• Biomedical Science Letters
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• v.24 no.4
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• pp.305-310
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• 2018

Microglia are emerging as critical regulators of innate immune responses in AD and other neurodegenerative disorders, highlighting the importance of understanding their molecular and cellular mechanisms. We attempted to determine the role of crosstalk signaling between $IFN-{\gamma}$ and $TGF-{\beta}$ in $A{\beta}$ clearance by microglia cells. We used in vitro and in vivo mouse models that recapitulated acute and chronic aspects of microglial responses to $A{\beta}$ peptides. We showed that crosstalk signaling between $TGF-{\beta}$ and Smad2 was an important mediator of neuro-inflammation. These findings suggest that microglial $TGF-{\beta}$ activity enhances the pathological progression to AD. As $TGF-{\beta}$ displays broad regulatory effects on beneficial microglial functions, the activation of inflammatory crosstalk signaling between $TGF-{\beta}$ and Smad2 may be a promising strategy to restore microglial functions, halt the progression of $A{\beta}$-driven pathology, and prevent AD development.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.8
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• pp.3173-3181
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• 2015

Background: It has been hypothesized that IL-18 (pro-) and IL-10 (anti-) inflammatory genetic variants at -607 C/A-137G/C and -819C/T,-592C/A, respectively, may generate susceptibility and severity risk with various modes of tobacco exposure in prostate carcinoma (PCa) patients. IL-18 is a pro-inflammatory cytokine expressed on various cells including prostate gland elements, and is a key mediator of immune responses with anti-cancerous properties. IL-10 is an anti-inflammatory cytokine that is associated with tumour malignancy which causes immune escape. Materials and Methods: The present study was conducted with 540 subjects, comprising 269 prostate carcinoma patients and 271 controls. Genotyping was performed by PCR-RFLP and confirmed by real time PCR probe-based methods. Results: The findings indicated that the mutant heterozygous and homozygous genotype CC and GC+CC showed significant negative associations (p=0.01, OR=0.21; 95% CI: 0.08-0.51 and p=0.011, OR=0.43; 95% CI: 0.22-0.81, respectively) thus, less chance to be diagnosed as cancer against GG genotype of tobacco smoking patients. In addition, a heterozygous GC genotype at the same locus of IL-18 pro-inflammatory cytokine may aggravate the severity (OR=2.82; 95%CI 1.09-7.29 :p=001) so that patients are more likely to be diagnosed in advanced stage than with the GG wild homozygous genotype. Our results also illustrated that anti-inflammatory cytokine (IL-10) genetic variants, although showing no significant association with susceptibility to cancer of the prostate, may gave profound effects on severity of the disease, as -819 TC (OR=4.60; 95%CI 1.35-15.73), and -592 AC (OR=5.04; 95%CI 1.08-25.43) of IL-10 in tobacco chewers and combined users (both chewers and smokers) respectively, are associated with diagnosis in more advanced stage than with other variants. Conclusions: We conclude that promoter genetic variants of IL-18 and IL-10 with various modes of tobacco exposure may affect not only susceptibility risk but also severity in prostate cancer.

• Journal of Physiology & Pathology in Korean Medicine
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• v.24 no.2
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• pp.310-318
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• 2010

Dioscorea bulbifera is one of the traditional medicinal herb. It commonly used in the treatment of hematemesis, epistaxis, tuberculous cervical lymphadenitis, laryngitis, acute infectious disease in East Asia. In the present study, we have demonstrated the anti-inflammatory effects of Dioscorea bulbifera MeOH extract (DBME) in macrophage cell line. To investigate mechanism of the anti-inflammatory activity, we examined the effects of the lipopolysaccaride (LPS)-induced production of nitric oxide (NO), prostaglandin $E_2$ ($PGE_2$), pro-inflammatory cytokines and expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), p-inhibitory ${\kappa}B{\alpha}$ (p-$I{\kappa}B{\alpha}$), and nuclear factor-${\kappa}B$ (NF-${\kappa}B$) in a murine macrophage cell line RAW 264.7. The RAW 264.7 cells were cultured in DMEM + serum medium for 24 hrs. After serum starvation for 24 hrs, the cells were treated with DBME 0.03, 0.10, 0.30 mg/$m{\ell}$ for 1 h, followed by stimulation with LPS (1 ${\mu}g/m{\ell}$) for activation of immune response. After treatment, cell viability was measured by MTT assay, and NO production was monitored by measuring the nitrite content in culture medium. The protein band of iNOS, COX-2, p-$I{\kappa}B{\alpha}$, and NF-${\kappa}B$ was determined by immunoblot analysis and levels of cytokine were analyzed by sandwich immunoassays. There were three experimental groups: carrageenan, DBME 0.3, 1.0 g/kg. Rats were administrated either carrageenan (40% PEG) or carrageenan + DBME (0.3, 1.0 g/kg body weight) for 4 days (p.o.). To induce acute paw edema, rats were injected 1% carrageenan (100 ${\mu}{\ell}$/rat, dissolved in sterilized saline). The effect of DBME in the carrageenan-induced rat paw edema. As results, DBME has an inhibitory effect on the production of NO, PGE2, TNF-${\alpha}$, IL-$1{\beta}$ and IL-6 and on the expression of iNOS, COX-2, p-$I{\kappa}B{\alpha}$ and translocation of NF-${\kappa}B$ to nuclear from cytosol. In addition, DBME effectively inhibited the increases of paw edema induced by carrageenan treatment in vivo. These results suggest that DBME can inhibit production of pro-inflammatory mediators and might be a useful source for treatment of acute inflammatory disease.

