Mitogen-activated Protein Kinase Inhibitor Research Articles

Chemical genetics analysis suggests the involvement of Aurora kinase and MAPKs in aluminum-induced malate secretion in Arabidopsis.

Chemical genetics is a multidisciplinary research method. In this study, it is used to screen compounds that promote aluminum-induced malate secretion in Arabidopsis thaliana. Inhibition of p38 mitogen-activated protein kinase (p38 MAPK; LY2228820) significantly increased the transcription of Arabidopsis thaliana aluminum-activated malate transporter 1 (AtALMT1) and sensitive to proton rhizotoxicity 1 (STOP1)-regulated genes, multidrug and toxic compound extrusion and aluminum sensitive 3, but not AtSTOP1 and the Al-biomarker genes At3g28510, At5g13320, suggesting that LY2228820 increased the early expression of STOP1-regulated genes without affecting AtSTOP1 expression. Inhibition of p38 MAPK (LY2228820) and Aurora A (MLN8237) increased aluminum-activated malate transport via AtALMT1, suggesting that both MLN8237 and LY2228820 interfere with AtALMT1 activity. An increase in root elongation was also observed in Arabidopsis after applying compounds LY2228820 and MLN8237. Thus, both LY2228820 and MLN8237 may play important roles in alleviating the inhibitory effects of aluminum on roots.

Childhood Langerhans cell histiocytosis hematological involvement: severity associated with BRAFV600E loads

Hematological involvement (HI) is one of the life-threatening risk organs (ROs) in Langerhans cell histiocytosis (LCH). Lahey criteria have defined HI since 1975 as hemoglobin <10 g/dL and/or platelets <100 G/L and/or leukopenia (white blood cell count <4 G/L) and/or neutrophils <1.5 G/. Among the 2313 patients <18 years old enrolled in the French National Histiocytosis Registry (1983-2023), 331 developed HI (median age at diagnosis: 1 year); median follow-up lasted 8.1 years. Bone-marrow aspirate smears and biopsies may show reactive histiocytes, hemophagocytosis or myelofibrosis but never confirm the diagnosis. Fifty-eight (17%) patients developed macrophage-activation syndrome, sometimes related to acute Epstein-Barr virus or cytomegalovirus infection, sometimes months before typical LCH manifestations appeared. Hemoglobin and platelet thresholds for initiating transfusion(s) appear to accurately distinguish 2 groups: mild HI (MHI; >7 g/dL and >20 G/L, respectively) and severe HI (SHI; ≤7 g/dL and ≤20 G/L). Each entity has different organ involvements, laboratory parameters, mutational status, blood BRAFV600E loads, drug sensitivities and outcomes (respective MHI and SHI 10-year survival rates: 98% and 73%). Since 1998, mortality first declined with combination Cladribine-cytarabine therapy, and then with mitogen-activated protein-kinase inhibitors since 2014. Forty-one (12%) patients developed neurodegenerative complications that have emerged as a risk for long-term survivors. These results suggest limiting the HI-RO definition to SHI, as it encompasses almost all medical complications of LCH. Future clinical trials might demonstrate that targeted-therapy approaches would be better adapted for these patients, while MHI can be managed with classic therapies.

Dual inhibition of butyrylcholinesterase and p38α mitogen-activated protein kinase: A new approach for the treatment of Alzheimer's disease

Dual inhibition of butyrylcholinesterase and p38α mitogen-activated protein kinase: A new approach for the treatment of Alzheimer's disease

Impact of Xerosis in Patients With Cancer Receiving Epidermal Growth Factor Receptor or Mitogen-Activated Protein Kinase Inhibitors: ATIXI, A Non-Interventional, Prospective, Pilot Study

Impact of Xerosis in Patients With Cancer Receiving Epidermal Growth Factor Receptor or Mitogen-Activated Protein Kinase Inhibitors: ATIXI, A Non-Interventional, Prospective, Pilot Study

Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is often resistant to therapy. An immune suppressive tumor microenvironment (TME) and oncogenic mutations in KRAS have both been implicated as drivers of resistance to therapy. Mitogen-activated protein kinase (MAPK) inhibition has not yet shown clinical efficacy, likely because of rapid acquisition of tumor-intrinsic resistance. However, the unique PDAC TME may also be a driver of resistance. We found that long-term focal adhesion kinase (FAK) inhibitor treatment led to hyperactivation of the RAS/MAPK pathway in PDAC cells in mouse models and tissues from patients with PDAC. Concomitant inhibition of both FAK (with VS-4718) and rapidly accelerated fibrosarcoma and MAPK kinase (RAF-MEK) (with avutometinib) induced tumor growth inhibition and increased survival across multiple PDAC mouse models. In the TME, cancer-associated fibroblasts (CAFs) impaired the down-regulation of MYC by RAF-MEK inhibition in PDAC cells, resulting in resistance. By contrast, FAK inhibition reprogramed CAFs to suppress the production of FGF1, which can drive resistance to RAF-MEK inhibition. The addition of chemotherapy to combined FAK and RAF-MEK inhibition led to tumor regression, a decrease in liver metastasis, and improved survival in KRAS-driven PDAC mouse models. Combination of FAK and RAF-MEK inhibition alone improved antitumor immunity and priming of T cell responses in response to chemotherapy. These findings provided the rationale for an ongoing clinical trial evaluating the efficacy of avutometinib and defactinib in combination with gemcitabine and nab-paclitaxel in patients with PDAC and may suggest further paths for combined stromal and tumor-targeting therapies.

Recurrent melanoma 25 years after initial diagnosis, presenting as metastatic disease early after heart transplantation

BackgroundCancer survivors (CS) comprise a particularly high-risk group for both de-novo and recurrent malignancies after solid organ transplantation.Case presentationWe report a case of relapsed melanoma, presented as metastatic disease seven months after heart transplantation in a patient who had an early-stage melanoma resected 25 years prior. Treatment with a combination of dabrafenib, a BRAF inhibitor, and trametinib, a mitogen-activated protein kinase (MEK) inhibitor resulted in a near-complete metabolic response, without major adverse effects.ConclusionThis case demonstrates the increased risk of recurrence in CS with melanoma, which can persist decades after cancer diagnosis. These patients may be amenable to treatment using modern treatment modalities in oncology.

Mechanistic insights on the role of Nrf-2 signalling in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder affecting individualsworldwide. It is characterized by progressive motor dysfunction, cognitive decline, and psychiatric disturbances.The pathogenesis of HD involves oxidative stress, neuroinflammation, and mitochondrial dysfunction.Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor regulating cellular responses to redox imbalance and inflammation, has emerged as a potential target for therapeutic intervention. Through the use of a number of different search engines like Scopus, PubMed, Elsevier and Bentham, aliterature review was carried out with the keywords 'Huntington's Disease, 'Pathology of HD' and 'Nrf2 signallingpathway'.Using the keywords that were given above, this review was carried out in order to collect the most recent publications and gain an understanding of the breadth of the extensive research that has been conducted on the role of Nrf2 in HD pathogenesis. Oxidative stress and neuroinflammation significantly contribute to HD progression. Activation of Nrf2 offers neuroprotection by enhancing anti-oxidant defense mechanisms.Furthermore, several signaling pathways, play crucial roles in HD pathophysiology.Pharmacological modulation of these pathways through selective inhibitors or agonists shows promise for the development of new therapeutic strategies. The various downstream pathways such as extracellular signal-related kinase (ERK), phosphoinositide3-Kinase (PI3-K), 5'-AMP-activated protein kinase (AMPK), Sirtuins, Mitogen-activated protein kinases (MAPK) plays a role in alleviating pathophysiology of HD.Diverse reports of these studies demonstrated PI3-K/AMPK/ERK/Sirtuins activators and MAPK inhibitors as encouraging targets in alleviating HD pathophysiology.

Trehalose Attenuates In Vitro Neurotoxicity of 6-Hydroxydopamine by Reducing Oxidative Stress and Activation of MAPK/AMPK Signaling Pathways.

