The objective of this study was to investigate the hepatoprotective efficacy and mechanism of action of ginger essential oil (GEO) against the development of nonalcoholic fatty liver disease (NAFLD). ...Mice were maintained on either a control diet or high-fat diet (HFD) supplemented with GEO (12.5, 62.5, and 125 mg/kg) or citral (2.5 and 25 mg/kg) for 12 weeks. We demonstrated that GEO and its major component (citral) lowered HFD-induced obesity in a dose-dependent manner, accompanied by anti-hyperlipidemic effects by reducing serum free fatty acid, triglyceride, and total cholesterol levels. Moreover, liver histological results showed that administration of 62.5 and 125 mg/kg GEO and 25 mg/kg citral significantly reduced hepatic lipid accumulation. Further assessment by Western blotting and investigation of the lipid metabolism revealed that hepatic protein expression of sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), and cytochrome P450 2E1 (CYP2E1) were down-regulated by GEO and citral, indicating that GEO and citral suppressed HFD-stimulated lipid biosynthesis and oxidative stress. Furthermore, GEO and citral effectively enhanced the antioxidant capacities and reduced inflammatory response in mouse liver, which exerted protective effects against steatohepatitis. Collectively, GEO and citral exhibited potent hepatoprotective effects against NAFLD induced by HFD in obese mice. Thus, GEO might be an effective dietary supplement to ameliorate NAFLD-related metabolic diseases, and citral could play a vital role in its management.
Gastrodia elata Blume is a highly valuable traditional Chinese medicine used in the treatment of depression. However, compounds with antidepressant effects in water extracts of G. elata Bl. (WGE) ...have not been identified. The aims of this study were to determine the major antidepressant compound in WGE and to evaluate the antidepressant effects of WGE and its active compounds which involved the monoaminergic system and neuronal cytoskeletal remodeling.
Gastrodin (GAS) and 4-hydroxybenzyl alcohol (HBA) in WGE, were analyzed with high-performance liquid chromatography (HPLC)-ultraviolet detection.
The forced swimming test (FST) was used to induce depression-like symptoms in 9 weeks old male Sprague-Dawley rats. The open field test (OFT) was used to measure anxiety after WGE, GAS, and HBA treatments. The levels of monoamine such as serotonin (5-HT), dopamine (DA), and their metabolites 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured using HPLC-electrochemical detection. Western blotting was used to examine the 5-HT1A receptor and the neuronal cytoskeleton remodeling-related proteins, Slit, dihydropyrimidinase-related protein 2 (DPYSL2, also called CRMP2), Ras homologous member A (RhoA), and profilin 1 (PFN1) in vivo. Slit1 expression was evaluated in Hs683 cell line after treated with WGE (0.5mg/mL), GAS (50, 100 and 100μM), and HBA (50, 100 and 100μM).
Oral administration of WGE (500mg/kg bw), GAS (100mg/kg bw), and HBA (100mg/kg bw) exhibited the anti-depressant effect by significantly reducing the immobility time in FST, monoamine metabolism including the 5-HT to 5-HIAA in the hippocampus and DA to DOPAC and HVA ratios in the frontal cortex, amygdala, and hippocampus. In the hippocampus, the expression of the neuronal cytoskeleton remodeling-related negative regulators Slit1 and RhoA were significantly down-regulated. In addition, the positive regulators CRMP2 and PFN1 were significantly up-regulated following GAS, HBA, and WGE treatments. Moreover, WGE, GAS, and HBA were directly down-regulated Slit1 expression in Hs683 cells.
WGE, GAS, and HBA exhibited potential anti-depressant effects in rats by decreasing monoamine metabolism and modulated cytoskeleton remodeling-related protein expression in the Slit-Robo pathway. These results suggest that WGE can be used as agent for depressive prevention.
