shogaol and Disease-Models--Animal

Gingerols are the major pungent compounds present in the rhizomes of ginger (Zingiber officinale Roscoe) and are renowned for their contribution to human health and nutrition. Medicinal properties of ginger, including the alleviation of nausea, arthritis and pain, have been associated with the gingerols. Gingerol analogues are thermally labile and easily undergo dehydration reactions to form the corresponding shogaols, which impart the characteristic pungent taste to dried ginger. Both gingerols and shogaols exhibit a host of biological activities, ranging from anticancer, anti-oxidant, antimicrobial, anti-inflammatory and anti-allergic to various central nervous system activities. Shogaols are important biomarkers used for the quality control of many ginger-containing products, due to their diverse biological activities. In this review, a large body of available knowledge on the biosynthesis, chemical synthesis and pharmacological activities, as well as on the structure-activity relationships of various gingerols and shogaols, have been collated, coherently summarised and discussed. The manuscript highlights convincing evidence indicating that these phenolic compounds could serve as important lead molecules for the development of therapeutic agents to treat various life-threatening human diseases, particularly cancer. Inclusion of ginger or ginger extracts in nutraceutical formulations could provide valuable protection against diabetes, cardiac and hepatic disorders.

Topics: Animals; Anti-Allergic Agents; Anti-Infective Agents; Anti-Obesity Agents; Antineoplastic Agents, Phytogenic; Catechols; Dietary Supplements; Disease Models, Animal; Fatty Alcohols; Humans; Hypoglycemic Agents; Plants, Medicinal; Zingiber officinale

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

Acute kidney injury (AKI) is a dose-limiting side effect of cisplatin therapy in cancer patients. However, effective therapies for cisplatin-induced AKI are not available. Oxidative stress, tubular cell death, and inflammation are known to be the major pathological processes of the disease. 6-Shogaol is a major component of ginger and exhibits anti-oxidative and anti-inflammatory effects. Accumulating evidence suggest that 6-shogaol may serve as a potential therapeutic agent for various inflammatory diseases. However, whether 6-shogaol exerts a protective effect on cisplatin-induced renal side effect has not yet been determined. The aim of this study was to evaluate the effect of 6-shogaol on cisplatin-induced AKI and to investigate its underlying mechanisms. An administration of 6-shogaol after cisplatin treatment ameliorated renal dysfunction and tubular injury, as shown by a reduction in serum levels of creatinine and blood urea nitrogen and an improvement in histological abnormalities. Mechanistically, 6-shogaol attenuated cisplatin-induced oxidative stress and modulated the renal expression of prooxidant and antioxidant enzymes. Apoptosis and necroptosis induced by cisplatin were also suppressed by 6-shogaol. Moreover, 6-shogaol inhibited cisplatin-induced cytokine production and immune cell infiltration. These results suggest that 6-shogaol exhibits therapeutic effects against cisplatin-induced AKI via the suppression of oxidative stress, tubular cell death, and inflammation.

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Antioxidants; Apoptosis; Catechols; Cisplatin; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Protective Agents; Zingiber officinale

Sepsis-associated liver dysfunction presents a significant public health problem. 6-Shogaol is the key bioactive component in dry ginger, which has antioxidant and anti-inflammation capacity. The present study aims to investigate the preventive effect of 6-shogaol on sepsis-induced liver injury. 6-Shogaol was administered to mice for 7 consecutive days before being intraperitoneally injected with lipopolysaccharide (LPS). After 24 h, mice were sacrificed, and biochemical and transcriptomic analyses were performed. Our results demonstrated that 6-shogaol prevented LPS-induced impairment in antioxidant enzymes and elevation in malondialdehyde level in the liver. The hepatic inflammatory response was significantly suppressed by 6-shogaol through suppressing the MAPK/NFκB pathway. RNA-sequencing data analysis revealed that 41 overlapped genes between the LPS vs. control group and 6-shogaol vs. LPS group were identified, among which 36 genes were upregulated, and 5 genes were downregulated for the LPS vs. control group. These overlapped genes are enriched in inflammation-related pathways, e.g., TNF and NFκB. The mRNA expression of the overlapped genes was also verified in the LPS-induced BRL-3A cell model. In summary, 6-shogaol shows great potential as a natural chemopreventive agent to treat sepsis-associated hepatic disorders.

