PD98059 / Wayne State University - LARVOL DELTA

Neuroprotective Mechanisms of Paeoniflorin in Parkinson's Models: Involvement of BDNF-Dependent PI3K/Akt and ERK/CREB Pathways. (PubMed, Curr Issues Mol Biol) - "A key innovation is the dual activation and coordinated activation of the two BDNF-dependent pathways: LY294002 abolished paeoniflorin-induced BDNF/PI3K/Akt activation, while PD98059 and ERK1/2 siRNA specifically suppressed paeoniflorin-triggered phosphorylation of ERK1/2, p90RSK, and CREB. Ultimately, paeoniflorin exerts robust neuroprotection against MPTP/MPP+ neurotoxicity by synergistically activating BDNF-downstream PI3K/Akt and ERK/CREB axes. This delineation of a dual-pathway mechanism provides novel insight into the pharmacological action of paeoniflorin and supports its potential as a multifaceted therapeutic agent for Parkinson's disease."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • BDNF

Luteolin alleviates myocardial fibrosis through the ERK1/2-GATA4 pathway by inhibiting oxidative stress and EndMT. (PubMed, Int Immunopharmacol) - "Our findings demonstrate that Lut attenuates myocardial fibrosis by regulating oxidative stress, apoptosis, and EndMT, at least in part, via activation of the ERK1/2-GATA4 phosphorylation axis, suggesting its therapeutic potential for myocardial fibrosis."

Journal • Cardiovascular • Fibrosis • Immunology • CD31 • CDH5 • PECAM1

MACF1 Mediates the Impairment of Mechanical Unloading on Osteoblast Differentiation via F-Actin/ERK/Runx2 Axis. (PubMed, Cells) - "Moreover, cytochalasin B and PD98059 were applied to disrupt F-actin and inhibit extracellular signal-regulated kinase (ERK) activity, respectively, to confirm the mechanism...Furthermore, F-actin disruption and ERK inhibition assays confirm that MACF1 mediates the impairment of mechanical unloading on osteoblast differentiation via the F-actin/ERK/Runx2 axis. In conclusion, this study reveals MACF1 as a mechanotransduction mediator for mechanical unloading, inhibiting osteoblast differentiation via F-actin/ERK/Runx2, and contributes to a novel mechanistic insight of cell mechanotransduction."

Journal • Osteoporosis • RUNX2

miR-204-5p attenuates inflammatory infiltration in early-stage chronic renal allograft dysfunction by modulating the IL-11/ERK1/2-NF-κB axis. (PubMed, Front Immunol) - "The ERK1/2 inhibitor PD98059 was used to assess downstream pathway activation...miR-204-5p attenuates early inflammatory injury in CRAD by directly targeting IL-11 and suppressing IL-11-associated ERK1/2-NF-κB inflammatory signaling. The miR-204-5p/IL-11 axis may represent a potential regulatory pathway and therapeutic target for early inflammatory injury in CRAD."

Journal • Fibrosis • Inflammation • Nephrology • Transplantation • MIR204 • TGFB1

Study on the Role of FGF9/ERK/MMP9 Pathway in Age-Related Cataract and in (-)-Epigallocatechin-3-gallate Protecting Lens Epithelial Cells From Apoptosis. (PubMed, Cell Biochem Funct) - "ERK activation by TBHQ increased the viability of H2O2-treated HLE-B3 cells, whereas ERK inhibition with PD98059 attenuated the protective effects of EGCG and decreased MMP9 expression. Moreover, MMP9 knockdown increased cleaved caspase-9 expression and was accompanied by increased apoptosis in LECs. These findings suggest that the FGF9/ERK/MMP9 pathway is involved in oxidative stress-induced LEC apoptosis and may contribute, at least in part, to the protective effects of EGCG in experimental models of ARC."

Journal • Cataract • Ophthalmology • CASP9 • MMP9

How GP96 upregulation shields against COPD: mitigating endoplasmic reticulum stress-induced cellular damage via p38/ERK pathway activation. (PubMed, Gen Physiol Biophys) - "The ERK inhibitor PD98059 offset the effects of GP96 overexpression, except for its impact on the p-P38/P38 levels, which remained unaffected. GP96 overexpression inhibits ERS-induced apoptosis, oxidative stress and inflammation in nicotineinduced in vitro COPD model through potentiating ERK activation."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Botulinum toxin type A attenuates trigeminal neuralgia-like pain by suppressing CGRP release and modulating NaV1.7-associated signaling. (PubMed, J Headache Pain) - "These findings suggest that BoNT/A alleviates CCI-ION-induced TN-like pain, at least in part, by suppressing CGRP-dependent ERK activation and subsequent NaV1.7 membrane recruitment in trigeminal ganglion neurons. The CGRP-ERK-NaV1.7 pathway may represent a peripheral mechanism of BoNT/A-mediated analgesia and a potential target for neuropathic facial pain."