• Journal of Life Science
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• v.33 no.12
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• pp.1062-1073
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• 2023

Although depression is a common psychiatric disorder that negatively affects individuals and societies, its exact pathogenesis is not well understood. Stress is a major risk factor for depression and is known to increase susceptibility by triggering inflammation. Indeed, many preclinical and clinical studies have suggested a strong link between depression and inflammation. Depression is associated with increased levels of pro-inflammatory cytokines, such as interleukin (IL-)1β, IL-6, IL-12, tumor necrosis factor-α, and interferon-γ, and decreased levels of the anti-inflammatory IL-4, IL-10, and transforming growth factor-β. Administering pro-inflammatory cytokines causes depression-like behaviors in rodents. Conversely, administering anti-inflammatory drugs appears to ameliorate depressive symptoms. Although the importance of inflammation as a mediator of depression has been demonstrated, the mechanisms by which inflammation is activated in depression remain unclear. To address this issue, recent studies have focused on the importance of stress-induced sterile inflammation. Sterile inflammation refers to the activation of inflammatory processes due to physical and/or psychological stress in the absence of pathogens. Stress promotes the release of endogenous factors known as damage-associated molecular patterns (DAMPs), thereby triggering sterile inflammation. In turn, DAMPs are recognized by pattern recognition receptors, leading to the production of pro-inflammatory cytokines. Here, we review the role of DAMPs in depression based on preclinical and clinical evidence on the dysregulation of sterile inflammation.

• Journal of the Korean Applied Science and Technology
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• v.40 no.6
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• pp.1278-1288
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• 2023

Hesperidin(HD) is a a potent antioxidant flavonoid found in various plants. In this study, the recovery of cell death, anti-inflammatory, and melanogenesis inhibitory activities of Hesperidin glucoside (HDG), a water-soluble HD, were compared with HD in vitro. HDG was prepared by an enzymatic glycosylation reaction from HD, and the water solubility of HDG was increased by more than 20,000 times compared to HD. Cell toxicity was significantly lower for HDG than HD. Both HD and HDG increase cell viability in UV damaged HaCaT cells. HD and HDG also reduced an inflammatory mediator such as nitric oxide (NO), and pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the cells irradiated with UV, and the reducing effect of HDG was slightly higher than that of HD. In the melanogenesis inhibition assay using the Melanoma B16F10 cells, HDG showed a superior inhibitory activity compared to HD. In conclusion, HDG, a glucosylated product of HD with high water solubility showed more than equal ability of cell recovery and anti-inflammatory potential, and higher melanogenesis inhibition activity compared to HD in vitro.

• The Journal of Korean Medicine
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• v.27 no.1 s.65
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• pp.184-195
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• 2006

Objectives : Betula Platyphylla(BP) is a traditional analgesic, anti-fungal, anti-inflammatory herb used in Chinese 1medicine. However, no information is available to explain its action. In this study. we investigated the anti-inflammatory 1effects of BP to elutidate the molecular pharmacological activity in the ethanol extract of BP(BPE). Methods : We performed WTS assay in lipopolysaccharide (LPS) stimulated RAW264.7 macrophages with BPE. Nitrite was measured by Griess assay, prostaglandin E2 (PGE2) by enzyme-linked immunosorbent assay (ELISA) in LPS induced RAW264.7 macrophages with BPE. Inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) were determined by Western blot. Activation of nuclear factor-kappaB (NF-kB) was measured by electrophoretic mobility shift assay (EMSA). Results : BPE significantly suppressed production of nitric oxide (NO) and PGE2 in LPS-induced RAW264.7 macrophages in a dose-dependent manner. The maximal inhibition rate of NO and PGE2 production by BPE was ca. 88.8% and 93% at the concentration of $100{\mu}g/ml$ (non-cytotoxic concentration), respectively. BPE also decreased iNOS protein and COX-2 protein in LPS-induced RAW264.7 macrophages. EMSA demonstrated that BPE inhibited the DNA binding activity of the NF-kB. Conclusions : These results suggest that BPE inhibits NF-${\kappa}B$-mediated gene expression and downregulates inflammatory mediator production in RAW264.7 macrophages.

