Indole-linked 1,2,3-triazole derivatives efficiently modulate COX-2 protein levels in human THP-1 monocytes by suppressing AGE-ROS-NF-kβ nexus

Medicinal plants have been used as alternative therapeutic tools to alleviate inflammatory diseases. The objective of this study was to evaluate anti-inflammatory properties of Kyungheechunggan-tang- (KCT-) 01, KCT-02, and Injinchunggan-tang (IJCGT) as newly developed decoctions containing 3–11 herbs in LPS-induced macrophages. KCT-01 showed the most potent inhibitory effects on LPS-induced NO, PGE2, TNF-α, and IL-6 production among those three herbal formulas. In addition, KCT-01 significantly inhibited LPS-induced iNOS and COX-2 at protein levels and expression of iNOS, COX-2, TNF-α, and IL-6 at mRNA levels. Molecular data revealed that KCT-01 attenuated the activation of JAK/STAT signaling cascade without affecting NF-κB or AP-1 activation. In ear inflammation induced by croton oil, KCT-01 significantly reduced edema, MPO activity, expression levels of iNOS and COX-2, and STAT3 phosphorylation in ear tissues. Taken together, our findings suggest that KCT-01 can downregulate the expression of proinflammatory genes by inhibiting JAK/STAT signaling pathway under inflammatory conditions. This study provides useful data for further exploration and application of KCT-01 as a potential anti-inflammatory medicine.

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Glucagon-Like Peptide-2 Analogue ZP1849 Augments Colonic Anastomotic Wound Healing

Gastroenterology Research and Practice ◽

10.1155/2020/8460508 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Marie Kjaer ◽

Wayne Russell ◽

Peter Schjerling ◽

Elena Cottarelli ◽

Kennet N. Christjansen ◽

...

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Breaking Strength ◽

Target Area ◽

Type I ◽

Mrna Levels ◽

Protein Levels ◽

Soluble Collagen ◽

Cox 2 ◽

Glucagon Like Peptide

Background. The enteroendocrine hormone glucagon-like peptide- (GLP-) 2 is a potent trophic factor in the gastrointestinal tract. The GLP-2 receptor (GLP-2R) is expressed in the stroma of the large bowel wall, which is the major therapeutic target area to prevent anastomotic leakage. We investigated the efficacy of the long-acting GLP-2 analogue ZP1849 on colonic anastomotic wound healing. Methods. Eighty-seven male Wistar rats were stratified into four groups and received daily treatment with vehicle or ZP1849 starting one day before (day -1) end-to-end anastomosis was constructed in the left colon on day 0, and on days 0 (resected colon segment), 3, and 5, gene expressions of GLP-2R, Ki67, insulin-like growth factor- (IGF-) 1, type I (COL1A1) and type III (COL3A1) procollagens, cyclooxygenase- (COX-) 1, COX-2, and matrix metalloproteinase- (MMP-) 7 were quantified by RT-qPCR. Breaking strength, myeloperoxidase (MPO), transforming growth factor- (TGF-) β1, and soluble collagen proteins were measured on days 3 and 5. Results. ZP1849 treatment increased Ki67 (P<0.0001) and IGF-1 (P<0.05) mRNA levels in noninjured colon day 0, and postoperatively in the anastomotic wounds compared to vehicle-treated rats. ZP1849-treated rats had increased (P=0.042) anastomotic breaking strength at day 5 compared with vehicle. COL1A1 and COL3A1 mRNA levels (P<0.0001) and soluble collagen proteins (P<0.05) increased from day 3 to day 5 in ZP1849-treated rats, but not in vehicle-treated rats. COX-2 mRNA and MPO protein levels decreased from day 3 to day 5 (P<0.001) in both groups. ZP1849 treatment reduced TGF-β1 protein levels on day 5 (P<0.001) but did not impact MMP-7 transcription. Conclusions. The GLP-2 analogue ZP1849 increased breaking strength, IGF-1 expression, and cell proliferation, which may be beneficial for colonic anastomotic wound healing.