The effects of trehalose, an autophagy-inducing disaccharide with neuroprotective properties, on the neurotoxicity of parkinsonian mimetics 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpiridinium (MPP+) are poorly understood. In our study, trehalose suppressed 6-OHDA-induced caspase-3/PARP1 cleavage (detected by immunoblotting), apoptotic DNA fragmentation/phosphatidylserine externalization, oxidative stress, mitochondrial depolarization (flow cytometry), and mitochondrial damage (electron microscopy) in SH-SY5Y neuroblastoma cells. The protection was not mediated by autophagy, autophagic receptor p62, or antioxidant enzymes superoxide dismutase and catalase. Trehalose suppressed 6-OHDA-induced activation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and AMP-activated protein kinase (AMPK), as revealed by immunoblotting. Pharmacological/genetic inhibition of JNK, p38 MAPK, or AMPK mimicked the trehalose-mediated cytoprotection. Trehalose did not affect the extracellular signal-regulated kinase (ERK) and mechanistic target of rapamycin complex 1 (mTORC1)/4EBP1 pathways, while it reduced the prosurvival mTORC2/AKT signaling. Finally, trehalose enhanced oxidative stress, mitochondrial damage, and apoptosis without decreasing JNK, p38 MAPK, AMPK, or AKT activation in SH-SY5Y cells exposed to MPP+. In conclusion, trehalose protects SH-SY5Y cells from 6-OHDA-induced oxidative stress, mitochondrial damage, and apoptosis through autophagy/p62-independent inhibition of JNK, p38 MAPK, and AMPK. The opposite effects of trehalose on the neurotoxicity of 6-OHDA and MPP+ suggest caution in its potential development as a neuroprotective agent.

Elevated serum GDF15 level as an early indicator of proximal tubular cell injury in acute kidney injury

Acute kidney injury (AKI) is a high-burden medical condition, and current diagnostic criteria can only assess AKI after full manifestation. Stress marker growth differentiation factor 15 (GDF15) was reported to have a role in kidney injury of critical patients. Herein, we evaluated dynamic changes in GDF15 across diverse AKI scenarios and explored the underlying mechanisms of its induction. Serum parameters and renal lesions were analyzed in mouse models of unilateral ischemia-reperfusion injury (uni-IRI) and unilateral ureteral obstruction (UUO). The human proximal tubular (HK−2) cell line was stimulated with various conditions, and induction of GDF15 expression was determined. Serum GDF15 levels were rapidly induced within hours after injury in both animal models and declined thereafter. Renal GDF15 expression exhibited a temporary and early increased induction and was mainly located in aquaporin 1-positive proximal tubules in both unilateral AKI model tissues. In cell experiments, rapid GDF15 production was highly induced by t-BHP and CoCl2. Treatment with either an antioxidant or mitogen-activated protein kinase inhibitors abolished t-BHP- and CoCl2-mediated GDF15 expression. In addition, silencing nuclear factor erythroid 2-related factor 2 expression also reduced the basal and t-BHP- or CoCl2-mediated GDF15 expression level in HK-2 cells. Our data showed that elevated serum GDF15 levels could be detected early in unilateral AKI models without notable alterations in kidney function parameters. GDF15 expression was associated with oxidative stress- and hypoxia-mediated proximal tubular cell injury. These data document that elevated serum GDF15 can possibly serve as an early biomarker for proximal tubular cell injury in AKI.

Sinapine suppresses ROS-induced C2C12 myoblast cell death through MAPK and autophagy pathways.

Oxidative stress in skeletal muscle can lead to muscle atrophy through reactive oxygen species (ROS)-induced damage and cell death. tert-Butyl hydroperoxide (TBHP), an exogenous ROS generator, induces oxidative stress and cell death in various cells. Sinapine from cruciferous plants possesses beneficial effects, but its role in protecting skeletal muscle cells against ROS-induced cell death remains unclear. This study demonstrates that sinapine pretreatment significantly reduced TBHP-induced cell death and ROS accumulation in a dose-dependent manner. TBHP activated mitogen-activated protein kinase (MAPK) pathways including Akt, p38, and JNK, and triggered autophagy. Sinapine suppressed the phosphorylation of Akt, MEK3/6, p38, MEK4, and JNK, and modulated key autophagy markers. Notably, the co-treatment of MAPK inhibitors attenuated TBHP-induced cell death and LC3B-II accumulation. These findings suggest that sinapine is a promising phytochemical for mitigating oxidative stress-mediated muscle injury, offering potential therapeutic strategies for maintaining skeletal muscle homeostasis and addressing muscle-related pathologies.