Journal • Neuralgia • Pain • Psychiatry • MBP • NAV1 • TRPV1

Dieckol suppresses lipid accumulation and promotes thermogenic markers in 3T3-L1 adipocytes via ERK/p38 MAPK signaling. (PubMed, J Physiol Biochem) - "Protein expression and signaling pathway activation were evaluated by Western blotting using pharmacological inhibitors of ERK1/2 (PD98059) and p38 MAPK (SB203580)...Inhibition of MAPK signaling, particularly ERK1/2, attenuated dieckol-induced thermogenesis-associated modulation and lipid metabolic regulation. In conclusion, dieckol promotes thermogenic markers in differentiating 3T3-L1 adipocytes through coordinated ERK/p38 MAPK and Nrf2 signaling, enhancing UCP1 expression and lipolysis while suppressing lipid accumulation and adipogenic markers."

Journal • PPARG • PRDM16

WISP-3 promotes tumor-monocyte adhesion through a MEK/ERK-dependent miR-12131/ICAM-4 axis in lung adenocarcinoma. (PubMed, Int J Med Sci) - "Pharmacological inhibition of MEK using PD98059 or U0126, as well as direct inhibition of ERK with SCH772984, markedly attenuated WISP-3-induced ICAM-4 expression and THP-1 adhesion. Collectively, these results demonstrate that WISP-3 promotes ICAM-4-dependent monocyte adhesion through activation of the MEK/ERK pathway and subsequent suppression of hsa-miR-12131. This WISP-3/MEK/ERK/miR-12131/ICAM-4 axis provides new insight into tumor-immune interactions in NSCLC and highlights potential therapeutic targets."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Neuregulin attenuates diaphragm muscle protein degradation via an intricate signaling network. (PubMed, Front Physiol) - "NRG effects were significantly blunted by rapamycin (p < 0.05 compared to NRG alone), but not by LY294002 or PD98059. We suggest that both the PI3K/Akt and MAP kinase pathways are important for NRG effects on protein degradation, but that mTOR may be a critical modulator of these effects and thus of protein balance in skeletal muscle."

Journal • Muscular Atrophy • Targeted Protein Degradation

Extracellular Signal-Regulated Kinase and Reactive Oxygen Species Regulate PD-L1 to Promote Migration and Proliferation of Triple-Negative Breast Cancer MDA-MB-231 Cells. (PubMed, Oncol Res) - " The ERK inhibitor (PD98059) suppressed MDA-MB-231 cell migration but not proliferation, whereas PD-L1 siRNA and the ROS scavenger dithiothreitol (DTT) reduced both cell migration and proliferation...Similar observations were noted in another TNBC cell line, Hs578T, which exhibits motility, but not in MDA-MB-453 cells, which lack motility. Since PD-L1 appears to function downstream of ERK and ROS and is required for TNBC progression, co-targeting both ERK and ROS signaling pathways may represent a promising therapeutic strategy for TNBC."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • MAPK8

ATO alleviates T-cell immunosuppression by inducing apoptosis-associated secretion of IL-2 in FLT3-ITD-mutated acute myeloid leukemia. (PubMed, Transl Oncol) - "This study confirms that ATO is a potential candidate drug for the treatment of FLT3-ITD-mutant AML and provides mechanistic insights into its cytotoxic and immunomodulatory functions."

IO biomarker • Journal • Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BAX • BCL2 • CASP3 • CD4 • CD8 • FLT3 • GZMB • IFNG • PML

Sugarcane Polyphenols Improve Depressive-like Behavior in CUMS Mice by Promoting the MAPK/ERK Signaling Pathway and Inhibiting NLRP3 Inflammasome Pyroptosis. (PubMed, Foods) - "Mechanistically, SP activates the MAPK/ERK pathway, which in turn suppresses NLRP3 inflammasome-mediated pyroptosis; this effect is attenuated by the MAPK/ERK inhibitor PD98059. Furthermore, SP synergizes with the caspase-1 inhibitor VX-765 to inhibit pyroptosis."

