shogaol and Inflammation

NLRP3 (Nod-like receptor protein 3) belongs to the NOD-like receptor family, which is activated by pathogen and damage-associated signals to form a multimeric protein complex, known as the NLRP3 inflammasome. NLRP3 inflammasome activation leads to release of proinflammatory cytokines IL-1β and IL-18, thus inducing pyroptosis, a programmed cell death mechanism. Dysregulation of the NLRP3 inflammasome pathway is closely related to the development of many human diseases, such as neuroinflammation, metabolic inflammation, and immune inflammation. Emerging studies have suggested NLRP3 inflammasome as a potential drug-target for inflammatory diseases. Several small molecules have recently been identified to target the NLRP3 inflammasome pathway directly or indirectly and alleviate related disease pathology. This review summarizes recent evolving landscape of small molecule inhibitor development targeting the NLRP3 inflammasome pathway.

Topics: Humans; Inflammasomes; Inflammation; Molecular Structure; NLR Family, Pyrin Domain-Containing 3 Protein; Small Molecule Libraries; Structure-Activity Relationship

The pathogenesis of osteoarthritis implicates a low-grade inflammation associated to the innate immune system activation. Toll like receptor (TLR) stimulation triggers the release of inflammatory mediators, which aggravate osteoarthritis. We studied the preventive effect of 6-shogaol, a potential TLR4 inhibitor, on the treatment of experimental knee osteoarthritis.. Osteoarthritis was induced in C57BL6 mice by surgical section of the medial meniscotibial ligament, which received 6-shogaol for eight weeks. Cartilage damage, inflammatory mediator presence and disease markers were assessed in joint tissues by immunohistochemistry. Computational modelling was used to predict binding modes of 6-shogaol into the TLR4/MD2 receptor and its permeability across cellular membranes. Employing LPS-stimulated chondrocytes and MAPK assay, we elucidated 6-shogaol action mechanisms.. 6-Shogaol treatment prevented articular cartilage lesions, synovitis and the presence of pro-inflammatory mediators, and disease markers in osteoarthritis animals. Molecular modelling studies predicted 6-shogaol interaction with the TLR4/MD-2 heterodimer in an antagonist conformation through its binding into the MD-2 pocket. In cell culture, we confirmed that 6-shogaol reduced LPS-induced TLR4 inflammatory signalling pathways. Besides, MAPK assay demonstrated that 6-shogaol directly inhibits the ERK1/2 phosphorylation activity.. 6-Shogaol evoked a preventive action on cartilage and synovial inflammation in osteoarthritis mice. 6-shogaol effect may take place not only by hindering the interaction between TLR4 ligands and the TLR4/MD-2 complex in chondrocytes, but also through inhibition of ERK phosphorylation, implying a pleiotropic effect on different mediators activated during osteoarthritis, which proposes it as an attractive drug for osteoarthritis treatments.

Topics: Animals; Catechols; Chondrocytes; Inflammation; Inflammation Mediators; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Osteoarthritis, Knee; Toll-Like Receptor 4; Toll-Like Receptors

