ABSTRACT
Parkinson's disease (PD) is a neurodegenerative disease caused by the death of dopaminergic neurons in the nigrostriatal pathway, leading to motor and non-motor dysfunctions, such as depression, olfactory dysfunction, and memory impairment. Although levodopa (L-dopa) has been the gold standard PD treatment for decades, it only relieves motor symptoms and has no effect on non-motor symptoms or disease progression. Prior studies have reported that 6-shogaol, the active ingredient in ginger, exerts a protective effect on dopaminergic neurons by suppressing neuroinflammation in PD mice. This study investigated whether cotreatment with 6-shogaol and L-dopa could attenuate both motor and non-motor symptoms and dopaminergic neuronal damage. Both 6-shogaol (20 mg/kg) and L-dopa (80 mg/kg) were orally administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid- induced PD model mice for 26 days. The experimental results showed that L-dopa alleviated motor symptoms, but had no significant effect on non-motor symptoms, loss of dopaminergic neuron, or neuroinflammation. However, when mice were treated with 6-shogaol alone or in combination L-dopa, an amelioration in both motor and non-motor symptoms such as depression-like behavior, olfactory dysfunction and memory impairment was observed. Moreover, 6-shogaol-only or co-treatment with 6-shogaol and L-dopa protected dopaminergic neurons in the striatum and reduced neuroinflammation in the striatum and substantia nigra. Overall, these results suggest that 6-shogaol can effectively complement L-dopa by improving non-motor dysfunction and restoring dopaminergic neurons via suppressing neuroinflammation.
ABSTRACT
Cancer is a major global health challenge that affects every nation and accounts for a large portion of the worldwide disease burden. Furthermore, cancer cases will rise significantly in the next few decades. The Food and Drug Administration has approved more than 600 drugs for treating diverse types of cancer. However, many conventional anticancer medications cause side effects, and drug resistance develops as the treatment proceeds with a concomitant impact on patients' quality of life. Thus, exploring natural products with antitumor properties and nontoxic action mechanisms is essential. Ginger (Zingiber officinale Roscoe) rhizome has a long history of use in traditional medicine, and it contains biologically active compounds, gingerols and shogaols. The main ginger shogaol is 6-shogaol, whose concentration dramatically increases during the processing of ginger, primarily due to the heat-induced conversion of 6-gingerol. Some studies have demonstrated that 6-shogaol possesses biological and pharmacological properties, such as antioxidant, anti-inflammatory, and anticancer activities. The mechanism of action of 6-shogaol as an anticancer drug includes induction of paraptosis, induction of apoptosis, increase in the production of reactive oxygen species, induction of autophagy, and the inhibition of AKT/mTOR signaling. Despite this knowledge, the mechanism of action of 6-shogaol is not fully understood, and the scientific data on its therapeutic dose, safety, and toxicity are not entirely described. This review article examines the potential of 6-shogaol as an anticancer drug, addressing the limitations of current medications; it covers 6-shogaol's attributes, mechanism of action in cancer cells, and opportunities for future research.
