scholarly journals Increase in soluble protein oligomers triggers the innate immune system promoting inflammation and vascular dysfunction in the pathogenesis of sepsis

2018 ◽  
Vol 132 (13) ◽  
pp. 1433-1438
Author(s):  
Amel Komic ◽  
Patricia Martinez-Quinones ◽  
Cameron G. McCarthy ◽  
R. Clinton Webb ◽  
Camilla F. Wenceslau
Keyword(s):  
Soluble Protein ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Formyl Peptide Receptor ◽  
Misfolded Proteins ◽  
Resistance Arteries ◽  
Oligomeric Protein ◽  
Formyl Peptide

Sepsis is a profoundly morbid and life-threatening condition, and an increasingly alarming burden on modern healthcare economies. Patients with septic shock exhibit persistent hypotension despite adequate volume resuscitation requiring pharmacological vasoconstrictors, but the molecular mechanisms of this phenomenon remain unclear. The accumulation of misfolded proteins is linked to numerous diseases, and it has been observed that soluble oligomeric protein intermediates are the primary cytotoxic species in these conditions. Oligomeric protein assemblies have been shown to bind and activate a variety of pattern recognition receptors (PRRs) including formyl peptide receptor (FPR). While inhibition of endoplasmic reticulum (ER) stress and stabilization of protein homeostasis have been promising lines of inquiry regarding sepsis therapy, little attention has been given to the potential effects that the accumulation of misfolded proteins may have in driving sepsis pathogenesis. Here we propose that in sepsis, there is an accumulation of toxic misfolded proteins in the form of soluble protein oligomers (SPOs) that contribute to the inflammation and vascular dysfunction observed in sepsis via the activation of one or more PRRs including FPR. Our laboratory has shown increased levels of SPOs in the heart and intrarenal arteries of septic mice. We have also observed that exposure of resistance arteries and vascular smooth muscle cells to SPOs is associated with increased mitogen-activated protein kinase (MAPK) signaling including phosphorylated extracellular signal-regulated kinase (p-ERK) and p-P38 MAPK pathways, and that this response is abolished with the knockout of FPR. This hypothesis has promising clinical implications as it proposes a novel mechanism that can be exploited as a therapeutic target in sepsis.

Abstract 22: Formyl Peptide Receptor-1 Activation Is Crucial For The Cause Of Spontaneous Hypertension In Dahl Salt Sensitive Rats

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Jonnelle M Edwards ◽  
Sarah Galla ◽  
Nicole R Bearss ◽  
Blair Mell ◽  
Xi Cheng ◽  
...  
Keyword(s):  
Vascular Injury ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Formyl Peptide Receptor ◽  
Spontaneous Hypertension ◽  
Leaky Gut ◽  
Cell Necrosis ◽  
Resistance Arteries ◽  
Peptide Receptor ◽  
Formyl Peptide

Mitochondria evolved from bacteria and use N-formylated peptides (NFPs) to synthetize protein. Bacterial and mitochondrial NFPs activate formyl peptide receptor 1 (FPR-1) and lead to vascular injury. We previously observed that Dahl Salt Sensitive rats (S) fed a low-salt (LS, 0.3% NaCl) diet presented spontaneous hypertension, vascular dysfunction, and overexpression of FPR-1 in arteries when compared to Dahl Salt Resistant (R) rats. High salt (HS, 2% NaCl) diet worsened these phenotypes in S rats. Interestingly, HS diet induced leaky gut and amoxicillin (AMO) treatment decreased BP in S-HS. Due to the dual sources of NFPs (microbiota and host mitochondria), we hypothesized that cell death-derived mitochondria and/or leaky gut-derived bacterial NFPs lead to FPR-1 activation, vascular injury and elevated BP in S rats independent of HS diet. For this, we used flow cytometry to measure cell necrosis and early and late apoptosis in kidney, bone marrow-derived macrophages and mesenteric resistance arteries (MRA) from male S and R rats (8-week old) on a LS diet. Zonulin, a biomarker for leaky gut, was measured in plasma. In another group, rats were treated with FPR-1 antagonist [Cyclosporin H (CsH), 0.3 mg/kg/day, osmotic mini-pump, 14 days], vehicle (VEH) or received water with AMO (5 mg/kg/day) for 21 days to deplete bacteria. BP was measured by telemetry and vascular function and structure were assessed in MRA. S rats presented increased kidney cell necrosis (R: 3.8±0.3 vs. S: 5.3±0.5* %). CsH decreased spontaneous elevation of BP [Diastolic: R+VEH: 77±2.7 vs. R+CsH: 81±1.2 vs. S+VEH: 126±3.0* vs. S+CsH:115±2.7 # ] and vascular hypercontractility [KCl (120mM): R+VEH: 9.4±1 vs. R+CsH: 10.2±0.4; S+VEH: 15.5±0.9* vs. S+CsH:11.7±0.8 # mN; Phenylephrine (10μM): R+VEH: 9.3±1 vs. R+CsH: 9.7±1; S+VEH: 14.5±1*vs. S+CsH: 11.4±0.6 # mN) in S-LS rats. AMO did not change vascular contraction or BP. Leaky gut was not observed in Dahl S-LS diet. In conclusion, FPR-1 can serve as a causative agent for the spontaneous elevation of BP and kidney-derived mitochondria, but not gut-derived microbiota, are the main source for NFPs.