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Rgx365, a Rare Protopanaxatriol-Type Ginsenoside Fraction from Black Ginseng, Suppresses Inflammatory Gene iNOS via the Iinhibition of p-STAT-1 and NF-κB

The American Journal of Chinese Medicine ◽

10.1142/s0192415x20500536 ◽

2020 ◽

Vol 48 (05) ◽

pp. 1091-1102

Author(s):

So Yeon Jeong ◽

Ji-Eun Kim ◽

Gyu-Yong Song ◽

Jong-Sup Bae

Keyword(s):

Lung Tissue ◽

Lavage Fluid ◽

Heme Oxygenase 1 ◽

Inos Protein ◽

Protein Levels ◽

Rna Transfection ◽

Inos Protein Expression ◽

Black Ginseng ◽

Cox 2 ◽

Human Pulmonary Artery

Black ginseng (BG), which is ginseng that has been steamed and dried nine times, and its main protopanaxatriol-type ginsenosides Rg4, Rg6, Rh4, and Rg2 have been reported to exhibit various forms of biological activity, including antiseptic, antidiabetic, wound-healing, immune-stimulatory, and anti-oxidant activity. The aim of the this study was to examine the effects of [Formula: see text] (a rare protopanaxatriol-type ginsenoside fraction; Rg2, Rg4, Rg6, Rh1, and Rh4) on heme oxygenase-1 (HO-1) induction and on the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-)2 in lipopolysaccharide (LPS)-activated human pulmonary artery endothelial cells (HPAECs). [Formula: see text] was tested to determine its effect on iNOS protein expression and inflammatory markers (interleukin [IL]-1[Formula: see text] and tumor necrosis factor [TNF]-[Formula: see text] in the lung tissue of LPS-treated mice. The results showed that [Formula: see text] induced the expression of HO-1, reduced LPS-activated NF-[Formula: see text]B-luciferase activity, and inhibited iNOS/NO and COX-2/PGE2, which contributed to the inhibition of STAT-1 phosphorylation. In particular, [Formula: see text] induced the translocation of Nrf2 from the cytosol to the nucleus by increasing Nrf2-ARE activity and decreased IL-1[Formula: see text] production in LPS-activated HPAECs. This reduction in iNOS/NO expression due to [Formula: see text] was reversed by siHO-1 RNA transfection. In LPS-treated mice, [Formula: see text] significantly reduced lung tissue iNOS protein levels and TNF-[Formula: see text] levels in the bronchoalveolar lavage fluid. In conclusion, these findings indicate that [Formula: see text] has a critical anti-inflammatory effect due to its ability to regulate iNOS via the inhibition of p-STAT-1 and NF-[Formula: see text]B, and thus it may be suitable for the treatment of inflammatory disease.

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Valproic Acid Impacts the Growth of Growth Plate Chondrocytes

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17103675 ◽

2020 ◽

Vol 17 (10) ◽

pp. 3675

Author(s):

Hueng-Chuen Fan ◽

Shih-Yu Wang ◽

Yi-Jen Peng ◽

Herng-Sheng Lee

Keyword(s):

Valproic Acid ◽

Short Stature ◽

Growth Plate ◽

Caspase 3 ◽

Skeletal Growth ◽

Growth Plate Chondrocytes ◽

Protein Levels ◽

Rat Growth ◽

Cox 2 ◽

Bone Abnormalities

A range of bone abnormalities including short stature have been reported to be associated with the use of antiepileptic drugs (AEDs) in children. Exactly how AEDs impact skeletal growth, however, is not clear. In the present study, rat growth plate chondrocytes were cultured to study the effects of AEDs, including valproic acid (VPA), oxcarbazepine (OXA), levetiracetam (LEV), lamotrigine (LTG), and topiramate (TPM) on the skeletal growth. VPA markedly reduced the number of chondrocytes by apoptosiswhile other AEDs had no effect. The apoptosis associated noncleaved and cleaved caspase 3, and caspases were increased by exposure to VPA, which up-regulated cyclooxygenase 2 (COX-2) mRNA and protein levels likely through histone acetylation. The COX-2 inhibitor NS-398 attenuated the effects of VPA up-regulating COX-2 expression and decreased VPA-induced caspase 3 expression. The use of VPA in children should be closely monitored or replaced, where appropriate, by AEDs which do not apparently affect the growth plate chondrocytes.

