Anticancer Effects of Helminthostachys zeylanica Ethyl acetate Extracts on Human Gastric Cancer Cells through Downregulation of the TNF-α-activated COX-2-cPLA2-PGE2 Pathway
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ABSTRACT:
SUBMITTER: Tsai M
PROVIDER: S-EPMC8558661 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundInhibition of tumor necrosis factor-α (TNF) signaling is beneficial in the management of ulcerative colitis (UC), but up to one-third of patients do not have a clinical response of relevance to TNF inhibitors during induction therapy (i.e. primary non-responders [PNRs]). Through production of prostaglandins (PGs) and thromboxanes, cyclooxygenase-2 (COX-2) affects inflammation and epithelial regeneration and may in this way be implicated in treatment resistance to TNF inhibitors.MethodsIn this study, COX-2 expression was analyzed in human intestinal biopsies and patient-derived monocytes, and the downstream consequences of COX-2 activity was evaluated by assessing the influence of the down-stream effector, PGE2, on intestinal epithelial stem cell self-renewal and differentiation using primary human intestinal organoids ("mini-guts").FindingsWe found that TNF stimulation induced COX-2 expression in monocytes isolated from responders (Rs), whereas COX-2 expression was constitutively high and non-inducible in monocytes from PNRs. Additionally, PGE2 in combination with proliferative signals transformed human intestinal epithelial cells to a proinflammatory state akin to flaring UC, whereas PGE2 in combination with differentiation signals supported robust mucin induction.InterpretationOur work indicates that COX-2-PGE2 signaling could be a novel target for the management of PNRs to TNF inhibitors. We additionally demonstrate that COX-2-PGE2 signaling has dual functions during tissue repair and normal lineage differentiation, explaining in part the lack of response to TNF inhibitors among PNRs. FUND: This work was funded by grants from the Novo Nordisk Foundation, the Lundbeck Foundation, the Vanderbilt Digestive Disease Research Center, NIH Grants, Aase and Ejnar Danielsen's Foundation and the A.P. Møller Foundation.
| S-EPMC6197735 | biostudies-literature
Project description:Because propolis contains many types of antioxidant compounds such as polyphenols and flavonoids, it can be useful in preventing oxidative damages. Ethyl acetate extracts of propolis from several Algerian regions show high activity by scavenging free radicals, preventing lipid peroxidation and inhibiting myeloperoxidase (MPO). By fractioning and assaying ethyl acetate extracts, it was observed that both polyphenols and flavonoids contribute to these activities. A correlation was observed between the polyphenol content and the MPO inhibition. However, it seems that kaempferol, a flavonoid, contributes mainly to the MPO inhibition. This molecule is in a high amount in the ethyl acetate extract and demonstrates the best efficiency towards the enzyme with an inhibiting concentration at 50% of 4 ± 2 µM.
| S-EPMC3958853 | biostudies-literature
Project description:Cytosolic phospholipase A(2) (cPLA(2)) is the rate-limiting enzyme responsible for the generation of prostaglandins (PGs), which are bioactive lipids that play critical roles in maintaining gastrointestinal (GI) homeostasis. There has been a long-standing association between administration of cyclooxygenase (COX) inhibitors and GI toxicity. GI injury is thought to be induced by suppressed production of GI-protective PGs as well as direct injury to enterocytes. The present study sought to determine how pan-suppression of PG production via a genetic deletion of cPLA(2) impacts the susceptibility to COX inhibitor-induced GI injury. A panel of COX inhibitors including celecoxib, rofecoxib, sulindac, and aspirin were administered via diet to cPLA(2)(-/-) and cPLA(2)(+/+) littermates. Administration of celecoxib, rofecoxib, and sulindac, but not aspirin, resulted in acute lethality (within 2 weeks) in cPLA(2)(-/-) mice, but not in wild-type littermates. Histomorphological analysis revealed severe GI damage following celecoxib exposure associated with acute bacteremia and sepsis. Intestinal PG levels were reduced equivalently in both genotypes following celecoxib exposure, indicating that PG production was not likely responsible for the differential sensitivity. Gene expression profiling in the small intestines of mice identified drug-related changes among a panel of genes including those involved in mitochondrial function in cPLA(2)(-/-) mice. Further analysis of enterocytic mitochondria showed abnormal morphology as well as impaired ATP production in the intestines from celecoxib-exposed cPLA(2)(-/-) mice. Our data demonstrate that cPLA(2) appears to be an important component in conferring protection against COX inhibitor-induced enteropathy, which may be mediated through affects on enterocytic mitochondria.