Topics: Animals; Biomarkers; Catechols; Computational Biology; Disease Management; Disease Models, Animal; Disease Susceptibility; Gene Expression Profiling; Gene Expression Regulation; Liver Diseases; Liver Function Tests; Mice; NF-kappa B; Oxidative Stress; Sepsis; Signal Transduction; Transcription, Genetic; Transcriptome

Asthma, a common disorder associated with airway inflammation and hyperresponsiveness, remains a significant clinical burden in need of novel therapeutic strategies. Patients are increasingly seeking complementary and alternative medicine approaches to control their symptoms, including the use of natural products. Ginger, a natural product that we previously demonstrated acutely relaxes airway smooth muscle (ASM), has long been reported to possess anti-inflammatory properties, although a precise mechanistic understanding is lacking. In these studies, we demonstrate that chronic administration of whole ginger extract or 6-shogaol, a bioactive component of ginger, mitigates in vivo house dust mite antigen-mediated lung inflammation in mice. We further show that this decrease in inflammation is associated with reduced in vivo airway responsiveness. Utilizing in vitro studies, we demonstrate that 6-shogaol augments cAMP concentrations in CD4 cells, consistent with phosphodiesterase inhibition, and limits the induction of nuclear factor-κB signaling and the production of proinflammatory cytokines in activated CD4 cells. Sustained elevations in cAMP concentration are well known to inhibit effector T cell function. Interestingly, regulatory T cells (Tregs) utilize cAMP as a mediator of their immunosuppressive effects, and we demonstrate here that 6-shogaol augments the Treg polarization of naïve CD4 cells in vitro. Taken together with previous reports, these studies suggest that ginger and 6-shogaol have the potential to combat asthma via two mechanisms: acute ASM relaxation and chronic inhibition of inflammation.

Topics: Airway Resistance; Animals; Antigens, CD; Antigens, Dermatophagoides; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Catechols; Cell Count; Cyclic AMP; Disease Models, Animal; Female; Interleukin-4; Lung; Male; Mice, Inbred C57BL; NF-kappa B; Plant Extracts; Pneumonia; Signal Transduction; T-Lymphocytes, Regulatory; Zingiber officinale

The anti-inflammatory drug candidate, 6-shogaol, has demonstrated excellent efficacies in various in vitro studies. However, its rapid metabolism after oral administration results in poor bioavailability and undetectable in vivo pharmacokinetics. Here, we constructed a natural-lipid (NL) nanoparticle drug delivery system (NP-DDS) to encapsulate 6-shogaol and undertake its controlled release to the proposed drug target (colon). Our in vitro drug-release assay revealed that NL-encapsulated 6-shogaol (6-S-NL) exhibits a delayed drug-release profile compared to free 6-shogaol (free-6-S). Consistent with our expectations, orally administrated 6-S-NL exhibits a superior anti-inflammatory efficacy likely due to the controlled release compared to free 6-S in a dextran sulfate sodium (DSS)-induced mouse model of colitis. Although 6-S-NL treatment yields an enhanced concentration of 6-shogaol at the target site (colon), this concentration is still far below the effective level. We hypothesize that the released 6-shogaol undergoes rapid metabolism and that the metabolites of 6-shogaol may contribute to the anti-inflammatory efficacy of 6-S-NL. We thus examined the in vitro anti-inflammatory efficacies of two highly abundant colonic metabolites, M2 (a cysteine-conjugated metabolite) and M13 (a glutathione-conjugated metabolite), against macrophage cells. Reverse transcription-polymerase chain reaction (RT-PCR) data showed that both M2 and M13 (at 1.0 μg/mL) could down-regulate pro-inflammatory factors (TNF-α, IL-1β, and IL-6) and up-regulate an anti-inflammatory factor (IL-10) in inflamed Raw 264.7 cells. Subsequent in vitro wound-healing assays also confirmed that M2 and M13 accelerate the wound recovery process of Caco-2 cells at the concentrations seen in the colon (1.0 μg/mL). Further, in the DSS-induced mouse model of colitis, oral administration of M2- or M13-loaded NL nanoparticles (M2-NL, M13-NL) demonstrated excellent in vivo wound-healing effects, and these activities were better than those observed for 6-S-NL. Combined with the 6-S-NL's bio-distribution assay, our data show that: the 6-shogaol metabolites, M2 and M13, are more potent anti-inflammatory compounds than 6-shogaol itself; NL nanoparticles can effectively deliver 6-shogaol to the colon, with little accumulation seen in the kidney or liver; and the actions of M2 and M13 mostly confer the anti-inflammatory effect of 6-S-NL. Our results explained the discrepancy between the low tissue concentration