Cold-heat combination is a common method in the treatment of ulcerative colitis, which is represented by classic drug pair, Coptidis Rhizoma and Zingiberis Rhizoma.The present study explored the synergetic effects of berberine and 6-shogaol, the primary components of Coptidis Rhizoma and Zingiberis Rhizoma, respectively, on intestinal inflammation and intestinal flora in mice with ulcerative colitis to reveal the effect and mechanism of cold-heat combination in the treatment of ulcerative colitis.The ulcerative colitis model was induced by dextran sulfate sodium(DSS) in mice.The model mice were administered with berberine(100 mg·kg~(-1)), 6-shogaol(100 mg·kg~(-1)), and berberine(50 mg·kg~(-1)) combined 6-shogaol(50 mg·kg~(-1)) by gavage, once per day.After 20 days of drug administration, mouse serum, colon tissues, and feces were sampled.Hematoxylin-eosin(HE) staining was used to observe histopathological changes in colon tissues.Alcian blue/periodic acid-Schiff(AB/PAS) staining was used to observe the changes in the mucus layer of colon tissues.Enzyme-linked immunosorbent assay(ELISA) was employed to detect the serum content of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and interleukin-6(IL-6).Immunohistochemical method was adopted to detect the protein expression of macrophage surface markers F4/80, mucin-2, claudin-1, and zonula occludens-1(ZO-1) in colon tissues.High-throughput Meta-amplicon library sequencing was used to detect changes in the intestinal flora of mice.The results indicated that the 6-shogaol group, the berberine group, and the combination group showed significantly relieved intestinal injury, reduced number of F4/80-labeled positive macrophages in colon tissues, increased protein expression of mucin-2, claudin-1, and ZO-1, and decreased serum le-vels of TNF-α, IL-1β, and IL-6.Shannon, Simpson, Chao, and Ace indexes of the intestinal flora of mice in the 6-shogaol group and the combination group significantly increased, and Chao and Ace indexes in the berberine group significantly increased.As revealed by the bioinformatics analysis of intestinal flora sequencing, the relative abundance of Verrucomicrobia at the phylum, class, and order levels decreased significantly in all treatment groups after drug administration, while that of Bacillibacteria gradually increased.In the 6-shogaol group and the combination group, Akkermansia muciniphila completely disappeared, but acid-producing bacillus still existed in large quantities.

Topics: Animals; Berberine; Catechols; Claudin-1; Colitis; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Drugs, Chinese Herbal; Inflammation; Interleukin-6; Mice; Mice, Inbred C57BL; Mucin-2; Tumor Necrosis Factor-alpha

Topics: Adenoma; Animals; Anti-Inflammatory Agents; Antioxidants; Azoxymethane; Colonic Neoplasms; Colorectal Neoplasms; Disease Models, Animal; Inflammation; Male; Mice

The current study investigated the preventive effect of 6-Shogaol on isoproterenol hydrochloride (ISO)-induced myocardial cardiac injury. 6-Shogaol (50 mg/kg b.w.) was administered for 14 days at pretreatment and ISO-induction (85 mg/kg b.w.) for the last two days (13th and 14th days) by subcutaneous injection. Cardiac markers in serum like creatine kinase (CK), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), cardiac troponins T (cTn T) and I (cTn I) increased in ISO-induced rats. Moreover, lipid peroxidative markers like thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides (LOOH) were raised, and the activities/level of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH) were diminished in ISO-treated heart tissue. In addition, inflammatory and nuclear respiratory factor (Nrf)-2 signalling molecules were upregulated in ISO-induced ischemic rats. 6-Shogaol pretreatment decreased the activities of cardiac and lipid peroxidative markers and enhanced the antioxidant status in ISO-induced cardiac injury rats. Further, 6-Shogaol pretreatment inhibited serum inflammatory markers: tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), nuclear factor-kappaB (NF-κB), Nrf-2 molecule and heme oxygenase (HO)-1 in ISO-induced cardial damage rats. We noticed the effect of 6-Shogaol inhibited pro-apoptotic genes like B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Fas, caspase-3, -8, -9, cytochrome C, and inflammatory genes and increased Bcl-2 expression in ISO-treated rats. The cardioprotective activity of 6-Shogaol in rats with ISO-induced myocardial damage may be due to its ability to reduce oxidative stress, inflammation, and apoptosis, perhaps via the Nrf-2/HO-1 signalling pathway.