scholarly journals Beneficial Actions of Orostachys japonica and Its Compounds against Tumors via MAPK Signaling Pathways

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 555
Author(s):  
Soyoung Hur ◽  
Eungyeong Jang ◽  
Jang-Hoon Lee
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Malignant Tumors ◽  
Treatment Options ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Antitumor Effects ◽  
Mesenchymal Transition ◽  
Perennial Plant

Tumors are one of the most life-threatening diseases, and a variety of cancer treatment options have been continuously introduced in order to overcome cancer and improve conventional therapy. Orostachys japonica (O. japonica), which is a perennial plant belonging to the genus Orostachys of the Crassulaceae family, has been revealed to exhibit pharmacological properties against various tumors in numerous studies. The present review aimed to discuss the biological actions and underlying molecular mechanisms of O. japonica and its representative compounds—kaempferol and quercetin—against tumors. O. japonica reportedly has antiproliferative, anti-angiogenic, and antimetastatic activities against various types of malignant tumors through the induction of apoptosis and cell cycle arrest, a blockade of downstream vascular endothelial growth factor (VEGF)-VEGFR2 pathways, and the regulation of epithelial-to-mesenchymal transition. In addition, emerging studies have highlighted the antitumor efficacy of kaempferol and quercetin. Interestingly, it was found that alterations of the mitogen-activated protein kinase (MAPK) signaling cascades are involved in the pivotal mechanisms of the antitumor effects of O. japonica and its two compounds against cancer cell overgrowth, angiogenesis, and metastasis. In summary, O. japonica could be considered a preventive and therapeutic medicinal plant which exhibits antitumor actions by reversing altered patterns of MAPK cascades, and kaempferol and quercetin might be potential components that can contribute to the efficacy and underlying mechanism of O. japonica.

scholarly journals A single amino acid substitution (N297A) in the conserved NPXXY sequence of the human N-formyl peptide receptor results in inhibition of desensitization and endocytosis, and a dose-dependent shift in p42/44 mitogen-activated protein kinase activation and chemotaxis

2000 ◽  
Vol 352 (2) ◽  
pp. 399-407 ◽  
Author(s):  
Jeannie M. GRIPENTROG ◽  
Algirdas J. JESAITIS ◽  
Heini M. MIETTINEN
Keyword(s):  
Protein Kinase ◽  
Transmembrane Domain ◽  
Mitogen Activated Protein Kinase ◽  
Formyl Peptide Receptor ◽  
Wild Type ◽  
Peptide Receptor ◽  
Formyl Peptide ◽  
Mitogen Activated Protein ◽  
Dose Dependent Increase ◽  
Dose Dependent

