P38 Mitogen-activated Protein Kinase Pathway Research Articles

Bmp4 in Zebrafish Enhances Antiviral Innate Immunity through p38 MAPK (Mitogen-Activated Protein Kinases) Pathway.

Bone morphogenetic proteins (BMPs) are a group of structurally and functionally related signaling molecules that comprise a subfamily, belonging to the TGF-β superfamily. Most BMPs play roles in the regulation of embryonic development, stem cell differentiation, tumor growth and some cardiovascular and cerebrovascular diseases. Although evidence is emerging for the antiviral immunity of a few BMPs, more BMPs are needed to determine whether this function is universal. Here, we identified the zebrafish bmp4 ortholog, whose expression is up-regulated through challenge with grass carp reovirus (GCRV) or its mimic poly(I:C). The overexpression of bmp4 in epithelioma papulosum cyprini (EPC) cells significantly decreased the viral titer of GCRV-infected cells. Moreover, compared to wild-type zebrafish, viral load and mortality were significantly increased in both larvae and adults of bmp4-/- mutant zebrafish infected with GCRV virus. We further demonstrated that Bmp4 promotes the phosphorylation of Tbk1 and Irf3 through the p38 MAPK pathway, thereby inducing the production of type I IFNs in response to virus infection. These data suggest that Bmp4 plays an important role in the host defense against virus infection. Our study expands the understanding of BMP protein functions and opens up new targets for the control of viral infection.

EGR1 Regulation of Vasculogenic Mimicry in the MDA-MB-231 Triple-Negative Breast Cancer Cell Line through the Upregulation of KLF4 Expression.

Vasculogenic mimicry (VM) is an intriguing phenomenon observed in tumor masses, in which cancer cells organize themselves into capillary-like channels that closely resemble the structure and function of blood vessels. Although VM is believed to contribute to alternative tumor vascularization, the detailed regulatory mechanisms controlling these cellular processes remain poorly understood. Our study aimed to investigate the role of Early Growth Response 1 (EGR1) in regulating VM in aggressive cancer cells, specifically MDA-MB-231 triple-negative breast cancer cells. Our study revealed that EGR1 promotes the formation of capillary-like tubes by MDA-MB-231 cells in a 3-dimensional Matrigel matrix. EGR1 was observed to upregulate Kruppel-like factor 4 (KLF4) expression, which regulates the formation of the capillary-like tube structure. Additionally, our findings highlight the involvement of the ERK1/2 and p38 mitogen-activated protein kinase pathways in mediating the expression of EGR1 and KLF4, underscoring their crucial role in VM in MDA-MB-231 cells. Understanding these regulatory mechanisms will provide valuable insights into potential therapeutic targets for preventing VM during the treatment of triple-negative breast cancer.

Protective role of boron on hepatotoxicity and oxidative stress induced by trichloroacetic acid

We conducted a comprehensive investigation into the protective roles of boron (B) against trichloroacetic acid (TCA)-induced hepatotoxicity by assessing TCA exposure in vivo and exploring the potential mechanisms by which B protects against TCA-induced hepatotoxicity in vitro. For the in vivo study, we evaluated TCA-induced hepatotoxicity in adult male B6C3F1 mice exposed to 25, 50, 125, and 500 mg/kg/day of TCA, respectively, for 21 days. We found that the mice’s liver weight was significantly increased, and that there were changes in hepatic histopathology, particularly in mice treated with the highest dosage (500 mg/kg/day). TCA also increased the hepatic oxidoreductase activity of medium-chain and long-chain acyl-coenzyme A (CoA), which are biomarkers of peroxisome proliferation, in a dose-dependent manner. Subsequently, we established a TCA-induced HepG2 cell model of oxidative damage to estimate the cytotoxicity and determine the positive effects of B administration in vitro. We found that B administration significantly reduced oxidative stress by attenuating the production of TCA-induced reactive oxygen species and malondialdehyde. B also significantly downregulated the concentrations of certain cytokines, including interleukin (IL)-6, IL-8, and transforming growth factor-beta, which are predominantly associated with the p38 mitogen-activated protein kinase (MAPK) signaling pathway. In addition, B significantly upregulated phospho-p38 levels and downregulated Bax and p21 levels in the cytoplasm and downregulated p38 and p21 levels in the nucleus. Taken together, our findings suggest that the protective role of B against TCA-induced hepatotoxicity primarily involves alleviation of oxidative damage and cell apoptosis caused by TCA and might be mediated via the p38 MAPK pathway.

