ginsenoside-m1 and Inflammation

Compound K (CK) is a secondary ginsenoside biotransformed from ginseng. This review discusses the function of CK as a potential ligand of the glucocorticoid receptor and a regulator of macrophage inflammatory responses. We provide findings on the ability of CK to inhibit the activation of M1 macrophages and promote the activation and differentiation of M2 macrophages. In addition, the effect of inhibiting the inflammasome response was collected. We summarized the evidences that CK is effective in the treatment of various inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, dermatitis, asthma, chronic obstructive pulmonary disease, sepsis associated encephalopathy, atherosclerosis, inflammatory bowel disease, and diabetes. These findings suggest the potential of CK as a therapeutic agent that can resolve inflammation and restore homeostasis.

Topics: Adjuvants, Immunologic; Ginsenosides; Humans; Immunologic Factors; Inflammation; Macrophages

Inflammation, an innate immune response mediated by macrophages, has been a hallmark leading to the pathophysiology of diseases. In this study, we examined the inhibitory effects of ginsenoside compound K (CK) on lipopolysaccharide (LPS)-induced inflammation and metabolic alteration in RAW 264.7 macrophages by regulating sirtuin 1 (SIRT1) and histone deacetylase 4 (HDAC4). LPS suppressed SIRT1 while promoting HDAC4 expression, accompanied by increases in cellular reactive oxygen species accumulation and pro-inflammatory gene expression; however, the addition of CK elicited the opposite effects. CK ameliorated the LPS-induced increase in glycolytic genes and abrogated the LPS-altered genes engaged in the NAD+ salvage pathway. LPS decreased basal, maximal, and non-mitochondrial respiration, reducing ATP production and proton leak in macrophages, which were abolished by CK. SIRT1 inhibition augmented

Topics: Humans; Inflammation; Lipopolysaccharides; Macrophages; Sirtuin 1

Ulcerative colitis (UC) has emerged as a global healthcare issue due to high prevalence and unsatisfying therapeutic measures. 20(S)- Protopanaxadiol saponins (PDS) from Panax notoginseng with anti-inflammatory properties is a potential anti-colitis agent. Herein, we explored the effects and mechanisms of PDS administration on experimental murine UC. Dextran sulfate sodium-induced murine UC model was employed to investigate anti-colitis effects of PDS, and associated mechanisms were further verified in HMGB1-exposed THP-1 macrophages. Results indicated that PDS administration exerted ameliorative effects against experimental UC. Moreover, PDS administration remarkably downregulated mRNA expressions and productions of related pro-inflammatory mediators, and reversed elevated expressions of proteins related to NLRP3 inflammasome after colitis induction. Furthermore, administration with PDS also suppressed the expression and translocation of HMGB1, interrupting the downstream TLR4/NF-κB pathway. In vitro, ginsenoside CK and 20(S)-protopanaxadiol, the metabolites of PDS, exhibited greater potential in anti-inflammation, and intervened with the TLR4-binding domain of HMGB1 predictably. Expectedly, ginsenoside CK and 20(S)-protopanaxadiol administrations inhibited the activation of TLR4/NF-κB/NLRP3 inflammasome pathway in HMGB1-exposed THP-1 macrophages. Summarily, PDS administration attenuated inflammatory injury in experimental colitis by blocking the binding of HMGB1 to TLR4, majorly attributed to the antagonistic efficacies of ginsenoside CK and 20(S)-protopanaxadiol.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colitis, Ulcerative; Dextran Sulfate; HMGB1 Protein; Inflammasomes; Inflammation; Mice; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Panax notoginseng; Saponins; Toll-Like Receptor 4

Alzheimer's disease (AD), has caused a mass of disability and mortality in elder populations, which increases global health burden. There are still limited effective disease-modifying drugs. Alleviating microglia-evoked neuroinflammation has become a promising treatment strategy for AD. Ginsenoside Compound K has been demonstrated to exhibit anti-inflammatory and neuroprotective benefits. Here we measured the effects of Ginsenoside Compound K in inhibiting amyloid-induced microglia inflammation and the possible molecular mechanisms and target of action in vitro.. The cytotoxicity of all chemical reagents on BV2 cells were evaluated using the MTT assay. qRT-PCR and ELISA were carried out to detect the inflammatory cytokines levels. Western blot was utilized to determine the effect of Ginsenoside Compound K on the nuclear factor-κB (NF-κB) p65 nuclear translocation. Antagonist Receptor Associated Protein (RAP) was used to verify the engagement of low-density lipoprotein receptor-related protein 1(LRP1).. Ginsenoside Compound K diminished inflammatory cytokine production and reversed NF-κB p65 nuclear translocation induced by Aβ. These observations provide evidence for anti-inflammatory effect of Ginsenoside Compound K through NF-κB pathway via LRP1 activation, and support further evaluation of Ginsenoside Compound K as a potential effective modulator for AD.