The formyl peptide receptor (FPR) is a G-protein-coupled receptor (GPCR) that mediates chemotaxis and stimulates the mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase pathway. We have examined the functional effects of substitutions of a conserved aspartic acid residue in the second transmembrane domain (D71A) and of residues in the conserved NPXXY motif in the seventh transmembrane domain (N297A and Y301A). These mutated receptors, expressed in Chinese hamster ovary (CHO) cells, bind ligand with affinities similar to wild-type FPR, but the D71A mutant is uncoupled from G-protein [Miettinen, Mills, Gripentrog, Dratz, Granger and Jesaitis (1997) J. Immunol 159, 4045–4054]. In the present study, we show that both the D71A and N297A mutations resulted in defective endocytosis. The N297A substitution also prevented desensitization, as determined by intracellular calcium mobilization by sequential stimulation with ligand. In chemotaxis assays, the N297A mutation resulted in cell migration towards gradients of up to 100nM N-formyl-methionyl-leucyl-phenylalanine (fMLF), whereas cells expressing the wild-type FPR and the Y301A mutant were no longer chemotactically responsive at 10–100nM fMLF. Maximal activation of p42/44 MAPK occurred in CHO cells expressing wild-type FPR at 10nM–100nM fMLF, whereas cells expressing the N297A mutant showed a dose-dependent increase in the amount of phosphorylated p42/44 MAPK up to 1–10µM fMLF. Since the MAPK kinase inhibitor PD98059 blocked fMLF-induced chemotaxis, our results suggest that the dose-dependent increase in p42/44 MAPK activation may correlate with the increased chemotactic migration of N297A transfectants at 10nM–100nM fMLF.

Abstract P217: Mitochondrial N-Formyl Peptides Elicit Changes in Endothelial Cell Cytoskeleton via Formyl Peptide Receptor Activation

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Camilla F Wenceslau ◽  
Cameron G McCarthy ◽  
R.Clinton Webb
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Vascular Dysfunction ◽  
Receptor Activation ◽  
Vascular Leakage ◽  
Formyl Peptide Receptor ◽  
Experimental Hypertension ◽  
Peptide Receptor ◽  
Formyl Peptide ◽  
Formyl Peptides

One major pathophysiological characteristic of cardiovascular disease, including hypertension, is vascular dysfunction. Recently, we demonstrated that mitochondrial damage-associated molecular patterns are elevated in the circulation of SHR. Mitochondria carry hallmarks of their bacterial ancestry and one of these hallmarks is that this organelle still uses an N-formyl-methionyl-tRNA as an initiator of protein synthesis. We observed that mitochondrial N-formyl peptides (F-MIT) infusion into rats induces inflammation and vascular dysfunction, including vascular leakage, via formyl peptide receptor (FPR) activation. However, neutrophil depletion did not change this response. Therefore, we hypothesize that F-MIT via FPR activation elicits changes directly to cytoskeleton-regulating proteins in vascular cells, which may lead to increased vascular permeability. To test this hypothesis we used vascular smooth muscle cells (VSMC) and endothelial cells harvested from aortas of Sprague-Dawley rats (n=5) and human donors (n=5), respectively. Cells were divided into three groups for Western blot analysis of cytoskeleton-regulating proteins. The cells were incubated for 20 minutes in medium with either vehicle (non-formylated peptide), F-MIT (10 μM), or F-MIT after a 5-minute pre-incubation with FPR1 and 2 antagonists (Cyclosporine H, CsH, 1 μM and WRW4, 10 μM). In endothelial cells, the treatment with F-MIT increased the protein expression of RhoA/ROCK (Rho: 1.8 fold vs. Veh; ROCK: 1.4 fold vs. Veh, p<0.05), cell division control protein 42 (CDC42) (2.0 fold vs. Veh, p<0.05) and phospho-myosin light chain (MLC) Thr/Ser19 (1.5 fold vs. Veh, p<0.05). These changes were all abolished in the presence of FPR antagonists. On the other hand, F-MIT decreased expression of phospho-MLC (0.6 fold vs. Veh, p<0.05) and CDC42 (0.5 fold vs. Veh, p<0.05) and did not change RhoA/ROCK expression in VSMC. In conclusion, F-MIT, via FPR activation, elicits direct changes in endothelial cell and VSMC cytoskeleton-regulating proteins. This interaction can lead to endothelial contraction, increased vascular leakage and attenuated barrier function as observed in clinical and experimental hypertension.

scholarly journals TIR-1/SARM1 Inhibits Axon Regeneration

2020 ◽  
Author(s):  
Victoria Julian ◽  
Alexandra B. Byrne
Keyword(s):  
Molecular Mechanisms ◽  
Axon Regeneration ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Axon Degeneration ◽  
Signaling Cascade ◽  
Mitogen Activated Protein ◽  
Critical Insight ◽  
Insight Into ◽  
Secondary Consequence