Cangxi Tongbi Capsules promote chondrocyte autophagy by regulating circRNA＿0008365/miR-1271/p38 MAPK pathway to inhibit development of knee osteoarthritis

To investigate the mechanism by which Cangxi Tongbi Capsules promote chondrocyte autophagy to inhibit knee osteoarthritis(KOA) progression by regulating the circRNA＿0008365/miR-1271/p38 mitogen-activated protein kinase(MAPK) pathway. The cell and animal models of KOA were established and intervened with Cangxi Tongbi Capsules, si-circRNA＿0008365, si-NC, and Cangxi Tongbi Capsules combined with si-circRNA＿0008365. Flow cytometry and transmission electron microscopy were employed to determine the level of apoptosis and observe autophagosomes, respectively. Western blot was employed to reveal the changes in the protein levels of microtubule-associated protein light chain 3(LC3)Ⅱ/Ⅰ, Beclin-1, selective autophagy junction protein p62/sequestosome 1, collagen Ⅱ, a disintegrin and metalloproteinase with thrombospondin motifs 5(ADAMTS-5), and p38 MAPK. The mRNA levels of circRNA＿0008365, miR-1271, collagen Ⅱ, and ADAMTS-5 were determined by qRT-PCR. Hematoxylin-eosin staining was employed to reveal the pathological changes of the cartilage tissue of the knee, and enzyme-linked immunosorbent assay to measure the levels of interleukin-1β(IL-1β) and tumor necrosis factor-alpha(TNF-α). The chondrocytes treated with IL-1β showed down-regulated expression of circRNA＿0008365, up-regulated expression of miR-1271 and p38 MAPK, lowered autophagy level, increased apoptosis rate, and accelerated catabolism of extracellular matrix. The intervention with Cangxi Tongbi Capsules up-regulated the expression of circRNA＿0008365, down-regulated the expression of miR-1271 and p38 MAPK, increased the autophagy level, decreased the apoptosis rate, and weakened the catabolism of extracellular matrix. However, the effect of Cangxi Tongbi Capsules was suppressed after interfering with circRNA＿0008365. The in vivo experiments showed that Cangxi Tongbi Capsules dose-dependently inhibited the p38 MAPK pathway, enhanced chondrocyte autophagy, and mitigated articular cartilage damage and inflammatory response, thereby inhibiting the progression of KOA in rats. This study indicated that Cangxi Tongbi Capsules promoted chondrocyte autophagy by regulating the circRNA＿0008365/miR-1271/p38 MAPK pathway to inhibit the development of KOA.

Hydrogen Sulfide Regulates Glucose Uptake in Skeletal Muscles via S-Sulfhydration of AMPK in Muscle Fiber Type-Dependent Way

BackgroundThe effect of hydrogen sulfide (H2S) on glucose homeostasis remains to be elucidated, especially in the state of insulin resistance. ObjectivesIn the present study, we aimed to investigate H2S-regulated glucose uptake in the M. pectoralis major (PM) muscle (which mainly consists of fast-twitch glycolytic fibers) and M. biceps femoris (BF) muscle (which mainly consists of slow-twitch oxidative fibers) of the chicken, a potential model of insulin resistance. MethodsChicks were subjected to intraperitoneal injection of sodium hydrosulfide (NaHS, 50 μmol/kg body mass/day) twice a day to explore glucose homeostasis. In vitro, myoblasts from PM and BF muscles were used to detect glucose uptake and utilization. Effects of AMP-activated protein kinase (AMPK) phosphorylation, AMPK S-sulfhydration, and mitogen-activated protein kinase (MAPK) pathway induction by NaHS were detected. ResultsNaHS enhanced glucose uptake and utilization in chicks (P < 0.05). In myoblasts from PM muscle, NaHS (100 μM) increased glucose uptake by activating AMPK S-sulfhydration, AMPK phosphorylation, and the AMPK/p38 MAPK pathway (P < 0.05). However, NaHS decreased glucose uptake in myoblasts from BF muscle by suppressing the p38 MAPK pathway (P < 0.05). Moreover, NaHS increased S-sulfhydration and, in turn, the phosphorylation of AMPK (P < 0.05). ConclusionsThis study reveals the role of H2S in enhancing glucose uptake and utilization in chicks. The results suggest that NaHS is involved in glucose uptake in skeletal muscle in a fiber type-dependent way. The AMPK/p38 pathway and protein S-sulfhydration promote glucose uptake in fast-twitch glycolytic muscle fibers, which provides a muscle fiber-specific potential therapeutic target to ameliorate glucose metabolism.

Inhibitory Effects of Simvastatin on IL-33-Induced MCP-1 via the Suppression of the JNK Pathway in Human Vascular Endothelial Cells.