Topics: Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Brain; Cell Line; Cell Nucleus; Cell Proliferation; Cell Survival; Cytokines; Ginsenosides; Inflammation; LDL-Receptor Related Protein-Associated Protein; Low Density Lipoprotein Receptor-Related Protein-1; Mice; Microglia; NF-kappa B; Transcription Factor RelA

Topics: Adipose Tissue; Animals; Diet, High-Fat; Ginsenosides; Inflammation; Insulin Resistance; Macrophages; Mice; Mice, Inbred C57BL; Obesity; Phosphatidylinositol 3-Kinases; PPAR gamma

The present study aimed to evaluate the anti-inflammatory and analgesic activities of the ginsenoside metabolite compound K (CK) and its mechanisms.. Mice model of xylene-induced ear swelling and rat model of carrageenan-induced paw swelling were used to evaluate the effect of CK on acute inflammation. The analgesic effect of CK was evaluated on heat-, acetic acid-, and carrageenan-induced hyperalgesia. The levels of prostaglandin E2 (PGE2), cyclooxygenase-1 (COX-1), and COX-2 in carrageenan-induced rat paw swelling and gastric mucosa were detected by enzyme-linked immunosorbent assay (ELISA). COX-1 and COX-2 expressions in carrageenan-induced rat paw swelling and gastric mucosa were detected by western blotting. In vitro effect of CK (10. CK at doses of 7, 14, 28, 56, 112, and 224 mg/kg alleviated xylene-induced ear oedema, whereas CK at 40, 80, and 160 mg/kg alleviated carrageenan-induced paw oedema. CK at 224 mg/kg showed an analgesic effect against acetic acid-induced pain. CK at 40, 80, and 160 mg/kg significantly increased rat inflammatory pain threshold, but had no effect on heat-induced pain threshold. CK at 10, 20, 40, 80, and 160 mg/kg reduced PGE2 level in the paw tissue, but showed no effect on that in the gastric mucosa. CK at 20, 40, 80, and 160 mg/kg decreased COX-2 expression in the paw tissue and gastric mucosa, but exhibited no effect on COX-1 expression or on COX-1 and COX-2 activities.. CK exerted anti-inflammatory and analgesic effects, possibly by reducing the catalytic synthesis of PGE2 via downregulation of COX-2 expression.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Down-Regulation; Edema; Female; Ginsenosides; Hyperalgesia; Inflammation; Male; Mice; Pain; Pain Threshold; Rats; Rats, Sprague-Dawley

Compound K (CK) is one of the major metabolites of ginsenosides exhibiting a variety of pharmacological properties such as anti-ageing, anti-oxidation and anti-inflammatory activities. However, the protective efficacy of CK in abnormal skin conditions with inflammatory responses was not examined. Here, we investigated the effects of CK on matrix metalloproteinase-1 (MMP-1) and type I procollagen production in tumor necrosis factor-α (TNF-α)-stimulated human skin fibroblasts HS68 cells and human skin equivalents. We found that CK suppressed MMP-1 secretion and increased the level of reduced type I procollagen secretion, caused by the inhibition of extracellular signal-regulated kinase (ERK) activation, but not p38 and c-Jun N-terminal kinase (JNK) activation in TNF-α-stimulated HS68 cells. Then, we focused on the involvement of the c-Src and epidermal growth factor receptor (EGFR) as upstream signalling molecules for ERK activation by TNF-α in HS68 cells. CK suppressed the phosphorylation of c-Src/EGFR by TNF-α, which led to the inactivation of downstream signalling molecules including AKT and MEK. In addition, CK suppressed AP-1 (c-jun and c-fos) phosphorylation as downstream transcription factors of active ERK for MMP-1 expression in TNFα-stimulated HS68 cells. These results showed novel mechanisms by which CK inhibits TNF-α-induced MMP-1 expression through the inactivation of c-Src/EGFR-dependent ERK/AP-1 signalling pathway, resulting in the inhibition of collagen degradation in human fibroblast cells. Therefore, CK may be a promising protective agent for the treatment of inflammatory skin conditions such as skin ageing and atopic dermatitis.

