ABSTRACT
BACKGROUND: Pain, the most common reasons for physician consultation, is a major symptom in many medical conditions that can significantly interfere with a person's life quality and general functioning. Almost all painkillers have its untoward effects. Therefore, seeking for a safe medication for pain relieve is notable nowadays. Paeonia lactiflora is a well-known traditional Chinese medicine. Paeoniflorin is an active component found in Paeonia lactiflora, which has been reported to inhibit formalin-induced nociceptive behavior in mice. Aims of this present study were to investigate effects of paeoniflorin on excitatory amino acid agonist- or high-dose morphine-induced nociceptive behaviors in mice. RESULTS: Paeoniflorin (100, 200, 500 nmol, i.c.v.) alone and combined with glutamatergic antagonists (MK-801 14.8 pmol, or NBQX 5 nmol, i.t.) inhibited nociception. Those agents also inhibited the clonic seizure-like excitation induced by high-dose morphine (250 nmol, i.t) in mice. Antisense oligodeoxynucleotides of NMDA receptor subunits NR1, NR2A, NR2B significantly enhanced the inhibition of paeoniflorin on excitatory amino acid-and high-dose morphine-induced nociception. Docking energy data revealed that paeoniflorin had stronger binding activity in NR2A and NR2B than NR2C of NMDA receptors. CONCLUSIONS: Results of this study indicate that paeoniflorin-induced inhibition of excitatory amino acid agonist- and high-dose morphine-induced nociceptive behaviors might be due to modulation of NMDA receptors, specifically the NR2B subunit.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Behavior, Animal/drug effects , Excitatory Amino Acid Agonists/pharmacology , Glucosides/pharmacology , Monoterpenes/pharmacology , Morphine/pharmacology , Receptors, N-Methyl-D-Aspartate/metabolism , Analgesics , Animals , Male , Mice , Mice, Inbred ICR , Oligodeoxyribonucleotides, Antisense/pharmacology , Receptors, N-Methyl-D-Aspartate/geneticsABSTRACT
BACKGROUND: Dysregulated epidermal growth factor receptor (EGFR)-phosphoinositide-3-kinase (PI3K)-AKT signaling is considered pivotal for oral cancer, and the pathway is a potential candidate for therapeutic targeting. RESULTS: A total of 108 archival samples which were from surgically resected oral cancer were examined. Immunohistochemical staining showed the protein expression of membranous wild-type EGFR and cytoplasmic phosphorylated AKT was detected in 63.9% and 86.9% of the specimens, respectively. In 49.1% of the samples, no phosphatase and tensin homolog (PTEN) expression was detected. With regard to the EGFR variant III (EGFRvIII), 75.0% of the samples showed positive expression for moderate to severe staining, 31.5% of which had high expression levels. Real-time polymerase chain reaction assays for gene copy number assessment of PIK3CA revealed that 24.8% of the samples had alterations, and of EGFR showed that 49.0% had amplification. Direct sequencing of PIK3CA gene showed 2.3% of the samples had a hotspot point mutation. Statistical assessment showed the expression of the EGFRvIII correlated with the T classification and TNM stage. The Kaplan-Meier analyses for patient survival showed that the individual status of phosphorylated AKT and EGFRvIII led to significant differences in survival outcome. The multivariate analysis indicated that phosphorylated AKT, EGFRvIII expression and disease stage were patient survival determinants. CONCLUSIONS: Aberrations in the EGFR-PI3K-AKT pathway were frequently found in oral cancers. EGFRvIII and phosphorylated AKT were predictors for the patient survival and clinical outcome.
