Phosphorylation Of P53 Protein Research Articles

Low-molecular-weight heparin sodium inhibits the MAPK pathway for psoriasis treatment in mice.

Low-molecular-weight heparin sodium inhibits the MAPK pathway for psoriasis treatment in mice.

Selective Gamma-Secretase Inhibition by CHF5074 Attenuates Inflammation and Neovascularization in a Murine Model of Choroidal Neovascularization

Purpose Chronic inflammation plays an important role in the pathogenesis of choroidal neovascularization (CNV). This study aimed to investigate the effect of the CHF5074, a γ-secretase inhibitor, on angiogenesis in a laser-induced CNV model and elucidate its possible molecular mechanism. Methods Male C57/BL6J mice aged between 6 to 8 weeks were employed to set up a laser-induced model of CNV. Then, CHF5074 was injected intraperitoneally on the day after laser modeling, as well as on the second, third, and fourth days. Immunofluorescence staining was used to evaluate the retinal and choroidal complex. The markers used were CD31 for neovascularization and IBA1 for microglia staining in ocular tissue slices. Fundus fluorescein angiography on days 3d, 7d, and 14d analyzed neovascularization and leakage areas. Inflammatory indicators were examined by Western blot (WB) and enzyme-linked immunosorbent assay (ELISA). High-throughput whole-tissue sequencing of retinal choroids identified relevant cell pathways. Key regulatory factors modulated by CHF5074 were identified via WB. Co-culture of BV2 cells and human umbilical vein endothelial cells (HUVEC) were used to explore the function of CHF5074 on the inhibition of tube formation. Results CHF5074 significantly decreased CD31 expression in the choroid on 3d, 7d, and 14d post-laser modeling (p < 0.05) and decreased both neovascularization and leakage areas (p < 0.05). Additionally, CHF5074 significantly lowered TNF-α, IL-10, and IL-1β expression levels in the choroid (p < 0.05), as demonstrated by WB analysis and ELISA. High-throughput whole-tissue sequencing identified P38-MAPK, JNK, and Wnt signaling pathways associated with neovascularization. CHF5074 decreased P38 protein phosphorylation (p < 0.05) as confirmed by WB analysis. CHF5074 inhibited the tube formation of HUVECs co-cultured with LPS and ATP-treated BV2 cells. Conclusion CHF5074 significantly suppresses angiogenesis in laser-induced choroidal neovascularization models, suggesting its potential as a novel agent for preventing and treating CNV.

Proton pump inhibitor effect on macrophage and neutrophil function: a systematic review.

Proton pump inhibitors (PPIs) are one of the most used drugs worldwide. While generally considered safe, the usage of PPIs is associated with several adverse outcomes including acute infectious diseases. PPIs influence macrophage and neutrophil function although a systematic review has never been undertaken. The purpose of this systematic review was to determine the potential mechanisms of how PPI-induced inhibition of macrophage and neutrophil function may increase infection risk in susceptible hosts. A database search using Scopus and PubMed was performed to identify studies that investigated the effects of PPIs on neutrophils or macrophage function. The final screening yielded 21 English-language research articles that focused on the impacts of PPIs on the function of macrophages and neutrophils. PPI mechanistic effects included cytotoxic effects on polymorphonuclear neutrophils, inhibition of reactive oxygen species (ROS) and reactive nitrogen species, phagocytosis and phagosomal degradation, inhibition of chemotaxis and migration, altering Toll-like receptor signaling and p38 protein phosphorylation in immune cells, and altering neutrophil and macrophage gene expression. The impact of PPIs on MΦs and neutrophils regarding their role in the immune response to bacterial pathogens was summarized. PPI effects on macrophages and neutrophils occurred due to the therapeutic mechanism of PPIs, the protonation of sulfhydryl groups and the subsequent formation of a disulfide bond, and other pleiotropic manners. Given the common use of PPIs, these results highlight the necessity to optimize PPI use and stewardship to curtail unnecessary drug use.

