2.Nuclear factor kappaB (NF-kappaB) pathway as a therapeutic target in rheumatoid arthritis.
Dae Myung JUE ; Kye Im JEON ; Jae Yeon JEONG
Journal of Korean Medical Science 1999;14(3):231-238
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint swelling and progressive destruction of cartilage and bone. Current RA treatments are largely empirical in origin and their precise mechanism of action is uncertain. Increasing evidence shows that chronic inflammatory diseases such as RA are caused by prolonged production of proinflammatory cytokines including tumor necrosis factor (TNF) and interleukin 1 (IL-1). The nuclear factor kappaB (NF-kappaB) plays an essential role in transcriptional activation of TNF and IL-1. NF-kappaB is induced by many stimuli including TNF and IL-1, forming a positive regulatory cycle that may amplify and maintain RA disease process. NF-kappaB and enzymes involved in its activation can be a target for anti-inflammatory treatment. Aspirin and sodium salicylate inhibit activation of NF-KB by blocking IkappaB kinase, a key enzyme in NF-kappaB activation. Glucocorticoids suppress expression of inflammatory genes by binding glucocorticoid receptor with NF-kappaB, and increasing expression of inhibitory protein of NF-kappaB, IkappaBalpha. Sulfasalazine and gold compounds also inhibit NF-kappaB activation. Continuing advances in our understanding of action mechanism of antirheumatic agents will benefit the future development of RA regimens with greater efficacy and less toxicity.
Animal
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Antirheumatic Agents/therapeutic use*
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Arthritis, Rheumatoid/therapy*
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Arthritis, Rheumatoid/metabolism
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Arthritis, Rheumatoid/immunology
;
Cytokines/immunology
;
Cytokines/genetics
;
Gene Expression Regulation
;
Human
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Macrophages/immunology
;
NF-kappa B/metabolism*
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NF-kappa B/immunology
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NF-kappa B/biosynthesis
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Tumor Necrosis Factor/genetics
3.The protective effect of MG132 on post-ischemia reperfusion injury of rat livers by activation of nuclear factor kappa B.
Shan JIN ; Xi-chun HAN ; Hong ZHANG ; Ning HAN
Chinese Journal of Hepatology 2005;13(10):791-792
Animals
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Female
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Leupeptins
;
therapeutic use
;
Liver
;
blood supply
;
NF-kappa B
;
metabolism
;
Rats
;
Rats, Wistar
;
Reperfusion Injury
;
drug therapy
;
pathology
4.Study on anti-inflammatory active components and mechanism of Corydalis Bungeanae Herba.
Mu-Zi LI ; Hao ZHANG ; Guo-Qian CUI ; Yan XIANG ; Fen-Xia ZHU
China Journal of Chinese Materia Medica 2020;45(11):2586-2594
Corydalis Bungeanae Herba is often used to treat a variety of inflammatory diseases in traditional Chinese medicine. In order to determine its chemical material basis, the components of Corydalis Bungeanae Herba were isolated by automated purification system. Flavonoids and alkaloids were prepared, and all such components were identified by mass spectrometry. The effects of the components on the production of inflammatory mediators and pharmacological mechanisms in the lipopolysaccharide(LPS)-induced RAW264.7 cell inflammation model were examined. Mouse macrophages(RAW264.7) were first treated with LPS. The relationship between cell viability and LPS concentration was observed. Then, the effects of flavonoids components and alkaloid components with different administration concentrations on cell viability were detected to determine the maximum administration concentration. Secondly, 2.5, 5, 10 and 20 μg·mL~(-1) flavonoids components and alkaloid components were added respectively to observe the effects and mechanism of different concentrations of flavonoids components and alkaloid components on LPS-induced inflammation of RAW264.7 macrophages. Griess reagent assay was used to detect NO content in cell supernatant. The inflammatory cytokines(TNF-α, IL-1β and IL-6) in cell supernatant were determined by ELISA method. Western blot method was used to detect the intracellular nuclear factor(NF-κB) IκBα phosphorylation(p-IκBα), p65 phosphorylation(p-p65) and protein expression of TLR4, TLR2. The results showed that the alkaloid components inhibited the production of NO, TNF-α, IL-1β and IL-6 in a dose-dependent mannerin the concentration range of 2.5-20 μg·mL~(-1). In inflammation upstream pathways, the inhibitory effect of the alkaloid components on the TLR2 expression level was weaker than that of TLR4. In inflammation downstream, alkaloid components significantly inhibited phosphorylation of IκBα and p65 in a dose-dependent manner. These data suggested that the alkaloid components were the material basis components of Corydalis Bungeanae Herba, and its anti-inflammatory mechanism might be related to inhibiting the transmission of inflammatory signals in TLRs/NF-κB signaling pathways dominated by TLR4, interfering with the activation of inflammatory genes and inhibiting their over expression, and down-regulating the secretion level of inflammatory factors.