Subject(s)
ErbB Receptors/metabolism , Mouth Neoplasms/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Adult , Aged , ErbB Receptors/genetics , Female , Humans , Male , Middle Aged , Mouth Neoplasms/genetics , Mutation , Phosphatidylinositol 3-Kinases/genetics , Phosphorylation , Proto-Oncogene Proteins c-akt/genetics , Signal TransductionABSTRACT
BACKGROUND: Dysmenorrhea is a major problem in the general gynecology clinic. It causes discomfort among healthcare staffs and significant losses in terms of time and finances. PURPOSE: The purpose of this study was to determine the affected factors of dysmenorrhea and evaluate the self-perceived efficacy of relief methods. METHODS: A cross-sectional research design was used to collect data. Participants included 586 female students enrolled at a college in southern Taiwan. Data was analyzed using a t-test, one-way ANOVA, and Scheffe test. RESULTS: Traditional Chinese medicine pattern identifications related significantly to dysmenorrhea frequency perception. Lifestyle characteristics related significantly to dysmenorrhea level perception. Using shenghua decoction, siwu and pig blood decoction, Angelica drink, ginger, ziziphus jujube, brown sugar tea, and analgesics all related significantly to dysmenorrhea relief efficacy. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Strategies found to help relieve dysmenorrhea level perception include increasing the duration and regularity of sleep and avoiding the consumption of pungent foods. Seeking and adhering to physician recommendations can also increase dysmenorrhea self-care efficacy. Dysmenorrhea-relief courses should be improved in hospitals and schools to assist women to self-manage dysmenorrhea more effectively.
Subject(s)
Dysmenorrhea/etiology , Adolescent , Adult , Cross-Sectional Studies , Dysmenorrhea/therapy , Female , Humans , Self Care , Self Concept , Students , TaiwanABSTRACT
Rationale: NRF2, a redox sensitive transcription factor, is up-regulated in head and neck squamous cell carcinoma (HNSCC), however, the associated impact and regulatory mechanisms remain unclear. Methods: The protein expression of NRF2 in HNSCC specimens was examined by IHC. The regulatory effect of c-MYC on NRF2 was validated by ChIP-qPCR, RT-qPCR and western blot. The impacts of NRF2 on malignant progression of HNSCC were determined through genetic manipulation and pharmacological inhibition in vitro and in vivo. The gene-set enrichment analysis (GSEA) on expression data of cDNA microarray combined with ChIP-qPCR, RT-qPCR, western blot, transwell migration/ invasion, cell proliferation and soft agar colony formation assays were used to investigate the regulatory mechanisms of NRF2. Results: NRF2 expression is positively correlated with malignant features of HNSCC. In addition, carcinogens, such as nicotine and arecoline, trigger c-MYC-directed NRF2 activation in HNSCC cells. NRF2 reprograms a wide range of cancer metabolic pathways and the most notable is the pentose phosphate pathway (PPP). Furthermore, glucose-6-phosphate dehydrogenase (G6PD) and transketolase (TKT) are critical downstream effectors of NRF2 that drive malignant progression of HNSCC; the coherently expressed signature NRF2/G6PD/TKT gene set is a potential prognostic biomarker for prediction of patient overall survival. Notably, G6PD- and TKT-regulated nucleotide biosynthesis is more important than redox regulation in determining malignant progression of HNSCC. Conclusions: Carcinogens trigger c-MYC-directed NRF2 activation. Over-activation of NRF2 promotes malignant progression of HNSCC through reprogramming G6PD- and TKT-mediated nucleotide biosynthesis. Targeting NRF2-directed cellular metabolism is an effective strategy for development of novel treatments for head and neck cancer.
Subject(s)
Glucosephosphate Dehydrogenase/genetics , Head and Neck Neoplasms/genetics , NF-E2-Related Factor 2/genetics , Proto-Oncogene Proteins c-myc/genetics , Transketolase/genetics , Biomarkers, Tumor/genetics , Cell Line , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Disease Progression , Gene Expression Regulation, Neoplastic/genetics , Head and Neck Neoplasms/pathology , Humans , Metabolic Networks and Pathways/genetics , Oxidation-Reduction , Pentose Phosphate Pathway/genetics , Prognosis , Signal Transduction/genetics , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/pathologyABSTRACT
The present study was aimed at assessing the effects of Ganoderma lucidum extract (GLE) on an established liver fibrosis model with reference to the previously reported hepatoprotective effect of GLE against CCl(4)-induced fibrosis in rats. Repeated administration of thioacetamide (TAA) for 12 weeks to mice induced liver fibrosis. Treatment with GLE after the induction of liver fibrosis decreased the hepatic hydroxyproline content and improved liver histology. RT-qPCR analysis showed that GLE treatment reduced the mRNA expression of collagen (alpha1)(I), smooth muscle alpha-actin, tissue inhibitor of metalloproteinase 1 and metalloproteinase-13. In addition, the TAA-induced decrease in total collagenase activity was reversed by GLE treatment. In conclusion, oral administration of GLE reversed TAA-induced liver fibrosis, the mechanism of which might be related to the enhancement of collagenase activity.