AbstractAn injured axon has two choices, regenerate or degenerate. In many neurons, the result is catastrophic axon degeneration and a failure to regenerate. To coerce the injured nervous system to regenerate, the molecular mechanisms that regulate both axon regeneration and degeneration need to be defined. We found that TIR-1/SARM1, a key regulator of axon degeneration, inhibits regeneration of injured motor axons. Loss of tir-1 function both reduces the frequency with which severed axon fragments degenerate and increases the frequency of axon regeneration. The increased regeneration in tir-1 mutants is not a secondary consequence of its effects on degeneration. Rather, TIR-1 carries out each of these opposing functions cell autonomously by regulating independent downstream genetic pathways. While promoting axon degeneration with the DLK-1 mitogen activated protein kinase (MAPK) signaling cascade, TIR-1 inhibits axon regeneration by activating the NSY-1/ASK1 MAPK signaling cascade. Our finding that TIR-1 regulates both axon regeneration and degeneration provides critical insight into how axons coordinately regulate the two key responses to injury, consequently informing approaches to manipulate the balance between these responses towards repair.

scholarly journals Silencing of SPARC represses heterotopic ossification via inhibition of the MAPK signaling pathway

2019 ◽  
Vol 39 (11) ◽  
Author(s):  
Qianjun Wang ◽  
Qianqian Yang ◽  
Ali Zhang ◽  
Zhiqiang Kang ◽  
Yingsheng Wang ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Loss Of Function ◽  
Alp Activity ◽  
Mechanistic Investigation

Abstract Heterotopic ossification (HO), the pathologic formation of extraskeletal bone, can be disabling and lethal. However, the underlying molecular mechanisms were largely unknown. The present study aimed to clarify the involvement of secreted protein acidic and rich in cysteine (SPARC) and the underlying mechanism in rat model of HO. The mechanistic investigation on roles of SPARC in HO was examined through gain- and loss-of-function approaches of SPARC, with alkaline-phosphatase (ALP) activity, mineralized nodules, and osteocalcin (OCN) content measured. To further confirm the regulatory role of SPARC, levels of mitogen-activated protein kinase (MAPK) signaling pathways-related proteins (extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), p38, nuclear factor κ-B (NF-κB), and IkB kinase β (IKKβ)) were determined. Bone marrow mesenchymal stem cells were treated with pathway inhibitor to investigate the relationship among SPARC, MAPK signaling pathway, and HO. The results suggested that SPARC expression was up-regulated in Achilles tendon tissues of HO rats. Silencing of SPARC could decrease phosphorylation of ERK, JNK, p38, NF-κB, and IKKβ. Additionally, silencing of SPARC or inhibition of MAPK signaling pathway could reduce the ALP activity, the number of mineralized nodules, and OCN content, thus impeding HO. To sum up, our study identifies the inhibitory role of SPARC gene silencing in HO via the MAPK signaling pathway, suggesting SPARC presents a potential target for HO therapy.

scholarly journals Downregulation of FPR1 abates lipopolysaccharide-induced inflammatory injury and apoptosis by upregulating MAPK signaling pathway in murine chondrogenic ATDC5 cells

2021 ◽  
Vol 49 (5) ◽  
pp. 56-62
Author(s):  
Hongtao Chen ◽  
Li Zhang
Keyword(s):  
Inflammatory Response ◽  
Western Blot ◽  
Signaling Pathway ◽  
Quantitative Polymerase Chain Reaction ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Expression Level ◽  
Formyl Peptide Receptor ◽  
Western Blot Assay

Background and objective: Osteoarthritis is the most common chronic osteoarthrosis disease. There are complex factors that lead to osteoarthritis. Therefore, it is essential to investigate the molecular mechanism of osteoarthritis, especially the mechanism of articular cartilage degeneration. In this study, the mechanism of FPR1 (formyl peptide receptor 1) in LPS (lipopolysaccharide) induced chondrogenic cell ATDC5 was investigated.Materials and methods: We employed real-time quantitative polymerase chain reaction (RT-qPCR) and western blot assay to analyze the expression level of FPR1 in ATDC5 cell linesinduced by LPS at 0, 2.5, 5, and 10 μg/mL concentrations. Then we constructed the FPR1 knockdown plasmid to transfect the LPS-ATDC5. MTT assay was used to test cell viability in control, LPS, LPS+shNC and LPS+shFPR1 groups. ELISA and RT-qPCR assay were employed to examine the TNF-α (tumor necrosis factor-α)、IL-6 and IL-1β expression level. Flow cytometry and western blot assay were employed to analyze the apoptosis of LPS-ATDC5. Finally, we utilized the western blot assay to text related protein expression level of MAPK (mitogen-activated protein kinase) signaling pathway.Results: In this study, we found the expression level of FPR1 was increased in LPS-ATDC5, downregulation of FPR1 improves the survival rate and alleviates inflammatory response of LPS-ATDC5. Meanwhile, downregulation of FPR1 alleviates apoptosis of LPS-ATDC5. Finally, downregulation of FPR1 inhibits the MAPK signal pathway.Conclusion: Present study revealed that FPR1 was highly expressed in LPS-induced chondrocytes ATDC5, and the downregulation of FPR1 abated the inflammatory response and apoptosis of LPS-ATDC5 cells by regulating the MAPK signaling pathway.

