GMT). Moreover, inhibitors of cAMP downstream signaling pathways, PKA or CREB-CBP, significantly improved the efficiency of reprogramming. Consistently, inhibition of p38/MAPK, another upstream regulator of CREB-CBP, also improved reprogramming efficiency. We then investigated if inhibition of these signaling pathways in primary cultured fibroblasts could improve their plasticity for reprogramming and found that preconditioning of cultured fibroblasts with CREB-CBP inhibitor significantly improved the cellular plasticity of fibroblasts to be reprogrammed, yielding ~2-fold more iCMs than untreated control cells. In conclusion, suppression of CREB-CBP signaling improves fibroblast plasticity for direct cardiac reprogramming.

scholarly journals Heme activates platelets and exacerbates rhabdomyolysis-induced acute kidney injury via CLEC-2 and GPVI/FcRγ

2021 ◽  
Vol 5 (7) ◽  
pp. 2017-2026
Author(s):  
Saori Oishi ◽  
Nagaharu Tsukiji ◽  
Shimon Otake ◽  
Naoki Oishi ◽  
Tomoyuki Sasaki ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Platelet Aggregation ◽  
Cancer Progression ◽  
Kidney Injury ◽  
Human Platelets ◽  
Double Knockout ◽  
Downstream Signaling ◽  
Glycoprotein Vi ◽  
Downstream Signaling Pathway

Abstract There is increasing evidence that platelets participate in multiple pathophysiological processes other than thrombosis and hemostasis, such as immunity, inflammation, embryonic development, and cancer progression. A recent study revealed that heme (hemin)-activated platelets induce macrophage extracellular traps (METs) and exacerbate rhabdomyolysis-induced acute kidney injury (RAKI); however, how hemin activates platelets remains unclear. Here, we report that both C-type lectin-like receptor-2 (CLEC-2) and glycoprotein VI (GPVI) are platelet hemin receptors and are involved in the exacerbation of RAKI. We investigated hemin-induced platelet aggregation in humans and mice, binding of hemin to CLEC-2 and GPVI, the RAKI-associated phenotype in a mouse model, and in vitro MET formation. Using western blotting and surface plasmon resonance, we showed that hemin activates human platelets by stimulating the phosphorylation of SYK and PLCγ2 and directly binding to both CLEC-2 and GPVI. Furthermore, hemin-induced murine platelet aggregation was partially reduced in CLEC-2–depleted and FcRγ-deficient (equivalent to GPVI-deficient) platelets and almost completely inhibited in CLEC-2–depleted FcRγ-deficient (double-knockout) platelets. In addition, hemin-induced murine platelet aggregation was inhibited by the CLEC-2 inhibitor cobalt hematoporphyrin or GPVI antibody (JAQ-1). Renal dysfunction, tubular injury, and MET formation were attenuated in double-knockout RAKI mice. Furthermore, in vitro MET formation assay showed that the downstream signaling pathway of CLEC-2 and GPVI is involved in MET formation. We propose that both CLEC-2 and GPVI in platelets play an important role in RAKI development.

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