Topics: Cell Survival; Cells, Cultured; Collagen; CSK Tyrosine-Protein Kinase; Cytokines; Enzyme-Linked Immunosorbent Assay; ErbB Receptors; Fibroblasts; Ginsenosides; Humans; Inflammation; JNK Mitogen-Activated Protein Kinases; Matrix Metalloproteinase 1; p38 Mitogen-Activated Protein Kinases; Signal Transduction; Skin; Skin Aging; Skin Diseases; src-Family Kinases; Tumor Necrosis Factor-alpha

In the preliminary study, ginsenoside Rb1, a main constituent of the root of Panax ginseng (family Araliaceae), and its metabolite compound K inhibited a key factor of inflammation, nuclear transcription factor κB (NF-κB) activation, in lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages. When ginsenoside Rb1 or compound K were orally administered to 2,4,6-trinitrobenzene sulfuric acid (TNBS)-induced colitic mice, these agents inhibited colon shortening, macroscopic score, and colonic thickening. Furthermore, treatment with ginsenoside Rb1 or compound K at 20mg/kg inhibited colonic myeloperoxidase activity by 84% and 88%, respectively, as compared with TNBS alone (p<0.05), and also potently inhibited the expression of tumor necrosis factor-α, interleukin (IL)-1β and IL-6, but increased the expression of IL-10. Both ginsenoside Rb1 and compound K blocked the TNBS-induced expressions of COX-2 and iNOS and the activation of NF-κB in mice. When ginsenoside Rb1 or compound K was treated in LPS-induced murine peritoneal macrophages, these agents potently inhibited the expression of the proinflammatory cytokines. Ginsenoside Rb1 and compound K also significantly inhibited the activation of interleukin-1 receptor-associated kinase-1 (IRAK-1), IKK-β, NF-κB, and MAP kinases (ERK, JNK, and p-38); however, interaction between LPS and Toll-like receptor-4, IRAK-4 activation and IRAK-2 activation were unaffected. Furthermore, compound K inhibited the production of proinflammatory cytokines more potently than did those of ginsenoside Rb1. On the basis of these findings, ginsenosides, particularly compounds K, could be used to treat inflammatory diseases, such as colitis, by targeting IRAK-1 activation.

Topics: Animals; Colitis; Enzyme Inhibitors; Ginsenosides; Inflammation; Interleukin-1 Receptor-Associated Kinases; Male; Mice; Mice, Inbred ICR; Molecular Structure; Panax; Trinitrobenzenesulfonic Acid

Compound K (C-K; 20-O-D-glucopyranosyl-20(S)-protopanaxadiol) is a functional ligand of the glucocorticoid receptor (GR) and regulates toll-like receptor-4-dependent inflammation. Here, the role of C-K in the regulation of zymosan-mediated inflammation was investigated in murine bone marrow-derived macrophages and the murine macrophage cell line RAW264.7.. The in vitro regulatory effects of C-K on zymosan-induced cytokine production were measured by enzyme-linked immunosorbent assay. Phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38, and p47phox was determined by detection of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase cytosolic subunit by Western blotting. The generation of reactive oxygen species (ROS) was assayed using specific immunofluorescent dyes. NADPH oxidase activities were measured by luminometric analysis. The histopathology of mouse livers and spleens was evaluated immunohistochemically. Dexamethasone, a well-known GR agonist, was used to study the effects of C-K.. Pre-treatment with C-K significantly inhibited zymosan-mediated secretion of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-12 p40, and the activation of ERK1/2 and p38. C-K also markedly suppressed zymosan-mediated superoxide generation, NADPH oxidase activities, and Ser345-p47phox phosphorylation in macrophages. Blockade of Dectin-1 profoundly attenuated the inhibitory effects of C-K in zymosan-induced inflammation and ROS generation by macrophages. The in vivo administration of C-K significantly rescued cells from zymosan-induced lethal shock through inhibition of systemic inflammatory cytokine production.. The ability of C-K to regulate zymosan-induced inflammation through Dectin-1 suggests a novel approach for the control of excessive lethal inflammation.

Topics: Animals; Cell Survival; Cells, Cultured; Cytokines; Dexamethasone; Female; Ginsenosides; Inflammation; Lectins, C-Type; Macrophages; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; NADPH Oxidases; Nerve Tissue Proteins; Reactive Oxygen Species; Receptors, Glucocorticoid; Sepsis; Signal Transduction; Zymosan