scholarly journals ETV2/ER71 regulates the generation of FLK1+ cells from mouse embryonic stem cells through miR-126-MAPK signaling

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Ju Young Kim ◽  
Dong Hun Lee ◽  
Joo Kyung Kim ◽  
Hong Seo Choi ◽  
Bhakti Dwivedi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Embryonic Stem ◽  
Mapk Signaling ◽  
Mouse Embryonic Stem Cells ◽  
Micro Rna ◽  
Mitogen Activated Protein Kinase ◽  
The Novel

AbstractPrevious studies including ours have demonstrated a critical function of the transcription factor ETV2 (ets variant 2; also known as ER71) in determining the fate of cardiovascular lineage development. However, the underlying mechanisms of ETV2 function remain largely unknown. In this study, we demonstrated the novel function of the miR (micro RNA)-126-MAPK (mitogen-activated protein kinase) pathway in ETV2-mediated FLK1 (fetal liver kinase 1; also known as VEGFR2)+ cell generation from the mouse embryonic stem cells (mESCs). By performing a series of experiments including miRNA sequencing and ChIP (chromatin immunoprecipitation)-PCR, we found that miR-126 is directly induced by ETV2. Further, we identified that miR-126 can positively regulate the generation of FLK1+ cells by activating the MAPK pathway through targeting SPRED1 (sprouty-related EVH1 domain containing 1). Further, we showed evidence that JUN/FOS activate the enhancer region of FLK1 through AP1 (activator protein 1) binding sequences. Our findings provide insight into the novel molecular mechanisms of ETV2 function in regulating cardiovascular lineage development from mESCs.

Formyl peptide receptor 1 promotes podocyte injury through regulation of mitogen-activated protein kinase pathways

2021 ◽  
pp. 153537022110474
Author(s):  
Jun Zhang ◽  
Ting Ding ◽  
Dongxing Tang ◽  
Jianping Wang ◽  
Peng Huang
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Intracellular Transport ◽  
Cell Model ◽  
Mitogen Activated Protein Kinase ◽  
Formyl Peptide Receptor ◽  
Glomerular Injury ◽  
Podocyte Injury ◽  
Peptide Receptor ◽  
Formyl Peptide

Podocyte injury contributes to glomerular injury and is implicated in the pathogenesis of diabetic nephropathy. Formyl peptide receptor (FPR) 1 is abundantly expressed in neutrophils and mediates intracellular transport of Ca 2+. Intracellular Ca 2+ regulates pathological process in renal podocyte and plays a role in diabetic nephropathy. However, the role of formyl peptide receptor 1 in podocyte injury of diabetic nephropathy has not been reported yet. Firstly, a rat model with diabetic nephropathy was established by streptozotocin injection, and a cell model was established via high glucose treatment of mouse podocytes (MPC5). Formyl peptide receptor 1 was enhanced in streptozotocin-induced rats and high glucose-treated MPC5. Secondly, streptozotocin injection promoted the glomerular injury with decreased nephrin and podocin. However, tail injection with adenovirus containing shRNA for silencing of formyl peptide receptor 1 attenuated streptozotocin-induced glomerular injury and the decrease in nephrin and podocin. Moreover, silencing of formyl peptide receptor 1 repressed cell apoptosis of podocytes in diabetic rats and high glucose-treated MPC5. Lastly, protein expression levels of p-p38, p-ERK, and p-JNK protein were up-regulated in streptozotocin-induced rats and high glucose-treated MPC5. Silencing of formyl peptide receptor 1 attenuated high glucose-induced increase in p-p38, p-ERK, and p-JNK in MPC5, and over-expression of formyl peptide receptor 1 aggravated high glucose-induced increase in p-p38, p-ERK, and p-JNK. In conclusion, inhibition of formyl peptide receptor 1 preserved glomerular function and protected against podocyte dysfunction in diabetic nephropathy.

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