| S-EPMC2923287 | biostudies-literature
Project description:BackgroundTriggering receptor expressed on myeloid cells-1 (TREM-1) is inducible on monocyte/macrophages and neutrophils and amplifies the inflammatory response. The aim of this study was to determine whether rheumatoid arthritis synovial fibroblasts (RASF) promote the expression of TREM-1 in monocytes and its potential regulatory mechanism.MethodsSynovial fluid and paired peripheral blood from rheumatoid arthritis (RA) patients were analyzed using flow cytometry. Expression of TREM-1 in monocytes was detected after co-culture with RASF, with or without pre-treatment with toll-like receptor (TLR) ligands. Whether RASF-regulated TREM-1 level in monocytes require direct cell contact or soluble factors was evaluated by transwell experiment. COX-2 expression and PGE2 secretion in RASF were determined by quantitative PCR (qPCR) and ELISA. RASF, with and without TLR ligand stimulation, were treated with COX-2 inhibitors, COX-2 siRNA (siCOX-2) or EP1-4 antagonists, and the resulting TREM-1 level in CD14+ monocytes was measured using flow cytometry.ResultsTREM-1 was highly expressed in CD14+ cells from peripheral blood and especially synovial fluid from RA patients. The expression of TREM-1 in monocytes was increased by co-culture with RASF. TLR-ligand-activated RASF further elevated TREM-1 level. Transwell assay indicated that soluble factors played a key role in RASF-promoted expression of TREM-1 in monocytes. RASF, with or without stimulation by TLR ligands, increased secretion of PGE2 in a cyclooxygenase (COX)-2-dependent manner. PGE2 enhanced the increase in TREM-1 level in monocytes. Finally, studies using COX-2 inhibitors, COX-2 siRNA (siCOX-2) and EP1-4 antagonists, showed that RASF promotion of TREM-1 expression in monocytes was mediated by COX-2/PGE2/EP2,4 signaling.ConclusionsOur data is the first report to reveal the critical role of RASF in upregulating TREM-1 expression in monocytes, which indicates that TREM-1 might be a novel target for RA therapy.
| S-EPMC6615166 | biostudies-literature
Project description:Conventional and modern cancer treatment were reported to manifest adverse effects to the patients. More researches were conducted to search for selective cytotoxic agent of plant natural product on cancer cells. The presences of wide range phytochemicals in Quercus infectoria (QI) extract have been implicated with the cytotoxic effect against various types of cancer cell which remain undiscovered. This present study aimed to evaluate cytotoxic effect of QI extracts on selected human cancer cells and then, the most potent extract was further analysed for general phytochemical constituents. QI galls were extracted successively with n-hexane, ethyl acetate and methanol yielded three main extracts; n-hexane (QIH), ethyl acetate (QIEA) and methanol (QIM), respectively. The most potent extract was qualitatively analysed for the present of tannin, alkaloids, glycosides, saponins, terpenoids, flavonoids and phenolic compounds. Next, the extracts were tested to determine the cytotoxic activity against cervical cancer cells (HeLa), breast cancer cells (MDA-MB-231) and liver cancer cells (Hep G2) using MTT assay. Cytotoxic activity of QI extracts against normal fibroblast (L929) cell line was also evaluated to determine the cytoselective property. Meanwhile, DMSO-treated cells served as negative control while cisplatin-treated cells served as positive control. The most potent extract then chosen to be further investigated for DNA fragmentation as hallmark of apoptosis using Hoechst staining. Qualitative phytochemical analysis revealed the presence of tannin, alkaloids, glycosides, saponins, terpenoids, flavonoids and phenolic compounds. QIEA extract exhibited the most potent cytotoxic activity against HeLa cells with (IC50 value = 6.33 ± 0.33 ?g/mL) and showed cytoselective property against L929 cells. DNA fragmentation revealed QIEA induced apoptosis in the treated cells. The richness of phytochemical constituents in QIEA extract might contribute to the potency of cytotoxic activity towards HeLa cells.