An alarmin, interleukin (IL)-33 is a danger signal that causes inflammation, inducing chemotactic proteins such as monocyte chemoattractant protein (MCP)-1 in various cells. As statins have pleiotropic actions including anti-inflammatory properties, we investigated the effects of simvastatin on IL-33-induced MCP-1 expression in human umbilical vein endothelial cells (HUVECs). HUVECs were stimulated with IL-33 in the presence or absence of simvastatin. Gene expression and protein secretion of MCP-1, phosphorylation of mitogen-activated protein kinase (MAPK), nuclear translocation of phosphorylated c-Jun, and human monocyte migration were investigated. Immunocytochemical staining and Western immunoblot analysis revealed that IL-33 augmented MCP-1 protein expression in HUVECs. Real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) showed that IL-33 significantly increased MCP-1 mRNA and protein secretion, which were suppressed by c-jun N-terminal kinase (JNK) inhibitor SP600125 and p38 MAPK inhibitor SB203580. Simvastatin inhibited IL-33-induced MCP-1 mRNA, protein secretion, phosphorylation of JNK and c-Jun. Additionally, the IL-33-induced nuclear translocation of phosphorylated c-Jun and THP-1 monocyte migration were also blocked by simvastatin. This study demonstrated that IL-33 induces MCP-1 expression via the JNK and p38 MAPK pathways in HUVECs, and that simvastatin inhibits MCP-1 production by selectively suppressing JNK. Simvastatin may inhibit the progression of IL-33-induced inflammation via suppressing JNK to prevent MCP-1 production.

Sesamin attenuates UVA-induced keratinocyte injury via inhibiting ASK-1-JNK/p38 MAPK pathways.

Ultraviolet (UV) exposure-stimulated reactive oxygen species (ROS) formation in keratinocytes is a crucial factor in skin aging. Phytochemicals have become widely popular for protecting the skin from UV-induced cell injury. Sesamin (SSM) has been shown to play a role in extensive pharmacological activity and exhibit photoprotective effects. To assess the protective effect of SSM on UVA-irradiated keratinocytes and determine its potential antiphotoaging effect. HaCaT keratinocytes pretreated with SSM were exposed to UVA radiation at 8 J/cm2 for 10 min. Cell viability and oxidative stress indicators were evaluated using a cell counting kit-8 and lactate dehydrogenase (LDH), malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) assay kits. Apoptosis and intracellular ROS levels were analyzed using annexin V-fluorescein isothiocyanate/propyridine iodide and dichlorodihydrofluorescein diacetate staining, respectively. Protein levels of matrix metalloprotein-1 (MMP-1), MMP-9, Bax/Bcl-2, and mitogen-activated protein kinase (MAPK) pathway proteins, phospho-apoptosis signal-regulating kinase-1 (p-ASK-1)/ASK-1, phospho-c-Jun N-terminal protein kinase (p-JNK)/JNK, and p-p38/p38 were determined using western blotting. Sesamin showed no cytotoxicity until 160 μmol/L on human keratinocytes. Sesamin pretreatment (20 and 40 μM) reversed the suppressed cell viability, increased LDH release and MDA content, decreased cellular antioxidants GSH and SOD, and elevated intracellular ROS levels, which were induced by UVA irradiation. Additionally, SSM inhibited the expression of Bax, MMP-1, and MMP-9 and stimulated Bcl-2 expression. In terms of the regulatory mechanisms, we demonstrated that SSM inhibits the phosphorylation of ASK-1, JNK, and p38. The results suggest that SSM attenuates UVA-induced keratinocyte injury by inhibiting the ASK-1-JNK/p38 MAPK pathways.

PKC-δ Promotes IL-1β-Induced Apoptosis of Rat Chondrocytes and Via Activating JNK and P38 MAPK Pathways.

Protein kinase C-delta (PKC-δ) is involved in apoptosis. This study aimed to establish whether PKC-δ can further promote IL-1β-induced chondrocyte apoptosis by mediating the phosphorylation of the JNK and p38 mitogen-activated protein kinase (MAPK) signaling pathways In osteoarthritis (OA). We employed chondrocyte staining to determine the extent of cartilage degeneration. PKC-δ and p38 signal expressions were used in the immunohistochemical (IHC) test and apoptosis was assayed at the TUNEL test in human osteoarthritic and controls. We stimulated rat cartilage cells using IL-1β (10 ng/ml)/rottlerin (10 μM) or lentivirus. To determine the apoptosis rate, we employed flow cytometry. The mRNA of both BCL2-related X (BAX) and cysteine aspartate protease 3 (caspase-3) could be measured via qRT-PCR. Western blot measured the protein levels of BAX, caspase-3, PKC-δ, p-JNK/JNK and p-p38/p38. The positive rate of PKC-δ and the apoptotic rate of chondrocytes in OA were higher than controls. The manifestation of PKC-δ was positively related to the degree of cartilage degeneration, p38 protein expression, and apoptosis rate. IL-1β exposure upregulated PKC-δ expression in chondrocytes in a dose-dependent manner. Decreasing PKC-δ expression and its phosphorylation in OA can inhibit MAPK signaling pathway activation (phosphorylation) by downregulating JNK and p38 protein phosphorylation and expression. This inhibition decreases caspase-3 and BAX levels, consequently lowering the apoptosis rate in chondrocytes. PKC-δ activation by IL-1β in OA promotes chondrocyte apoptosis via activation of the JNK and p38 MAPK signal pathways, thereby promoting the OA progression.