Animals
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Anti-Inflammatory Agents
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therapeutic use
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Corydalis
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Inflammation
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drug therapy
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Lipopolysaccharides
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Mice
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NF-kappa B
;
RAW 264.7 Cells
5.Relation of miR-140 Expression Level with Therapeutic Effect of Decitabine and Its Mechanism.
Pei-Min SHI ; Chun-Mei YE ; Zheng-Dong WU ; Zhi-Chao ZHANG
Journal of Experimental Hematology 2019;27(5):1424-1430
OBJECTIVE:
To investigate the relationship of miR-140 expression level with the therapeutic effect of decitabine, and to explore whether the molecular mechanism is dependent on the regulation of TLR4 expression.
METHODS:
Forty-seven patients with acute myeloid leukaemia (AML) were enrolled in our study and divided into decitabine combination treatment group (22 cases) and traditional treatment group (25 cases). The clinical efficacy was compared between these two groups. Real-time PCR was used to determine the plasma level of miR-140 in AML patients. Decitabine, miR-140 mimic and miR140 inhibitor were used to treat AML HL-60 cells in vitro, the real-time PCR and Western blot were used to detect the expressions of miR-140, TLR4 and NF-κB at both mRNA and protein levels.
RESULTS:
Compared with traditional treatment group, decitabine combination treatment group showed more significant clinical efficacy. Plasma miR-140 level in both 2 treatment groups both decreased, but the plasma miR-140 level was higher in decitabine combination treatment group as compared with traditional treatment group. Experiment in vitro showed that 0.3 μmol/L decitabine significantly inhibited the HL-60 cell proliferation accompanied by up-regulation of miR-140 expression and down-regulation of expression of TLR4 and NF-κB. These effects induced by decitabine were partly reversed by pretreating the cells with 200 nmol/L miR-140 inhibitor.
CONCLUSION
Decitabine-induced up-regulation of miR-140 expression may be related with its chemotherapeutic effects, and miR-140/TLR4/NF-κB pathway may partly mediate the pharmacologic action of decitabine.
Decitabine
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therapeutic use
;
Down-Regulation
;
HL-60 Cells
;
Humans
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Leukemia, Myeloid, Acute
;
drug therapy
;
MicroRNAs
;
NF-kappa B
6.Molecular Mechanisms Underlying Anti-Tumor Promoting Activities of Heat-Processed Panax ginseng C.A. Meyer.
Young Joon SURH ; Hye Kyung NA ; Ji Yoon LEE ; Young Sam KEUM
Journal of Korean Medical Science 2001;16(Suppl):S38-S41
Recently, there have been considerable efforts to search for naturally occurring substances that can inhibit, reverse, or retard the multi-stage carcinogenesis. A wide array of phenolic substances derived from edible and medicinal plants have been reported to possess anticarcinogenic and antimutagenic activities and in many cases, the chemopreventive activities of phytochemicals are associated with their anti-inflammatory and/or antioxidative properties. Panax ginseng C.A. Meyer cultivated in Korea has been widely used in traditional herbal medicine for the treatment of various diseases. Certain fractions or purified ingredients of ginseng have been shown to exert anticarcinogenic and antimutagenic activities. Our previous studies have revealed that the methanol extract of heat-processed Panax ginseng C.A. Meyer attenuates the lipid peroxidation in rat brain homogenates and is also capable of scavenging superoxide generated by xanthine- xanthine oxidase or by 12-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated human promyelocytic leukemia (HL-60) cells. Topical application of the same extract onto shaven backs of female ICR mice also suppressed TPA-induced skin tumor promotion. Likewise, topical application of ginsenoside Rg3, one of the constituents of heat-treated ginseng, significantly inhibited TPA-induced mouse epidermal ornithine decarboxylase activity and skin tumor promotion. Expression of cyclooxygenase-2 (COX-2) in TPA-stimulated mouse skin was markedly suppressed by Rg3 pretreatment. In addition, Rg3 inhibited TPA-stimulated activation of NF-kB and extracellular-regulated protein kinase (ERK), one of the mitogen-activated protein (MAP) kinase in mouse skin and also in cultured human breast epithelial cells (MCF-10A).