ABSTRACT
Colorectal cancer (CRC) poses a significant global health burden, being the third most prevalent cancer and the second most significant contributor to cancer-related deaths worldwide. Preventive strategies are crucial to combat this rising incidence. 6-shogaol, derived from ginger, has shown promise in preventing and treating various cancers. This study investigated the preventive effects of 6-shogaol on azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced CRC in mice. Forty male BALB/c mice were randomly divided into control, 6-shogaol, AOM + DSS, and 6-shogaol + AOM + DSS. Mice in the control group received corn oil for 16 weeks, while those in the 6-Shogaol group were administered 20 mg/kg of 6-shogaol for 16 weeks. The AOM + DSS group received a single intraperitoneal dose (ip) of 10 mg/kg of AOM, followed by three cycles of 2.5% DSS in drinking water. The 6-shogaol + AOM + DSS group received both 6-shogaol for 16 weeks and a single ip of 10 mg/kg of AOM, followed by three cycles of 2.5% DSS in drinking water. The AOM + DSS-treated mice exhibited reduced food consumption, colon weight, and colon length, along with increased tumor formation. Co-administration of 6-shogaol effectively reversed these changes, inhibiting CRC development. Histopathological analysis revealed protective effects of 6-shogaol against colonic insults and modulation of inflammatory responses. 6-shogaol significantly reduced Carcinoembryonic antigen and Kiel 67 levels, indicating inhibition of tumor cell proliferation. Mechanistically, 6-shogaol promoted apoptosis by upregulating protein 53 and caspase-3 expression, and it effectively restored the balance of the Wingless-related integration site signaling pathway by regulating ß-catenin and adenomatous polyposis coli levels. Moreover, 6-shogaol demonstrated anti-inflammatory effects, reducing myeloperoxidase, Tumor necrosis factor alpha, and cyclooxygenase-2 levels in AOM/DSS-treated mice. Additionally, 6-shogaol restored redox homeostasis by reducing lipid peroxidation and nitrosative stress and enhancing antioxidant enzyme activities. The findings suggest that 6-shogaol inhibits cell proliferation, induces apoptosis, regulates Wnt signaling, suppresses inflammation, and restores redox homeostasis, providing comprehensive insights into its potential therapeutic benefits for CRC.
ABSTRACT
Background: The available in vitro evidences suggest the inherent instability and interconvertibility of [6]-gingerol and [6]-shogaol. However, limited data on their in vivo interconversion hinder understanding of their influence on the pharmacokinetic profiles. Purpose: This study presents the first comprehensive in vivo investigation aiming to determine the interconversion pharmacokinetics in rats, and elucidate the oral bioavailability, target distribution, biotransformation, and excretion profiles of the key ginger constituents, [6]-gingerol, [6]-shogaol, and zingerone. Methods: The pharmacokinetics was investigated through single intravenous (3 mg/kg) or oral (30 mg/kg) administration of [6]-gingerol, [6]-shogaol, or zingerone, followed by the determination of their tissue distribution after oral dosing (30 mg/kg). Intravenous pharmacokinetics was leveraged to evaluate the interconversion, circumventing potential confounders associated with the oral route. Results: All rats tolerated these compounds throughout the pharmacokinetic study. The parent compounds exhibited rapid but partial absorption, and extensive organ distribution with substantial biotransformation, thereby limiting the oral bioavailability of each compound to below 2% when administered as pure compounds. Conversion of [6]-gingerol to [6]-shogaol after intravenous administration, demonstrated a significantly larger clearance compared to the reverse conversion ([6]-shogaol to [6]-gingerol). The irreversible metabolic clearance for both compounds was significantly greater than their reversible bioconversions. Furthermore, [6]-gingerol underwent biotransformation to zingerone. Conjugated glucuronides were eliminated partly through renal excretion, with minimal fecal excretion. Conclusion: This in vivo investigation demonstrates the influence of interconversion on the disposition kinetics of [6]-gingerol, [6]-shogaol, and zingerone, as evidenced by the findings in the systemic circulation. The study further highlights the importance of considering this interconversion and tissue distribution when determining the administration dosage of ginger constituent combinations for therapeutic benefits and clinical applications.
ABSTRACT
The purpose of this study is to investigate the mechanism by which 6-shogaol ameliorates hepatic steatosis via miRNA-mRNA interaction analysis. C57BL/6 J mice were fed a high-fat diet (HFD) for 12 weeks, during which 6-shogaol was administered orally. The liver lipid level, liver function and oxidative damage in mice were evaluated. mRNA sequencing, miRNA sequencing, and RT-qPCR were employed to compare the expression profiles between the HFD group and the 6-shogaol-treated group. High-throughput sequencing was used to construct the mRNA and miRNA libraries. Target prediction and integration analysis identified eight potential miRNA-mRNA pairs involved in hepatic steatosis, which were subsequently validated in liver tissues and AML12 cells. The findings revealed that 6-shogaol modulates the miR-3066-5p/Grem2 pathway, thereby improving hepatic steatosis. This study provides new insights into the mechanisms through which 6-shogaol alleviates hepatic steatosis, establishing a foundation for future research on natural active compounds for the treatment of metabolic diseases.