BNIP3 overexpression may promote myeloma cell apoptosis by enhancing sensitivity to bortezomib via the p38 MAPK pathway

ABSTRACTBackground:BCL2-interacting protein 3 (BNIP3) expression varies among cancers, and its role in myeloma cells remains unknown. We investigated the role of BNIP3 overexpression in myeloma cells, and particularly its effects on apoptosis and mitochondria.Methods:A BNIP3-overexpressing plasmid was transfected into the MM.1S and RPMI8226 myeloma cell lines. Transfected cell apoptosis rate and mitochondrial function were determined via flow cytometry and western blotting. We verified the signaling pathway underlying myeloma cell sensitivity to bortezomib (BTZ).Results:Cell lines carrying the BNIP3-overexpressing plasmid exhibited higher rates of apoptosis and expression of Bax and Cleaved caspase 3 protein than the vector group, and less Bcl-2 protein expression than the control cells. Relative to the vector group, BNIP3-overexpressing strains contained more reactive oxygen species (ROS) and exhibited mitochondrial membrane potential (MMP) and dynamin-related protein 1 (Drp1) upregulation and mitofusin-1 (Mfn1) downregulation. BTZ supplementation increased BNIP3 expression. Relative to the BNIP3-OE group, the BNIP3-OE BTZ-treated group exhibited upregulated Bax and Cleaved caspase 3 protein expression, downregulated Bcl-2 protein expression, higher apoptosis rates, ROS levels, MMP, and Drp1 expression, and lower Mfn1 expression. BTZ treatment induced p38 MAPK (mitogen-activated protein kinase) signaling pathway activation in BNIP3-OE cells. Upon adding N-acetylcysteine (NAC) and the p38 MAPK inhibitor SB203580, the affected index levels returned to the baseline.Conclusions:BNIP3 overexpression induced apoptosis in myeloma cells and increased myeloma cell sensitivity to BTZ. These effects may be mediated by the ROS/p38 MAPK signaling pathway.

SARS-CoV-2 hijacks p38β/MAPK11 to promote virus replication.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, drastically modifies infected cells to optimize virus replication. One such modification is the activation of the host p38 mitogen-activated protein kinase (MAPK) pathway, which plays a major role in inflammatory cytokine production, a hallmark of severe COVID-19. We previously demonstrated that inhibition of p38/MAPK activity in SARS-CoV-2-infected cells reduced both cytokine production and viral replication. Here, we combined quantitative genetic screening, genomics, proteomics, and phosphoproteomics to better understand mechanisms underlying the dependence of SARS-CoV-2 on the p38 pathway. We found that p38β is a critical host factor for SARS-CoV-2 replication in multiple relevant cell lines and that it functions at a step after viral mRNA expression. We identified putative host and viral p38β substrates in the context of SARS-CoV-2 infection and found that most host substrates have intrinsic antiviral activities. Taken together, this study reveals a unique proviral function for p38β and supports exploring p38β inhibitor development as a strategy toward creating a new class of COVID-19 therapies. IMPORTANCE SARS-CoV-2 is the causative agent of the COVID-19 pandemic that has claimed millions of lives since its emergence in 2019. SARS-CoV-2 infection of human cells requires the activity of several cellular pathways for successful replication. One such pathway, the p38 MAPK pathway, is required for virus replication and disease pathogenesis. Here, we applied systems biology approaches to understand how MAPK pathways benefit SARS-CoV-2 replication to inform the development of novel COVID-19 drug therapies.

Overexpression of Eimeria tenella Rhoptry Kinase 2 Induces Early Production of Schizonts.