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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of its late diagnosis and chemoresistance. Primary cilia, the cellular antennae, are observed in most human cells to ...maintain development and differentiation. Primary cilia are gradually lost during the progression of pancreatic cancer and are eventually absent in PDAC. Here, we showed that cisplatin‐resistant PDAC regrew primary cilia. Additionally, genetic or pharmacological disruption of primary cilia sensitized PDAC to cisplatin treatment. Mechanistically, ataxia telangiectasia mutated (ATM) and ATM and RAD3‐related (ATR), tumor suppressors that initiate DNA damage responses, promoted the excessive formation of centriolar satellites (EFoCS) and autophagy activation. Disruption of EFoCS and autophagy inhibited primary ciliogenesis, sensitizing PDAC cells to cisplatin treatment. Collectively, our findings revealed an unexpected interplay among the DNA damage response, primary cilia, and chemoresistance in PDAC and deciphered the molecular mechanism by which ATM/ATR‐mediated EFoCS and autophagy cooperatively regulate primary ciliogenesis.
Schematic overview of cisplatin treatment induces primary cilia regrowth which causes chemoresistance occurred in pancreatic cancer cells.
Cisplatin treatment in pancreatic cancer cells induces ATM and ATR activation, which trigger excessive formation of centriolar satellites (EFoCS) and autophagy cooperatively contribute to primary ciliogenesis, thus leading to chemoresistance.
Because of the high incidence of cardiovascular diseases in Asian countries, traditional fermented foods from Asia have been increasingly investigated for antiatherosclerotic effects. This study ...investigated the production of nattokinase, a serine fibrinolytic enzyme, in pigeon pea by Bacillus subtilis fermentation. B. subtilis 14714, B. subtilis 14715, B. subtilis 14716, and B. subtilis 14718 were employed to produce nattokinase. The highest nattokinase activity in pigeon pea was obtained using B. subtilis 14715 fermentation for 32 hours. In addition, the levels of antioxidants (phenolics and flavonoids) and angiotensin converting enzyme inhibitory activity were increased in B. subtilis 14715-fermented pigeon pea, compared with those in nonfermented pigeon pea. In an animal model, we found that both water extracts of pigeon pea (100 mg/kg body weight) and water extracts of B. subtilis-fermented pigeon pea (100 mg/kg body weight) significantly improved systolic blood pressure (21 mmHg) and diastolic blood pressure (30 mmHg) in spontaneously hypertensive rats. These results suggest that Bacillus-fermented pigeon pea has benefits for cardiovascular health and can be developed as a new dietary supplement or functional food that prevents hypertension.
Gastrodia elata Blume (GE) is a traditional herbal medicine belonging to the Orchidaceae family, and has been used to manage neurological disorders for centuries. We have previously reported that its ...water extract (WGE) could improve the depressive-like behaviours in the forced swimming test (FST), an animal model of depression.
To investigate the antidepressant-like effects of WGE in rats exposed to unpredictable chronic mild stress (UCMS) model, and to explore its possible molecular mechanisms.
UCMS rats were orally administered with WGE (0.5g/kg body weight) daily within the 4 weeks UCMS procedure. The sucrose preference test and the open field test were conducted to assess anhedonia and spontaneous behaviours, respectively. The cerebral turnover rates of monoamine neurotransmitters and the serum corticosterone levels were measured. In vitro direct and indirect monoamine oxidase A (MAO-A) inhibitory assays were employed to assess the possible antidepressant-like mechanisms of WGE (0.5mg/mL) and its major component, gastrodin (GAS, 15, 30 and 60μg/mL). Western blot was used to examine the expression of protein related to monoamine regulation, such as MAO-A and tyrosine hydroxylase (TH).
WGE significantly reversed the sucrose preference and other abnormal behaviours induced by 4 weeks of UCMS. WGE significantly restored the cerebral turnover rates of serotonin and dopamine and decreased serum corticosterone levels. WGE and gastrodin inhibited the activity and protein expression of MAO-A, and increased TH levels in PC12 cells.
The antidepressant-like effects of WGE and gastrodin might be mediated by the regulation of monoamine neurotransmitters, and therefore were beneficial in depression treatment as a complementary approach.