Subject(s)
Liver Cirrhosis/drug therapy , Reishi/chemistry , Animals , Body Weight/drug effects , Collagenases/metabolism , Drug Evaluation, Preclinical , Hydroxyproline/metabolism , Liver/drug effects , Liver/enzymology , Liver/pathology , Liver Cirrhosis/chemically induced , Liver Cirrhosis/pathology , Male , Medicine, Chinese Traditional , Mice , Mice, Inbred BALB C , Organ Size , Reverse Transcriptase Polymerase Chain Reaction , ThioacetamideABSTRACT
Lipid peroxidation (LPO) is known to be associated with liver fibrosis in chronic liver injury. However, direct effects of the products of LPO on liver fibrogenesis are still not clear. In this study, we examined the LPO products, such as malondiladehyde (MDA), 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)), and 15-keto-13,14-dihydro-PGF(2alpha) (15-keto-PGF(2alpha)), on the activation of hepatic stellate cells (HSCs) in vivo and in vitro. Carbon tetrachloride (CCl(4)) was given orally to rats twice a week for 8 weeks. Corn oil was given daily to rats for 8 weeks. CCl(4) induced both free-radical-medicated and cyclooxygenase-2-dependent LPO. Free radical-medicated LPO showed an increase with corn oil treatment, whereas no effect was reflected on COX-2-dependent LPO. CCl(4) induced liver fibrosis in rats, but no liver fibrosis was observed in rats treated with corn oil. In vitro studies demonstrated that MDA, 8-iso-PGF(2alpha) and 15-keto-PGF(2alpha), did not activate HSCs, which were preactivated or not preactivated by TGF-beta1. Our results clearly indicate that LPO products, such as MDA, 8-iso-PGF(2alpha) and 15-keto-PGF(2alpha), cannot directly activate HSCs.
Subject(s)
Hepatic Stellate Cells/metabolism , Lipid Peroxidation , Liver Cirrhosis/metabolism , Liver/metabolism , Alanine Transaminase/blood , Animals , Apoptosis , Aspartate Aminotransferases/blood , Carbon Tetrachloride/toxicity , Cell Survival , Collagen Type I/genetics , Collagen Type I/metabolism , Corn Oil/administration & dosage , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Dinoprost/analogs & derivatives , Dinoprost/metabolism , Dinoprost/pharmacology , Hepatic Stellate Cells/drug effects , Hydroxyproline/metabolism , Liver/drug effects , Liver/pathology , Liver Cirrhosis/chemically induced , Liver Cirrhosis/pathology , Liver Function Tests , Male , Malondialdehyde/metabolism , Malondialdehyde/pharmacology , Microscopy, Confocal , Protein Carbonylation/drug effects , Rats , Rats, Wistar , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism , Transforming Growth Factor beta1/pharmacologyABSTRACT
The protective effect of a fermented substance from Saccharomyces cerevisiae (FSSC) on liver injury caused by acetaminophen (AAP) was studied in mice. Mice were pretreated with FSSC (0.5-2.0 g/kg, p.o.) for 4 d, and on the fourth day, the mice received an overdose of AAP (500 mg/kg, i.p.). Subsequently, they were sacrificed at 7 h, and blood was drawn from the abdominal vein and liver samples were collected. Histological and biochemical examinations revealed that the administration of AAP caused liver injury in the mice, including increases in plasma alanine aminotransferase and asparate aminotransferase activities and decreases in the hepatic reduced form of glutathione (GSH) content and antioxidant enzyme activities. Prior to AAP treatment, the mice pretreated with FSSC showed significantly reduced levels of alanine aminotransferase (ALT) and aspirate aminotransferase (AST) activity. Liver histology in the FSSC-pretreated mice was significant. In these mice, pretreatment with FSSC also served to reduce hepatic GSH depletion and the inhibition of antioxidant enzyme activity caused by AAP overdose. In conclusion, oral administration of FSSC significantly reduced AAP-induced hepatic injury in the mice.