Eimeria tenella is an obligate intracellular parasite responsible for avian coccidiosis. Like other apicomplexan parasites, such as Toxoplasma gondii, cell invasion and intracellular development rely on apical organelle content discharge, named micronemes and rhoptries. Some rhoptry (ROP) kinases (ROPK) are key virulence factors in T. gondii. To date, among the 28 ropk genes carried by E. tenella, only two to four were confirmed by proteomic analysis or immunostaining to be expressed at the sporozoite stage. We have previously shown that EtROP1 is implicated in the inhibition of host cell apoptosis by interacting with the cellular p53. This work functionally described the second ROP kinase expressed at the sporozoite stage in E. tenella. EtROP2 is an active kinase that phosphorylates cell substrates of approximately 50 kDa. Its overexpression leads to the shortening of the prepatent period and to the early development of first-generation schizonts. Conduction of RNA sequencing analysis and reverse transcriptase quantitative PCR (RT-qPCR) on the host cell allowed us to identify the mitogen-activated protein kinase (MAPK) pathway and the transcription factor cFos to be upregulated by EtROP2. We also showed by immunofluorescence assay that the active kinase EtROP2 is implicated in the p38 MAPK pathway activation. We established here that EtROP2 activates the p38 MAPK pathway through a direct or indirect phosphorylation, leading to the overexpression of the master transcription factor cFos known to be implicated in E. tenella development. IMPORTANCE Rhoptries are specialized secretory organelles found in zoite stages of apicomplexan parasites. In addition to well-conserved rhoptry neck proteins, their protein consists mostly of kinase proteins, highly divergent from eukaryotic kinases. Some of those kinases are described as major virulence factors in Toxoplasma gondii, secreted into the host cell to hijack signaling pathways. Most of those kinases remain to be characterized in Eimeria tenella. Deciphering their cellular function is a prerequisite to supporting their relevance as a druggable target in development of new means of Eimeria tenella control. Secreted divergent kinases that interact with host cell partners to modulate pathways are good candidates, as they coevolve with their host targets to ensure their function within the host and are less prone to mutations that would lead to drug resistance. The absence of any orthologous kinase in host cells makes these parasite kinases a promising drug target candidate.

PD-1 Carried on Small Extracellular Vesicles Leads to OSCC Metastasis

Immune checkpoint molecule PD-1, expressed on the cell surface, impairs antigen-driven activation of T cells and thus plays a critical role in tumorigenesis, progression, and the poor prognosis of oral squamous cell carcinoma (OSCC). In addition, increasing evidence indicates that PD-1 carried on small extracellular vesicles (sEVs) also mediates tumor immunity, although their contributions to OSCC are yet unclear. Here, we investigated the biological functions of sEV PD-1 in patients with OSCC. The cell cycle, proliferation, apoptosis, migration, and invasion of CAL27 cell lines treated with or without sEV PD-1 were examined in vitro. We performed mass spectrometry to investigate the underlying biological process, combined with an immunohistochemical study of SCC7-bearing mice models and OSCC patient samples. In vitro data demonstrated that sEV PD-1 induced senescence and subsequent epithelial-mesenchymal transition (EMT) in CAL27 cells by ligating with tumor cell surface PD-L1 and activating the p38 mitogen-activated protein kinase (MAPK) pathway. Comprehensive immunohistochemical analysis of the xenograft mice models and OSCC patient samples revealed a very close correlation between the level of circulating sEV PD-1 and lymph node metastasis. These results demonstrate that circulating sEV PD-1 triggers senescence-initiated EMT in a PD-L1-p38 MAPK-dependent manner, contributing to tumor metastasis. It also suggests that the inhibition of sEV PD-1 may be a promising therapeutic target for the treatment of OSCC.

Glucocorticoid Receptors Drive Breast Cancer Cell Migration and Metabolic Reprogramming via PDK4.

Corticosteroids act on the glucocorticoid receptor (GR; NR3C1) to resolve inflammation and are routinely prescribed to breast cancer patients undergoing chemotherapy treatment to alleviate side effects. Triple-negative breast cancers (TNBCs) account for 15% to 20% of diagnoses and lack expression of estrogen and progesterone receptors as well as amplified HER2, but they often express high GR levels. GR is a mediator of TNBC progression to advanced metastatic disease; however, the mechanisms underpinning this transition to more aggressive behavior remain elusive. We previously showed that tissue/cellular stress (hypoxia, chemotherapies) as well as factors in the tumor microenvironment (transforming growth factor β [TGF-β], hepatocyte growth factor [HGF]) activate p38 mitogen-activated protein kinase (MAPK), which phosphorylates GR on Ser134. In the absence of ligand, pSer134-GR further upregulates genes important for responses to cellular stress, including key components of the p38 MAPK pathway. Herein, we show that pSer134-GR is required for TNBC metastatic colonization to the lungs of female mice. To understand the mechanisms of pSer134-GR action in the presence of GR agonists, we examined glucocorticoid-driven transcriptomes in CRISPR knock-in models of TNBC cells expressing wild-type or phospho-mutant (S134A) GR. We identified dexamethasone- and pSer134-GR-dependent regulation of specific gene sets controlling TNBC migration (NEDD9, CSF1, RUNX3) and metabolic adaptation (PDK4, PGK1, PFKFB4). TNBC cells harboring S134A-GR displayed metabolic reprogramming that was phenocopied by pyruvate dehydrogenase kinase 4 (PDK4) knockdown. PDK4 knockdown or chemical inhibition also blocked cancer cell migration. Our results reveal a convergence of GR agonists (ie, host stress) with cellular stress signaling whereby pSer134-GR critically regulates TNBC metabolism, an exploitable target for the treatment of this deadly disease.