Subject(s)
Catechols , Diet, High-Fat , Mice, Inbred C57BL , MicroRNAs , Animals , MicroRNAs/genetics , MicroRNAs/metabolism , Mice , Diet, High-Fat/adverse effects , Male , Catechols/pharmacology , Catechols/administration & dosage , Humans , Liver/metabolism , Liver/drug effects , Fatty Liver/genetics , Fatty Liver/metabolism , Fatty Liver/drug therapy , Fatty Liver/prevention & control , Fatty Liver/etiologyABSTRACT
The dynamically evolving science of pharmacology requires AI technology to advance a new path for drug development. The author proposes generative AI for future drugs, identifying suitable drug molecules, uncharacteristically to previous generations of medicines, incorporating the wisdom, experience, and intuit of traditional materia medica and the respective traditional medicine practitioners. This paper describes the guiding principles of the new drug development, springing from the tradition and practice of Tibetan medicine, defined as the Interactive Nutrient Process (INP). The INP provides traditional knowledge and practitioner's experience, contextualizing and teaching the new drug therapy. An illustrative example of the outcome of the INP is a potential small molecule drug, 6-Shogaol and related shogaol derivatives, from ginger roots (Zingiber officinalis fam. Zingiberaceae) evaluated clinically for 12 months for biological markers of iron homeostasis in patients with the myelodysplastic syndromes (MDS). The study's preliminary results indicate that 6-Shogaol and related shogaols may improve iron homeostasis in low-risk/intermediate-1 MDS patients without objective or subjective side effects.
Subject(s)
Catechols , Nutrients , Humans , Catechols/pharmacology , IronABSTRACT
Sunitinib (SUN) is the first-line targeted therapeutic drug for advanced renal cell carcinoma (RCC). However, SUN resistance is frequently observed to result in tumor metastasis, with a poor survival rate. Therefore, finding an effective and safe adjuvant to reduce drug resistance is important for RCC treatment. Pterostilbene (PTE) and 6-shogaol (6-S) are natural phytochemicals found in edible sources and have potential applications against various cancers. However, the biological mechanisms of PTE and 6-S in SUN-resistant RCC are still unclear. Accordingly, this study investigated the regulatory effects of PTE and 6-S on cell survival, drug resistance, and cell invasion in 786-O and SUN-resistant 786-O (786-O SUNR) cells, respectively. The results demonstrated that PTE and 6-S induced apoptosis in both cell lines by upregulating the Bax/Bcl-2 ratio. Additionally, PTE and 6-S increased SUN sensitivity by inhibiting the expression of the RLIP76 transport protein, reduced cell invasion and downregulated MMP expression in both 786-O and 786-O SUNR cells. Mechanistically, PTE, and 6-S significantly and dose-dependently suppressed the RLIP76-initiated Ras/ERK and Akt/mTOR pathways. In summary, PTE and 6-S induce apoptosis, enhance SUN sensitivity, and inhibit migration in both 786-O and 786-O SUNR cells. These novel findings demonstrate the potential of PTE and 6-S as target therapeutic adjuvants for RCC treatment.
Subject(s)
Carcinoma, Renal Cell , Catechols , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/metabolism , Sunitinib/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Kidney Neoplasms/pathology , TOR Serine-Threonine Kinases/metabolism , Cell Line, TumorABSTRACT
BACKGROUND/AIMS: Bladder cancer is considered one of the most aggressive neoplasms due to its recurrence and progression profile, and even with the improvement in diagnosis and treatment methods, the mortality rate has not shown a declining trend in recent decades. From this perspective, the search and development of more effective and safer therapeutic alternatives are necessary. Phytochemicals are excellent sources of active principles with therapeutic potential. [6]-Shogaol is a phenolic compound extracted from the ginger rhizomes that has shown antitumor effects in a wide variety of cancer models. However, there is no record in the literature of studies reporting these effects in models of bladder cancer. Thus, this study aimed to investigate the in vitro cytotoxic and pro-apoptotic potential of [6]-Shogaol against murine bladder cancer urothelial cells (MB49). METHODS: The cytotoxic effects of [6]-Shogaol on cell viability (MTT method), cell morphology (light microscopy), alteration of proliferative processes (clonogenic assay), oxidative stress pathway (levels of reactive oxygen species) and the induction of apoptotic events (flow cytometry and high-resolution epifluorescence imaging) were evaluated in murine urothelial bladder cancer cell lines (MB49), relative to non-tumor murine fibroblasts (L929). RESULTS: The results showed that [6]-Shogaol was able to induce concentration-dependent cytotoxic effects, which compromised cell viability, exhibiting an inhibitory concentration of 50% of cells (IC50) of 146.8 µM for MB49 tumor cells and 236.0 µM for L929 non-tumor fibroblasts. In addition to inhibiting and altering the proliferative processes if colony formation, it presented pro-apoptotic activity identified through a quantitative analysis and the observation of apoptotic phenotypes, events apparently mediated by the induction of nuclear fragmentation. CONCLUSION: The data presented suggest that [6]-Shogaol has a higher concentration-dependent cytotoxic and apoptosis-inducing potential in MB49 cells than in L929 fibroblasts. These results may contribute to the development of therapeutic alternatives for bladder cancer.