Clarithromycin Modulates Neutrophilic Inflammation Induced by Prevotella intermedia in Human Airway Epithelial Cells.

Objectives: In the present study, we aimed to clarify the mechanisms by which periodontal pathogens, particularly Prevotella intermedia, induce severe neutrophilic inflammation. In addition, we aimed to test the efficacy of macrolides, which has not been resolved in the neutrophilic inflammation induced by P. intermedia. Methods: NCl-H292 human airway epithelial cells were pre-incubated with clarithromycin for 2 h before incubation with P. intermedia supernatants. Then, C-X-C motif chemokine ligand 8 (CXCL8) transcription and interleukin (IL)-8 production were measured. To elucidate the signaling pathway, mitogen-activated protein kinase inhibitors were added to the cell culture, and the cells were subjected to Western blotting. Results:P. intermedia supernatants promoted CXCL8 transcription and IL-8 production, and the reactions were significantly suppressed by clarithromycin pretreatment. Only trametinib, the selective mitogen-activated extracellular signal-regulated kinase inhibitor, downregulated CXCL8 transcription and IL-8 production. Furthermore, Western blotting revealed that stimulation with P. intermedia supernatants specifically induces extracellular signal-regulated kinases (ERK) 1/2 phosphorylation, which is suppressed by clarithromycin pretreatment. Notably, the interference analysis revealed that ERK3 might be dispensable for IL-8 production under the stimulation of P. intermedia supernatants. Conclusions: Our results provide new insight into the mechanism underlying P. intermedia-induced production of IL-8 from human airway epithelial cells. Furthermore, macrolides might have therapeutic potential in regulating periodontal pathogen-induced neutrophilic inflammation in the lungs.

P38α Mitogen-Activated Protein Kinase-An Emerging Drug Target for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by the formation of amyloid β and tau protein aggregates in the brain, neuroinflammation, impaired cholinergic neurotransmission, and oxidative stress, resulting in the gradual loss of neurons and neuronal function, which leads to cognitive and memory deficits in AD patients. Chronic neuroinflammation plays a particularly important role in the progression of AD since the excessive release of proinflammatory cytokines from glial cells (microglia and astrocytes) induces neuronal damage, which subsequently causes microglial activation, thus facilitating further neurodegenerative changes. Mitogen-activated protein kinase (MAPK) p38α is one of the key enzymes involved in the control of innate immune response. The increased activation of the p38α MAPK pathway, observed in AD, has been for a long time associated not only with the maintenance of excessive inflammatory process but is also linked with pathophysiological hallmarks of this disease, and therefore is currently considered an attractive drug target for novel AD therapeutics. This review aims to summarize the current state of knowledge about the involvement of p38α MAPK in different aspects of AD pathophysiology and also provides insight into the possible therapeutic effects of novel p38α MAPK inhibitors, which are currently studied as potential drug candidates for AD treatment.

Mu-Opioid Receptor (MOR) Dependence of Pain in Chemotherapy-Induced Peripheral Neuropathy.