• Nutrition Research and Practice
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• v.15 no.6
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• pp.715-731
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• 2021

BACKGROUND/OBJECTIVES: Premenstrual syndrome (PMS) is a disorder characterized by repeated emotional, behavioral, and physical symptoms before menstruation, and the exact cause and mechanism are uncertain. Hyperprolactinemia interferes with the normal production of estrogen and progesterone, leading to PMS symptoms. Thus, we judged that the inhibition of prolactin hypersecretion could mitigate PMS symptoms. MATERIALS/METHODS: Hordeum vulgare L. extract (HVE), Chrysanthemum zawadskii var. latilobum extract (CZE), and Lomens-P0 the mixture of these extracts were tested in subsequent experiments. The effect of extracts on prolactin secretion at the in vitro level was measured in GH3 cells. Nitric oxide and pro-inflammatory mediator expression were measured in RAW 264.7 cells to confirm the anti-inflammatory effect. Also, the hyperprolactinemic Institute for Cancer Research (ICR) mice model was used to measure extract effects on prolactin and hormone secretion and uterine inflammation. RESULTS: Anti-inflammatory effects of and prolactin secretion suppress by HVE and CZE were confirmed through in vitro experiments (P < 0.05). Treatment with Lomens-P0 inhibited prolactin secretion (P < 0.05) and restored normal sex hormone secretion in the hyperprolactinemia mice model. In addition, extracts significantly inhibited the expression of pro-inflammatory biomarkers, including interleukin-1𝛽, and -6, tumor necrosis factor-𝛼, inducible nitric oxide synthase, and cyclooxygenase-2 (P < 0.01). We used high-performance liquid chromatography analyses to identify tricin and chlorogenic acid as the respective components of HVE and CZE that inhibit prolactin secretion. The Lomens-P0, which includes tricin and chlorogenic acid, is expected to be effective in improving PMS symptoms in the human body. CONCLUSIONS: The Lomens-P0 suppressed the prolactin secretion in hyperprolactinemia mice, normalized the sex hormone imbalance, and significantly suppressed the expression of inflammatory markers in uterine tissue. This study suggests that Lomens-P0 may have the potential to prevent or remedy materials to PMS symptoms.

• Journal of Microbiology and Biotechnology
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• v.32 no.4
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• pp.405-418
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• 2022

Simotang oral liquid (SMT) is a traditional Chinese medicine (TCM) consisting of four natural plants and is used to alleviate gastrointestinal side effects after chemotherapy and functional dyspepsia (FD). However, the mechanism by which SMT helps cure these gastrointestinal diseases is still unknown. Here, we discovered that SMT could alleviate gastrointestinal side effects after chemotherapy by altering gut microbiota. C57BL/6J mice were treated with cisplatin (DDP) and SMT, and biological samples were collected. Pathological changes in the small intestine were observed, and the intestinal injury score was assessed. The expression levels of the inflammatory factors IL-1β and IL-6 and the adhesive factors Occludin and ZO-1 in mouse blood or small intestine tissue were also detected. Moreover, the gut microbiota was analyzed by high-throughput sequencing of 16S rRNA amplicons. SMT was found to effectively reduce gastrointestinal mucositis after DDP injection, which lowered inflammation and tightened the intestinal epithelial cells. Gut microbiota analysis showed that the abundance of the anti-inflammatory microbiota was downregulated and that the inflammatory microbiota was upregulated in DDP-treated mice. SMT upregulated anti-inflammatory and anticancer microbiota abundance, while the inflammatory microbiota was downregulated. An antibiotic cocktail (ABX) was also used to delete mice gut microbiota to test the importance of gut microbiota, and we found that SMT could not alleviate gastrointestinal mucositis after DDP injection, showing that gut microbiota might be an important mediator of SMT treatment. Our study provides evidence that SMT might moderate gastrointestinal mucositis after chemotherapy by altering gut microbiota.