Topics: Animals; Caco-2 Cells; Catechols; Colitis; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Humans; Lipids; Nanoparticles

To observe the regulatory effect of 6-Shogaol on Notch signal pathway in colonic epithelial cells of mice with ulcerative colitis.. Forty Kunming mice were randomly divided into normal group (n=10) and model group (n=30). The model of ulcerative colitis was induced by free drinking of 2% dextran sulfate sodium salt(DSS). After 15 days, the mice were divided into model group, 6-gingerenol group and positive control group with 10 mice in each group. Normal group and model group were treated with normal saline, 6-gingerenol group was treated with 6-Shogaol 100 mg/(kg·d), positive control group was treated with sulfasalazine 100 mg/(kg·d), for 20 days. The histopathological changes of colon were observed, and the expressions of Hes-1 and Math-1protein in colonic epithelial cells were detected by immunofluorescence double labeling method. The expressions of Notch-1, Hes-1 and Math-1 mRNA in colonic epithelial tissue were detected by RT-PCR. The expressions of Notch-1, Hes-1 and Math-1 protein in colonic epithelial tissue was detected by Western blot.. Compared with the normal group, the expression of Notch-1 and Hes-1 protein and the relative expression of mRNA in colonic epithelium of model group were significantly increased (P＜0.01), while the relative expressions of Math-1 mRNA and protein were decreased significantly (P＜0.01). Compared with the model group, the expressions of Notch-1 and Hes-1 protein and the relative expression of mRNA in colonic epithelium of 6-Shogaol group and sulfasalazine group were decreased significantly(P＜0.01), while the relative expressions of Math-1 mRNA and protein were increased significantly(P＜0.01).. 6-Shogaol can inhibit the over activation of Notch pathway and regulate the balance of differentiation between colonic epithelialabsorptive cell line and secretory cell line and repair damaged mucosal tissue.

Topics: Animals; Catechols; Colitis, Ulcerative; Colon; Disease Models, Animal; Epithelial Cells; Intestinal Mucosa; Mice; Receptors, Notch; Signal Transduction

Acute kidney injury (AKI) due to renal ischemia-reperfusion (I/R) is a major clinical problem without effective therapy. Ginger is one of the most widely consumed spices in the world, and 6-shogaol, a major ginger metabolite, has anti-inflammatory effects in neuronal and epithelial cells. Here, we demonstrate our novel findings that 6-shogaol treatment protected against renal I/R injury with decreased plasma creatinine, blood urea nitrogen, and kidney neutrophil gelatinase-associated lipocalin mRNA synthesis compared with vehicle-treated mice subjected to renal I/R. Additionally, 6-shogaol treatment reduced kidney inflammation (decreased proinflammatory cytokine and chemokine synthesis as well as neutrophil infiltration) and apoptosis (decreased TUNEL-positive renal tubular cells) compared with vehicle-treated mice subjected to renal I/R. In cultured human and mouse kidney proximal tubule cells, 6-shogaol significantly attenuated TNF-α-induced inflammatory cytokine and chemokine mRNA synthesis. Mechanistically, 6-shogaol significantly attenuated TNF-α-induced NF-κB activation in human renal proximal tubule cells by reducing IKKαβ/IκBα phosphorylation. Furthermore, 6-shogaol induced a cytoprotective chaperone heme oxygenase (HO)-1 via p38 MAPK activation in vitro and in vivo. Consistent with these findings, pretreatment with the HO-1 inhibitor zinc protoporphyrin IX completely prevented 6-shogaol-mediated protection against ischemic AKI in mice. Taken together, our study showed that 6-shogaol protects against ischemic AKI by attenuating NF-κB activation and inducing HO-1 expression. 6-Shogaol may provide a potential therapy for ischemic AKI during the perioperative period.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Apoptosis; Catechols; Cell Line; Cytokines; Disease Models, Animal; Heme Oxygenase-1; Humans; Inflammation Mediators; Kidney; Male; Membrane Proteins; Mice, Inbred C57BL; Neutrophil Infiltration; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Reperfusion Injury; Signal Transduction