Resveratrol Enhances Cytotoxic Effects of Cisplatin by Inducing Cell Cycle Arrest and Apoptosis in Ovarian Adenocarcinoma SKOV-3 Cells through Activating the p38 MAPK and Suppressing AKT.

In the current study, we identified a mechanism of resveratrol (RES) underlying its anti-cancer properties against human ovarian adenocarcinoma SKOV-3 cells. We investigated its anti-proliferative and apoptosis-inducing effects in combination with cisplatin, using cell viability assay, flow cytometry, immunofluorescence study and Western blot analysis. We discovered that RES suppressed cancer cell proliferation and stimulated apoptosis, especially when combined with cisplatin. This compound also inhibited SKOV-3 cell survival, which may partly be due to its potential to inhibit protein kinase B (AKT) phosphorylation and induce the S-phase cell cycle arrest. RES in combination with cisplatin strongly induced cancer cell apoptosis through activating the caspase-dependent cascade, which was associated with its ability to stimulate nuclear phosphorylation of p38 mitogen-activated protein kinase (MAPK), well recognized to be involved in transducing environmental stress signals. RES-induced p38 phosphorylation was very specific, and the activation status of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) was not mainly affected. Taken together, our study provides accumulated evidence that RES represses proliferation and promotes apoptosis in SKOV-3 ovarian cancer cells through activating the p38 MAPK pathway. It is interesting that this active compound may be used as an effective agent to sensitize ovarian cancer to apoptosis induced by standard chemotherapies.

Selenium nanoparticles improve nickel-induced testosterone synthesis disturbance by down-regulating miR-708-5p/p38 MAPK pathway in Leydig cells.

The present study was designed to investigate the role of miR-708-5p/p38 mitogen-activated protein kinase (MAPK) pathway during the mechanism of selenium nanoparticles (Nano-Se) against nickel (Ni)-induced testosterone synthesis disorder in rat Leydig cells. We conducted all procedures based on in vitro culture of rat primary Leydig cells. After treating Leydig cells with Nano-Se and NiSO4 alone or in combination for 24 h, we determined the cell viability, reactive oxygen species (ROS) levels, testosterone production, and the protein expression of key enzymes involved in testosterone biosynthesis: steroidogenic acute regulatory (StAR) and cytochrome P450 cholesterol side chain cleavage enzyme (CYP11A1). The results indicated that Nano-Se antagonized cytotoxicity and eliminated ROS generation induced by NiSO4 , suppressed p38 MAPK protein phosphorylation and reduced miR-708-5p expression. Importantly, we found that Nano-Se upregulated the expression of testosterone synthase and increased testosterone production in Leydig cells. Furthermore, we investigated the effects of p38 MAPK and miR-708-5p using their specific inhibitor during Nano-Se against Ni-induced testosterone synthesis disorder. The results showed that Ni-inhibited testosterone secretion was alleviated by Nano-Se co-treatment with p38 MAPK specific inhibitor SB203580 and miR-708-5p inhibitor, respectively. In conclusion, these findings suggested Nano-Se could inhibit miR-708-5p/p38 MAPK pathway, and up-regulate the key enzymes protein expression for testosterone synthesis, thereby antagonizing Ni-induced disorder of testosterone synthesis in Leydig cells.

Ferulic Acid: A Review of Pharmacology, Toxicology, and Therapeutic Effects on Pulmonary Diseases.

