Phyllanthin from <i>Phyllanthus amarus</i> inhibits <scp>LPS</scp>‐induced proinflammatory responses in <scp>U937</scp> macrophages via downregulation of <scp>NF‐κB/MAPK/PI3K‐Akt</scp> signaling pathways

Harikrishnan, Hemavathy; Jantan, Ibrahim; Haque, Md. Areeful; Kumolosasi, Endang

doi:10.1002/ptr.6190

Cited by 36 publications

(26 citation statements)

References 36 publications

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“…How LPS-induced pathways react is not fully understood. Previous studies have reported that NF-ĸB/MAPK is very important in the MyD88 signaling pathway induced by LPS (26)(27)(28). The NF-ĸB/MAPK signaling pathway plays important roles in inflammatory responses.…”

Section: Expression Of Proteins Of the Lipopolysaccharide (Lps)-myementioning

confidence: 99%

MyD88 Regulates LPS-induced NF-ĸB/MAPK Cytokines and Promotes Inflammation and Malignancy in Colorectal Cancer Cells

Zhu

Cheng

Lin

et al. 2019

Cancer Genomics Proteomics

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Background/Aim: Inflammation may play a role in cancer initiation and progression. The molecular mechanisms by which inflammation causes colorectal cancer, remains unclear. The present study investigated a signaling pathway that affects inflammation in colorectal cancer. Materials and Methods: SW480 cells, HCT116 cells, and cells with knockdown of myeloid differentiation 88 (MyD88), and forced expression of MyD88 were treated with lipopolysaccharide (LPS; 1 μg/ml). Inflammation-related mRNA expression was analyzed by the quantitative reverse transcription polymerase chain reaction and inflammatory cytokines were detected by western blotting. The enzymelinked immunosorbent assay (ELISA) was used to quantify inflammation-related cytokines in colorectal cancer cells. Cancer cell properties were evaluated using the woundhealing assay, transwell migration assay, transwell invasion assay, colony-formation assay, and CCK-8 assay. Results: LPS up-regulated mRNA and protein levels of inflammatory factors in colorectal cancer cells. Knockdown of MyD88 inhibited LPS-induced mRNA expression and inflammatory protein expression in colorectal cancer cells. Similarly, silencing of MyD88 expression suppressed LPS-induced changes in the biological behavior of colorectal cancer cells. Silencing of MyD88 expression down-regulated expression of proteins of the LPS/nuclear factor kappa-light-chainenhancer of activated B-cells (NF-ĸB)/mitogen-activated protein kinase (MAPK) signaling pathway. Restoration of the expression of MyD88 reversed the effects in LPS-treated HCT116 cells. Conclusion: MyD88-regulated LPS/NF-ĸB/MAPK signaling pathway affects the inflammatory and biological behavior of LPS-induced colorectal cancer cells. Colorectal cancer is the fourth leading cause of cancerrelated death in the world and the fifth in China, with increasing incidence and mortality (1, 2). For more than two centuries, it has been known that inflammation and coexist. Some studies have indicated that inflammation promotes the progression of cancer (3-5). Long-term microbial infection may cause colorectal mucosa metaplasia, atypical hyperplasia and carcinoma in situ, finally leading to colorectal cancer (6, 7). However, the mechanisms by which inflammation promotes cancer progression remain unclear. Lipopolysaccharide (LPS) is present in the cell wall of Gram-negative bacteria (6, 7). Gram-negative bacterial infection leads to release of LPS in colorectal tumors in situ. Previous studies have reported that LPS can promote cell migration, invasion and the epithelial-mesenchymal transition and contribute to the progression of cancer (8-10). LPS may contribute to metastasis by accelerating cell 409 This article is freely accessible online.

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Section: Expression Of Proteins Of the Lipopolysaccharide (Lps)-myementioning

confidence: 99%

MyD88 Regulates LPS-induced NF-ĸB/MAPK Cytokines and Promotes Inflammation and Malignancy in Colorectal Cancer Cells

Zhu

Cheng

Lin

et al. 2019

Cancer Genomics Proteomics

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“…Akt signal transduction pathway was reported to be responsible for the proinflammatory molecules expression through the NF-κB activation in LPS-triggered cell through numerous studies. 29,30) For that reason, inhibition of the Akt phosphorylation has been identified as a primary key to handle inflammatory diseases. Hence, the stimulation of Akt, possibly correlated with NF-κB activation in LPSstimulated cells, could provide the generation of inflammatory signaling molecules.…”

Section: Discussionmentioning

confidence: 99%

ECa 233 Suppresses LPS-Induced Proinflammatory Responses in Macrophages <i>via</i> Suppressing ERK1/2, p38 MAPK and Akt Pathways