Subject(s)
Acetaminophen/toxicity , Chemical and Drug Induced Liver Injury , Fermentation , Liver Diseases/prevention & control , Liver/drug effects , Liver/pathology , Saccharomyces cerevisiae/metabolism , Alanine Transaminase/metabolism , Animals , Aspartate Aminotransferases/metabolism , Disulfides/metabolism , Glutathione/metabolism , Lipid Peroxidation/drug effects , Liver/injuries , Liver/metabolism , Liver Diseases/metabolism , Liver Diseases/pathology , Male , Mice , Mice, Inbred BALB CABSTRACT
UNLABELLED: Lipid peroxidation (LPO) is known to be associated with liver fibrosis in chronic liver injury. However, direct effects of the products of LPO on liver fibrogenesis have not been demonstrated. In this study, we examined the LPO products of carbon tetrachloride (CCl4)+corn oil to evaluate the effect of LPO products on liver fibrosis. CCl4 was given twice a week for 8 weeks. Corn oil was given daily to rats at a dose of 2 or 10ml/kg via gastrogavage throughout the whole experiment period. CCl4 induced both cyclooxygenase (COX)-2 independent and COX-2 dependent LPO. COX-2 independent LPO was enhanced by corn oil treatment while no effect was reflected on COX-2 dependent LPO. CCl4-induced liver fibrosis in rats was not aggravated by corn oil treatment. In addition, the amount of fatty liver induced by CCl4 was increased by corn oil treatment. Though the inflammation-related UCP-2 mRNA expression was induced by CCl4, it was not aggravated by the enhancement of corn oil. CONCLUSION: corn oil enriches polyunsaturated fatty acids through COX-2 independent pathways to increase LPO products that do not enhance liver fibrosis induced by CCl4.
Subject(s)
Carbon Tetrachloride/toxicity , Corn Oil/toxicity , Lipid Peroxidation/drug effects , Liver Cirrhosis/chemically induced , Liver Cirrhosis/pathology , Liver/metabolism , Animals , Aspartate Aminotransferases/blood , Dinoprost/analogs & derivatives , Dinoprost/metabolism , Hydroxyproline/metabolism , Liver/drug effects , Liver/pathology , Liver Function Tests , Male , Malondialdehyde/metabolism , Organ Size/drug effects , Protein Carbonylation/drug effects , Rats , Rats, Wistar , Reproducibility of Results , Reverse Transcriptase Polymerase Chain Reaction , Serum Albumin/metabolism , Triglycerides/metabolismABSTRACT
AIM: Solanum nigrum (Solanaceae) has been used in traditional folk medicine for its hepatoprotective agent. The purpose of this study was to investigate the effects of Solanum nigrum extract (SNE) on thioacetamide (TAA)-induced liver fibrosis in mice. MATERIALS AND METHODS: Hepatic fibrosis was produced by TAA (0.2 g/kg, i.p.) three times a week for 12 weeks. Mice in the three TAA groups were treated daily with distilled water and SNE (0.2 or 1.0 g/kg) via gastrogavage throughout the experimental period. RESULTS: SNE reduced the hepatic hydroxyproline and alpha-smooth muscle actin protein levels of TAA-treated mice. SNE inhibited TAA-induced collagene (alpha1)(I) and transforming growth factor-beta1 (TGF-beta1) mRNA levels in the liver. Histological examination also confirmed that SNE reduced the degree of fibrosis caused by TAA treatment. CONCLUSION: Oral administration of SNE significantly reduces TAA-induced hepatic fibrosis in mice, probably through the reduction of TGF-beta1 secretion.
