• Fisheries and Aquatic Sciences
• /
• 제19권9호
• /
• pp.35.1-35.6
• /
• 2016

Gliotoxin has been recognized as an immunosuppressive agent for a long time. Recently, it was reported to have antitumor properties. However, the mechanisms by which it inhibits tumors remain unclear. Here, we showed that gliotoxin isolated from the marine fungus Aspergillus fumigatus inhibited proliferation and induced apoptosis in HT1080 human fibrosarcoma cells. Gliotoxin repressed phosphorylation-dependent degradation of $I{\kappa}B-{\alpha}$, an antagonist of nuclear factor kappa B ($NF-{\kappa}B$), which is a known tumor-promoting factor. This coincided with a decrease in nuclear import of $NF-{\kappa}B$, suggesting its signaling activity was impaired. Moreover, gliotoxin increased intracellular reactive oxygen species (ROS). Since ROS have been known to inhibit $NF-{\kappa}B$, this may also contribute to gliotoxin's antitumorigenic effects. These results suggest that gliotoxin suppressed the activation of $NF-{\kappa}B$ by inhibiting phosphorylation and degradation of $I{\kappa}B-{\alpha}$ and by increasing ROS, which resulted in apoptosis of HT1080 cells. Cumulatively, gliotoxin is a promising candidate antagonist of $NF-{\kappa}B$, and it should be investigated for its possible use as a selective inhibitor of human fibrosarcoma cells.

• 대한한방내과학회지
• /
• 제28권3호
• /
• pp.442-452
• /
• 2007

Objectives : The purpose of this study was to investigate the toll-like receptor (TLR)-4 mediated anti-inflammatory effects of extract from Shigyungbanha-tang (SBT) on the peritoneal macrophage. Methods : To evaluate of TLR-4 mediated inflammatory of SBT. we examined NO and cytokine production in TRL-4 ligand (LPS : lipopolysaccharide) induced macrophages. Furthermore, we examined its molecular mechanism using western blot. Results : Extract from SBT itself does not have any cytotoxic effect in the peritoneal macrophages. Extract from SBT reduced LPS-induced nitric oxide (NO). tumor necrosis factor-alpha ($TNF-{\alpha}$), interleukin (IL)-6 and IL-12 production in peritoneal macrophages. SBT inhibited degradation of inhibitor kappa B-alpha ($I{\kappa}B-{\alpha}$) in the TLR-4 mediated peritoneal macrophages. Conclusions : These results suggest that SBT inhibits NO and cytokines production through inhibiting nuclear factor-kappaB (NF-${\kappa}$B) activation in peritoneal macrophage and that SBT may be beneficial oriental medicine for inflammation.

• Structural Engineering and Mechanics
• /
• 제17권5호
• /
• pp.627-639
• /
• 2004

The objective of this research was to evaluate the performance of metal-plate-connected truss joints subjected to cyclic loading conditions that simulated seismic events in the lives of the joints. We also investigated the duration of load factor for these joints. We tested tension splice joints and heel joints from a standard 9.2-m Fink truss constructed from $38-{\times}89-mm$ Douglas-fir lumber: 10 tension splice joints for static condition and for each of 6 cyclic loading conditions (70 joints total) and 10 heel joints for static condition and for each of 3 cyclic loading conditions (40 joints total). We evaluated results by comparing the strengths of the control group (static) with those of the cyclic loading groups. None of the cyclic loading conditions showed any strength degradation; however, there was significant stiffness degradation for both types of joint. The results of this research show that the current duration of load factor of 1.6 for earthquake loading is adequate for these joints.

• Journal of Microbiology and Biotechnology
• /
• 제32권8호
• /
• pp.982-988
• /
• 2022

Licorice (Glycyrrhiza) has been used as preventive and therapeutic material for hyperpigmentation disorders. Previously, we isolated noble compounds including dehydroglyasperin C (DGC), dehydroglyasperin D (DGD) and isoangustone A (IAA) from licorice hexane/ethanol extracts. However, their anti-melanogenic effects and underlying molecular mechanisms are unknown. The present study compared effects of DGC, DGD and IAA on pigmentation in melan-a melanocytes and human epidermal melanocytes (HEMn). DGD exerted the most excellent anti-melanogenic effect, followed by DGC and IAA at non-cytotoxic concentrations. In addition, DGD significantly inhibited tyrosinase activity in vitro cell-free system and cell system. Western blot result showed that DGD decreased expression of microphthalmia-associated transcription factor (MITF), tyrosinase and tyrosinase-related protein-1 (TRP-1) in melan-a cells and HEMn cells. DGD induced phosphorylation of MITF, ERK and Akt signal pathway promoting MITF degradation system. However, DGD did not influence p38 and cAMP-dependent protein kinase (PKA)/CREB signal pathway in melan-a cells. These result indicated that DGD inhibited melanogenesis not only direct regulation of tyrosinase but also modulating intracellular signaling related with MITF level. Collectively, these results suggested a protective role for DGD against melanogenesis.