Subject(s)
Antineoplastic Agents , Urinary Bladder Neoplasms , Mice , Animals , Humans , Apoptosis , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Catechols/pharmacology , Catechols/therapeutic use , Catechols/chemistry , Antineoplastic Agents/pharmacology , Cell Line, TumorABSTRACT
Ginger (Zingiber officinale Roscoe, Zingeberaceae) is a medicinal plant widely used as food, spice, or flavoring agent worldwide. 6-Shogaol is a compound of prime interest in exhibiting anti-inflammatory, antioxidant and chemopreventive effects. The objective of the study is to investigate the effect of microwave-assisted drying (MAD) followed by microwave-assisted extraction (MAE) so as to produce 6-Shogaol enriched Ginger with improved therapeutic benefits. Various drying techniques viz. shade drying, tray drying, microwave-assisted drying and osmotic dehydration as a pretreatment were used for drying Ginger rhizomes. The dried rhizomes were extracted by conventional solvent extraction and microwave-assisted extraction techniques and tested for content of 6-Shogaol using the newly developed HPLC method whereas total flavonoid and polyphenol content were determined using the UV spectrophotometric method. Subjecting the microwave dried Ginger to microwave-assisted extraction for 45 min at constant power level of 284 W resulted in a significant rise in the extractability of 6-Shogaol (1.660 ± 0.018), total polyphenols (855.46 ± 5.33) and flavonoids (617.97 ± 6.40) compared to the conventional method of extraction. The proposed Ginger processing method of microwave drying followed by microwave extraction outperforms traditional methods in terms of speed, convenience, and performance thus can be scaled up to industrial levels.
Subject(s)
Catechols , Desiccation , Microwaves , Plant Extracts , Zingiber officinale , Zingiber officinale/chemistry , Catechols/isolation & purification , Catechols/chemistry , Desiccation/methods , Chromatography, High Pressure Liquid/methods , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Flavonoids/isolation & purification , Flavonoids/analysis , Flavonoids/chemistry , Rhizome/chemistry , Polyphenols/isolation & purification , Polyphenols/analysisABSTRACT
Non-alcoholic steatohepatitis (NASH) is becoming an increasingly serious global health threat, distinguished by hepatic lipid accumulation, inflammation, and fibrosis. There is a lack of approved pharmaceutical interventions for this disease, highlighting the urgent need for effective treatment. This study explores the hepatoprotective potential of 6-shogaol, a natural compound derived from ginger, in a methionine- and choline-deficient (MCD) dietary mouse model of NASH. Male C57BL/6J mice were subjected to the MCD diet for 4 weeks to induce NASH, with concurrent intraperitoneal administration of 6-shogaol (20 mg/kg) three times a week. While 6-shogaol did not impact body weight, liver weight, or hepatic lipid accumulation, it effectively mitigated liver injury, inflammation, and fibrosis in MCD diet-fed mice. Mechanistically, 6-shogaol inhibited lipid and DNA oxidation, restored hepatic glutathione levels, and regulated the expression of pro-oxidant and antioxidant enzymes. Furthermore, 6-shogaol inhibited apoptosis and necroptosis, as indicated by a decrease in TUNEL-stained cells and downregulation of apoptosis- and necroptosis-associated proteins. Additionally, 6-shogaol alleviated endoplasmic reticulum (ER) stress, as demonstrated by decreased expression of molecules associated with unfolded protein response pathways. These findings underscore the potential of 6-shogaol as a therapeutic intervention for NASH by targeting pathways related to oxidative stress, cell death, and ER stress.