Dihydrotanshinone I induces necroptosis and cell cycle arrest in gastric cancer through the PTPN11/p38 pathway

Dihydrotanshinone I induces necroptosis and cell cycle arrest in gastric cancer through the PTPN11/p38 pathway

EtROP38 suppresses apoptosis of host cells infected with Eimeria tenella by inhibition of the p38MAPK pathway

EtROP38 suppresses apoptosis of host cells infected with Eimeria tenella by inhibition of the p38MAPK pathway

The cytochrome P4501A1 (CYP1A1) inhibitor bergamottin enhances host tolerance to multidrug-resistant Vibrio vulnificus infection

The cytochrome P4501A1 (CYP1A1) inhibitor bergamottin enhances host tolerance to multidrug-resistant Vibrio vulnificus infection

P53 lysine-lactylated modification contributes to lipopolysaccharide-induced proinflammatory activation in BV2 cell under hypoxic conditions

p53 lysine-lactylated modification contributes to lipopolysaccharide-induced proinflammatory activation in BV2 cell under hypoxic conditions

Carnosol attenuates angiotensin II-induced cardiac remodeling and inflammation via directly binding to p38 and inhibiting p38 activation

Carnosol attenuates angiotensin II-induced cardiac remodeling and inflammation via directly binding to p38 and inhibiting p38 activation

Beauvericin, produced by Fusarium oxysporum inhibits bisphenol A-induced proliferation of human breast cancer cell line by regulating ERα/p38 pathway

Beauvericin, produced by Fusarium oxysporum inhibits bisphenol A-induced proliferation of human breast cancer cell line by regulating ERα/p38 pathway

UHRF1-Mediated Epigenetic Reprogramming Regulates Glycolysis to Promote Progression of B-Cell Acute Lymphoblastic Leukemia

UHRF1-Mediated Epigenetic Reprogramming Regulates Glycolysis to Promote Progression of B-Cell Acute Lymphoblastic Leukemia

PF-04449913 Inhibits Proliferation and Metastasis of Colorectal Cancer Cells by Down-regulating MMP9 Expression through the ERK/p65 Pathway.

Colorectal cancer remains a life-threatening malignancy with increasing morbidity and mortality worldwide. Therefore, new and effective anti-colorectal cancer therapeutics are urgently needed. In this study, we have studied the anti-tumor properties and potential mechanisms of PF-04449913. Colorectal cancer cell viability was reduced by PF-04449913 in a dose-dependent manner. The migration and invasion ability of malignant colon cells were attenuated by the drug, as demonstrated by the Transwell test. Moreover, PF-04449913 repressed the phosphorylation levels of ERK and other proteins, and the expression levels of MMP9. The anti-tumor effects of the drug in vivo were demonstrated in BALB/c-nude mice models, and PF-04449913 inhibited the malignant phenotype of colorectal cancer cells, including reduction of tumor size and promotion of apoptosis. At the molecular level, PF-04449913 induced a significant decrease in ERK and p65 protein phosphorylation levels and inhibited MMP9 protein expression. Both in vivo and in vitro results showed PF-04449913 to demonstrate antitumor effects, which have been proposed to be mediated through blockade of the ERK/p65 signaling pathway, and subsequent repression of MMP9 expression. Our study provides a new perspective on the potential clinical application of PF-04449913 in the treatment of colorectal cancer.

Rabdosichuanin C inhibits productions of pro-inflammatory mediators regulated by NF-κB signaling in LPS-stimulated RAW264.7 cells.

Chronic pharyngitis (CP) is an inflammatory disease of the pharyngeal mucosa and its lymphatic tissues that is difficult to treat clinically. However, research on the exact therapeutic agents and molecular mechanisms of CP is still unclear. In this study, we investigated Rabdosichuanin C (RC) to attenuate lipopolysaccharide (LPS)-induced inflammatory damage in RAW264.7 cells by a combination of targeted virtual screening and in vitro activity assay and further clarified its molecular mechanism of action centering on the IκB/nuclear factor kappa B (NF-κB) pathway. Molecular docking and pharmacophore simulation methods were used to screen compounds with IκB inhibitory effects. Expression of genes and proteins related to the IκB/NF-κB signaling pathway by RC in LPS-induced inflammatory injury model of RAW264.7 cells was detected by PCR, enzyme-linked immunosorbent assay, and Western blot. The docking of RC with IκB protein showed good binding energy, and pharmacophore simulations further confirmed the active effect of RC in inhibiting IκB protein. RC intervention in LPS-induced RAW264.7 cells significantly reduced the expression levels of inflammatory factors tumor necrosis factor-α, interleukins-6, iNOS, and CD-86 at the messenger RNA and protein levels, downregulated IκB, p65 protein phosphorylation levels, and significantly inhibited IκB/NF-κB signaling pathway activation. Virtual screening provided us with an effective method to rapidly identify compounds RC that target inhibit the action of IκB, and the activity results showed that RC inhibits NF-κB signaling pathway activation. It is suggested that RC may play a role in the treatment of CP by inhibiting the IκB/NF-κB signaling pathway.

