• Journal of Life Science
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• v.29 no.11
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• pp.1251-1257
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• 2019

Peptidoglycan (PG) is found in atheromatous lesions of arteries, where monocytes/macrophages express inflammatory cytokines, including tumor necrosis factor-alpha ($TNF-{\alpha}$). This study investigated the effects of PG on $TNF-{\alpha}$ expression and examined possible cellular factors involved in $TNF-{\alpha}$ upregulation. The overall aim was to identify the molecular mechanisms underlying inflammatory responses to bacterial pathogen-associated molecular patterns in the artery. Exposure of human THP-1 monocytic cells to PG enhanced the secretion of $TNF-{\alpha}$ and induced its gene transcription. Inhibition of TLR-2/4 with OxPAPC significantly inhibited $TNF-{\alpha}$ gene expression, whereas inhibition of LPS by polymyxin B did not. The PG-induced expression of $TNF-{\alpha}$ was also significantly suppressed by pharmacological inhibitors that modulate activities of cellular signaling molecules; for example, U0126 (an ERK inhibitor), SB202190 (a p38 MAPK inhibitor), and SP6001250 (a JNK inhibitor) significantly attenuated PG-induced transcription of $TNF-{\alpha}$ and secretion of its gene product. $TNF-{\alpha}$ expression was also inhibited by rapamycin (an mTOR inhibitor), LY294002 (a PI3K inhibitor), and Akt inhibitor IV (an Akt inhibitor). ROS-regulating compounds, like NAC and DPI, also significantly attenuated $TNF{\alpha}$ expression induced by PG. These results suggest that PG induces $TNF-{\alpha}$ expression in monocytes/macrophages by multiple molecules, including TLR-2, PI3K, Akt, mTOR, MAPKs, and ROS.

• Korean Journal of Clinical Pharmacy
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• v.28 no.4
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• pp.333-341
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• 2018

Objective: Tumor necrosis factor-alpha (TNF-alpha) inhibitors are used as a treatment in various immune-mediated inflammatory diseases (IMIDs). Tuberculosis (TB) risk is reported in several meta-analyses in patients treated with TNF-alpha inhibitors. The purpose of this study is to collect, review, and evaluate the TB risk in TNF-alpha inhibitors according to IMIDs indications and between soluble-receptor TNF-alpha inhibitor and monoclonal-antibody TNF-alpha inhibitors. Methods: A systematic literature search on systematic reviews and meta-analyses was performed in PubMed, MEDLINE, Cochrane library, and EMBASE. We identified meta-analyses that evaluated TB infection risk of TNF-alpha inhibitors in IMIDs patients. Results: Thirteen meta-analyses including 41 study results were included in this umbrella review. IMIDs patients treated with TNF-alpha inhibitors had an increased risk of TB than control group (placebo with or without standard therapy patients) (relative risk ratio (RR) 2.057, 95% confidence interval (CI) 1.697 to 2.495). Among them, RA patients with TNF-alpha inhibitors had a higher risk of TB than control group (RR 1.847, 95% CI 1.385 to 2.464), and non-RA patients with TNF-alpha inhibitors had an increased risk of TB (RR 2.236, 95% CI 1.284 to 3.894). In subgroup analysis on TB risk between soluble-receptor TNF-alpha inhibitor and monoclonal-antibody TNF-alpha inhibitors in RA patients, the analysis indicated that monoclonal-antibody TNF-alpha inhibitors had higher risk of TB than soluble-receptor TNF-alpha inhibitor (RR 2.880, 95% CI 1.730 to 4.792). Conclusion: This umbrella review confirms that the risk of TB is significantly increased in TNF-alpha inhibitor treated patients compared to control group.