Oral drug delivery is the most attractive pathway for ulcerative colitis [UC] therapy, since it has many advantages. However, this strategy has encountered many challenges, including the instability of drugs in the gastrointestinal tract [GT], low targeting of disease tissues, and severe adverse effects. Nanoparticles capable of colitis tissue-targeted delivery and site-specific drug release may offer a unique and therapeutically effective system that addresses these formidable challenges.. We used a versatile single-step surface-functionalising technique to prepare PLGA/PLA-PEG-FA nanoparticles loaded with the ginger active compound, 6-shogaol [NPs-PEG-FA/6-shogaol]. The therapeutic efficacy of NPs-PEG-FA/6-shogaol was evaluated in the well-established mouse model of dextran sulphate sodium [DSS]-induced colitis.. NPs-PEG-FA exhibited very good biocompatibility both in vitro and in vivo. Subsequent cellular uptake experiments demonstrated that NPs-PEG-FA could undergo efficient receptor-mediated uptake by colon-26 cells and activated Raw 264.7 macrophage cells. In vivo, oral administration of NPs-PEG-FA/6-shogaol encapsulated in a hydrogel system [chitosan/alginate] significantly alleviated colitis symptoms and accelerated colitis wound repair in DSS-treated mice by regulating the expression levels of pro-inflammatory [TNF-α, IL-6, IL-1β, and iNOS] and anti-inflammatory [Nrf-2 and HO-1] factors.. Our study demonstrates a convenient, orally administered 6-shogaol drug delivery system that effectively targets colitis tissue, alleviates colitis symptoms, and accelerates colitis wound repair. This system may represent a promising therapeutic approach for treating inflammatory bowel disease [IBD].

Topics: Alginates; Animals; Biocompatible Materials; Catechols; Cell Line; Chitosan; Colitis, Ulcerative; Dextran Sulfate; Disease Models, Animal; Drug Delivery Systems; Epithelial Cells; Folic Acid; Glucuronic Acid; Heme Oxygenase-1; Hexuronic Acids; Hydrogels; Interleukin-1beta; Interleukin-6; Intestinal Mucosa; Macrophages; Membrane Proteins; Mice; Nanoparticles; NF-E2-Related Factor 2; Nitric Oxide Synthase Type II; Polyethylene Glycols; RNA, Messenger; Tumor Necrosis Factor-alpha; Wound Healing

Chemopreventive agents can be identified from botanicals. Recently, there has been strong support for the potential of 6-shogaol, a natural compound from dietary ginger (Zingiber officinale), in cancer chemoprevention. However, whether 6-shogaol inhibits the growth of colorectal tumors in vivo remains unknown, and the underlying anticancer mechanisms have not been well characterized. In this work, we observed that 6-shogaol (15 mg/kg) significantly inhibited colorectal tumor growth in a xenograft mouse model. We show that 6-shogaol inhibited HCT-116 and SW-480 cell proliferation with IC50 of 7.5 and 10 μM, respectively. Growth of HCT-116 cells was arrested at the G2/M phase of the cell cycle, primarily mediated by the up-regulation of p53, the CDK inhibitor p21(waf1/cip1) and GADD45α, and by the down-regulation of cdc2 and cdc25A. Using p53(-/-) and p53(+/+) HCT-116 cells, we confirmed that p53/p21 was the main pathway that contributed to the G2/M cell cycle arrest by 6-shogaol. 6-Shogaol induced apoptosis, mainly through the mitochondrial pathway, and the bcl-2 family might act as a key regulator. Our results demonstrated that 6-shogaol induces cancer cell death by inducing G2/M cell cycle arrest and apoptosis. 6-Shogaol could be an active natural product in colon cancer chemoprevention.