Anti-aging formula protects skin from oxidative stress-induced senescence through the inhibition of CXCR2 expression

Anti-aging formula protects skin from oxidative stress-induced senescence through the inhibition of CXCR2 expression

Cell cycle-specific phosphorylation of p53 protein in A549 cells exposed to cisplatin and standardized air pollutants.

Exposure to particulate matter is associated with DNA damage and the risk of lung cancer. Protein p53 is activated by multi-site phosphorylation in the early stages of DNA damage and affects cell outcome. Our study aimed to assess the effect of (100µg/mL-1/24h) standardized air pollutants: carbon black (CB), urban dust (UD), and nanoparticle carbon black (NPCB) on cell cycle, DNA damage and 53 phosphorylation at Ser 9, Ser 20, Ser 46, and Ser 392 in proliferating and quiescent A549 cells and in cells that survived cisplatin (CisPT) exposure. Phosphorylated p53 was quantified in cell subpopulations by flow cytometry using specific fluorochrome-tagged monoclonal antibodies and analysis of bivariate fluorescence distribution scatterplots. CisPT, UD and NPCB increased site-specific p53 phosphorylation producing unique patterns. NPCB activated all sites irrespectively on the cell cycle, while the UD was more selective. p53 Ser 9-P and p53 Ser 20-P positively correlated with the numbers of CisPT-treated cells at G0/G1, and NPCB and NPCB + CisPT produced a similar effect. A positive correlation and integrated response were also found between Ser 20-P and Ser 392-P in resting A549 cells treated with NPCB and CisPT but not UD. Interdependence between the expression of p53 phosphorylated at Ser 20, and Ser 392 and cell cycle arrest show that posttranslational alterations are related to functional activation. Our data suggest that p53 protein phosphorylation in response to specific DNA damage is driven by multiple independent and integrated pathways to produce functional activation critical in cancer prevention and treatment.

Telmisartan inhibits microglia-induced neurotoxic A1 astrocyte conversion via PPARγ-mediated NF-κB/p65 degradation

Telmisartan inhibits microglia-induced neurotoxic A1 astrocyte conversion via PPARγ-mediated NF-κB/p65 degradation

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.

Downregulation of XBP1s aggravates lipopolysaccharide-induced inflammation by promoting NF-κB and NLRP3 pathways’ activation in goat endometrial epithelial cells

Downregulation of XBP1s aggravates lipopolysaccharide-induced inflammation by promoting NF-κB and NLRP3 pathways’ activation in goat endometrial epithelial cells

PQBP1 regulates the cellular inflammation induced by avian reovirus and interacts with the viral p17 protein

Avian reovirus (ARV) can commonly infect a flock and cause immunosuppressive diseases in poultry. The nonstructural protein p17 is involved in viral replication, and significant progress has been made in showing its ability to regulate cellular signaling pathways. In our previous study, to further investigate the effect of ARV p17 protein on viral replication, the host protein polyglu-tamine binding protein 1 (PQBP1) was identified to interact with p17 by a yeast two-hybrid system. In the current study, the interaction between PQBP1 and p17 protein was further confirmed by laser confocal microscopy and coimmunoprecipitation assays. In addition, the N-terminal WWD of PQBP1 was found to mediate the process of binding to the p17 protein. Interestingly, we found that ARV infection significantly inhibited PQBP1 expression. While the quantity of ARV replication was largely influenced by PQBP1, PQBP1 overexpression decreased ARV replication. In contrast, upon PQBP1 knockdown, the quantity of ARV was notably increased. ARV infection and p17 protein expression were both proven to induce PQBP1 to mediate cellular inflammation. In the current study, we revealed through qRT‒PCR, ELISA and Western blotting methods that PQBP1 plays a positive role in ARV-induced inflammation. Furthermore, the mechanism of this process was shown to involve the NFκB-dependent transcription of inflammatory genes. In addition, PQBP1 was shown to regulate the phosphorylation of p65 protein. In conclusion, this research provides clues to elucidating the function of the p17 protein and the pathogenic mechanism of ARV, especially the cause of the inflammatory response. It also provides new ideas for the study of therapeutic targets of ARV.