Journal • Preclinical • CNS Disorders • Depression • Inflammation • Psychiatry • NLRP3

Identification of two MAPK transcripts in the colonial ascidian Botryllus schlosseri: involvement in immune and stress responses and potential roles in colony growth. (PubMed, Fish Shellfish Immunol) - "Since phagocytic activity is essential for the cyclical renewal of the colony throughout the blastogenetic cycle, we also investigated the effects of colony exposure to MAPK inhibitors, PD98059 and SP600125, targeting the ERK and JNK signalling pathways, respectively. The inhibition of MAPK activity altered colony development and modulated the expression of genes associated with oxidative stress protection (sod, gpx-5) and stress granule dynamics (tiar, ttp), processes involved in post-transcriptional regulation. These findings suggest that MAPK signalling is indispensable for the proper progression of the blastogenetic cycle in B. schlosseri, integrating oxidative stress defence and post-transcriptional control to maintain colony homeostasis."

Journal

Impact of WFDC2 on the biological functions of cervical cancer cells and the regulation of the ERK/NF‑κB signaling pathway. (PubMed, Oncol Rep) - "When cells with overexpressed WFDC2 were treated with ERK inhibitor PD98059 and NF‑κB inhibitor PDTC, cell activity decreased, along with decreased invasion and migration. The animal experiments further showed that WFDC2 promoted the proliferation and invasion of cervical carcinoma cells. WFDC2 enhanced the migration, invasion and proliferation of cervical cancer cells via the ERK/NF‑κB signaling pathway."

Journal • Cervical Cancer • Gynecologic Cancers • Oncology • Solid Tumor • CDH1 • CDH2 • NFKBIA • VIM

MEK-ERK inhibition enhances synaptic input-output coupling and neuronal excitability in the rat dentate gyrus: association with site-specific Kv4.2 phosphorylation. (PubMed, Cogn Neurodyn) - "Inhibition of MEK with PD98059 did not alter basal field excitatory postsynaptic potential (fEPSP) slopes but significantly increased population spike (PS) amplitudes. Site-specific Kv4.2 phosphorylation at Thr602/Thr607, together with reduced total Kv4.2 expression, may contribute to the observed E-S potentiation. This mechanism may underlie hyperexcitability associated with neurological disorders."

Journal • Preclinical • CNS Disorders

Role of (pro) renin receptor in adriamycin-induced cardiomyopathy. (PubMed, Int J Cardiol Heart Vasc) - "(Pro) renin receptor (PRR) is a newly recognized element of the renin-angiotensin system associated with cardiovascular diseases. PD98059 attenuated cardiomyocyte fibrosis, inflammatory response, apoptosis, and reduced NOX2 abundance and NOX activity in ADR-treated NRCFs. PRR is involved in the pathological progression of ADR-CM, and inhibition of PRR may represent a novel and promising therapeutic strategy for ADR-CM."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Fibrosis • Gene Therapies • Heart Failure • Immunology • Inflammation • ATP6AP2

Prenatal and Lactational Exposure to Polystyrene Nanoplastics Induces Lipid Accumulation in Vascular Smooth Muscle Cells of Male Offspring via the MAPK/ERK/UHRF1 Signaling Pathway. (PubMed, Cardiovasc Toxicol) - "Further pharmacological inhibition of ERK using PD98059 significantly attenuated both UHRF1 expression and lipid accumulation, providing additional evidence supporting the critical role of the MAPK/ERK/UHRF1 axis in PS-NPs-induced lipid dysregulation. Additionally, siRNA-mediated knockdown of UHRF1 alleviated PS-NPs-induced lipid accumulation, supporting the pivotal role of UHRF1 in the cellular response to PS-NPs exposure. Overall, these findings demonstrate that prenatal and lactational exposure to PS-NPs disrupts early vascular lipid homeostasis in male offspring by activating the MAPK/ERK/UHRF1 signaling pathway in vascular smooth muscle cells."