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Obesity, dyslipidemia, insulin resistance, oxidative stress, and inflammation are key clinical risk factors for the progression of non-alcoholic fatty liver disease (NAFLD). Currently, there is no ...comprehensive metabolic profile of a well-established animal model that effectively mimics the etiology and pathogenesis of NAFLD in humans. Here, we report the pathophysiological and metabolomic changes associated with NAFLD development in a C57BL/6J mouse model in which NAFLD was induced by feeding a high-fat diet (HFD) for 4, 8, 12, and 16 weeks. Serum metabolomic analysis was conducted using ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC–QTOF–MS) and gas chromatography–mass spectrometry (GC–MS) to establish a metabolomic profile. Analysis of the metabolomic profile in combination with principal component analysis revealed marked differences in metabolites between the control and HFD group depending upon NAFLD severity. A total of 30 potential biomarkers were strongly associated with the development of NAFLD. Among these, 11 metabolites were mainly related to carbohydrate metabolism, hepatic biotransformation, collagen synthesis, and gut microbial metabolism, which are characteristics of obesity, as well as significantly increased serum glucose, total cholesterol, and hepatic triglyceride levels during the onset of NAFLD (4 weeks). At 8 weeks, 5 additional metabolites that are chiefly involved in perturbation of lipid metabolism and insulin secretion were found to be associated with hyperinsulinemia, hyperlipidemia, and hepatic steatosis in the mid-term of NAFLD progression. At the end of 12 and 16 weeks, 14 additional metabolites were predominantly correlated to abnormal bile acid synthesis, oxidative stress, and inflammation, representing hepatic inflammatory infiltration during NAFLD development. These results provide potential biomarkers for early risk assessment of NAFLD and further insights into NAFLD development.
Background and aim: Garlic essential oil (GEO) isolated from Garlic (Allium sativum L.) exerts biological activities in disease prevention, particularly in metabolic and liver diseases, and is used ...for a dietary therapy for centuries. However, due to the side effects associated with the excessive consumption of GEO, there is a need to evaluate the safety of the GEO. Experimental procedure: Ames test using five Salmonella typhimurium strains (TA98, TA100, TA102, TA1535, and TA1537) and Chinese hamster ovary (CHO-K1) cells with or without metabolic activation (S9 system), and mammalian erythrocyte micronucleus test were used to assess the genotoxicity and clastogenic effects of GEO. A repeated dose of GEO (15, 25, and 50 mg/kg body weight, p.o.) were administrated to ICR mice for 28 days to ascertain the subacute toxicity of GEO. Results and conclusions: The results of the Ames test with or without S9 system indicated that GEO did not induce mutagenicity nor have clastogenic effects in CHO-K1 cells with or without S9 activation. Furthermore, GEO did not affect the ratio of immature to total erythrocytes or the number of micronuclei in immature erythrocytes of ICR mice after 24 and 48 h. In a 28-day oral toxicity assessment, GEO (15, 25, and 50 mg/kg body weight, p.o.)-fed ICR mice exhibited normal behaviors, mortality, body weight, daily intake, hematology, clinical biochemistry, and organ weight. GEO shows no genotoxicity, and the no-observed- adverse-effect level (NOAEL) for GEO is considered to be greater than 50 mg/kg bw/day orally for 28 days in mice.
Abstract
Background
Esophageal squamous cell carcinoma (ESCC) is widely prevalent in Taiwan, and high metastatic spread of ESCC leads to poor survival rate. Fibronectin (FN) assembly on the cell ...membrane may induce ESCC mobility. MicroRNAs (MiRNAs) are abundant in and participate in tumorigenesis in many cancers. However, the role of MiRNA in FN assembly-related ESCC mobility remains unexplored.
Methods
We divided ESCC CE81T cells into high-FN assembly (CE81
FN+
) and low-FN assembly (CE81
FN−
) groups by flow cytometry. MiRNA microarray analysis identified
miR-146a
expression as the most down-regulated miRNA in comparison of CE81
FN+
and CE81
FN−
cells.