Subject(s)
Catechols , Hepatitis , Non-alcoholic Fatty Liver Disease , Male , Animals , Mice , Mice, Inbred C57BL , Methionine , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/etiology , Racemethionine , Diet , Cell Death , Oxidative Stress , Endoplasmic Reticulum Stress , Inflammation/drug therapy , Choline , Fibrosis , Liver Cirrhosis/drug therapy , Liver Cirrhosis/etiology , LipidsABSTRACT
In this study, we have investigated the chemopreventive role of 6-shogaol (6-SGL) on benzopyrene (BaP) exposed lung carcinogenesis by modulating PRDX1-associated oxidative stress, inflammation, and proliferation in Swiss albino mouse models. Mice were exposed to BaP (50 mg/kg b.wt) orally twice a week for four consecutive weeks and maintained for 16 weeks, respectively. 6-SGL (30 mg/kg b.wt) were orally administered to mouse 1 h before BaP exposure for 16 weeks. After the experiment's termination, 6-SGL (30 mg/kg b.wt) prevented the loss in body weight, increased lung weight, and the total number of tumors in the mice. Moreover, we observed that 6-SGL treatment reverted the activity of BaP-induced lipid peroxidation and antioxidants in mice. Also, 6-SGL impeded the phosphorylation of MAPK family proteins such as Erk1, p38, and Jnk1 in BaP-exposed mice. PRDX1 is an essential antioxidant protein that scavenges toxic radicals and enhances several antioxidant proteins. Overexpression of PRDX1 substantially inhibits MAPKs, proliferation, and inflammation signaling axis. Hence, PRDX1 is thought to be a novel targeting protein for preventing BaP-induced lung cancer. In this study, we have obtained the 6-SGL treatment in a mouse model that reverted BaP-induced depletion of PRDX1 expression. Moreover, pretreatment of 6-SGL (30 mg/kg b.wt) significantly inhibited enhanced proinflammatory cytokines (TNF-α, IL-6, IL-ß1, IL-10) and proliferative markers (Cyclin-D1, Cyclin-D2, and PCNA) in BaP-exposed mice. The histopathological studies also confirmed that 6-SGL effectively protected the cells with less damage. Thus, the study demonstrated that 6-SGL could be a potential phytochemical and act as a chemopreventive agent in BaP-induced lung cancer by enhancing PRDX1 expression.
Subject(s)
Antioxidants , Lung Neoplasms , Mice , Animals , Antioxidants/metabolism , Benzo(a)pyrene/toxicity , Oxidative Stress , Lung , Carcinogenesis , Inflammation/metabolism , Lung Neoplasms/chemically induced , Lung Neoplasms/prevention & control , Lung Neoplasms/metabolism , Disease Models, Animal , Cell Proliferation , Cyclins/metabolism , Cyclins/pharmacologyABSTRACT
[This corrects the article DOI: 10.3389/fmolb.2022.808162.].
ABSTRACT
Cancer is a malignant disease that has plagued human beings all the time, but the treatment effect of commonly used anticancer drugs in clinical practice is not ideal by reason of their drug tolerance and Strong adverse reactions to patients. Therefore, it is imperative to find effective and low-toxic anticancer drugs. Many research works have shown that natural products in Chinese herbal medicine have great anticancer potential, such as 6-shogaol, a monomer composition obtained from Chinese herbal ginger, which has been confirmed by numerous in vitro or vivo studies to be an excellent anti-cancer active substance. In addition, most notably, 6-shogaol has different selectivity for normal and cancer cells during treatment, which makes it valuable for further research and clinical development. Therefore, this review focus on the anti-cancer attributes, the mechanism and the regulation of related signaling pathways of 6-shogaol. In addition, its synergy with commonly used anticancer drugs, potential drug delivery systems and prospects for future research are discussed. This is the first review to comprehensively summarize the anti-cancer mechanism of 6-shogaol, hoping to provide a theoretical basis and guiding significance for future anti-cancer research and clinical development of 6-shogaol.