SALL4 correlates with proliferation, metastasis, and poor prognosis in prostate cancer by affecting MAPK pathway.

The mechanism involved in prostate cancer (PCa) metastasis is still poorly understood, and several oncogenes are known to regulate this process. However, the role of spalt-like transcription factor 4 (SALL4) in PCa metastasis remains unclear. We performed RNA-sequencing to compare the mRNA expression profiles of seven localized PCa tissues and six metastatic PCa tissues. SALL4 was then identified and compared in the localized PCa and metastatic PCa. Immunohistochemical studies, qRT-PCR, and Western blot were performed to analyze the expression of SALL4 in PCa patients and cell lines. SALL4 expression and its relevance to clinical traits and prognosis were further explored in the TCGA database and in our 68 clinical samples. Subsequently, we knocked down SALL4 in DU145 and PC3 cells and performed a series of functional assays to explore the effect of SALL4 on PCa progression. Finally, protein levels of SALL4 and core components of the MAPK pathway were measured by Western blot, and cells were treated with PD0325901 to observe proliferation and metastasis. Significantly higher expression of SALL4 was found in metastatic PCa than in localized PCa. In addition, high SALL4 expression was significantly associated with high pathological T stage, N stage, Gleason score, and poor disease-free survival in TCGA database and in our clinical samples. Functional studies indicated that knockdown of SALL4 in DU145 and PC3 inhibited proliferation, migration, and angiogenesis. Furthermore, the ERK and P38 protein phosphorylation significantly reduced after knockdown of SALL4 in DU145 and PC3, indicating the inactivation of the MAPK signaling pathway. Finally, the proliferation and migration ability of DU145 and PC3 cells were significantly decreased after PD0325901 treatment. SALL4 predicts unfavorable outcome and is closely associated with PCa progression, suggesting that SALL4 may be a promising prognostic marker and potential therapeutic target for PCa.

The kinesin light chain-2, a target of mRNA stabilizing protein HuR, inhibits p53 protein phosphorylation to promote radioresistance in NSCLC.

Radioresistance hinders radiotherapy for the treatment of lung cancer. Kinesin light chain-2 (KLC2) has been found to be upregulated in lung cancer and also to be associated with poor prognosis. This study aimed to investigate the effect of KLC2 on radiosensitivity in lung cancer. The radioresistant role of KLC2 was determined by colony formation, neutral comet assay, and γH2AX immunofluorescent staining assay. We further verified the function of KLC2 in a xenograft tumor model. The downstream of KLC2 was identified through gene set enrichment analysis and validated by western blot. Finally, we analyzed clinical data from the TCGA database to reveal the upstream transcription factor of KLC2, which was validated by RNA binding protein immunoprecipitation assay. Here, we found that downregulation of KLC2 could significantly reduce colony formation, increase γH2AX level, and double-stranded DNA breaks in vitro. Meanwhile, overexpressed KLC2 significantly increased the proportion of the S phase in lung cancer cells. KLC2 knockdown could activate P53 pathway, and ultimately promoting radiosensitivity. The mRNA of KLC2 was observed to bind with Hu-antigen R (HuR). The mRNA and protein expression of KLC2 in lung cancer cells was significantly reduced when combined with siRNA-HuR. Interestingly, KLC2 overexpression significantly increased the expression of HuR in lung cancer cells. Taken together, these results indicated that HuR-KLC2 forms a positive feedback loop, which decreases the phosphorylation of p53 and thereby weaken the radiosensitivity of lung cancer cells. Our findings highlight the potential prognosis and therapeutic target value of KLC2 in lung cancer patients treated with radiotherapy.