We recently demonstrated that transient attenuation of Toll-like receptor 4 (TLR4) in dorsal root ganglion (DRG) neurons, can both prevent and reverse pain associated with chemotherapy-induced peripheral neuropathy (CIPN), a severe side effect of cancer chemotherapy, for which treatment options are limited. Given the reduced efficacy of opioid analgesics to treat neuropathic, compared to inflammatory, pain, the crosstalk between nociceptor TLR4 and mu-opioid receptors (MOR), and that MOR and TLR4 agonists induce hyperalgesic priming (priming), which also occurs in CIPN, we determined, using male rats, whether: i ) antisense knockdown of nociceptor MOR attenuates CIPN, ii ) and attenuates the priming associated with CIPN, and iii ) CIPN also produces opioid-induced hyperalgesia (OIH). We found that intrathecal MOR antisense prevents and reverses hyperalgesia induced by oxaliplatin and paclitaxel, two common clinical chemotherapy agents. Oxaliplatin induced-priming was also markedly attenuated by MOR antisense. Additionally, intradermal morphine, at a dose that does not affect nociceptive threshold in controls, exacerbates mechanical hyperalgesia (OIH) in rats with CIPN, suggesting the presence of OIH. This OIH associated with CIPN is inhibited by interventions that reverse Type II priming (the combination of an inhibitor of Src and mitogen-activated protein kinase (MAPK)), a MOR antagonist, as well as a TLR4 antagonist. Our findings support a role of nociceptor MOR in oxaliplatin-induced pain and priming. We propose that priming and OIH are central to the symptom burden in CIPN, contributing to its chronicity and the limited efficacy of opioid analgesics to treat neuropathic pain.Significance Statement It remains unknown why opioid analgesics are less effective against neuropathic pain, including that induced by cancer chemotherapy. Here we demonstrate a crucial role of nociceptor mu-opioid receptors (MOR) in chemotherapy-induced peripheral neuropathy (CIPN) pain and hyperalgesic priming (priming), the latter a mechanism involved in the transition from acute to chronic pain. In addition to neuropathic pain and priming, opioid-induced hyperalgesia (OIH) also develops in chemotherapy-treated rats, which is reversed by inhibitors of second messengers that also reverse Type II priming, as well as by MOR and TLR4 antagonists. Taken together our results support the suggestion that priming and OIH contribute to CIPN and its limited responsiveness to opioid analgesics.

Downregulation of nuclear receptor-binding SET domain protein 1 induces proinflammatory cytokine expression via mitogen-activated protein kinase pathways in U87MG cells

Haploinsufficiency of the nuclear receptor binding SET domain-containing protein 1 gene (NSD1) leads to a neurodevelopmental disorder known as Sotos syndrome (SOTOS). This study investigated the effects of NSD1 knockdown in glial cells. U87MG glioma cells were transfected with siRNA targeting NSD1, which resulted in morphological changes characteristic of activated astrocytes. These activated phenotypes were accompanied by specific activation of mitogen-activated protein kinase (MAPK) signaling pathways, particularly those mediated by p38 MAPK and c-Jun N-terminal kinase (JNK). Transcriptome analysis showed increased expression of proinflammatory cytokine genes, particularly interleukin (IL)-1α, IL-1β, and IL-6, following NSD1 knockdown. Treatment with MAPK inhibitors significantly reduced the cytokine induction caused by NSD1 knockdown, with the p38 MAPK inhibitor being more effective than the JNK inhibitor. These findings provide new insights into the role of NSD1 loss in neurological dysfunctions associated with SOTOS.

β-glucan improves intestinal health of pearl gentian grouper via activation of the p38 mitogen-activated protein kinase signaling pathway

Our previous study has demonstrated that supplementation of yeast β-glucan improves intestinal health in pearl gentian grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀), accompanied by the activation of the mitogen-activated protein kinase (MAPK) signaling pathway. In this study, we investigated the effects of perturbing p38 MAPK activity using an inhibitor on the intestinal health of β-glucan-injected pearl gentian grouper to elucidate the potential molecular mechanism underlying the protective effects of β-glucan on the fish gut. The pearl gentian grouper was categorized into four groups: PBS injected (CD group), β-glucan injected at a dose of 80 mg/kg (βG group), p38 MAPK inhibitor SB203580 injected at a dose of 1 mg/kg (SB203580 group), and a combination of β-glucan (80 mg/kg) and SB203580 (1 mg/kg) injected together (βG + SB203580 group). The results revealed that the introduction of SB203580 significantly suppressed the β-glucan-induced increase in p38α and p38β mRNA expression, as well as the phosphorylation of p38 MAPK. Both the βG group and SB203580 group exhibited reduced plica height and muscularis thickness. The βG + SB203580 group displayed a significant reduction in mucin cell level; interleukin 1β (il1β) mRNA expression; induced nitric oxide synthase, tumor necrosis factor α, and IL1β concentration; catalase and total antioxidant capacity activities. Additionally, there was a significant increase in the levels of intestinal malondialdehyde in the βG + SB203580 group compared to the βG group. The inhibition of the p38 MAPK signaling halted the trend of apoptosis-related caspase molecular expression induced by β-glucan. In conclusion, β-glucan injection resulted in elevated levels of mucous cells, nonspecific immunity, antioxidant capacity, and anti-apoptosis in grouper by modulating the p38 MAPK pathway. This study offers insights into the potential molecular mechanism underlying the protective effects of β-glucan on intestinal health in pearl gentian grouper.