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Integrin-mediated Adhesion and Soluble Ligand Binding Stabilize COX-2 Protein Levels in Endothelial Cells by Inducing Expression and Preventing Degradation

Journal of Biological Chemistry ◽

10.1074/jbc.m410006200 ◽

2004 ◽

Vol 280 (2) ◽

pp. 1077-1085 ◽

Cited By ~ 41

Author(s):

Jelena Zaric ◽

Curzio Rüegg

Keyword(s):

Endothelial Cells ◽

Ligand Binding ◽

Protein Levels ◽

Soluble Ligand ◽

Cox 2

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Effect of the Arctic terrestrial plant Ranunculus hyperboreus on LPS-induced inflammatory response via MAPK pathways

Zeitschrift für Naturforschung C ◽

10.1515/znc-2017-0173 ◽

2018 ◽

Vol 73 (7-8) ◽

pp. 273-279 ◽

Cited By ~ 1

Author(s):

Chang-Suk Kong ◽

Jung Im Lee ◽

Fatih Karadeniz ◽

Hojun Kim ◽

Youngwan Seo

Keyword(s):

Inflammatory Response ◽

The Arctic ◽

Mouse Macrophage ◽

Ongoing Research ◽

Protein Levels ◽

Mapk Pathways ◽

Tnf Α ◽

Cox 2 ◽

Bioactive Agents ◽

Pro Inflammatory Cytokines

Abstract The Arctic flora hosts a limited number of species due to its extreme environmental conditions which also yield novel and unique secondary metabolites from withstanding plants. Considering a lack of research on bioactivity potential of Arctic flora, Ranunculus hyperboreus, an Arctic plant, was studied for its anti-inflammatory potential as a part of ongoing research on discovering novel natural bioactive products. Solvent-based fractions (H2O, n-BuOH, 85% aq. MeOH, n-hexane) from R. hyperboreus extract were observed to decrease the elevated nitrate amount during the inflammatory response of lipopolysaccharide-induced mouse macrophage RAW264.7 cells. To some extent, treatment with fractions was able to regulate the expression and protein levels of inflammation-related enzymes, iNOS and COX-2, and pro-inflammatory cytokines, TNF-α, IL-1β, and IL-6. The most active fractions, H2O and 85% aq. MeOH, were suggested to exert their effect through suppressed activation of MAPK pathways, especially JNK. Based on the studies of same species, phenolic glycosides were suggested to be the main active ingredients. To our knowledge, this is the first report of any bioactivity of R. hyperboreus which could be a valuable source of natural bioactive agents against inflammation.

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The Effect of Rice Bran Extract on Arterial Blood Pressure, Hepatic Steatosis, and Inflammation in Mice Fed with a High-Fat Diet

Journal of Nutrition and Metabolism ◽

10.1155/2020/8374287 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Naphatsanan Duansak ◽

Pritsana Piyabhan ◽

Umarat Srisawat ◽

Jarinyaporn Naowaboot ◽

Nusiri Lerdvuthisopon ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Diastolic Blood Pressure ◽