Topics: Animals; Apoptosis; Catechols; CDC2 Protein Kinase; cdc25 Phosphatases; Cell Proliferation; Colorectal Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Disease Models, Animal; Dose-Response Relationship, Drug; Female; G2 Phase Cell Cycle Checkpoints; Gene Expression; Heterografts; Humans; Mice, Nude; Neoplasm Transplantation; Phytotherapy; Receptor Cross-Talk; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Up-Regulation

6-Shogaol [1-(4-hydroxy-methoxyphenyl)-4-decen-one], a pungent compound isolated from ginger, has shown various neurobiological and anti-inflammatory effects. The aim of this study was to examine the effects of 6-shogaol on neuroinflammatory-induced damage of dopaminergic (DA) neurons in Parkinson's disease (PD) models.. Cultured rat mesencephalic cells were treated with 6-shogaol (0.001 and 0.01 μmol/L) for 1 h, then with MPP(+)(10 μmol/L) for another 23 h. The levels of TNF-α and NO in medium were analyzed spectrophotometrically. C57/BL mice were administered 6-shogaol (10 mg·kg(-1)·d(-1), po) for 3 d, and then MPTP (30 mg/kg, ip) for 5 d. Seven days after the last MPTP injection, behavioral testings were performed. The levels of tyrosine hydroxylase (TH) and macrophage antigen (MAC)-1 were determined with immunohistochemistry. The expression of iNOS and COX-2 was measured using RT PCR.. In MPP(+)-treated rat mesencephalic cultures, 6-shogaol significantly increased the number of TH-IR neurons and suppressed TNF-α and NO levels. In C57/BL mice, treatment with 6-shogaol reversed MPTP-induced changes in motor coordination and bradykinesia. Furthermore, 6-shogaol reversed MPTP-induced reductions in TH-positive cell number in the substantia nigra pars compacta (SNpc) and TH-IR fiber intensity in stratum (ST). Moreover, 6-shogaol significantly inhibited the MPTP-induced microglial activation and increases in the levels of TNF-α, NO, iNOS, and COX-2 in both SNpc and ST.. 6-Shogaol exerts neuroprotective effects on DA neurons in in vitro and in vivo PD models.

Topics: Animals; Catechols; Cells, Cultured; Disease Models, Animal; Dopaminergic Neurons; Female; Male; Mesencephalon; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Parkinsonian Disorders; Plant Extracts; Pregnancy; Rats; Rats, Sprague-Dawley; Zingiber officinale

6-Shogaol is one of the major compounds in the ginger rhizome that may contribute to its anti-inflammatory properties. Confirmation of this contribution was sought in this study in Sprague- Dawley rats (200-250 g) treated with a single injection (0.5 ml of 1 mg/ml) of a commercial preparation of complete Freund's Adjuvant (CFA) to induce monoarthritis in the right knee over a period of 28 days. During this development of arthritis, each rat received a daily oral dose of either peanut oil (0.2 ml-control) or 6-shogaol (6.2 mg/Kg in 0.2 ml peanut oil).. Within 2 days of CFA injection, the control group produced maximum edematous swelling of the knee that was sustained up to the end of the investigation period. But, in the 6-shogaol treated group, significantly lower magnitudes of unsustained swelling of the knees (from 5.1 +/- 0.2 mm to 1.0 +/- 0.2 mm, p < 0.002, n = 6) were produced during the investigation period. Unsustained swelling of the knees (from 3.2 +/- 0.6 mm to 0.8 +/- 1.1 mm, p < 0.00008, n = 6) was also produced after 3 days of treatment with indomethacin (2 mg/Kg/day) as a standard anti-inflammatory drug, but during the first 2 days of drug treatment swelling of the knees was significantly larger (11.6 +/- 2.0 mm, p < 0.0002, n = 6) than either the controls or the 6-shogaol treated group of rats. This exaggerated effect in the early stage of indomethacin treatment was inhibited by montelukast, a cysteinyl leukotriene receptor antagonist. Also, 6-shogaol and indomethacin were most effective in reducing swelling of the knees on day 28 when the controls still had maximum swelling. The effect of 6-shogaol compared to the controls was associated with significantly lower concentration of soluble vascular cell adhesion molecule-1 (VCAM-1) in the blood and infiltration of leukocytes, including lymphocytes and monocytes/macrophages, into the synovial cavity of the knee. There was also preservation of the morphological integrity of the cartilage lining the femur compared to damage to this tissue in the peanut oil treated control group of rats.. From these results, it is concluded that 6-shogaol reduced the inflammatory response and protected the femoral cartilage from damage produced in a CFA monoarthritic model of the knee joint of rats.

Topics: Animals; Arthritis, Experimental; Catechols; Disease Models, Animal; Edema; Freund's Adjuvant; Knee Joint; Rats; Rats, Sprague-Dawley; Rhizome; Zingiber officinale