Porous Gelatin Methacrylate Gel Engineered by Freeze-Ultraviolet Promotes Osteogenesis and Angiogenesis.

Alveolar bone defect reconstruction is a common challenge in stomatology. To address this, a thermosensitive/photosensitive gelatin methacrylate (GelMA) gel was developed based on various air solubilities and light-curing technologies. The gel was synthesized by using a freeze-ultraviolet (FUV) method to form a porous and quickly (within 15 min) solidifying modified network structure. Unlike other gel scaffolds limited by complex preparation procedures and residual products, this FUV-GelMA gel shows favorable manufacturing ability, promising biocompatibility, and adjustable macroporous structures. The results from a rat model suggested that this gel scaffold creates a conducive microenvironment for mandible reconstruction and vascularization. In vitro experiments further confirmed that the FUV-GelMA gel promotes osteogenic differentiation of human bone marrow mesenchymal stem cells and angiogenesis of human umbilical vein endothelial cells. Investigation of the underlying mechanism focused on the p38 mitogen-activated protein kinase (MAPK) pathway. We found that SB203580, a specific inhibitor of p38 MAPK, abolished the therapeutic effects of the FUV-GelMA gel on osteogenesis and angiogenesis, both in vitro and in vivo. These findings introduced a novel approach for scaffold-based tissue regeneration in future clinical applications.

Diagnosis and management of neurofibromatosis type 1 in Arabian Gulf Cooperation Council Region: challenges and recommendations.

Neurofibromatosis type 1 (NF1) is a complex multisystem genetic disorder that requires long-term, age-specific monitoring and multidisciplinary care. NF1 symptom burden can significantly affect the quality of life and impose a substantial economic burden on patients and their families. The approval and widespread availability of mitogen-activated protein kinase (MEK) inhibitors such as selumetinib for NF1-related plexiform neurofibromas have revolutionized the standard of care for patients with NF1, however their effective utilization hinges on early recognition of NF1. We present a consensus manuscript describing the challenges observed in the Arabian Gulf Cooperation Council (GCC) for diagnosing and managing NF1. Experts from the GCC also present recommendations for the early recognition and management of NF1 and its complications. A referral pathway that can play a crucial role in helping primary healthcare providers refer their patients to experts is also proposed. Increasing the availability and accessibility of genetic testing at an affordable cost and optimizing personalized NF1 care are essential for NF1 management. Developing regional guidelines for NF1 management and establishing NF1 centers of excellence may facilitate better care and outcomes for patients with NF1 in the GCC region.

Efficacy of BRAF/MEK-inhibitor therapy for epithelioid glioblastoma with a novel BRAFV600 mutation

Epithelioid glioblastoma (eGB), a very aggressive and rare brain tumour, is associated with a dismal median overall survival. Effective therapies for patients with eGB, particularly with leptomeningeal dissemination, are still lacking. Here, we describe a case of a 25-year-old male diagnosed with an intramedullary cervical tumour with subsequent leptomeningeal disease. Histopathology identified a highly necrotising, epithelioid-type tumour with high cell density, most compatible with the diagnosis of an eGB. DNA analysis revealed an unprecedented B-Raf protooncogene, serine/threonine kinase (BRAF) gene variant in exon 15 (ENST00000288602.6, c.1799_1810delinsATG, p.(V600_W604delinsDG)), triggering activation of the mitogen-activated protein kinase (MAPK) pathway. Consequently, we initiated MAPK inhibitor (MAPKi) therapy, utilizing a combination of BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors. Liquid chromatography–tandem mass spectrometry analysis confirmed the drugs’ presence in the patient’s cerebrospinal fluid, indicating their capacity to cross the blood-brain barrier. Remarkably, the patient responded very well to therapy and transitioned from a near-comatose state to significantly improved health, sustained for over three months. This study highlights that MAPKi, particularly targeted towards novel BRAFV600 mutations, might offer promising advancements in eGB treatment strategies.