ABSTRACT
Oxaliplatin is a chemotherapy drug that can induce severe acute neuropathy in patients within hours of treatment. In our previous study, 10 mg/kg [6]-shogaol (i.p.) significantly alleviated cold and mechanical allodynia induced by a 6 mg/kg oxaliplatin injection (i.p.); however, the precise serotonin-modulatory effect has not been investigated. In this study, we showed that intrathecal injections of NAN-190 (5-HT1A receptor antagonist, 1 µg) and MDL-72222 (5-HT3 receptor antagonist, 15 µg), but not ketanserin (5-HT2A receptor antagonist, 1 µg), significantly blocked the analgesic effect of [6]-shogaol (10 mg/kg, i.p.). Furthermore, the gene expression of the serotonin-synthesizing enzyme tryptophan hydroxylase 2 (TPH2) and serotonin levels in the spinal cord and serum were significantly downregulated (p < 0.0001 and p = 0.0002) and upregulated (p = 0.0298 and p = 0.0099) after oxaliplatin and [6]-shogaol administration, respectively. Moreover, both the gene and protein expression of the spinal serotonin receptors 5-HT1A and 5-HT3 significantly increased after [6]-shogaol injections (p < 0.0001). Finally, intrathecal injections of both receptor agonists (8-OH-DPAT; 5-HT1A receptor agonist, 10 µg and m-CPBG; 5-HT3 receptor agonist, 15 µg) mimicked the effects of [6]-shogaol in oxaliplatin-injected mice. Taken together, these results demonstrate that [6]-shogaol attenuates oxaliplatin-induced neuropathic pain by modulating the spinal serotoninergic system.
ABSTRACT
Under physiological or pathological conditions, transient receptor potential (TRP) channel vanilloid type 1 (TRPV1) and TRP ankyrin 1 (TRPA1) possess the ability to detect a vast array of stimuli and execute diverse functions. Interestingly, increasing works have reported that activation of TRPV1 and TRPA1 could also be beneficial for ameliorating postoperative ileus (POI). Increasing research has revealed that the gastrointestinal (GI) tract is rich in TRPV1/TRPA1, which can be stimulated by capsaicin, allicin and other compounds. This activation stimulates a variety of neurotransmitters, leading to increased intestinal motility and providing protective effects against GI injury. POI is the most common emergent complication following abdominal and pelvic surgery, and is characterized by postoperative bowel dysfunction, pain, and inflammatory responses. It is noteworthy that natural herbs are gradually gaining recognition as a potential therapeutic option for POI due to the lack of effective pharmacological interventions. Therefore, the focus of this paper is on the TRPV1/TRPA1 channel, and an analysis and summary of the processes and mechanism by which natural herbs activate TRPV1/TRPA1 to enhance GI motility and relieve pain are provided, which will lay the foundation for the development of natural herb treatments for this disease.
Subject(s)
Ileus , Plants, Medicinal , Humans , TRPA1 Cation Channel , Ileus/drug therapy , Pain , Plant Extracts , TRPV Cation Channels/physiologyABSTRACT
Hypertrophic stress-induced cardiac remodeling is a compensatory mechanism associated with cardiomyocyte hypertrophy and cardiac fibrosis. Continuation of this response eventually leads to heart failure. The histone acetyltransferase p300 plays an important role in the development of heart failure, and may be a target for heart failure therapy. The phenolic phytochemical 6-shogaol, a pungent component of raw ginger, has various bioactive effects; however, its effect on cardiovascular diseases has not been investigated. One micromolar of 6-shogaol suppressed phenylephrine (PE)-induced increases in cardiomyocyte hypertrophy in rat primary cultured cardiomyocytes. In rat primary cultured cardiac fibroblasts, 6-shogaol suppressed transforming growth factor-beta (TGF-ß)-induced increases in L-proline incorporation. It also blocked PE- and TGF-ß-induced increases in histone H3K9 acetylation in the same cells and in vitro. An in vitro p300-HAT assay revealed that 6-shogaol suppressed histone acetylation. The mice underwent transverse aortic constriction (TAC) surgery, and were administered 0.2 or 1 mg/kg of 6-shogaol daily for 8 weeks. 6-shogaol prevented TAC-induced systolic dysfunction and cardiac hypertrophy in a dose-dependent manner. Furthermore, it also significantly inhibited TAC-induced increases in histone H3K9 acetylation. These results suggest that 6-shogaol may ameliorate heart failure through a variety of mechanisms, including the inhibition of p300-HAT activity.