Topics: Animals; Antioxidants; Apoptosis; Catechols; Creatine Kinase; GA-Binding Protein Transcription Factor; Heart Injuries; Heme Oxygenase-1; Inflammation; Isoproterenol; Lipids; Myocardium; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Rats; Signal Transduction

Disclosure of ultraviolet (UV) radiation is the key feature from environment to cause redness of the skin, inflammation, photoaging and skin cancer. 6-Shogaol, a spicy compound secluded from ginger, which shows anti-inflammatory effects. Present study was demonstrated the role of 6-Shogaol on UVB induced oxidative stress and photoaging signaling in human epidermal keratinocytes (HaCaT cells). In this study, UVB-irratiation (180 mJ/cm

Topics: Apoptosis; bcl-2-Associated X Protein; Catechols; Cell Line; Cyclooxygenase 2; Humans; Inflammation; Keratinocytes; Mitogen-Activated Protein Kinases; NF-E2-Related Factor 2; Nitric Oxide Synthase Type II; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Signal Transduction; Ultraviolet Rays; Zingiber officinale

Nuclear factor-kappaB (NF-κB) and activator protein 1 (AP-1) is a major transcription factor which regulates many biological and pathological processes such as inflammation and cell proliferation, which are major implicates in cancer progression. [6]-Shogaol ([6]-SHO) is a major constituent of ginger, exhibits various biological properties such as anti-oxidants, anti-inflammation and anti-tumor. Recently, we proven that [6]-SHO prevents oral squamous cell carcinoma by activating proapoptotic factors in in vitro and in vivo experimental model. However, the preventive efficacy of [6]-SHO in 7,12-dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch carcinogenesis (HBP) has not been fully elucidated, so far. Hence, we aimed to investigate the effect of [6]-SHO on inflammation and cell proliferation by inhibiting the translocation of NF-κB and AP-1 in DMBA induced HBP carcinogenesis. In this study, we observed upregulation of inflammatory markers (COX-2, iNOS, TNF-α, interleukin-1 and -6), cell proliferative markers (Cyclin D1, PCNA and Ki-67) and aberrant activation of NF-κB, AP-1, IKKβ, c-jun, c-fos and decreased IκB-α in DMBA induced hamsters. Conversely, oral administration of [6]-SHO strongly inhibited constitutive phosphorylation and degradation of IκB and inhibit phosphorylation of c-jun, c-fos, resulting in inhibition of nuclear translocation of NF-κBp65 and AP-1. Thus, inhibition of NF-κB and AP-1 activation by [6]-SHO attenuates inflammation and cell proliferative response in DMBA induced hamsters. Our finding suggested that [6]-SHO is a novel functional agent capable of preventing DMBA induced inflammation and cell proliferation associated tumorigenesis by modulating multiple signalling molecules.

Topics: Animals; Anthracenes; Biomarkers, Tumor; Carcinogenesis; Carcinoma, Squamous Cell; Catechols; Cell Proliferation; Inflammation; Male; Mesocricetus; Mouth Mucosa; Mouth Neoplasms; NF-kappa B; Oncogenes; Signal Transduction; Transcription Factor AP-1; Zingiber officinale

6-Shogaol, a pungent agent isolated from Zingiber officinale Roscoe, has been known to have anti-tumor and anti-inflammatory effects. However, the anti-inflammatory effects and biological mechanism of 6-Shogaol in LPS-activated BV2 microglia remains largely unknown. In this study, we evaluated the anti-inflammatory effects of 6-Shogaol in LPS-activated BV2 microglia. 6-Shogaol was administrated 1 h before LPS treatment. The production of inflammatory mediators were detected by ELISA. The expression of NF-κB and PPAR-γ were detected by western blot analysis. Our results revealed that 6-Shogaol inhibited LPS-induced TNF-α, IL-1β, IL-6, and PGE2 production in a concentration dependent manner. Furthermore, 6-Shogaol inhibited LPS-induced NF-κB activation by inhibiting phosphorylation and nuclear translocation of NF-κB p65. In addition, 6-Shogaol could increase the expression of PPAR-γ. Moreover, inhibition of PPAR-γ by GW9662 could prevent the inhibition of 6-Shogaol on LPS-induced inflammatory mediator production. In conclusion, 6-Shogaol inhibits LPS-induced inflammation by activating PPAR-γ.

