zerumbone and Inflammation

Biological, biochemical and physical stimuli activate inflammatory leukocytes, such as macrophages, resulting in induction and synthesis of proinflammatory proteins and enzymes, together with free radicals, as innate immune responses. On the other hand, chronic and dysregulated activation of some inducible enzymes, including NADPH oxidase (NOX), inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, have been shown to play pivotal roles in the development of certain inflammatory diseases such as oncogenesis. While the use of synthetic agents, especially those targeting molecules, is an attractive and reasonable approach to prevent carcinogenesis, it should be noted that traditional herbs and spices also exist along with their active constituents, which have been demonstrated to disrupt inflammatory signal transduction pathways. In this mini-review, the molecular mechanisms of activation or induction of NOX, iNOS and COX-2, as well as some food phytochemicals with marked potential to regulate those key inflammatory molecules, are highlighted. For example, 1'-acetoxychavicol acetate, which occurs in the rhizomes of the subtropical Zingiberaceae plant, has been shown to attenuate NOX-derived superoxide generation in macrophages, as well as lipopolysaccharide-induced nitric oxide and prostaglandin E(2) production through the suppression of iNOS and COX-2 synthesis, respectively. Notably, this phytochemical has exhibited a wide range of cancer prevention activities in several rodent models of inflammation-associated carcinogenesis. Herein, the cancer preventive potentials of several food phytochemicals targeting the induction of NOX, iNOS and COX-2 are described.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Benzyl Alcohols; Curcumin; Cyclooxygenase 2; Dinoprostone; Enzyme Induction; Enzyme Inhibitors; Food; Humans; Inflammation; Lipopolysaccharides; NADPH Oxidases; Nitric Oxide Synthase Type II; Plant Extracts; Sesquiterpenes; Terpenes

Diabetes mellitus is characterized by hyperglycemia. Low-grade bacterial infection with hyperglycemia in patients with diabetes is associated with atherosclerosis development. Therefore, this study hypothesized that macrophages lead to more severe diabetic complications under combined conditions of high glucose and lipopolysaccharide (LPS)-induced inflammation than under normoglycemic conditions. Zerumbone is the main component of Zingiber zerumbet Smith essential oil, a type of wild ginger. It possesses various biomedical activities, including antibacterial, antioxidant, anti-inflammatory, and anticancer activities; however, the precise mechanism of its anti-inflammatory and epigenetic effects is not fully understood. In this study, the effects of zerumbone on the secretion of proinflammatory cytokines and its underlying regulatory mechanism were investigated in THP-1-derived macrophages exposed to high glucose and LPS. THP-1-derived macrophages were cultured under normoglycemic (5.5 mmol/L glucose) or hyperglycemic (25 mmol/L glucose) conditions in the absence or presence of zerumbone (5-50 μM) for 48 hours and then treated with 100 ng/mL LPS for 6 hours. Zerumbone (25 and 50 μM) suppressed the production of tumor necrosis factor-α and interleukin-6 and the activation of cyclooxygenase-2, nuclear factor-κB, histone deacetylases 3 proteins, and Toll-like receptor messenger RNA (mRNA) and increased the transcription of the sirtuin 1 (SIRT1), SIRT3, and SIRT6 mRNAs. Taken together, our results suggest that zerumbone may exert beneficial effects on diabetes and its complications.

Topics: Glucose; Humans; Inflammation; Lipopolysaccharides; Macrophages; NF-kappa B; Sesquiterpenes; Signal Transduction; Sirtuins

Cross-talk among inflammation and colorectal cancer cells is chiefly reported through a complex of cytokines, chemokines, and growth factors. MicroRNA performs strategic roles in controlling a variety of signaling cascades. miR-34a is known as a master regulator of tumor suppression. Combined application of different miRNA-based agents and chemotherapeutic drugs has been used to augment drug sensitivity and may reinforce the antitumor effect. A lot of studies specify a substantial increase in the effectiveness of combination therapies. The anti-inflammatory activity of Zerumbone (ZER) was investigated in many cancers. In this study the level of the inflammatory cytokines including CXCL-12 (SDF-1), CCL-2 (MCP-1), TGF-β and IL-33 has been measured in pmiR-34a-5p transfected and pmiR-34a-5p +ZER treated CRC cell lines (HCT-116 and SW48) by QRT-PCR and ELISA methods, respectively. The results showed that miR-34a could significantly inhibit cytokine expression in both cell lines for 48 and 72 h except SDF-1 which no inhibition was observed in SW48 cells. ZER suppressed SDF-1 for all three time points in both cell lines, while in SW48 cells IL-33 and TGF-β were inhibited in 72 h and in HCT-116 cells MCP-1 diminished for only 24 h and TGF-β diminished for all three times. Combination of both miR-34a and ZER suppressed TGF-β, SDF-1 and MCP-1 in HCT-116 cells in all time points while in SW48 cells, suppression of most cytokines was observed in 48 and 72 h. Furthermore Colony formation assay and scratch test were employed to detect changes of proliferation and migration in CRC transfected and treated cells. Generally, we found that miR-34a could considerably decrease the expression of inflammatory cytokines and the combination of ZER+ miR-34 boosted this effect. Moreover the migration and proliferation decreased in treated and transfected cells and this reduction was more severe in miR-34a +ZER treatment. It is important to note that in the case of cell resistance to each of these therapeutic agents, inhibition of cytokines can be compensated by another one.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemokine CCL2; Chemokine CXCL12; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Inflammation; Interleukin-33; MicroRNAs; Sesquiterpenes; Transforming Growth Factor beta