• The Korean Journal of Pharmacology
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• v.30 no.2
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• pp.243-254
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• 1994

Inflammatory diseases, allergic and asthmatic disorders are caused by the mediator release from the activation of the phospholipase C (PLC), phospholipase D (PLD), methyltransferase or adenylate cyclase etc. during IgG or IgE cross-linking of high affinity receptors on mast cells or basophil surface. One important enzyme activated after IgG or IgE receptor cross-linking is PLD, the enzyme which converts phosphatidylcholine (PC) to phosphatidic acid (PA). Under the hypothesis that these may be some differences in mediator release according to the difference in PLD activity, we attempted to confirm the ginseng saponin effects on the PLD activity. We examined the PLD activity during the passively sensitized mast cell activation in the presence of single component of ginsenosides $(Rc,\;Rg_1,\;Rg_2,\;Rg_3)$. We also measured the amount of mediators (histamine and leukotrienes) released by stimulating with ovalbumin (OA) or calcium ionophore (CaI), Guinea Pig lung mast cells were purified using enzyme digestion, count current elutriation, and discontinuous Percoll density gradient. In purified mast cells prelabeled with $[^3H]$ arachidonic acid or $[^3H]$ palmitic acid, PLD activity was assessed more directly by the production of labeled PEt by PLD-mediated transphosphatidylation in the presence of ethanol. Histanine release was determined by Spectrophotofluorometry, and leukotrienes by radioimmunoassay. The PLD activity during the passively sensitized mast cell activation is increased up to $3{\sim}5times$. The PLD activity during the passively sensitized mast cell activation in the presence of all ginsenosides is decreased up to $4{\sim}11$ times. $Rg_l\;and\;Rg_2$ ginsenoside pretreatment decreased histamine and leukotrienes by 50% in the OA-induced or by 40% in the Cal-induced mast cell after passively sensitization. Rc pretreatment poorly decreased histamine but leukotrienes decreased by 70% in the OA-induced or by 35% in the Cal-induced mast cell. $Rg_3$ ginsenoside pretreatment increased histamine release without challenging OA or Cal but leukotrienes decreased. These observations indicate that single unit of ginsenosldes may be an important contributor to inhibit the release of histamine and leukotrienes in the guinea pig lung mast cells, that inhibits the PLD-mediated formation of DAG evoked by mast cell activation.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.1
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• pp.119-131
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• 1998

It has been reported that the glycoprotein extracted from Aloe has strong anti-inflammatory response. However, there has been no research report yet about the effect of Aloe on allergic hypersensitivity reactivity. By using guinea pig lung mast cells, this study aimed to examine the effects of Aloe glycoprotein (NY945) on the mediator releases caused by mast cell activation, and also aimed to assess the effects of NY945 on the mechanism of mediator releases in the mast cell activation. We partially purified mast cell from guinea pig lung tissues by using the enzyme digestion, the rough and the discontinuous density percoll gradient method. Mast cells were sensitized with IgG1 (anti-OA) and challenged with ovalbumin. Histamine was assayed by fluorometric analyzer, leukotrienes by radioimmunoassay. The phospholipase D activity was assessed by the production of labeled phosphatidylalcohol. The amount of mass 1, 2-diacylglycerol (DAG) was measured by the $[^3H]DAG$ produced when prelabeled with $[^3H]myristic$ acid. The phospholipid methylation was assessed by measuring the incorporation of the $[^3H]methyl$ moiety into phospholipids of cellular membranes. Pretreatment of NY945 (10 ${\mu}g$) significantly decreased histamine and leukotrienes releases during mast cell activation. The decrease of histamine release was stronger than that of leukotriene during mast cell activation. The phospholipase D activity increased by the mast cell activation was decreased by the dose-dependent manner in the pretreatment of NY945. The amount of DAG produced by PLC activity was decreased by NY945 pretreatment. The amount of mass 1, 2-diacylglycerol produced by activation of mast cells was decreased in the pretreatment of NY945. NY945 pretreatment strongly inhibited the incorporation of the $[^3H]methyl$ moiety into phospholipids. The data suggest that NY945 purified from Aloe inhibits in part an increase of 1, 2-diacylglycerol which is produced by activating mast cells with antigen-antibody reactions, which is mediated via phosphatidylcholine-phospholipase D and phosphatidylinositol-phospholipase C systems, and then followed by the inhibition of histamine release. Furthermore, NY945 reduces the production of phosphatidylcholine by inhibiting the methyltransferase I and II, which decreases the conversion of phosphatidylcholine into arachidonic acid and inhibits the production of leukotrienes.