Topics: Anilides; Animals; Catechols; Cell Line; Cell Survival; Cytokines; Inflammation; Inflammation Mediators; Lipopolysaccharides; Mice; Microglia; NF-kappa B; PPAR gamma

6-Shogaol can be extracted from ginger and has been shown to exert anti-inflammatory and antioxidant activities, which are potentially relevant to the treatment of central nervous system disorders. Oxidative stress and inflammation are closely associated with ischemic injury and can eventually result in neuronal death. The aim of this study was to evaluate if 6-shogaol exerts neuroprotective activity. To this end, we determined its effects on oxidative stress and inflammation in a mouse model of middle cerebral artery occlusion (MCAO)-induced brain damage. In this model, MCAO was induced in C57BL/6 mice (30-35g, 9 weeks) for 1h, followed by 24h reperfusion. Mice were treated orally with 6-shogaol (0.1ml, 5 or 20mg/kg) once daily for 7 consecutive days prior to MCAO. We found that 6-shogaol significantly reduced neurological deficit scores and the mean infarct area. Moreover, 6-shogaol improved the behavioral deficits in the MCAO group. In addition, 6-shogaol pretreatment dampened MCAO-mediated production of reactive oxygen species and inflammatory cytokines. Mechanistic studies revealed that 6-shogaol inhibits the cysteinyl leukotriene 1 receptor (CysLT1R) and mitogen-activated protein kinase (MAPK) signaling proteins, thus providing a potential pharmacological mechanism for our observations. These results suggest that 6-shogaol can ameliorate the outcomes of MCAO and could thus be used as a potential preventive of stroke.

Topics: Animals; Behavior, Animal; Catechols; Cytokines; Gene Expression Regulation, Enzymologic; Infarction, Middle Cerebral Artery; Inflammation; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Oxidative Stress; Reactive Oxygen Species; Receptors, Leukotriene; Signal Transduction

[6]-Shogaol is a major bioactive component of Zingiber officinale. Although [6]-shogaol has a number of pharmacological activities including antipyretic, analgesic, antitussive and anti-inflammatory effects, the specific mechanisms of its anti-allergic effects have not been studied. In this study, we present the effects of [6]-shogaol on mast cell-mediated allergic reactions in vivo and in vitro. Sprague-Dawley rats received intradermal injections of anti-DNP IgE was injected into dorsal skin sites. After 48 h, [6]-shogaol was administered orally 1 h prior to challenge with DNP-HSA in saline containing 4% Evans blue through the dorsal vein of the penis. In addition, rat peritoneal mast cells (RPMCs) were cultured and purified to investigate histamine release. In vitro, we evaluated the regulatory effects of [6]-shogaol on the level of inflammatory mediators in phorbol 12-myristate 13-acetate plus calcium ionomycin A23187-stimulated human mast cells (HMC-1). [6]-Shogaol reduced the passive cutaneous anaphylaxis reaction compared to the control group, and histamine release decreased significantly following the treatment of RPMCs with [6]-shogaol. In HMC-1 cells, [6]-shogaol inhibited the production of TNF-α, IL-6 and IL-8, as well as the activation of nuclear factor-κB (NF-κB) and phosphorylation of JNK in compound 48/80-induced HMC-1 cells. [6]-shogaol inhibited mast cell-mediated allergic reactions by inhibiting the release of histamine and the production of proinflammatory cytokines with the involvement of regulation of NF-κB and phosphorylation of JNK.