Unregulated inflammatory responses lead to massive production of macrophages-activating inflammatory cytokines and chemokines, which may induce diabetes, cancer, and atherosclerosis. Macrophages differentiated from human monocyte (THP-1) have been extensively used in in vitro inflammation models in recent studies. Zerumbone is a major component of the essential oil of Zingiber zerumbet Smith, a type of wild ginger. In this study, we investigated the effects of zerumbone on the secretion of pro-inflammatory cytokines and its underlying mechanistic regulation in lipopolysaccharide (LPS)-activated inflammation of THP-1 cell-derived macrophages. Nuclear factor (NF)-κB and toll-like receptors (TLRs) are known to play important roles in inflammation and immunity. If pathogens enter the host, TLRs recognize the pathogens and signal for the activation of NF-κB to induce inflammatory gene products, such as cytokines. We demonstrated that zerumbone inhibits the secretion of pro-inflammatory cytokines and the induction of NF-κB p65 in LPS-activated inflammation of THP-1 cell-derived macrophages. In addition, zerumbone significantly inhibited mRNA and protein levels of TLR-2/4, and the expression of myeloid differentiation factor 88 (MyD88) adaptor proteins in the LPS-activated inflammation of THP-1 cell-derived macrophages. Moreover, we showed that zerumbone (1-10 μM) regulated histone deacetylase (HDAC) activity and the expression of HDAC genes. H3K9ac, H3K27ac, and H3K4me2 are inducible histone marks that activate gene expression. Treatment with LPS upregulated H3K9ac, H3K27ac, and H3K4me2 in THP-1 cell-derived macrophages; however, this upregulation was decreased by zerumbone treatment. Therefore, these results provide evidence that zerumbone may have therapeutic benefits for chronic inflammatory diseases.

Topics: Cytokines; Histone Deacetylases; Humans; Inflammation; Lipopolysaccharides; Macrophages; Myeloid Differentiation Factor 88; NF-kappa B; Phytotherapy; Plant Extracts; RNA, Messenger; Sesquiterpenes; Signal Transduction; THP-1 Cells; Toll-Like Receptors; Transcription Factor RelA; Up-Regulation; Zingiberaceae

Zingiber zerumbet rhizome has been used as spices and in traditional medicine to heal various immune-inflammatory related ailments. Although the plant was reported to have potent anti-inflammatory and immunosuppressive properties by several studies, the molecular mechanisms underlying the effects have not been well justified.. The study was carried out to investigate the molecular mechanisms underlying the anti-inflammatory properties of the standardized 80% ethanol extract of Z. zerumbet through its effect on mitogen-activated protein kinase (MyD88)-dependent nuclear factor-kappa B (NF-кB), mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/Akt (PI3K-Akt) signaling pathways in lipopolysaccharide (LPS)-induced U937 human macrophages.. Standardization of the 80% ethanol extract of Z. zerumbet was performed by using a validated reversed-phase HPLC method, while LC-MS/MS was used to profile the secondary metabolites. The release of pro-inflammatory markers, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and prostaglandin E. The quantitative and qualitative analyses of Z. zerumbet extract showed the presence of several compounds including the major chemical marker zerumbone. Z. zerumbet extract suppressed the release of pro-inflammatory mediators, COX-2 protein expression and downregulated the mRNA expression of pro-inflammatory markers. Z. zerumbet-treatment also blocked NF-κB activation by preventing the phosphorylation of IKKα/β and NF-κB (p65) as well as the phosphorylation and degradation of IκBα. Z. zerumbet extract concentration-dependently inhibited the phosphorylation of respective MAPKs (JNK, ERK, and p38) as well as Akt. Correspondingly, Z. zerumbet extract suppressed the upstream signaling adaptor molecules, TLR4 and MyD88 prerequisite for the NF-κB, MAPKs, and PI3K-Akt activation.. The findings suggest that Z. zerumbet has impressive role in suppressing inflammation and related immune disorders by inhibition of various pro-inflammatory markers through the imperative MyD88-dependent NF-κB, MAPKs, and PI3K-Akt activation.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Chromatography, Liquid; Humans; Inflammation; Lipopolysaccharides; Mitogen-Activated Protein Kinases; NF-kappa B; Phosphatidylinositol 3-Kinases; Plant Extracts; Proto-Oncogene Proteins c-akt; Sesquiterpenes; Signal Transduction; Tandem Mass Spectrometry; U937 Cells; Zingiberaceae