Subject(s)
Liver Cirrhosis/drug therapy , Plant Extracts/pharmacology , Solanum nigrum/chemistry , Actins/drug effects , Actins/metabolism , Administration, Oral , Animals , Collagen Type I/drug effects , Collagen Type I/metabolism , Dose-Response Relationship, Drug , Hydroxyproline/drug effects , Hydroxyproline/metabolism , Liver Cirrhosis/chemically induced , Male , Medicine, Traditional , Mice , Mice, Inbred BALB C , Plant Extracts/administration & dosage , Thioacetamide/toxicity , Transforming Growth Factor beta1/drug effects , Transforming Growth Factor beta1/metabolismABSTRACT
The purpose of this study was to investigate the hepatoprotective effects of Anoectochilus formosanus effective fraction (AFEF) on chronic liver damage induced by carbon tetrachloride (CCl4) in mice. CCl4 (5%; 0.1 mL/10 g body weight) was given twice a week for 9 weeks, and mice received AFEF throughout the whole experimental period. Plasma GPT, hepatic levels of hydroxyproline and malondialdehyde were significantly lower in mice treated with AFEF compared with those treated with CCl4 only. Liver pathology in the AFEF-treated mice was also improved. RT-PCR analysis showed that AFEF treatment increased the expression of methionine adenosyltransferase 1A and decreased the expression of collagen(alpha1)(I) and transforming growth factor-beta1. These results clearly demonstrated that AFEF reduced the hepatic damage induced by CCl4 in mice.
Subject(s)
Gene Expression Regulation/drug effects , Liver/drug effects , Orchidaceae/chemistry , Plant Extracts/pharmacology , Alanine Transaminase/blood , Animals , Chloroform/administration & dosage , Collagen Type I/analysis , Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/analysis , Hepatitis, Animal/chemically induced , Hydroxyproline/analysis , Lipid Peroxidation/drug effects , Liver/pathology , Male , Malondialdehyde/analysis , Methionine Adenosyltransferase/analysis , Mice , Mice, Inbred ICR , Random Allocation , Time Factors , Transforming Growth Factor beta1/analysisABSTRACT
The present study examined the effects of an ethanolic extract of the fruit of Hovenia dulcis (EHD) on chronic hepatitis induced by carbon tetrachloride (CCl(4)) in mice. CCl(4) (5%; 0.1 ml/10 g body weight) was given twice a week for 9 weeks, and mice received EHD throughout the entire experimental period. Plasma activities of GPT and GOT, and hepatic levels of malondialdehyde were significantly lowered in mice treated with EHD as compared to mice treated with CCl(4) only. Histological evaluation showed that EHD could attenuate the liver fibrosis and necrosis caused by CCl(4). RT-qPCR analysis also showed that EHD treatment decreased hepatic collagen (alpha1)(I) and collagen (alpha1)(III) mRNA expressions. Chronic CCl(4) treatment caused liver injuries in mice, characterized by an increase in hepatic methionine adenosyltransferase (MAT) 2A gene expression, and decreased MAT1A gene expression. EHD significantly reduced the changes in MAT gene expression due to the chronic CCl(4) treatment. These results clearly demonstrate that the EHD can reduce hepatic injuries in mice induced by CCl(4).
