Preventive treatment with sodium para-aminosalicylic acid inhibits manganese-induced apoptosis and inflammation via the MAPK pathway in rat thalamus

2021 ◽  
pp. 1-10
Author(s):  
Yue Deng ◽  
Dongjie Peng ◽  
Chun Yang ◽  
Lin Zhao ◽  
Junyan Li ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Preventive Treatment ◽  
Aminosalicylic Acid ◽  
Induced Apoptosis ◽  
Apoptosis And Inflammation

scholarly journals Intranasal insulin rescues repeated anesthesia-induced deficits in synaptic plasticity and memory and prevents apoptosis in neonatal mice via mTORC1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Patricia Soriano Roque ◽  
Mehdi Hooshmandi ◽  
Laura Neagu-Lund ◽  
Shelly Yin ◽  
Noosha Yousefpour ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Synaptic Plasticity ◽  
General Anesthesia ◽  
Preventive Treatment ◽  
Intranasal Insulin ◽  
Translational Repressor ◽  
Beneficial Effects ◽  
Underlying Mechanisms ◽  
Induced Apoptosis ◽  
Preclinical And Clinical Studies

AbstractLong-lasting cognitive impairment in juveniles undergoing repeated general anesthesia has been observed in numerous preclinical and clinical studies, yet, the underlying mechanisms remain unknown and no preventive treatment is available. We found that daily intranasal insulin administration to juvenile mice for 7 days prior to repeated isoflurane anesthesia rescues deficits in hippocampus-dependent memory and synaptic plasticity in adulthood. Moreover, intranasal insulin prevented anesthesia-induced apoptosis of hippocampal cells, which is thought to underlie cognitive impairment. Inhibition of the mechanistic target of rapamycin complex 1 (mTORC1), a major intracellular effector of insulin receptor, blocked the beneficial effects of intranasal insulin on anesthesia-induced apoptosis. Consistent with this finding, mice lacking mTORC1 downstream translational repressor 4E-BP2 showed no induction of repeated anesthesia-induced apoptosis. Our study demonstrates that intranasal insulin prevents general anesthesia-induced apoptosis of hippocampal cells, and deficits in synaptic plasticity and memory, and suggests that the rescue effect is mediated via mTORC1/4E-BP2 signaling.

scholarly journals Gambogic acid protects LPS-induced apoptosis and inflammation in a cell model of neonatal pneumonia through the regulation of TrkA/Akt signaling pathway

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xu Gao ◽  
Jingya Dai ◽  
Guifang Li ◽  
Xinya Dai
Keyword(s):  
Western Blot ◽  
Signaling Pathway ◽  
Cell Model ◽  
Akt Signaling ◽  
Gambogic Acid ◽  
Akt Signaling Pathway ◽  
Western Blot Assay ◽  
A Cell ◽  
Induced Apoptosis ◽  
Apoptosis And Inflammation

Abstract Objective In this work, we investigated the effects of gambogic acid (GA) on lipopolysaccharide (LPS)-induced apoptosis and inflammation in a cell model of neonatal pneumonia. Method Human WI-38 cells were maintained in vitro and incubated with various concentrations of GA to examine WI-38 survival. GA-preincubated WI-38 cells were then treated with LPS to investigate the protective effects of GA on LPS-induced death, apoptosis and inflammation. Western blot assay was utilized to analyze the effect of GA on tropomyosin receptor kinase A (TrkA) signaling pathway in LPS-treated WI-38 cells. In addition, human AKT serine/threonine kinase 1 (Akt) gene was knocked down in WI-38 cells to further investigate the associated genetic mechanisms of GA in protecting LPS-induced inflammation and apoptosis. Results Pre-incubating WI-38 cells with low and medium concentrations GA protected LPS-induced cell death, apoptosis and inflammatory protein productions of IL-6 and MCP-1. Using western blot assay, it was demonstrated that GA promoted TrkA phosphorylation and Akt activation in LPS-treated WI-38 cells. Knocking down Akt gene in WI-38 cells showed that GA-associated protections against LPS-induced apoptosis and inflammation were significantly reduced. Conclusions GA protected LPS-induced apoptosis and inflammation, possibly through the activations of TrkA and Akt signaling pathway. This work may broaden our understanding on the molecular mechanisms of human neonatal pneumonia.

scholarly journals Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in NRAS-Mutant Melanoma Cell Lines

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2012
Author(s):  
Kathryn M. Appleton ◽  
Charuta C. Palsuledesai ◽  
Sean A. Misek ◽  
Maja Blake ◽  
Joseph Zagorski ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Therapeutic Potential ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Intrinsic Resistance ◽  
Primary Resistance ◽  
Induced Apoptosis ◽  
Melanoma Cell Lines

The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (≈50% BRAFV600 mutations and ≈30% NRAS mutations). While drugs targeting the MAPK pathway have yielded success in BRAFV600 mutant melanoma patients, such therapies have been ineffective in patients with NRAS mutant melanomas in part due to their cytostatic effects and primary resistance. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines. A combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells, which are highly resistant to trametinib. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlight the therapeutic potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas.

MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney

2007 ◽  
Vol 293 (5) ◽  
pp. F1556-F1563 ◽  
Author(s):  
Frank Y. Ma ◽  
Greg H. Tesch ◽  
Richard A. Flavell ◽  
Roger J. Davis ◽  
David J. Nikolic-Paterson
Keyword(s):  
Inflammatory Response ◽  
P38 Mapk ◽  
Renal Injury ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Direct Role ◽  
Mitogen Activated Protein ◽  
Early Inflammatory Response ◽  
Induced Apoptosis

Activation of the p38 mitogen-activated protein kinase (MAPK) pathway induces inflammation, apoptosis, and fibrosis. However, little is known of the contribution of the upstream kinases, MMK3 and MKK6, to activation of the p38 kinase in the kidney and consequent renal injury. This study investigated the contribution of MKK3 to p38 MAPK activation and renal injury in the obstructed kidney. Groups of eight wild-type (WT) or Mkk3−/− mice underwent unilateral ureteric obstruction (UUO) and were killed 3 or 7 days later. Western blotting showed a marked increase in phospho-p38 (p-p38) MAPK in UUO WT kidney. The same trend of increased p-p38 MAPK was seen in the UUO Mkk3−/− kidney, although the actual level of p-p38 MAPK was significantly reduced compared with WT, and this could not be entirely compensated for by the increase in MKK6 expression in the Mkk3−/− kidney. Apoptosis of tubular and interstitial cells in WT UUO mice was reduced by 50% in Mkk3−/− UUO mice. Furthermore, cultured Mkk3−/− tubular epithelial cells showed resistance to H2O2-induced apoptosis, suggesting a direct role for MKK3-p38 signaling in tubular apoptosis. Upregulation of MCP-1 mRNA levels and macrophage infiltration seen on day 3 in WT UUO mice was significantly reduced in Mkk3−/− mice, but this difference was not evident by day 7. The development of renal fibrosis in Mkk3−/− UUO mice was not different from that seen in WT UUO mice. In conclusion, these studies identify discrete roles for MKK3-p38 signaling in renal cell apoptosis and the early inflammatory response in the obstructed kidney.

scholarly journals The ameliorating effect of silymarin against vancomycin-induced apoptosis and inflammation in rat liver

2019 ◽  
Vol 23 (4) ◽  
pp. 719-728
Author(s):  
Sevda GÜZEL ◽  
Zuhal UÇKUN ŞAHİNOĞULLARI ◽  
Necmiye CANACANKATAN ◽  
Şerife Efsun ANTMEN ◽  
Deniz KİBAR
Keyword(s):  
Rat Liver ◽  
Induced Apoptosis ◽  
Apoptosis And Inflammation

Induction of apoptosis by particulate matter: role of TNF-α and MAPK

1998 ◽  
Vol 275 (5) ◽  
pp. L942-L949 ◽  
Author(s):  
Beek Yoke Chin ◽  
Mary E. Choi ◽  
Marie D. Burdick ◽  
Robert M. Strieter ◽  
Terence H. Risby ◽  
...  
Keyword(s):  
Particulate Matter ◽  
Carbon Black ◽  
Mapk Pathway ◽  
Time Dependent ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Dependent Manner ◽  
Mapk Kinase ◽  
Tnf Α ◽  
Induced Apoptosis

Particulate matter (PM) is a major by-product from the combustion of fossil fuels. The biological target of inhaled PM is the pulmonary epithelium and resident macrophages. In this study, we demonstrate that cultured macrophages (RAW 264.7 cells) exposed continously to a well-defined model of PM [benzo[ a]pyrene adsorbed on carbon black (CB+BaP)] exhibit a time-dependent expression and release of the cytokine tumor necrosis factor-α (TNF-α). CB+BaP also evoked programmed cell death or apoptosis in cultured macrophages as assessed by genomic DNA-laddering assays. The CB+BaP-induced apoptosis was inhibited when macrophages were treated with CB+BaP in the presence of a neutralizing antibody to TNF-α, suggesting that TNF-α plays an important role in mediating CB+BaP-induced apoptosis in macrophages. Interestingly, neither untreated carbon black nor benzo[ a]pyrene alone induced apoptosis or caused the release of TNF-α in RAW 264.7 cells. Moreover, we observed that TNF-α activates mitogen-activated protein kinase (MAPK) activity, the extracellular signal-regulated kinases p42/p44, in a time-dependent manner. RAW 264.7 cells treated with PD-098059, a selective inhibitor of MAPK kinase activity, did not exhibit CB+BaP-induced apoptosis and TNF-α secretion. Furthermore, cells treated with the MAPK kinase inhibitor did not undergo TNF-α-induced apoptosis. Taken together, our data suggest that TNF-α mediates PM-induced apoptosis and that the MAPK pathway may play an important role in regulating this pathway.