• Journal of Microbiology and Biotechnology
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• v.30 no.12
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• pp.1810-1818
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• 2020

Inhibitor K562 (IK) protein was first isolated from the culture medium of K562 cells, a leukemia cell line, and is an inhibitory regulator of interferon-γ-induced major histocompatibility complex class II expression. Recently, exogenous truncated IK (tIK) protein showed potential as a therapeutic agent for inflammation-related diseases. In this study, we designed a novel putative anti-inflammatory peptide derived from tIK protein based on homology modeling of the human interleukin-10 (hIL-10) structure, and investigated whether the peptide exerted inhibitory effects against pro-inflammatory cytokines such as IL-17 and tumor necrosis factor-α (TNF-α). The peptide contains key residues involved in binding hIL-10 to the IL-10 receptor, and exerted strong inhibitory effects on IL-17 (43.8%) and TNF-α (50.7%). In addition, we used circular dichroism spectroscopy to confirm that the peptide is usually present in a random coil configuration in aqueous solution. In terms of toxicity, the peptide was found to be biologically safe. The mechanisms by which the short peptide derived from human tIK protein exerts inhibitory effects against IL-17 and TNF-α should be explored further. We also evaluated the feasibility of using this novel peptide in skincare products.

• Journal of Applied Biological Chemistry
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• v.66
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• pp.53-59
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• 2023

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has no effect on normal cells, but selectively can induce apoptosis in tumor cells. Gartanin, a xanthone compound in mangosteen, has been shown to inhibit cancer cell growth by arresting the cell cycle and inducing autophage. In this study, we revealed that gartanin can sensitize TRAIL-induced human liver cancer cell death. We also found that gartanin enhances DR5 expression, a death receptor for TRAIL. This effect appears to be related to CHOP activation associated with the response of endoplasmic reticulum stress. Gartanin treatment also inhibited p62 protein expression and cleaved LC3 to activate autophagy flux, which is related with TRAIL-induced cell death. Pretreatment with autophagy flux inhibitor, LY294002, inhibited gartanin-induced DR5 expression. In summary, our results reveal that the combined treatment of gartanin and TRAIL can be a valuable tool for cancer treatment.

• Advances in Traditional Medicine
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• v.7 no.4
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• pp.341-347
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• 2007

Red seaweed (Callophyllis japonica) has long formed part of the diet of Asians, but the pharmacological properties of this plant have not been evaluated. In this study, we examined the effect of an ethanol extract of C. japonica on the generation of nitric oxide (NO) in RAW 264.7 cells. The C. japonica extract increased the generation of NO and tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$), which were detected by the Griess method and an enzyme-linked immunosorbent assay, respectively. The increased production of NO by C. japonica extract was inhibited by $N^G$-monomethyl-L-arginine ($100{\mu}M$), a specific inhibitor of NO production in the L-arginine-dependent pathway, and by the nuclear $factor-{\kappa}B$ ($NF-{\kappa}B$) inhibitor, pyrrolidine dithiocarbamate ($10-100{\mu}M$) in a dose-dependent manner. These findings demonstrate that C. japonica extract stimulates the production of NO and $TNF-{\alpha}$ in RAW 264.7 cells through the activation of $NF-{\kappa}B$ and that this extract might also inhibit the growth of the human leukemic cells.

• Journal of Life Science
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• v.16 no.7 s.80
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• pp.1207-1213
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• 2006

Tumor necrosis $factor-{\alpha}\;(TNF-{\alpha})$ has been implicated in skeletal diseases by promoting bone loss in inflammatory bone diseases. In the present study, we examined the effects of $TNF-{\alpha}$ on osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). $TNF-{\alpha}$ dose-dependently promoted matrix mineralization of hBMSCs with a maximal stimulation at 2ng/ml. $TNF-{\alpha}$ increased expression of alkaline phosphatase, which plays a crucial role for the matrix deposition. The $TNF-{\alpha}-stimulated$ osteoblastic differentiation was not affected by $NF_kB$ inhibitors, BAY and SN50. However, a JNK-specific inhibitor, SP600125 completely abolished the $TNF-{\alpha}-stimulated$ matrix mineralization and expression of alkaline phosphatase. These results suggest that $TNF-{\alpha}$ enhances osteoblastic differentiation of hBMSCs through JNK-dependent pathway.