Results
Cell proliferation and migration were decreased when CE81
FN+
cells overexpressed transgenic
miR-146a
compared to the parental cells, indicating an inverse correlation between low
miR-146a
expression and high proliferation as well as motility of FN assembly ESCC cells. Furthermore, vimentin is the target gene of
miR-146a
involved in ESCC tumorigenesis.
MiR-146a
suppressed cell proliferation, migration and invasion of CE81
FN+
cells through the inhibition of vimentin expression, as confirmed by real-time PCR, Western blotting and Transwell™ assay. Analysis of one hundred and thirty-six paired ESCC patient specimens revealed that low
miR-146a
and high vimentin levels were frequently detected in tumor, and that the former was associated with late tumor stages (III and IV). Notably, either low
miR-146a
expression or high vimentin level was significantly associated with poor overall survival rate among ESCC patients.
Conclusions
This is the first report to link FN assembly in the cell membrane with
miR-146a
, vimentin and ESCC tumorigenesis both in vitro and in ESCC patients.
This study investigated the protective properties of garlic essential oil (GEO) and its major organosulfur component (diallyl disulfide, DADS) against the development of nonalcoholic fatty liver ...disease (NAFLD). C57BL/6J mice were fed a normal or high-fat diet (HFD) with/without GEO (25, 50, and 100 mg/kg) or DADS (10 and 20 mg/kg) for 12 weeks. GEO and DADS dose-dependently exerted antiobesity and antihyperlipidemic effects by reducing HFD-induced body weight gain, adipose tissue weight, and serum biochemical parameters. Administration of 50 and 100 mg/kg GEO and 20 mg/kg DADS significantly decreased the release of pro-inflammatory cytokines in liver, accompanied by elevated antioxidant capacity via inhibition of cytochrome P450 2E1 expression during NAFLD development. The anti-NAFLD effects of GEO and DADS were mediated through down-regulation of sterol regulatory element binding protein-1c, acetyl-CoA carboxylase, fatty acid synthase, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase, as well as stimulation of peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase-1. These results demonstrate that GEO and DADS dose-dependently protected obese mice with long-term HFD-induced NAFLD from lipid accumulation, inflammation, and oxidative damage by ameliorating lipid metabolic disorders and oxidative stress. The dose of 20 mg/kg DADS was equally as effective in preventing NAFLD as 50 mg/kg GEO containing the same amount of DADS, which demonstrates that DADS may be the main bioactive component in GEO.
The intestinal microbiome plays an important role in the pathogenesis of liver diseases. Alcohol intake induces gut microbiota dysbiosis and alters its function. This study investigated the ...antibiotic effect of allicin in mice with hepatic steatosis. Male C57BL/6 mice were administered an ethanol diet supplemented with allicin (5 and 20 mg/(kg bw day)) for 4 weeks. Allicin modified the gut microbiota composition. Cecal microbiota exhibited a positive correlation with alcohol and hepatic triacylglycerol, but were suppressed with allicin. Ethanol diet with 5 mg of allicin induced a lower intestinal permeability compared to the ethanol diet alone. Allicin mediated the lipopolysaccharide (LPS)–CD14–toll-like receptor 4 (TLR4)-induced hepatic inflammation pathway by reducing LPS, CD14, TLR4, and pro-inflammatory cytokinestumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. However, hepatic inflammation primarily resulted from alcohol toxicity rather than LPS production in the gut. The prediction of functional profiles from metagenomic 16S ribosomal RNA (rRNA) data revealed different functional profiles in each group. The predicted aldehyde dehydrogenase tended to increase in alcoholic mice administered allicin. The predicted LPS-related pathway and LPS biosynthesis protein results exhibited a similar trend as plasma LPS levels. Thus, alcohol and allicin intake shapes the gut microbiota and its functional profile and improves the CD14–TLR4 pathway to alleviate inflammation in the liver.
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