scholarly journals 1-Cinnamoyltrichilinin from Melia azedarach Causes Apoptosis through the p38 MAPK Pathway in HL-60 Human Leukemia Cells

2020 ◽  
Vol 21 (20) ◽  
pp. 7506
Author(s):  
Hoibin Jeong ◽  
SeonJu Park ◽  
Seo-Young Kim ◽  
Su-Hyeon Cho ◽  
Myeong Seon Jeong ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Leukemia Cells ◽  
Therapeutic Window ◽  
Melia Azedarach ◽  
Human Leukemia ◽  
Dependent Manner ◽  
P38 Inhibitor ◽  
Human Leukemia Cells ◽  
Induced Apoptosis ◽  
P38 Pathway

Acute myeloid leukemia (AML) is an aggressive type of human leukemia with a low survival rate, and its complete remission remains challenging. Although chemotherapy is the first-line treatment of AML, it exerts toxicity in noncancerous cells when used in high doses, thus necessitating the development of novel compounds with a high therapeutic window. This study aimed to investigate the anticancer effects of several compounds derived from the fruits of Melia azedarach (a tree with medicinal properties). Among them, 1-cinnamoyltrichilinin (CT) was found to strongly suppress the viability of HL-60 human leukemia cells. CT treatment induced apoptosis and increased nuclear fragmentation and fractional DNA content in HL-60 cells in a dose-dependent manner. CT induced phosphorylation of p38 mitogen-activated protein kinases (p38), though not of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), and activated Bcl-2 family proteins towards the proapoptosis and cleavage of caspase-3 and poly (ADP-ribose) polymerase. Both CT-mediated apoptosis and apoptotic protein expression were reversed by treatment with the p38 inhibitor, thereby indicating the p38 pathway to be critical in CT-stimulated apoptosis. The results collectively indicated CT to suppress HL-60 survival by activating the p38 pathway and inducing apoptosis, hence being a novel potential therapeutic agent for AML.

scholarly journals Dihydrochalcone Derivative Induces Breast Cancer Cell Apoptosis via Intrinsic, Extrinsic, and ER Stress Pathways but Abolishes EGFR/MAPK Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Wasitta Rachakhom ◽  
Patompong Khaw-on ◽  
Wilart Pompimon ◽  
Ratana Banjerdpongchai
Keyword(s):  
Breast Cancer ◽  
Er Stress ◽  
Cell Lines ◽  
Cell Apoptosis ◽  
Mapk Pathway ◽  
Annexin V ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Induced Apoptosis ◽  
Mcf 7

Dihydrochalcone derivatives are active compounds that have been purified from the Thai medicinal plant Cyathostemma argenteum. The objectives of this study were to investigate the effects of two dihydrochalcone derivatives on human breast cancer MDA-MB-231 and MCF-7 cell proliferation and to study the relevant mechanisms involved. The two dihydrochalcone derivatives are 4′,6′-dihydroxy-2′,4-dimethoxy-5′-(2″-hydroxybenzyl)dihydrochalcone (compound 1) and calomelanone (2′,6′-dihydroxy-4,4′-dimethoxydihydrochalcone, compound 2), both of which induced cytotoxicity toward both cell lines in a dose-dependent manner by using MTT assay. Treatment with both derivatives induced apoptosis as determined by annexin V-FITC/propidium iodide employing flow cytometry. The reduction of mitochondrial transmembrane potential (staining with 3,3′-dihexyloxacarbocyanine iodide, DiOC6, employing a flow cytometer) was established in the compound 1-treated cells. Compound 1 induced caspase-3, caspase-8, and caspase-9 activities in both cell lines, as has been determined by specific colorimetric substrates and a spectrophotometric microplate reader which indicated the involvement of both the extrinsic and intrinsic pathways. Calcium ion levels in mitochondrial and cytosolic compartments increased in compound 1-treated cells as detected by Rhod-2AM and Fluo-3AM intensity, respectively, indicating the involvement of the endoplasmic reticulum (ER) stress pathway. Compound 1 induced cell cycle arrest via enhanced atm and atr expressions and by upregulating proapoptotic proteins, namely, Bim, Bad, and tBid. Moreover, compound 1 significantly inhibited the EGFR/MAPK signaling pathway. In conclusion, compound 1 induced MDA-MB-231 and MCF-7 cell apoptosis via intrinsic, extrinsic, and ER stress pathways, whereas it ameliorated the EGFR/MAPK pathway in the MCF-7 cell line. Consequently, it is believed that compound 1 could be effectively developed for cancer treatments.

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