• International Journal of Oncology
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• v.54 no.2
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• pp.665-672
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• 2019

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a dynamic cytokine that initiates the apoptosis of cancer cells, but exhibits little or no toxicity in normal cells. Luteolin is a flavonoid compound frequently used in the treatment of cancer. In the current study, we demonstrate that treatment with luteolin and TRAIL exerts a synergistic effect and the mechanisms on TRAIL-resistant Huh7 cells. The results demonstrated that luteolin induced an autophagic flux in human liver cancer cells. The attenuation of the autophagic flux by applying the specific inhibitor of autophagy, chloroquine, significantly suppressed DR5 expression. Treatment with genetically modified autophagy-related 5 siRNA abrogated the luteolin-mediated sensitizing effect of TRAIL. Furthermore, pre-treatment with the c-Jun N-terminal kinase (JNK) inhibitor, SP600125, significantly attenuated the luteolin-induced upregulation of DR5 expression, thereby suggesting that JNK activation promotes DR5 expression. Our findings also revealed that Akt phosphorylation was required for TRAIL sensitization. On the whole, the findings of this study indicated that luteolin effectively enhanced TRAIL-initiated apoptosis, and that these effects were likely to be mediated by autophagy and JNK-mediated DR5 expression.

• The Korean Journal of Physiology and Pharmacology
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• v.7 no.5
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• pp.283-287
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• 2003

While nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) is beneficial for host survival, it is also detrimental to the host. Thus, regulation of iNOS gene expression may be an effective therapeutic strategy for the prevention of unwanted reactions at various pathologic conditions. During the screening process for the possible iNOS regulators, we observed that esculetin is a potent inhibitor of cytokine-induced iNOS expression. The treatment of 3T3-L1 adipocytes with the tumor necrosis factor-${\alpha}$ (TNF) induced iNOS expression, leading to enhanced NO production. TNF-induced NO production was inhibited by esculetin in a dose-dependent manner. Esculetin inhibited the TNF-induced NO production at the transcriptional level through suppression of iNOS mRNA and subsequent iNOS protein expression. These results suggest esculetin, a component of natural products, as a naturally occurring, nontoxic means to attenuate iNOS expression and NO-mediated cytotoxicity.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.2
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• pp.135-143
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• 2018

Tumor necrosis $factor-{\alpha}$ ($TNF{\alpha}$) and the angiotensin system are involved in inflammatory diseases and may contribute to acute kidney injury. We investigated the mechanisms by which $TNF{\alpha}$-converting enzyme (TACE) contributes to lipopolysaccharide (LPS)-induced renal inflammation and the effect of TACE inhibitor treatment on LPS-induced cellular injury in human renal proximal tubule epithelial (HK-2) cells. Mice were treated with LPS (10 mg/kg, i.p.) and HK-2 cells were cultured with or without LPS ($10{\mu}g/ml$) in the presence or absence of a type 1 TACE inhibitor ($1{\mu}M$) or type 2 TACE inhibitor ($10{\mu}M$). LPS treatment induced increased serum creatinine, $TNF{\alpha}$, and urinary neutrophil gelatinase-associated lipocalin. Angiotensin II type 1 receptor, mitogen activated protein kinase (MAPK), and TACE increased, while angiotensin-converting enzyme-2 (ACE2) expression decreased in LPS-induced acute kidney injury and LPS-treated HK-2 cells. LPS induced reactive oxygen species and the down-regulation of ACE2, and these responses were prevented by TACE inhibitors in HK-2 cells. TACE inhibitors increased cell viability in LPS-treated HK-2 cells and attenuated oxidative stress and inflammatory cytokines. Our findings indicate that LPS activates renin angiotensin system components via the activation of TACE. Furthermore, inhibitors of TACE are potential therapeutic agents for kidney injury.

• Korean Journal of Medicinal Crop Science
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• v.16 no.5
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• pp.326-331
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• 2008

To search for immunoactive natural products exerting anti-inflammatory activity, we have evaluated the effects on the water extracts of Artemisia princeps Pampanini (APP) on lipopolysaccharide-induced nitric oxide (NO), tumor necrosis factor-$\alpha$ (TNF-$\alpha$), and prostaglandin $E_2$ ($PGE_2$) production by RAW 264.7 macrophage cell line. Our data indicate that this extract is a potent inhibitor of NO production and it also significantly decreased PGE2 and TNF-$\alpha$ production. Consistent with these results, the protein and mRNA expression level of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) was inhibited by water extracts of APP in a dose-dependent manner. These results suggest that APP may exert anti-inflammatory and analgesic effects possibly by suppressing the inducible NO synthase and COX-2 expressions.