Arterial Blood Pressure ◽

High Fat Diet ◽

High Fat ◽

Protein Levels ◽

Arterial Blood ◽

Cox 2 ◽

And Oxidative Stress

Background. Inflammation and hypertension are primary mechanisms involving in obesity-associated adverse effects of a high-fat diet. The aim of this study was to evaluate the effects of rice bran extract (RBE) on arterial blood pressure, hepatic steatosis, inflammation, and oxidative stress in high-fat diet (HFD)-induced obese mice. Methods. Male ICR mice were divided into four groups, including a normal-diet control group, a high-fat diet (HFD) (60% kcal from fat) group, an HFD group treated with RBE (220 mg/kg/day), and an HFD group treated with 1100 mg/kg/day for eight weeks. Besides body weight and arterial blood pressure, we determined liver values of total cholesterol, triglyceride, as well as percent body fat, tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), nuclear factor kappa-B (NF-κB), matrix metalloprotease-9 (MMP-9), cyclooxygenase-2 (COX-2), and mRNA endothelial nitric oxide synthase (eNOS). Results. The HFD group had increased body weight, increased systolic and diastolic blood pressure, liver total cholesterol, triglyceride, NF-κB, COX-2 and MMP-9 protein levels, and decreased mRNA eNOS in the aorta. Mice of the HFD group receiving RBE had reduced diastolic blood pressure, as well as significantly decreased liver and serum TNF-α and MDA levels in the liver, and reduced NF-κB levels in both the liver and heart. Conclusions. These results demonstrate that RBE decreases diastolic blood pressure, the liver lipid droplet accumulation, liver and myocardial NF-κB, myocardial COX-2 and MMP-9 protein levels, and oxidative stress. Moreover, RBE may improve endothelial function and may alleviate adverse health effects associated with obesity including obesity-associated hypertension.

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Tumor necrosis factor-α stimulates gastric epithelial cell proliferation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00093.2004 ◽

2005 ◽

Vol 288 (1) ◽

pp. G32-G38 ◽

Cited By ~ 20

Author(s):

Jiing Chyuan Luo ◽

Vivian Yvonne Shin ◽

Ying Hua Yang ◽

William Ka Kei Wu ◽

Yi Ni Ye ◽

...

Keyword(s):

Cell Proliferation ◽

Epithelial Cell ◽

Mucosal Injury ◽

Epithelial Cell Line ◽

Epithelial Cell Proliferation ◽

Protein Levels ◽

Tnf Α ◽

Cox 2 ◽

Underlying Mechanisms ◽

Factor Α

TNF-α is a cytokine produced during gastric mucosal injury. We examined whether TNF-α could promote mucosal repair by stimulation of epithelial cell proliferation and explored further the underlying mechanisms in a rat gastric mucosal epithelial cell line (RGM-1). TNF-α treatment (1–10 ng/ml) for 12 or 24 h significantly increased cell proliferation but did not induce apoptosis in RGM-1 cells. TNF-α treatment significantly increased cytosolic phospholipase A2 and cyclooxygenase-2 (COX-2) protein expression and PGE2 level but did not affect the protein levels of EGF, basic fibroblast growth factor, and COX-1 in RGM-1 cells. The mRNA of TNF receptor (TNF-R) 2 but not of TNF-R1 was also increased. Dexamethasone dose dependently inhibited the stimulatory effect of TNF-α on cell proliferation, which was associated with a significant decrease in cellular COX-2 expression and PGE2 level. A selective COX-2 inhibitor 3-(3-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan-2-one (DFU) by itself had no effect on basal cell proliferation but significantly reduced the stimulatory effect of TNF-α on RMG-1 cells. Combination of dexamethasone and DFU did not produce an additive effect. PGE2 significantly reversed the depressive action of dexamethasone on cell proliferation. These results suggest that TNF-α plays a regulatory role in epithelial cell repair in the gastric mucosa via the TNF-α receptor and activation of the arachidonic acid/PG pathway.