• Molecules and Cells
• /
• 제45권12호
• /
• pp.869-876
• /
• 2022

Methylglyoxal (MG) is a dicarbonyl compound formed in cells mainly by the spontaneous degradation of the triose phosphate intermediates of glycolysis. MG is a powerful precursor of advanced glycation end products, which lead to strong dicarbonyl and oxidative stress. Although divergent functions of MG have been observed depending on its concentration, MG is considered to be a potential antitumor factor due to its cytotoxic effects within the oncologic domain. MG detoxification is carried out by the glyoxalase system. Glyoxalase 1 (Glo1), the ubiquitous glutathionedependent enzyme responsible for MG degradation, is considered to be a tumor promoting factor due to it catalyzing the removal of cytotoxic MG. Indeed, various cancer types exhibit increased expression and activity of Glo1 that closely correlate with tumor cell growth and metastasis. Furthermore, mounting evidence suggests that Glo1 contributes to cancer stem cell survival. In this review, we discuss the role of Glo1 in the malignant progression of cancer and its possible use as a promising therapeutic target for tumor therapy. We also summarize therapeutic outcomes of Glo1 inhibitors as prospective treatments for the prevention of cancer.

• Archives of Pharmacal Research
• /
• 제23권4호
• /
• pp.267-282
• /
• 2000

Cytochrome P45O (CYP) 2E1 catalyzes the metabolism of a wide variety of therapeutic agents, procarcinogens, and low molecular weight solvents. CYP2E1-catalyzed metabolism may cause toxicity or DNA damage through the production of toxic metabolites, oxygen radicals, and lipid peroxidation. CYP2E1 also plays a role in the metabolism of endogenous compounds including fatty acids and ketone bodies. The regulation of CYP2E1 expression is complex, and involves transcriptional, post-transcriptional, translational, and post-translational mechanisms. CYP2E1 is transcriptionally activated in the first few hours after birth. Xenobiotic inducers elevate CYP2E1 protein levels through both increased translational efficiency and stabilization of the protein from degradation, which appears to occur primarily through ubiquitination and proteasomal degradation. CYP2E1 mRNA and protein levels are altered in response to pathophysiologic conditions by hormones including insulin, glucagon, growth hormone, and leptin, and growth factors including epidermal growth factor and hepatocyte growth factor, providing evidence that CYP2E1 expression is under tight homeostatic control.

• Archives of Pharmacal Research
• /
• 제26권7호
• /
• pp.545-553
• /
• 2003

The expression of cyclooxygenase-2 (COX-2) is a characteristic response to inflammation, which can be inhibited with sodium salicylate. IL-1$\beta$ and TNF-$\alpha$ can induce extracellular signal-regulated kinase (ERK), IKK, IkB degradation and NF-$\kappa$B activation. Salicylate inhibited the IL-1$\beta$ and TNF-$\alpha$-induced COX-2 expressions, regulated the activation of ERK, IKK and IkB degradation, and the subsequent activation of NF-$\kappa$B, in neonatal rat ventricular cardiomyocytes. The inhibition of the ERK pathway, with a selective inhibitor, PD098059, blocked the expressions of IL-1$\beta$ and TNF-$\alpha$-induced COX-2 and $PGE_2$ release. The antioxidant, N-acetyl-cysteine, also reduced the glutathione or catalase- attenuated COX-2 expressions in IL-1$\beta$ and TNF-$\alpha$-treated cells. This antioxidant also inhibited the activation of ERK and NF-$\kappa$B in neonatal rat cardiomyocytes. In addition, IL-1$\beta$ and TNF-$\alpha$-stimulated the release of reactive oxygen species (ROS) in the cardiomyocytes. However, salicylate had no inhibitory effect on the release of ROS in the DCFDA assay. The results showed that salicylate inhibited the activation of ERK and IKK, I$\kappa$B degradation and NF-$\kappa$B activation, independently of the release of ROS, which suggested that salicylate exerts its anti-inflammatory action through the inhibition of ERK, IKK, IkB and NF-$\kappa$B, and the resultant COX-2 expression pathway in neonatal rat ventricular cardiomyocytes.