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Drugs, Chinese Herbal/therapeutic use , Phytotherapy/methods , Rhamnaceae , Administration, Oral , Animals , Aspartate Aminotransferase, Cytoplasmic/blood , Carbon Tetrachloride , Chemical and Drug Induced Liver Injury, Chronic/pathology , Collagen Type I/metabolism , Collagen Type III/metabolism , Disease Models, Animal , Drugs, Chinese Herbal/administration & dosage , Hydroxyproline/metabolism , Lipid Peroxidation/drug effects , Lipid Peroxidation/physiology , Liver/metabolism , Liver/pathology , Male , Methionine Adenosyltransferase/genetics , Methionine Adenosyltransferase/metabolism , Mice , Mice, Inbred ICRABSTRACT
AIM: To investigate the effects of filtrate of fermented mycelia from Antrodia camphorata (FMAC) on liver fibrosis induced by carbon tetrachloride (CCl(4)) in rats. METHODS: Forty Wistar rats were divided randomly into control group and model group. All model rats were given 200 mL/L CCl(4) (2 mL/Kg, po) twice a week for 8 wk. Four weeks after CCl(4) treatment, thirty model rats were further divided randomly into 3 subgroups: CCl(4) and two FMAC subgroups. Rats in CCl(4) and 2 FMAC subgroups were treated with FMAC 0, 0.5 and 1.0 g/kg, daily via gastrogavage beginning at the fifth week and the end of the eighth week. Spleen weight, blood synthetic markers (albumin and prothrombin time) and hepatic malondialdehyde (MDA) and hydroxyproline (HP) concentrations were determined. Expression of collagen I, tissue inhibitor of metalloproteinases (TIMP)-1 and transforming growth factor beta1 (TGF-beta1) mRNA were detected by RT-PCR. Histochemical staining of Masson's trichrome was performed. RESULTS: CCl(4) caused liver fibrosis, featuring increased prothrombin time, hepatic MDA and HP contents, and spleen weight and decreased plasma albumin level. Compared with CCl(4) subgroup, FMAC subgroup (1 g/kg) significantly decreased the prothrombin time (36.7+/-7.2 and 25.1+/-10.2 in CCl(4) and FMAC groups, respectively, P<0.05) and increased plasma albumin concentration (22.7+/-1.0 and 30.7+/-2.5 in CCl(4) and FMAC groups, respectively, P<0.05). Spleen weight was significantly lower in rats treated with CCl(4) and FMAC (1 g/kg) compared to CCl(4) treated rats only (2.7+/-0.1 and 2.4+/-0.2 in CCl(4) and FMAC groups, respectively, P<0.05). The amounts of hepatic MDA and HP in CCl(4)+FAMC (1 g/kg) subgroup were also lower than those in CCl(4) subgroup (MDA: 3.9+/-0.1 and 2.4+/-0.6 in CCl(4) and CCl(4)+FMAC groups, respectively, P<0.01; HP: 1730.7+/-258.0 and 1311.5+/-238.8 in CCl(4) and CCl(4)+FMAC groups, respectively, P<0.01). Histologic examinations showed that CCl(4)+FMAC subgroups had thinner or less fibrotic septa than CCl(4) group. RT-PCR analysis indicated that FMAC (1 g/kg) reduced mRNA levels of collagen I, TIMP-1 and TGF-beta1 (collagen I: 5.63+/-2.08 and 1.78+/-0.48 in CCl(4) and CCl(4)+FMAC groups, respectively, P<0.01; TIMP-1: 1.70+/-0.82 and 0.34+/-0.02 in CCl(4) and CCl(4)+FMAC groups, respectively, P<0.01; TGF-beta1:38.03+/-11.9 and 4.26+/-2.17 in CCl(4) and CCl(4)+FMAC groups, respectively, P<0.01) in the CCl(4)-treated liver. CONCLUSION: It demonstrates that FMAC can retard the progression of liver fibrosis induced by CCl(4) in rats.