Zerumbone has been reported to exert anti-inflammatory, anti-ulcer and anti-hyperglycemic effects but the specific mechanism through which zerumbone exerts its anti-inflammatory action through inhibiting reactive oxygen species was not well studied. Hence, this paper studied the zerumbone capacity to inhibit intracellular and extracellular Reactive Oxygen Species (ROS) produced by whole blood cell, polymorphoneutrophil (PMNs) and macrophage cells due to the zymogen and phorbolmyristerate acetate (PMA) oxidant effect.. Zymogen and PMA based chemiluminescence assay were used to determine the immunomodulatory effect of zerumbone at concentrations (100, 10 and 1 μg mL-1) toward production of Reactive Oxygen Species (ROS) from whole blood, PMNs and macrophage.. Zerumbone significantly inhibited intracellular and extracellular ROS production by the zymosan/PMA-activated phagocyte cells with IC50 values of (16.3±0.1, 23.7±0.1 and 4.97±0.1 μg mL-1) against whole blood, PMNs and macrophage respectively.. The anti-inflammatory activity of zerumbone was so much significant that even strong oxidant (zymogen and PMA) were not able to produce reactive oxygen species when incubated together in phagocytic cells, thus suppress production of ROS. Therefore, it is highly used in herbal medicine as a potent immunomodulatory therapy in various inflammation associated diseases.

Topics: Animals; Dose-Response Relationship, Drug; Enzyme Precursors; Humans; Immune System; Immunomodulation; Inflammation; Inhibitory Concentration 50; Luminescence; Macrophages; Mice; Neutrophils; Plant Preparations; Reactive Oxygen Species; Respiratory Burst; Sesquiterpenes; Tetradecanoylphorbol Acetate

Zerumbone, a cyclic eleven-membered sesquiterpene, is the major component of the essential oil isolated from the wild ginger, Zingiber zerumbet. There are several beneficial pharmacological activities of zerumbone including anti-inflammatory, antioxidant, and anticancer activities. Acute lung injury (ALI) is an acute pulmonary inflammatory disorder with high morbidity and mortality rate. In present study, we aimed to investigate the protective effects and mechanisms of zerumbone on endotoxin, lipopolysaccharide (LPS)-induced ALI. Mice were pretreated with zerumbone at various concentrations for 30 min followed by intratracheal administration of LPS for 6 h. Pretreatment with zerumbone not only reduced leukocytes infiltration into the alveolar space but also inhibited lung edema in LPS-induced ALI. Decreased secretion of proinflammatory cytokines such as TNFα and IL-6 caused by LPS were reversed by zerumbone. LPS-induced expressions of proinflammatory mediators, iNOS and COX-2, were inhibited by zerumbone. In addition, NFκB activation and Akt phosphorylation were inhibited by zerumbone in LPS-induced ALI. All these results suggested that the protective mechanisms of zerumbone on endotoxin-induced ALI were via inhibition of Akt-NFκB activation.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Endotoxins; Enzyme Activation; Inflammation; Male; Mice; NF-kappa B; Oncogene Protein v-akt; Sesquiterpenes; Signal Transduction; Zingiber officinale

The anti-inflammatory activity of zerumbone (1), a natural cyclic sesquiterpene isolated from Zingiber zerumbet Smith was investigated using carrageenan-induced paw edema and cotton pellet-induced granuloma tissue formation test in mice. It was demonstrated that intraperitoneal administration of 1 at a dose of 5, 10, 50 and 100 mg/kg produced significant dose-dependent inhibition of paw edema induced by carrageenan. It was also demonstrated that 1 at similar doses significantly suppressed granulomatous tissue formation in cotton pellet-induced granuloma test.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Disease Models, Animal; Edema; Gossypium; Granuloma; Inflammation; Male; Mice; Mice, Inbred ICR; Phytotherapy; Plant Extracts; Rhizome; Sesquiterpenes; Zingiberaceae

Zerumbone, a sesquiterpene occurring in zingiberaceous plants in Southeast Asian countries, has been shown to have anti-inflammatory effects in several independent experimental studies. We examined its effect on the expression of proinflammatory genes in human colon adenocarcinoma cell lines, Caco-2, Colo320DM, and HT-29, using reverse transcription-polymerase chain reaction (RT-PCR) assays. Surprisingly, zerumbone markedly induced the expression of interleukin (IL)-1alpha, IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha in each cell line in concentration- and time-dependent manners. Results of a previous pharmacological approach using specific inhibitors of mitogen-activated protein kinases (MAPKs) suggested that the activation of both c-Jun N-terminal kinase and extracellular signal-regulated protein kinase, however, not that of p38 MAPK, may be involved in zerumbone-induced IL-1beta expression pathways in Caco-2 cells. The present results imply that zerumbone increases the production of proinflammatory cytokines in cancerous tissues in the colon and that this biochemical property may cause side-effects.

Topics: Adenocarcinoma; Anti-Inflammatory Agents, Non-Steroidal; Cell Line, Tumor; Colonic Neoplasms; Cytokines; Gene Expression Regulation; Humans; Inflammation; Phytotherapy; Plant Extracts; Reverse Transcriptase Polymerase Chain Reaction; Sesquiterpenes