Topics: Animals; Calcimycin; Calcium Ionophores; Carcinogens; Catechols; Cell Line; Cytokines; Histamine Release; Humans; Inflammation; Male; MAP Kinase Kinase 4; Mast Cells; Mutagens; NF-kappa B; Phosphorylation; Rats; Rats, Sprague-Dawley; Tetradecanoylphorbol Acetate

Natural compounds containing vanilloid and Michael acceptor moieties appear to possess anti-cancer and chemopreventive properties. The ginger constituent shogaol represents one such compound. In this study, the anti-cancer potential of a synthetic novel shogaol analog 3-phenyl-3-shogaol (3-Ph-3-SG) was assessed by evaluating its effects on signaling pathways. At non-toxic concentrations, 3-Ph-3-SG suppressed cancer cell invasion in MDA-MB-231 and MCF-7 breast carcinoma cells through inhibition of PMA-activated MMP-9 expression. At similar concentrations, 3-Ph-3-SG reduced expression of the inflammatory mediators nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and prostanglandin-E2 (PGE2) in RAW 264.7 macrophage-like cells. Inhibition of cancer cell invasion and inflammation by 3-Ph-3-SG were mediated through suppression of the nuclear factor-kappaB (NF-κB) signaling pathway. The 3-Ph-3-SG also demonstrated cytoprotective effects by inducing the antioxidant response element (ARE)-driven genes NAD(P)H quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1). Cytoprotection by 3-Ph-3-SG was achieved at least partly through modification of cysteine residues in the E3 ubiquitin ligase substrate adaptor Kelch-like ECH-associated protein 1 (Keap1), which resulted in accumulation of transcription factor NF-E2 p45-related factor 2 (Nrf2). The activities of 3-Ph-3-SG were comparable to those of 6-shogaol, the most abundant naturally-occurring shogaol, and stronger than those of 4-hydroxyl-null deshydroxy-3-phenyl-3-shogaol, which attested the importance of the 4-hydroxy substituent in the vanilloid moiety for bioactivity. In summary, 3-Ph-3-SG is shown to possess activities that modulate stress-associated pathways relevant to multiple steps in carcinogenesis. Therefore, it warrants further investigation of this compound as a promising candidate for use in chemotherapeutic and chemopreventive strategies.

Topics: Animals; Catechols; Cytoprotection; Down-Regulation; HEK293 Cells; Humans; Inflammation; Intracellular Signaling Peptides and Proteins; Kelch-Like ECH-Associated Protein 1; MCF-7 Cells; Mice; Neoplasm Invasiveness; NF-E2-Related Factor 2; NF-kappa B; Plant Extracts; Signal Transduction

Gout is a rheumatic disease that is manifestated by an intense inflammation secondary to monosodium urate crystal deposition in joints. In the present study, we assessed the effect of 6-shogaol (isolated active principle from ginger) on monosodium urate crystal-induced inflammation in mice; an experimental model for gouty arthritis and compared it with that of the non-steroidal anti-inflammatory drug, indomethacin. Paw volume and levels/activities of lysosomal enzymes, lipid peroxidation, anti-oxidant status and inflammatory mediator TNF-alpha were determined in control and monosodium urate crystal-induced mice. The levels of beta-glucuronidase and lactate dehydrogenase were also measured in monosodium urate crystal-incubated polymorphonuclear leucocytes (PMNL) in vitro. The levels of lysosomal enzymes, lipid peroxidation, and inflammatory mediator tumour necrosis factor-alpha and paw volume were increased significantly and the activities of anti-oxidant status were in turn decreased in monosodium urate crystal-induced mice, whereas these changes were reverted to near normal levels upon 6-shogaol administration. In vitro, 6-shogaol reduced the level of beta-glucuronidase and lactate dehydrogenase in monosodium urate crystal-incubated polymorphonuclear leucocytes in concentration dependent manner when compared to control cells. The present results clearly indicated that 6-shogaol exerted a strong anti-inflammatory effect and can be regarded as useful tool for the treatment of acute gouty arthritis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Catechols; Crystallization; Dose-Response Relationship, Drug; Edema; Female; In Vitro Techniques; Indomethacin; Inflammation; Liver; Lysosomes; Male; Mice; Neutrophils; Spleen; Tumor Necrosis Factor-alpha; Uric Acid; Zingiber officinale