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Cyclooxygenase-2 induction by bradykinin in aortic vascular smooth muscle cells

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00349.2005 ◽

2006 ◽

Vol 290 (1) ◽

pp. H30-H36 ◽

Cited By ~ 20

Author(s):

Jorge A. Rodriguez ◽

Paula De la Cerda ◽

Eileen Collyer ◽

Valerie Decap ◽

Carlos P. Vio ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Receptor Antagonist ◽

Vascular Smooth Muscle Cells ◽

Muscle Cells ◽

Receptor Activation ◽

Atheromatous Plaque ◽

Protein Levels ◽

Cox 2

Vascular smooth muscle cell proliferation and migration play an important role in the pathophysiology of several vascular diseases, including atherosclerosis. Prostaglandins that have been implicated in this process are synthesized by two isoforms of cyclooxygenase (COX), with the expression of the regulated COX-2 isoform increased in atherosclerotic plaques. Bradykinin (BK), a vasoactive peptide increased in inflammation, induces the formation of prostaglandins through specific receptor activation. We hypothesized that BK plays an important role in the regulation of COX-2, contributing to the increase in production of prostaglandins in vascular smooth muscle cells. Herein we examined the signaling pathways that participate in the BK regulation of COX-2 protein levels in primary cultured aortic vascular smooth muscle cells. We observed an increase in COX-2 protein levels induced by BK that was maximal at 24 h. This increase was blocked by a B2 kinin receptor antagonist but not a B1 receptor antagonist, suggesting that the B2 receptor is involved in this pathway. In addition, we conclude that the activation of mitogen-activated protein kinases p42/p44, protein kinase C, and nitric oxide synthase is necessary for the increase in COX-2 levels induced by BK because either of the specific inhibitors for these enzymes blocked the effect of BK. Using a similar approach, we further demonstrated that reactive oxygen species and cAMP were not mediators on this pathway. These results suggest that BK activates several intracellular pathways that act in combination to increase COX-2 protein levels. This study suggests a role for BK on the evolution of the atheromatous plaque by virtue of controlling the levels of COX-2.

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Increased cyclooxygenase-2 expression and prostaglandin E2production in pressurized renal medullary interstitial cells

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00544.2009 ◽

2010 ◽

Vol 299 (3) ◽

pp. R823-R831 ◽

Cited By ~ 16

Author(s):

Inge Carlsen ◽

Kaitlin E. Donohue ◽

Anja M. Jensen ◽

Angela L. Selzer ◽

Jie Chen ◽

...

Keyword(s):

Mechanical Stress ◽

Ureteral Obstruction ◽

Interstitial Cells ◽

Inflammatory Stress ◽

Protein Levels ◽

Cox 2 ◽

Cox 1 ◽

Expression And Activity

Renal medullary interstitial cells (RMICs) are subjected to osmotic, inflammatory, and mechanical stress as a result of ureteral obstruction, which may influence the expression and activity of cyclooxygenase type 2 (COX-2). Inflammatory stress strongly induces COX-2 in RMICs. To explore the direct effect of mechanical stress on the expression and activity of COX-2, cultured RMICs were subjected to varying amounts of pressure over time using a novel pressure apparatus. COX-2 mRNA and protein were induced following 60 mmHg pressure for 4 and 6 h, respectively. COX-1 mRNA and protein levels were unchanged. PGE2production in the RMICs was increased when cells were subjected to 60 mmHg pressure for 6 h and was prevented by a selective COX-2 inhibitor. Pharmacological inhibition indicating that pressure-induced COX-2 expression is dependent on p38 MAPK and biochemical knockdown experiments showed that NF-κB might be involved in the COX-2 induction by pressure. Importantly, terminal deoxyneucleotidyl transferase-mediated dUTP nick-end labeling and methylthiazoletetetrazolium assay studies showed that subjecting RMICs to 60 mmHg pressure for 6 h does not affect cell viability, apoptosis, and proliferation. To further examine the regulation of COX-2 in vivo, rats were subjected to unilateral ureteral obstruction (UUO) for 6 and 12 h. COX-2 mRNA and protein level was increased in inner medulla in response to 6- and 12-h UUO. COX-1 mRNA and protein levels were unchanged. These findings suggest that in vitro application of pressure recapitulates the effects on RMICs found after in vivo UUO. This directly implicates pressure as an important regulator of renal COX-2 expression.

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