Subject(s)
Aortic Valve Stenosis , Heart Failure , Zingiber officinale , Animals , Mice , Rats , Acetylation , Histones , Heart Failure/drug therapy , Heart Failure/etiology , Anti-Arrhythmia Agents , Cardiotonic Agents , Diuretics , GlycosidesABSTRACT
Parkinson's disease (PD) which has various pathological mechanisms, recently, it is attracting attention to the mechanism via microbiome-gut-brain axis. 6-Shogaol, a representative compound of ginger, have been known for improving PD phenotypes by reducing neuroinflammatory responses. In the present study, we investigated whether 6-shogaol and ginger attenuate degeneration induced by Proteus mirabilis (P. mirabilis) on the intestine and brain, simultaneously. C57BL/6J mice received P. mirabilis for 5 days. Ginger (300 mg/kg) and 6-shogaol (10 mg/kg) were treated by gavage feeding for 22 days including the period of P. mirabilis treatment. Results showed that 6-shogaol and ginger improved motor dysfunction and dopaminergic neuronal death induced by P. mirabilis treatment. In addition, they suppressed P. mirabilis-induced intestinal barrier disruption, pro-inflammatory signals such as toll-like receptor and TNF-α, and intestinal α-synuclein aggregation. Moreover, ginger and 6-shogaol significantly inhibited neuroinflammation and α-synuclein in the brain. Taken together, 6-shogaol and ginger have the potential to ameliorate PD-like motor behavior and degeneration of dopaminergic neurons induced by P. mirabilis in mice. Here, these findings are meaningful in that they provide the first experimental evidence that 6-shogaol might attenuate PD via regulating gut-brain axis.
ABSTRACT
6-Shogaol from ginger has anti-inflammatory, anti-oxidation and anti-cancer effects. Aim of the Study: To study the effects and possible mechanisms of 6-Shogaol on inhibiting the migration of colon cancer cells Caco2 and HCT116 and prove the effects on proliferation and apoptosis. Materials and methods: The cells were treated with 6-Shogaol at the concentrations of 20, 40, 60, 80, and 100 µM, the cytotoxicity was tested by Colony formation assays and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and the Western blot was used to evaluate IKKß/NF-κB/Snail pathway and EMT-related proteins. In addition, in order to eliminate the interference of proliferation inhibition on the experiment, Caco2 cells were treated with 6-Shogaol at the concentrations of 0, 40, and 80 µM, HCT116 cells were treated with 6-Shogaol at the concentrations of 0, 20, and 40 µM, apoptosis was measured by Annex V/PI staining, and migration was measured by Wound healing assays and Transwell test. Results: 6-Shogaol significantly inhibited the growth of cells. The maximum inhibitory concentration of half of them was 86.63 µM in Caco2 cells and 45.25 µM in HCT116 cells. At 80 µM and 40 µM concentrations, 6-Shogaol significantly promoted apoptosis of colon cancer Caco2 cells and HCT116 cells, and also significantly inhibited cell migration (P < .05). In addition, Western blot analysis showed that at 80 µM dose of 6-Shogaol significantly reduced MMP-2, N-cadherin, IKKß, P-NF-κB and Snail expression in Caco2 cells (P < .05). 40 µM dose of 6-Shogaol significantly reduced VEGF, IKKß, and P-NF-κB expression, and MMP-2, N-cadherin and Snail was significantly decreased at 60 µM of 6-Shogaol in HCT116 cells(P < .05). However, there was no significant change in E-cadherin in Caco2 cells, and the expression of E-cadherin protein in HCT116 cells decreased. Conclusion: This study proposes and confirms that 6-Shogaol can significantly inhibit the migration of colon cancer cells Caco2 and HCT116, and its mechanism may be produced by inhibiting EMT through IKKß/NF-κB/Snail signaling pathway. It was also confirmed that 6-Shogaol inhibited the proliferation and promoted apoptosis of Caco2 and HCT116 cells.