• Nutrition Research and Practice
• /
• 제14권6호
• /
• pp.593-605
• /
• 2020

BACKGROUND/OBJECTIVES: Alzheimer's disease is common age-related neurodegenerative condition characterized by amyloid beta (Aβ) accumulation that leads cognitive impairment. In the present study, we investigated the protective effect of paeoniflorin (PF) against Aβ-induced neuroinflammation and the underlying mechanism in C6 glial cells. MATERIALS/METHODS: C6 glial cells were treated with PF and Aβ_25-35, and cell viability, nitric oxide (NO) production, and pro-inflammatory cytokine release were measured. Furthermore, the mechanism underlying the effect of PF on inflammatory responses and Aβ degradation was determined by Western blot. RESULTS: Aβ_25-35 significantly reduced cell viability, but this reduction was prevented by the pretreatment with PF. In addition, PF significantly inhibited Aβ_25-35-induced NO production in C6 glial cells. The secretion of interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha was also significantly reduced by PF. Further mechanistic studies indicated that PF suppressed the production of these pro-inflammatory cytokines by regulating the nuclear factor-kappa B (NF-κB) pathway. The protein levels of inducible NO synthase and cyclooxygenase-2 were downregulated and phosphorylation of NF-κB was blocked by PF. However, PF elevated the protein expression of inhibitor kappa B-alpha and those of Aβ degrading enzymes, insulin degrading enzyme and neprilysin. CONCLUSIONS: These findings indicate that PF exerts protective effects against Aβ-mediated neuroinflammation by inhibiting NF-κB signaling, and these effects were associated with the enhanced activity of Aβ degradation enzymes.

• Molecules and Cells
• /
• 제43권11호
• /
• pp.935-944
• /
• 2020

Aryl hydrocarbon receptor nuclear translocator (ARNT) plays an essential role in maintaining cellular homeostasis in response to environmental stress. Under conditions of hypoxia or xenobiotic exposure, ARNT regulates the subset of genes involved in adaptive responses, by forming heterodimers with hypoxia-inducible transcription factors (HIF1α and HIF2α) or aryl hydrocarbon receptor (AhR). Here, we have shown that ARNT interacts with DDB1 and CUL4-associated factor 15 (DCAF15), and the aryl sulfonamides, indisulam and E7820, induce its proteasomal degradation through Cullin-RING finger ligase 4 containing DCAF15 (CRL4^DCAF15) E3 ligase. Moreover, the two known neo-substrates of aryl sulfonamide, RNA-binding motif protein 39 (RBM39) and RNA-binding motif protein 23 (RBM23), are not required for ARNT degradation. In line with this finding, aryl sulfonamides inhibited the transcriptional activities of HIFs and AhR associated with ARNT. Our results collectively support novel regulatory roles of aryl sulfonamides in both hypoxic and xenobiotic responses.

• Journal of Applied Biological Chemistry
• /
• 제53권3호
• /
• pp.147-153
• /
• 2010

$\beta$-glycyrrhetinic acid (GA), the active principle of licorice (Glycyrrhiza glabra L.) has been reported to exhibit anti-inflammatory properties in different animal models. In this study, the effects of GA on the production of inflammatory mediators including tumor necrosis factor (TNF)-$\alpha$, interleukin (IL)-6, nitric oxide (NO), and prostaglandin E (pGE)-2 were examined in RAW 264.7 cells in vitro. Furthermore, to elucidate a possible mechanism for the inhibitory effect of GA on the production of TNF-$\alpha$, it was investigated whether the treatment of GA affects the I-${\kappa}B{\alpha}$ degradation and subsequent nuclear translocation of NF-${\kappa}B$. Various inflammatory responses were induced in the culture system by treating with a lipopolysaccharide (LPS). GA showed anti-inflammatory activities in dose-dependant manner with $IC_{50}$ of $5.4{\mu}M$ by inhibiting the production of TNF-$\alpha$ in RAW 264.7 cells. In addition, the treatment of GA blocked both I-${\kappa}B{\alpha}$ degradation and the nuclear translocation of NF-${\kappa}B$ from cytosol to nucleus. However, it did not affect the production of IL-6, NO, and PGE-2, implying the direct blocking of the production of TNF-$\alpha$ resulting from both the I-${\kappa}B{\alpha}$ degradation and the nuclear translocation of NF-${\kappa}B$. This finding might provide the underlying mechanism to explain the reported anti-inflammatory activities of GA in animal models.