Ferulic acid (FA), a prevalent dietary phytochemical, has many pharmacological effects, including anti-oxidation and anti-inflammation effects, and has been widely used in the pharmaceutical, food, and cosmetics industries. Many studies have shown that FA can significantly downregulate the expression of reactive oxygen species and activate nuclear factor erythroid-2-related factor-2/heme oxygenase-1 signaling, exerting anti-oxidative effects. The anti-inflammatory effect of FA is mainly related to the p38 mitogen-activated protein kinase and nuclear factor-kappaB signaling pathways. FA has demonstrated potential clinical applications in the treatment of pulmonary diseases. The transforming growth factor-β1/small mothers against decapentaplegic 3 signaling pathway can be blocked by FA, thereby alleviating pulmonary fibrosis. Moreover, in the context of asthma, the T helper cell 1/2 imbalance is restored by FA. Furthermore, FA ameliorates acute lung injury by inhibiting nuclear factor-kappaB and mitogen-activated protein kinase pathways via toll-like receptor 4, consequently decreasing the expression of downstream inflammatory mediators. Additionally, there is a moderate neuraminidase inhibitory activity showing a tendency to reduce the interleukin-8 level in response to influenza virus infections. Although the application of FA has broad prospects, more preclinical mechanism-based research should be carried out to test these applications in clinical settings. This review not only covers the literature on the pharmacological effects and mechanisms of FA, but also discusses the therapeutic role and toxicology of FA in several pulmonary diseases.

Effects of CCN6 overexpression on the cell motility and activation of p38/bone morphogenetic protein signaling pathways in pancreatic cancer cells

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancer types that is highly resistant to conventional treatments, such as chemotherapy and radiotherapy. As the demand for more effective therapeutics for PDAC treatment increases, various approaches have been studied to develop novel targets. The cellular communication network (CCN) family is a matricellular protein that modulates various cellular functions, including cell adhesion, proliferation, migration, and invasiveness. Despite this, little is known about the role of CCN6 in PDAC. The current study investigated the role of CCN6 in PDAC by generating CCN6-overexpressing PANC-1 cells (PANC-1-CCN6) by infecting lentivirus particles containing CCN6. PANC-1-CCN6 induces cell viability and tumorigenesis than PANC-1 cells with empty vector (control). The PANC-1-CCN6 formed more colonies, and the size of spheroids increased compared to the control. The upregulation of CCN6 enhances the expression of bone morphogenetic proteins (BMPs) genes and the upregulation of p38 mitogen-activated protein kinases (MAPKs). In PANC-1-CCN6 cells, the levels of N-cadherin, VEGF, and Snail expression were higher than the control, while E-cadherin expression was lower, which is associated with upregulation of epithelial-to-mesenchymal transition (EMT). Consistent with the changes in EMT-related proteins in PANC-1-CCN6, the migratory ability and invasiveness were enhanced in PANC-1-CCN6. Xenografted PANC-1-CCN6 in immunocompromised mice exhibited accelerated tumor growth than the control group. In immunohistochemistry (IHC), the PANC-1-CCN6 xenografted tumor showed an increased positive area of PCNA and Ki-67 than the control. These results suggest that CCN6 plays a tumorigenic role and induces the metastatic potential by the p38 MAPK and BMPs signaling pathways. Although the role of CCN6 has been introduced as an antitumor factor, there was evidence of CCN6 acting to cause tumorigenesis and invasion in PANC-1.

A comprehensive toxicological analysis of trans-fatty acids (TFAs) reveals a pro-apoptotic action specific to industrial TFAs counteracted by polyunsaturated FAs

trans-Fatty acids (TFAs) are unsaturated fatty acids containing at least one carbon–carbon double bond in trans configuration, which are classified into two groups according to their food source: industrial TFAs (iTFAs) and ruminant TFAs (rTFAs). Previous epidemiological evidence has demonstrated a preferential association of iTFAs, rather than rTFAs, with various diseases including cardiovascular diseases. However, it is still unknown how iTFAs exert their specific toxicity and what effective treatments are available to mitigate their toxicity. Here, we performed a comprehensive toxicological assessment of TFAs based on the toxicity mechanism that we established previously. We found that iTFAs including elaidic acid (EA), but not other types of fatty acids including rTFAs, had a strong pro-apoptotic effect upon treatment of extracellular ATP, a damage-associated molecular pattern that induces apoptosis through the apoptosis signal-regulating kinase 1 (ASK1)-p38 MAP kinase pathway. We also found that polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), potently suppressed EA-dependent increase in ASK1 activation and apoptosis. These results demonstrate that iTFAs specifically exert toxicity by targeting ASK1, and that PUFAs serve as their effective suppressor. Our study provides a molecular basis for risk assessment of foods, and for new prevention and treatment strategies for TFA-related diseases.