Abstract Mo002: Pharmacological Inhibition of p38 MAPK Attenuates Doxorubicin-induced Cardiotoxicity, Senescence, and Inflammation in C57BL/6 mice

Introduction: Doxorubicin (DOX)-induced cardiotoxicity has been associated with induction of senescence, inflammation, and activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Losmapimod (LOSM), an orally active p38 MAPK inhibitor, is an anti-inflammatory agent with cardioprotective effects. Nevertheless, the effect of LOSM against DOX-induced cardiotoxicity has not been reported. The objective of the current work is to determine the effects of LOSM on DOX-induced chronic cardiotoxicity in C57BL/6 mice with particular focus on senescence and inflammatory pathways. Methods: Five-week-old C57BL/6 mice were fed diet containing LOSM (estimated daily intake 12 mg/kg/day) or a control diet for four days. Thereafter, mice were randomized to receive six weekly intraperitoneal injections of either DOX (4 mg/kg/week for 6 weeks) or saline. Three days after the last injection, cardiac function was assessed by trans-thoracic echocardiography. Gene expressions of senescence and inflammatory markers were quantified using real-time PCR and serum inflammatory markers were assessed by Luminex. Results: LOSM ameliorated DOX-induced cardiac dysfunction as evidenced by mitigated DOX-induced reduction in left ventricular fraction and fractional shortening. Notably, LOSM attenuating DOX-induced upregulation of p21 Cip1 , a marker of senescence, in the heart and the liver. Additionally, LOSM demonstrated anti-inflammatory effects, with reduced cardiac interleukin-1α and interleuken-6 gene expression in DOX-treated mice suggesting a senomorphic effect of LOSM. Systemic inflammation, assessed by serum cytokine levels, showed decreased interleukin-6 concentration in both DOX-treated mice and LOSM-treated mice. Conclusion: This is the first study to determine the effect of pharmacological inhibition of p38 MAPK against DOX-induced cardiotoxicity in vivo. Our study underscores the potential therapeutic efficacy of p38 MAPK inhibition in ameliorating DOX-induced cardiotoxicity, offering insights into novel strategies for mitigating chemotherapy-related cardiac complications, and suggesting a possible senomorphic effects of losmapimod.

Effects of Angiogenic Factors on the Epithelial-to-Mesenchymal Transition and Their Impact on the Onset and Progression of Oral Squamous Cell Carcinoma: An Overview.

High levels of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2 and angiopoietin (ANG)-2 are found in tissues from oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs). As might be expected, VEGF, FGF-2, and ANG-2 overexpression parallels the development of new blood and lymphatic vessels that nourish the growing OPMDs or OSCCs and provide the latter with metastatic routes. Notably, VEGF, FGF-2, and ANG-2 are also linked to the epithelial-to-mesenchymal transition (EMT), a trans-differentiation process that respectively promotes or exasperates the invasiveness of normal and neoplastic oral epithelial cells. Here, we have summarized published work regarding the impact that the interplay among VEGF, FGF-2, ANG-2, vessel generation, and EMT has on oral carcinogenesis. Results from the reviewed studies indicate that VEGF, FGF-2, and ANG-2 spark either protein kinase B (AKT) or mitogen-activated protein kinases (MAPK), two signaling pathways that can promote both EMT and new vessels' formation in OPMDs and OSCCs. Since EMT and vessel generation are key to the onset and progression of OSCC, as well as to its radio- and chemo-resistance, these data encourage including AKT or MAPK inhibitors and/or antiangiogenic drugs in the treatment of this malignancy.