Subject(s)
Colonic Neoplasms , NF-kappa B , Humans , NF-kappa B/metabolism , I-kappa B Kinase/pharmacology , I-kappa B Kinase/therapeutic use , Matrix Metalloproteinase 2 , Caco-2 Cells , Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , Cadherins/metabolism , Cadherins/pharmacology , Cadherins/therapeutic use , Cell Movement , Cell Proliferation , Cell Line, Tumor , Epithelial-Mesenchymal TransitionABSTRACT
SCOPE: Intestinal ischemia-reperfusion (II/R) injury is a common pathological process with high morbidity and mortality. Effective prevention and treatment therapies for II/R are clinically necessary. 6-Shogaol (6-SG), the main active ingredient in dried ginger, behaviors multiple biological activities, including anti-inflammation, antioxidation, and anti-apoptosis. This study aims to elucidate the protective effects and mechanism of 6-SG against II/R-induced injury. METHODS AND RESULTS: Sprague-Dawley rats are pre-treated orally with 6-SG and subjected to II/R injury by clamping superior mesenteric artery for 1 h and reperfusion for 2 h. Caco-2 cells are challenged by hypoxia/reoxygenation to mimic II/R in vitro. 6-SG pre-treatment protects against II/R injury by reducing intestinal morphological damage and intestinal barrier injury via inhibiting cell apoptosis. Network pharmacology and molecular docking analyses reveal that 6-SG has a high affinity with brain-derived neurotrophic factor (BDNF) formed homodimer or heterodimer with NT4 instead of the monomer, and thus the dimer configuration is stabilized, activating BDNF/TrkB/PI3K/AKT signaling pathway and inhibiting II/R-induced cell apoptosis. The outcome is further validated both in vivo and in vitro. CONCLUSION: 6-Shogaol protects against II/R injury by inhibiting cell apoptosis through the BDNF/TrkB/PI3K/AKT pathway. This study offers a new understanding of the protection mechanism of 6-SG against II/R-induced injury.
Subject(s)
Intestinal Diseases , Reperfusion Injury , Zingiber officinale , Humans , Rats , Animals , Proto-Oncogene Proteins c-akt/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Rats, Sprague-Dawley , Caco-2 Cells , Molecular Docking Simulation , Reperfusion Injury/drug therapy , Reperfusion Injury/prevention & control , Reperfusion , IschemiaABSTRACT
Inhibition of thioredoxin reductase (TrxR) is a crucial strategy for the discovery of antineoplastic drugs. 6-Shogaol (6-S), a primary bioactive compound in ginger, has high anticancer activity. However, its potential mechanism of action has not been thoroughly investigated. In this study, we demonstrated for the first time that 6-S, a novel TrxR inhibitor, promoted oxidative-stress-mediated apoptosis in HeLa cells. The other two constituents of ginger, 6-gingerol (6-G) and 6-dehydrogingerduone (6-DG), have a similar structure to 6-S but fail to kill HeLa cells at low concentrations. 6-Shogaol specifically inhibits purified TrxR1 activity by targeting selenocysteine residues. It also induced apoptosis and was more cytotoxic to HeLa cells than normal cells. The molecular mechanism of 6-S-mediated apoptosis involves TrxR inhibition, followed by an outburst of reactive oxygen species (ROS) production. Furthermore, TrxR knockdown enhanced the cytotoxic sensitivity of 6-S cells, highlighting the physiological significance of targeting TrxR by 6-S. Our findings show that targeting TrxR by 6-S reveals a new mechanism underlying the biological activity of 6-S and provides meaningful insights into its action in cancer therapeutics.