Journal • Metabolic Disorders • UHRF1

C/EBP alpha agonist ICCB280 overcomes doxorubicin resistance in osteosarcoma through mitochondrial dynamics-dependent GREM1-MAPK activation. (PubMed, Cell Death Dis) - "The resistance of doxorubicin (DOX), the first-line chemotherapeutic drug for osteosarcoma (OS), stands as a pivotal obstacle in the effective treatment of OS. When ICCB280 and PD98059 are co-administered, the activation of GREM1 by C/EBPα and the inhibition of ERK phosphorylation are intensified. This suppresses OPA1 expression, promotes mitochondrial fission, and effectively counteracts chemotherapy resistance in osteosarcoma."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CEBPA

The crucial role of RIG-I in upregulating neutrophil CXCR2 expression through the MAPK signaling pathway in viral pneumonia. (PubMed, Respir Res) - "Our study identifies the RIG-I-MAPK-CXCR2 axis as a novel pathogenic signaling cascade that drives dysregulated neutrophilic inflammation in COVID-19, providing a basis for novel therapeutic strategies against respiratory viral infections."

Journal • Acute Lung Injury • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases • CXCL1 • CXCL8 • CXCR2 • IL6 • TNFA

Integrating single-cell and spatial transcriptomics to decipher the neuro-immune microenvironment of breast cancer brain metastasis: a key regulatory axis, prognostic model, and drug discovery. (PubMed, Transl Cancer Res) - "This study delineates the neuro-immune landscape of BCBM progression and proposes the IL-18/MYLK axis as a critical driver of neuroinflammation and cytoskeletal remodeling. The prognostic model and the candidate compound PD98059 provide avenues for novel targeted therapeutic strategies."

Journal • Breast Cancer • Oncology • Solid Tumor • BRCA • IL18 • MYLK

Neurotensin Receptor 1 Regulates HER4 Tyrosine Phosphorylation in Lung Cancer Cells. (PubMed, Biology (Basel)) - "Adding NTS to NSCLC cells increased both P-ERK and P-AKT, which were inhibited by PD98059 and LY294002, respectively. The growth of NCI-H522 or NCI-H661 cells was stimulated by NTS or neuregulin 1 (NRG1), a HER4 ligand, but inhibited by SR48692 or ibrutinib. The results indicate that NTSR1 regulates HER4 transactivation, thereby increasing the proliferation of lung cancer cells."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • ERBB3 • ERBB4 • HER-2 • NRG1

Cigarette Smoke Extract Suppresses PEPT2 Function in Alveolar Epithelial Cells via Aryl Hydrocarbon Receptor Signaling. (PubMed, Toxicol Sci) - "Among signaling inhibitors, only PD98059 reversed the CSE-induced suppression, whereas U0126 had no effect...Other AhR ligands, including leflunomide and omeprazole, produced similar inhibitory effects...These findings suggest that PEPT2 is a previously unrecognized target of cigarette smoke-related transporter regulation and are consistent with the involvement of AhR signaling in its suppression. These findings provide insight into potential alterations in epithelial transport function and their possible implications for pulmonary defense and drug disposition in smokers."

Journal • Respiratory Diseases

Colchicine alleviates severe acute pancreatitis in rats by inhibiting acinar cell ferroptosis via LCN2/MAPK/ERK signaling axis. (PubMed, Eur J Histochem) - "Mechanistic validation utilized AAV-mediated lipocalin-2 (LCN2) overexpression, the ferroptosis inhibitor ferrostatin-1 (Fer-1), and the ERK inhibitor PD98059. This study is the first to elucidate that COL inhibits ferroptosis in pancreatic acinar cells by downregulating LCN2 and subsequently suppressing the LCN2/MAPK/ERK signaling axis. These findings provide a novel molecular basis for COL and highlight a potential target for therapeutic intervention in SAP."

Journal • Preclinical • Pancreatitis • LCN2

Lycorine hydrochloride reveals a novel role in preventing neointimal hyperplasia through MAPK-mediated phenotypic switching of smooth muscle cells. (PubMed, J Mol Cell Cardiol) - "Specific inhibitors (PD98059, SP600125, SB203580) diminished PDGF-BB-mediated MOVAS cell phenotypic switching, the potential mechanism involves binding to Erk1 to repress Erk1/2 activation. Therefore, LH suppressed PDGF-BB-mediated VSMCs phenotypic switching and attenuated vascular neointimal hyperplasia at least in part by targeting Ekr1 to regulate the MAPK cascade, indicating its potential as a prevention for restenosis."

Journal • Inflammation • JUN