Subject(s)
Liver Cirrhosis/prevention & control , Polyporales/chemistry , Animals , Base Sequence , Carbon Tetrachloride/toxicity , Collagen Type I/genetics , Fermentation , Hydroxyproline/metabolism , Liver Cirrhosis/chemically induced , Liver Cirrhosis/genetics , Liver Cirrhosis/pathology , Male , Malondialdehyde/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Wistar , Tissue Inhibitor of Metalloproteinase-1/genetics , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta1ABSTRACT
In previous research, we found α-enolase to be inversely correlated with progression-free and overall survival in lung cancer patients and detected α-enolase on the surface of lung cancer cells. Based on these findings, we hypothesized that surface α-enolase has a significant role in cancer metastasis and tested this hypothesis in the current study. We found that α-enolase was co-immunoprecipitated with urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, and plasminogen in lung cancer cells and interacted with these proteins in a cell-free dot blotting assay, which can be interrupted by α-enolase-specific antibody. α-Enolase in lung cancer cells co-localized with these proteins and was present at the site of pericellular degradation of extracellular matrix components. Treatment with antibody against α-enolase in vitro suppressed cell-associated plasminogen and matrix metalloproteinase activation, collagen and gelatin degradation, and cell invasion. Examination of the effect of treatment with shRNA plasmids revealed that down regulation of α-enolase decreases extracellular matrix degradation by and the invasion capacity of lung cancer cells. Adoptive transfer of α-enolase-specific antibody to mice resulted in accumulation of antibody in subcutaneous tumor and inhibited the formation of tumor metastasis in lung and bone. This study demonstrated that surface α-enolase promotes extracellular matrix degradation and invasion of cancer cells and that targeting surface α-enolase is a promising approach to suppress tumor metastasis.
Subject(s)
Cell Membrane/metabolism , Extracellular Matrix/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Phosphopyruvate Hydratase/metabolism , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/pharmacology , Biomarkers, Tumor/antagonists & inhibitors , Biomarkers, Tumor/metabolism , Bone Neoplasms/drug therapy , Bone Neoplasms/secondary , Cell Line, Tumor , Cell Movement , DNA-Binding Proteins/antagonists & inhibitors , DNA-Binding Proteins/metabolism , Humans , Immunocompromised Host , Lung Neoplasms/metabolism , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Mice , Neoplasm Metastasis , Neoplasms/mortality , Phosphopyruvate Hydratase/antagonists & inhibitors , Plasminogen/metabolism , Protein Binding , Receptors, Urokinase Plasminogen Activator/metabolism , Tumor Suppressor Proteins/antagonists & inhibitors , Tumor Suppressor Proteins/metabolism , Urokinase-Type Plasminogen Activator/metabolism , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND & AIMS: The aim of this study was to investigate the effect of a fermented substance from Saccharomyces cerevisiae (FSSC) on the liver fibrosis induced by chronic carbon tetrachloride (CCl(4)) administration in rats. METHODS: Rats were divided randomly into four groups: control, CCl(4), and two FSSC groups. Except for rats in the control group, all rats were orally administered CCl(4) twice a week for 8 weeks. Rats in the FSSC groups were treated daily with FSSC (0.5 or 1.5 g/kg) through gastrogavage for the entire experimental period. RESULTS: CCl(4) caused liver damage, as characterized by increases in levels of plasma transaminase, hepatic malondialdehyde, and hydroxyproline, in addition to increases in spleen and liver weights and decreases in plasma albumin levels. Compared with CCl(4) group, FSSC (1.5 g/kg) treatment significantly decreased the spleen (P<0.01) and liver (P<0.01) weights, the activities of transaminase (P<0.05), and levels of hepatic malondialdehyde (P<0.05) and hydroxyproline (P<0.01); however, the treatment increased plasma albumin level (P<0.05). The pathological results also showed that FSSC (1.5 g/kg) suppressed hepatic inflammation, steatosis and necrosis. Data for hepatic fibrosis were expressed as the mean percentage of the total hepatic area in the tissue sections. FSSC (1.5 g/kg) treatment significantly decreased the hepatic fibrosis (12.8+/-1.2 and 6.4+/-0.7 in CCl(4) and FSSC group, respectively, P<0.001). RT-PCR analysis showed that FSSC (1.5 g/kg) treatment decreased the expression of methionine adenosyltransferase 2A (P<0.01), collagen (alpha1)(I) (3.15+/-0.05 and 1.52+/-0.04 in CCl(4) and FSSC groups, respectively, P<0.001), and transforming growth factor-beta1 (2.50+/-0.05 and 1.21+/-0.04 in CCl(4) and FSSC groups, respectively, P<0.001), apart from increasing the expression of methionine adenosyltransferase 1A (P<0.05). CONCLUSION: These results showed that FSSC protects the liver against CCl(4) damage in rats.