| S-EPMC7485533 | biostudies-literature
Project description:In the search for novel potent fungi-derived bioactive compounds for bioinsecticide applications, crude ethyl acetate culture filtrate extracts from 110 mangrove fungal endophytes were screened for their toxicity. Toxicity tests of all extracts against brine shrimp (Artemia salina) larvae were performed. The extracts with the highest toxicity were further examined for insecticidal activity against Spodoptera litura larvae and acetylcholinesterase (AChE) inhibition activity. The results showed that the extracts of five isolates exhibited the highest toxicity to brine shrimp at 50% lethal concentration (LC50) values of 7.45 to 10.24 ppm. These five fungal isolates that obtained from Rhizophora mucronata were identified based on sequence data analysis of the internal transcribed spacer region of rDNA as Aspergillus oryzae (strain BPPTCC 6036), Emericella nidulans (strains BPPTCC 6035 and BPPTCC 6038), A. tamarii (strain BPPTCC 6037), and A. versicolor (strain BPPTCC 6039). The mean percentage of S. litura larval mortality following topical application of the five extracts ranged from 16.7% to 43.3%. In the AChE inhibition assay, the inhibition rates of the five extracts ranged from 40.7% to 48.9%, while eserine (positive control) had an inhibition rate of 96.8%, at a concentration of 100 ppm. The extracts used were crude extracts, so their potential as sources of AChE inhibition compounds makes them likely candidates as neurotoxins. The high-performance liquid chromatography profiles of the five extracts differed, indicating variations in their chemical constituents. This study highlights the potential of culture filtrate ethyl acetate extracts of mangrove fungal endophytes as a source of new potential bioactive compounds for bioinsecticide applications.
| S-EPMC4505002 | biostudies-literature
Project description:Toll-like receptors (TLRs) can be expressed by tumor cells, and each TLR exhibits different biological functions. Evidences showed the activation of some certain TLRs could promote tumor progression. One of which TLR4 has been found to promote hepatocellular carcinoma (HCC) cells proliferation, but the detailed mechanism is still unknown. In the present study, we verified that TLR4 was functionally expressed on HCC cells, and TLR4 agonist lipopolysaccharide (LPS) could stimulate the proliferation and clone formation of HCC cells. Most importantly, we found a COX-2/PGE2/STAT3 positive feedback loop exists in HCC cells, which could be provoked by TLR4 activation. Consistently, the expression of TLR4, COX-2 and p-STAT3Y705 was positively correlated with each other in liver tumor tissues from patients with primary HCC. Further investigation demonstrated this loop played a dominant role in TLR4-induced HCC cell proliferation and multidrug resistance (MDR) to chemotherapy. Inhibition of TLR4 or COX-2/PGE2/STAT3 loop would attenuate LPS-induced inflammation and proliferation of HCC cells, and enhance the sensitivity of HCC cells to chemotherapeutics in vitro. By using a primary HCC model, we observed COX-2/PGE2/STAT3 loop was significantly blocked in TLR4-/- mice compared to wild type mice, and there was no obvious tumorgenesis sign in TLR4-/- mice. Therefore, these findings provided the precise molecular mechanism of TLR4 signaling pathway involved in HCC progress, and suggested that TLR4 may be a promising target for HCC treatment.
| S-EPMC4801438 | biostudies-literature
Project description:COX-1/PGE2 is an important protective mediator in ulcerative colitis (UC). β-arrestin1 (β-arr1), which acts as a scaffold protein, is involved in PGE2-mediated signaling pathways. However, the interaction between PGE2 and β-arr1 in maintaining mucosal barrier integrity remains unexplored. In this study, we demonstrated that COX-1 and PGE2 were significantly decreased, and EP4 mRNA was downregulated in both UC patients and mice during the injury phase. PGE2 treatment was found to alleviate mucosal injury and induce EP4 expression during dextran sulfate sodium (DSS)-induced colitis in wild-type (WT) mice. Following DSS-induced injury, β-arr1 deficient mice showed increased signs of colitis compared to β-arr1 WT mice, and the expression of PI3K and p-Akt were remarkably downregulated in β-arr1 deficient mice. In parallel, HCT116 cells transfected with β-arr1 siRNA were examined in the presence or absence of PGE2 in vitro. PGE2 treatment in the β-arr1 WT/KO DSS model and β-arr1 siRNA transfection of HCT116 cells confirmed that PGE2 upregulated β-arr1 in vivo and in vitro. Collectively, our results indicate that COX-1/PGE2/EP4 upregulates the β-arr1 mediated Akt signaling pathway to provide mucosal protection in colitis. Thus, these findings provide support for the future development and clinical application of COX-1/PGE2 in UC.