Animal
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Antineoplastic Agents, Phytogenic/*therapeutic use
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Antioxidants
;
Heating
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Human
;
Mitogen-Activated Protein Kinases/metabolism
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Molecular Structure
;
NF-kappa B/metabolism
;
*Panax
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Plant Extracts/*therapeutic use
7.An experimental study on the reverse mechanism of PPAR-gamma agonist rosiglitazone in rats with non-alcoholic steatohepatitis.
Cai-yan ZHAO ; Ya-dong WANG ; Jun-ying ZHOU ; Bei JIA ; Jun-feng CUI
Chinese Journal of Hepatology 2007;15(6):450-455
<b>OBJECTIVEb>To investigate the influence and significance of peroxisome proliferator- activated receptor-gamma (PPAR-gamma) agonist rosiglitazone on the expression of I kappa B kinase-beta(IKK-beta) mRNA and protein induced by LPS in Kupffer cells (KCs) cultured in vitro and to investigate the activity of nuclear factor-kappa B (NF-kappa B) together with the expression of cyclooxygenase-2 (COX-2) in livers of rats with non-alcoholic steatohepatitis (NASH).
<b>METHODSb>(1) KCs from healthy Wistar rats were isolated and purified with IV collagenase digestion and gradient centrifugalization, and then were incubated in the presence or absence of LPS (1 microg/ml) together with two different concentrations of rosiglitazone (10 nmol/L and 50 nmol/L). (2) Thirty-eight healthy Wistar rats were randomly divided into a normal blank control group (10 rats) fed with a normal diet and a NASH model group (28 rats) fed with a fat-rich diet (10% lard + 2% cholesterol + 5% corn oil). After the NASH model was established successfully and confirmed by pathological examination of the livers of 4 rats, 24 rats that continued with the high fat-rich diet, were divided into three groups (8 rats in each group): a control group fed normal saline (NS), a lower dose rosiglitazone group (1 mg.kg(-1).d(-1)) and a higher dose rosiglitazone group (4 mg.kg(-1).d(-1)) for 12 weeks. The mRNA expression of IKK-beta in KCs and COX-2 in livers were measured using reverse transcription-polymerase chain reaction (RT-PCR). The IKK-beta protein in KCs and the NF-kappa B activity of hepatic tissues were determined respectively by Western blot and electrophoretic mobility shift assay (EMSA). The concentration of tumor necrosis factor alpha (TNF alpha) in the supernatant of KCs cultures and serum of the rats was quantified by enzyme linked immunosorbent assay (ELISA).
<b>RESULTSb>LPS significantly increased the expression of IKK-beta mRNA and protein in the KCs and the concentration of TNF alpha in the supernatant of the KCs cultures. The expressions of COX-2 mRNA and protein were more obvious in rats with NASH than those in the normal control group, and the binding activity of NF-kB correlated positively with the expression of COX-2 in the livers and the level of serum TNF alpha of model rats as well. Rosiglitazone blocked the expression of IKK-beta mRNA and protein induced by LPS in KCs, and also inhibited NF-kappa B activation and reduced COX-2 expression in the rats.
<b>CONCLUSIONSb>PPAR-gamma specific agonist rosiglitazone can play an anti-inflammatory role by IKK-beta/I kappa B/NF-kappa B/TNF alpha signal ways, and minimize inflammatory reaction at cellular and molecular levels. This may help to provide a new idea for treating NASH effectively.
Animals ; Cyclooxygenase 2 ; metabolism ; Fatty Liver ; drug therapy ; metabolism ; pathology ; Hypoglycemic Agents ; therapeutic use ; I-kappa B Kinase ; metabolism ; Male ; NF-kappa B ; metabolism ; PPAR gamma ; agonists ; Rats ; Rats, Wistar ; Signal Transduction ; Thiazolidinediones ; therapeutic use ; Tumor Necrosis Factor-alpha ; metabolism
8.Research status quo and progression in targeted therapy for advanced gastric cancer.