Subject(s)
Fermentation , Liver Cirrhosis, Experimental/metabolism , Liver Cirrhosis, Experimental/prevention & control , Saccharomyces cerevisiae/metabolism , Animals , Carbon Tetrachloride/toxicity , Collagen Type I/genetics , Collagen Type I/metabolism , Dose-Response Relationship, Drug , Hydroxyproline/metabolism , Liver Cirrhosis, Experimental/chemically induced , Liver Cirrhosis, Experimental/pathology , Male , Malondialdehyde/metabolism , Methionine Adenosyltransferase/genetics , Methionine Adenosyltransferase/metabolism , Organ Size , RNA, Messenger/genetics , RNA, Messenger/metabolism , Random Allocation , Rats , Rats, Wistar , Serum Albumin/metabolism , Transaminases/metabolism , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolismABSTRACT
BACKGROUND & AIMS: In this study, the inhibitory effect of olive oil on liver fibrosis induced by carbon tetrachloride (CCl(4)) has been investigated in rats. METHODS: Rats were divided randomly into four groups: control, CCl(4), and two olive oil groups. Except for rats in the control group, all rats were orally administered CCl(4) twice a week for 8 weeks. Rats in the olive oil groups were treated daily with olive oil (2 or 10 ml/kg) through gastrogavage for the entire experimental period. RESULTS: RT-PCR analysis showed that CCl(4) increased the hepatic mRNA expressions of lipopolysaccharide binding protein, CD14, Toll-like receptor-4, NADPH oxidase, nuclear factor-kappa beta, collagen (alpha1) (I), collagen (alpha1) (III), and transforming growth factor beta1. The expression of these mRNAs could be decreased by olive oil treatment. In addition, Western blot analysis also supported these results. CCl(4)-induced liver damage, as characterized by the increase in hepatic malondialdehyde and hydroxyproline levels. Olive oil treatment decreased the hepatic malondialdehyde and hydroxyproline levels. Histological evaluations showed that olive oil could attenuate the liver fibrosis, necrosis, and expression of smooth muscle alpha-actin that are induced by CCl(4). CONCLUSION: It is speculated that the phenolic compounds in olive oil significantly reduced CCl(4)-induced hepatic fibrosis in rats.
Subject(s)
Carbon Tetrachloride/toxicity , Liver Cirrhosis/chemically induced , Liver Cirrhosis/prevention & control , Plant Oils/pharmacology , Animals , Blotting, Western , Body Weight/drug effects , Carbon Tetrachloride/antagonists & inhibitors , Catalase/metabolism , Collagen/genetics , Collagen/metabolism , Glutathione Peroxidase/metabolism , Hydroxyproline/metabolism , Immunohistochemistry , Lipid Peroxidation/drug effects , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Male , Malondialdehyde/metabolism , Olive Oil , Random Allocation , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Superoxide Dismutase/metabolism , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolismABSTRACT
The purpose of this study was to investigate the hepatoprotective effects of a fermented substance from Aspergillus phoenicis (FSAP) on chronic liver injuries induced by carbon tetrachloride (CCl(4)) in rats. CCl(4) (20%; 0.2 ml/100 g body weight) was given twice a week for 9 weeks, and the rats received FSAP throughout the whole experimental period. Plasma ALT and AST, spleen weight, and hepatic levels of lipid peroxidation and hydroxyproline were significantly lower in the rats treated with FSAP as compared to CCl(4) only. Liver pathology in the FSAP-treated rats was also improved. Real-time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) analysis showed that FSAP treatment increased the expression of matrix metalloproteinase 13 and decreased the expression of methionine adenosyltransferase 2A, collagen (alpha1)(I), collagen (alpha1)(III), transforming growth factor-beta1, and tissue inhibitor of metalloproteinase 1. These results clearly indicate that FSAP partially reduced the liver fibrosis in rats induced by CCl(4).