Sukketsiri

Tanasawet

Moolsap

et al. 2019

Biological & Pharmaceutical Bulletin

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A current anti-inflammatory agent often targets the prevention of inflammatory disorder development. The standardized Centella asiatica ECa 233 extract has been previously reported for anti-inflammatory effect. This study aimed to investigate its anti-inflammatory effect and mechanisms of ECa 233 in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages, through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, nitric oxide (NO) assay, reactive oxygen species (ROS) production assay, enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Our results found that ECa 233 significantly inhibited LPS-stimulated pro-inflammatory mediators production including ROS, NO and prostaglandin E 2 (PGE 2), and pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-1β without cytotoxicity. In addition, ECa 233 downregulated not only the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), but also the activation of nuclear factor-kappa B (NF-κB), activated protein kinase B (Akt), extracellular signal-regulated kinase (ERK1/2) and p38 mitogenactivated protein kinases (MAPK) induced by LPS. The inhibition of LPS-induced inflammation due to ECa 233 offered an opportunity as a tentatively potential candidate for the prevention and treatment of inflammatory diseases.

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“…The levels of cytokines in LPS-primed cells after treatment with T. crispa extract was investigated by placing 5 × 10 5 cells/mL of differentiated macrophages into 24 well plates supplemented with 4.68 to 75 μg/ mL of T. crispa extract or 0.125 to 2 μg/mL of levamisole (positive control) for 2 h, preceding treatment with LPS (1 μg/mL) for 24 h. DuoSet®ELISA System was employed to analyze the effect of the extract and levamisole on TNF-α and IL-1β synthesis following the manufacturer's directions [11][12][13].…”

Section: Cytokines Immunoassaymentioning

confidence: 99%

“…The extracts were kept at − 70°C until further use. CFX96 Touch Real-Time PCR Detection system, together with SYBR Green RT-PCR Master Mix were utilized for qRT-PCR for mRNA quantification as previously reported [11,12,14].…”

Section: Quantitative Rt-pcr For Determination Of Level Of Relative Gmentioning

confidence: 99%

Standardized ethanol extract of Tinospora crispa upregulates pro-inflammatory mediators release in LPS-primed U937 human macrophages through stimulation of MAPK, NF-κB and PI3K-Akt signaling networks

Haque

Jantan

Harikrishnan

et al. 2020

BMC Complement Med Ther

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Background: Immunomodulatory effects of Tinospora crispa have been investigated due to its traditional use to treat several inflammatory disorders associated to the immune system. The present study reports the underlying mechanisms involved in the stimulation of 80% ethanol extract of T. crispa stems on pro-inflammatory mediators release in lipopolysaccharide (LPS)-primed U937 human macrophages via MyD88-dependent pathways. Methods: Release of interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and production of prostaglandin E 2 (PGE 2) were determined by using enzyme-linked immunosorbent assay (ELISA). Immunoblot technique was executed to determine the activation of MAPKs molecules, NF-κB, PI3K-Akt and cyclooxygenase-2 (COX-2) protein. Determination of pro-inflammatory cytokines and COX-2 relative gene expression levels was by performing the realtime quantitative reverse transcription polymerase chain reaction (qRT-PCR). A reversed-phase HPLC method was developed and validated to standardize the T. crispa extract and chemical profiling of its secondary metabolites was performed by LC-MS/MS. Results: Qualitative and quantitative analyses of chromatographic data indicated that syringin and magnoflorine were found as the major components of the extract. T. crispa-treatment prompted activation of NF-κB by enhancing IKKα/β and NF-κB (p65) phosphorylation, and degradation of IκBα. The extract upregulated COX-2 protein expression, release of pro-inflammatory mediators and MAPKs (ERK, p38 and JNK) phosphorylation as well as Akt dose-dependently. T. crispa extract also upregulated the upstream signaling adaptor molecules, toll-like receptor 4 (TLR4) and MyD88. T. crispa-treatment also upregulated the pro-inflammatory markers mRNA expression. Conclusion: The results suggested that T. crispa extract stimulated the MyD88-dependent signaling pathways by upregulating the various immune inflammatory related parameters.

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Phyllanthin from Phyllanthus amarus inhibits LPS‐induced proinflammatory responses in U937 macrophages via downregulation of NF‐κB/MAPK/PI3K‐Akt signaling pathways

Cited by 36 publications

References 36 publications

MyD88 Regulates LPS-induced NF-ĸB/MAPK Cytokines and Promotes Inflammation and Malignancy in Colorectal Cancer Cells

MyD88 Regulates LPS-induced NF-ĸB/MAPK Cytokines and Promotes Inflammation and Malignancy in Colorectal Cancer Cells

ECa 233 Suppresses LPS-Induced Proinflammatory Responses in Macrophages <i>via</i> Suppressing ERK1/2, p38 MAPK and Akt Pathways

Standardized ethanol extract of Tinospora crispa upregulates pro-inflammatory mediators release in LPS-primed U937 human macrophages through stimulation of MAPK, NF-κB and PI3K-Akt signaling networks

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