| S-EPMC5430694 | biostudies-literature
Project description:Saururus chinensis is a perennial herb found in the northeastern regions of Asia, including Korea, China, and Japan, and is used in traditional medicine. Studies have identified the four major constituents in Saururus chinensis water extract (LHF618®) as miquelianin (11.75 ± 0.092 mg/g), rutin (1.20 ± 0.008 mg/g), quercitrin (2.38 ± 0.389 mg/g), and quercetin (0.068 ± 0.017 mg/g). Saururus chinensis can improve the symptoms of ovalbumin- or fine dust-induced allergic pulmonary disease by suppressing the effects of WBCs and neutrophils in BALF and IgE in the serum. Saururus chinensis dose-dependently recovered morphological changes such as mucous hyper secretion (from 2.7 ± 0.46 to 0.6 ± 0.65), pulmonary epithelial cell hyperplasia (from 2.4 ± 0.55 to 0.7 ± 0.67), and inflammatory cell infiltration (from 2.3 ± 0.45 to 0.6 ± 0.43), and effectively controlled cDNA levels and protein levels of IL-13. It inhibited NF-κB translocation and COX-2 protein synthesis and suppressed the expression of PGE2. Our results show that Saururus chinensis controlled allergic pulmonary disease via the anti-inflammatory pathways, NF-κB/COX-2 and PGE2. Saururus chinensis may be a promising drug candidate against fine dust-induced allergic pulmonary disease.
| S-EPMC7520084 | biostudies-literature
Project description:Inflammation is a hallmark in severe diseases such as atherosclerosis and non-alcohol-induced steatohepatitis (NASH). In the development of inflammation, prostaglandins, especially prostaglandin E2 (PGE2), are major players alongside with chemo- and cytokines, like tumor-necrosis-factor alpha (TNFα) and interleukin-1 beta (IL-1β). During inflammation, PGE2 synthesis can be increased by the transcriptional induction of the two key enzymes: cyclooxygenase 2 (COX-2), which converts arachidonic acid to PGH2, and microsomal prostaglandin E2 synthase 1 (mPGES-1), which synthesizes PGE2 from PGH2. Both COX-2 and mPGES-2 were induced by a dietary intervention where mice were fed a fatty acid-rich and, more importantly, cholesterol-rich diet, leading to the development of NASH. Since macrophages are the main source of PGE2 synthesis and cholesterol is predominantly transported as LDL, the regulation of COX-2 and mPGES-1 expression by native LDL was analyzed in human macrophage cell lines. THP-1 and U937 monocytes were differentiated into macrophages, through which TNFα and PGE-2 induced COX-2 and mPGES-1 expression by LDL could be analyzed on both mRNA and protein levels. In addition, the interaction of LDL- and EP receptor signal chains in COX-2/mPGES-1 expression and PGE2-synthesis were analyzed in more detail using EP receptor specific agonists. Furthermore, the LDL-mediated signal transduction in THP-1 macrophages was analyzed by measuring ERK and Akt phosphorylation as well as transcriptional regulation of transcription factor Egr-1. COX-2 and mPGES-1 were induced in both THP-1 and U937 macrophages by the combination of TNFα and PGE2. Surprisingly, LDL dose-dependently increased the expression of mPGES-1 but repressed the expression of COX-2 on mRNA and protein levels in both cell lines. The interaction of LDL and PGE2 signal chains in mPGES-1 induction as well as PGE2-synthesis could be mimicked by through simultaneous stimulation with EP2 and EP4 agonists. In THP-1 macrophages, LDL induced Akt-phosphorylation, which could be blocked by a PI3 kinase inhibitor. Alongside blocking Akt-phosphorylation, the PI3K inhibitor inhibited LDL-mediated mPGES-1 induction; however, it did not attenuate the repression of COX-2 expression. LDL repressed basal ERK phosphorylation and expression of downstream transcription factor Egr-1, which might lead to inhibition of COX-2 expression. These findings suggest that simultaneous stimulation with a combination of TNFα, PGE2, and native LDL-activated signal chains in macrophage cell lines leads to maximal mPGES-1 activity, as well repression of COX-2 expression, by activating PI3K as well as repression of ERK/Egr-1 signal chains.
| S-EPMC10188574 | biostudies-literature