Rui FENG ; Xiaotian ZHANG ; Sheng YANG
Chinese Journal of Gastrointestinal Surgery 2016;19(10):1191-1196
With the deeper research of the proliferation, invasion and metastasis mechanisms of the gastric cancer, targeted therapy has become a hot spot in this field. The exploration of targeted agents for gastric cancer is mainly concentrated upon the drugs that target human epidermal growth factor receptor (HER) family, the vascular endothelial growth factor (VEGF), the phosphatidylinositol 3-kinase-protein kinase/mammalian target of rapamycin (PI3K/mTOR) and the NF-κB signaling pathways. The targeted drugs relevant to HER family include the Cetuximab, Nimotuzumab, Matuzumab, Panitumumab and Erlotinib which are aimed at HER-1, the Trastuzumab, Pertuzumab and T-DM1 (trastuzumab emtansine) which are aimed at HER-2, and the Lapatinib and Afatinib which are the multi-target agents of HER. The agents which target VEGF signaling pathway include the anti-VEGF monoclonal antibody (Bevacizumab), the anti-VEGFR drugs (Ramucirumab, Apatinib, Sorafenib, Sunitinib and cediranib), and the recombinant fusion protein (Aflibercept). The LY294002, BEZ235 and Everolimus which are aimed at PI3K/mTOR signaling pathway have shown great promise. Bortezomib has been researched more as a new agent which targets NF-κB signaling pathway. Currently, only Trastuzumab, Ramucirumab and Apatinib have been completed the stage 3 clinical trials and succeeded. In future, researches should focus on multi-target agents or applications in combination treatment. This review collects the recent researches and the clinical trials to summarize the current state and progress of research on gastric cancer targeted therapy.
Antibodies, Monoclonal, Humanized
;
therapeutic use
;
Antineoplastic Agents
;
Humans
;
Molecular Targeted Therapy
;
NF-kappa B
;
drug effects
;
physiology
;
Phosphatidylinositol 3-Kinases
;
Stomach Neoplasms
;
therapy
;
Vascular Endothelial Growth Factor A
9.Effects of erythropoietin pretreatment on pro-and anti-inflammatory balance in rats with severe acute pancreatitis.
Jiexing LI ; Yuhong LUO ; Zhendong LI ; Yong LIU ; Zhaoxiang LIU
Journal of Southern Medical University 2012;32(1):93-96
<b>OBJECTIVEb>To evaluate the effect of pretreatment with erythropoietin (EPO) on disordered pro- and anti- inflammatory balance in rats with severe acute pancreatitis (SAP) and explore the underlying mechanisms.
<b>METHODSb>Ninety healthy male SD rats were randomized equally into sham-operated group, SAP group and EPO pretreatment group. SAP model was induced in the latter two groups by retrograde injection of 1 ml/kg 3.5% sodium traurocholate into the biliopancreatic duct. In EPO group, 3000 U/kg EPO (1000 U/ml) was administered intravenously 1 h before SAP, and normal saline was administered in the other two groups. Serum amylase activity, interleukin-10 (IL-10)and IL-18 levels were measured at different time points after the operation. The translocation and activation of nuclear factor-κB (NF-κB) in the pancreatic tissue was detected using immunofluorescence staining, and pancreatic pathologies were evaluated.
<b>RESULTSb>Compared with SAP group, EPO group showed a markedly decreased activation rate of NF-κB after SAP except for 12 h (P<0.05), significantly decreased serum amylase activity at 3, 6, and 12 h (P<0.05) and decreased serum IL-18 levels at 3, 6, 24 h (P<0.05), whereas serum IL-10 underwent no significant changes. The rats in EPO group showed an obviously milder pancreatic pathology than those in SAP group at 6, 12, and 24 h (P<0.05).
<b>CONCLUSIONb>EPO can effectively inhibit NF-κB activation by regulating the inflammatory mediators and restoring the pro-and anti-inflammatory balance to alleviate SAP in rats.
Acute Disease ; Animals ; Cytokines ; metabolism ; Erythropoietin ; therapeutic use ; Interleukin-10 ; metabolism ; Interleukin-18 ; metabolism ; Male ; NF-kappa B ; metabolism ; Pancreatitis ; drug therapy ; Rats ; Rats, Sprague-Dawley