Abstract 2545: NNMT is a novel effector of EGFR driven glioblastoma malignancy

Abstract Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the conversion of methyl groups from S-adenosyl-L-methionine (SAM) to nicotinamide (NAM) to generate S-adenosine hyperblastoids (SAH) and 1-methylnicotinamide (MNA). Upregulation of NNMT has been observed in a variety of cancers, including glioblastoma. The mechanism by which NNMT is overexpressed in glioblastoma remains largely unknown. Epidermal growth factor receptor (EGFR) gene amplification or mutation is one of the most common genetic lesions in glioblastoma, and EGFRvIII is the most common mutant contributing to glioblastoma cell proliferation, invasion, therapeutic resistance, metastasis, and stemness. In this study, we show that activation of wild-type EGFR by EGF or the constitutively active mutant EGFRvIII promoted NNMT expression in established glioblastoma cell lines and glioblastoma stem-like cells via the p38 mitogen-activated protein kinase pathway. Furthermore, we identified STAT1 as a downstream transcription factor required for EGFR/EGFRvIII-induced NNMT upregulation. Knockdown of NNMT by RNA interference in glioblastoma cells significantly inhibited EGFRvIII-promoted glioblastoma cell invasion and proliferation in vitro. Targeting NNMT inhibited EGFRvIII-driven glioblastoma tumorigenicity and prolonged survival of tumor-bearing mice. Clinically, NNMT was highly expressed and positively correlated with EGFR expression in human glioblastoma tumors. Taken together, these findings establish NNMT as a previously unknown downstream target gene of EGFR/EGFRvIII expression and nominate it as a new potential therapeutic target for inhibiting EGFRvIII-driven glioblastoma. Citation Format: Lianping Ma, Ming Li. NNMT is a novel effector of EGFR driven glioblastoma malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2545.

PD17-03 REDOX IMBALANCE AND MAPK ACTIVATION MEDIATES PNEUMOPERITONEUM-INDUCED KIDNEY INJURY DURING MINIMALLY INVASIVE SURGERY

You have accessJournal of UrologyCME1 Apr 2023PD17-03 REDOX IMBALANCE AND MAPK ACTIVATION MEDIATES PNEUMOPERITONEUM-INDUCED KIDNEY INJURY DURING MINIMALLY INVASIVE SURGERY Charbel Chalouhy, Nassim Fares, Youakim Saliba, Pedro Maria, Ahmed Aboumoouhamed, Marwan Kassis, Alexander Small, and Justin Loloi Charbel ChalouhyCharbel Chalouhy More articles by this author , Nassim FaresNassim Fares More articles by this author , Youakim SalibaYouakim Saliba More articles by this author , Pedro MariaPedro Maria More articles by this author , Ahmed AboumoouhamedAhmed Aboumoouhamed More articles by this author , Marwan KassisMarwan Kassis More articles by this author , Alexander SmallAlexander Small More articles by this author , and Justin LoloiJustin Loloi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003272.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Given the widespread use of laparoscopic and robotic surgeries, the effects of pneumoperitoneum (PNP) during minimally invasive surgery on kidney function become of great interest. PNP during laparoscopy causes transient renal functional impairment via various detrimental factors, such as oxidative stress. We, therefore, investigated the oxidative signaling pathways inherent to PNP-induced kidney injury. METHODS: PNP was established at an intraperitoneal CO 2 pressure of 12 mmHg in Wistar rats randomly allocated into three groups: Sham, PNP1, and PNP24. PNP1 and PNP24 animals were sacrificed at one and 24 hours following PNP deflation, respectively. Renal histology, function, redox status, and signaling pathways were assessed. RESULTS: PNP induced kidney injury and dysfunction with altered KIM-1 profile. Both expression and activity of antioxidant (CAT, SOD1/2) and oxidant (NOS3) enzymes, lipid peroxidation, and renal RNA/DNA damage biomarkers revealed redox imbalance after PNP, with an excess H2O2 production. Moreover, the antioxidant gene regulators FoxO3a and Nrf2 were activated. Nevertheless, PNP had no effect on the cellular apoptotic pathways Bcl2, Bid, Caspase 3 and 8. Finally, PNP stimulated the p38 and JNK mitogen-activated protein kinase (MAPK) pathways in the kidney. CONCLUSIONS: Our results demonstrate for the first time that PNP induces acute kidney injury due to renal redox imbalance linked to MAPK activation. These insights may open the way for further investigation into the renal therapeutic impact of managing PNP-associated oxidative stress during robotic surgery and explore procedure-specific kidney function recovery patterns i.e. after robotic partial nephrectomy or robotic kidney transplant. Source of Funding: none © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e495 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Charbel Chalouhy More articles by this author Nassim Fares More articles by this author Youakim Saliba More articles by this author Pedro Maria More articles by this author Ahmed Aboumoouhamed More articles by this author Marwan Kassis More articles by this author Alexander Small More articles by this author Justin Loloi More articles by this author Expand All Advertisement PDF downloadLoading ...