This study aims to investigate the ameliorating effect of Corni Fructus(CF) on the myocardial ischemic injury and the pharmacokinetic properties of characteristic components of CF. The mouse model of isoproterenol-induced myocardial ischemia was established and administrated with the aqueous extract of CF. The general efficacy of CF in ameliorating the myocardial ischemic injury was evaluated based on the cardiac histopathology and the levels of myocardial injury markers: creatine kinase isoenzyme(CK-MB) and cardiac troponin I(cTn-I). The metabolomics analysis was carried out for the heart and serum samples of mice to screen the biomarkers of CF in ameliorating the myocardial ischemic injury and then the predicted biomarkers were submitted to metabolic pathway enrichment. The pharmacokinetic analysis was performed for morroniside, loganin, and cornuside Ⅰ in mouse heart and serum samples to obtain the pharmacokinetic parameters of these components. The pharmacokinetic parameters were then integrated on the basis of self-defined weighting coefficients to simulate an integrated pharmacokinetic profile of CF iridoid glycosides in the heart and serum of the mouse model of myocardial ischemia. The results indicated that CF reduced the pathological damage to cardiac cells and tissue(hematoxylin-eosin staining) and lowered the levels of CK-MB and cTn-I in the serum of the mouse model of myocardial ischemia(P<0.01). Metabolomics analysis screed out 31 endogenous metabolites in the heart and 35 in the serum as biomarkers of CF in ameliorating the myocardial ischemic injury. These biomarkers were altered by modeling and restored by CF. Six metabolic pathways in the heart and 5 in the serum were enriched based on these metabolic markers. The main integrated pharmacokinetic parameters of CF iridoid glycosides were T_(max)=1 h, t_(1/2)=(1.52±0.05) h in the heart and T_(max)=1 h, t_(1/2)=(1.56±0.50) h in the serum. Both concentration-time curves showed a double-peak phenomenon. In conclusion, CF demonstrated the cardioprotective effect by regulating metabolic pathways such as taurine and hypotaurine metabolism, and pantothenic acid and coenzyme A biosynthesis. The integrated pharmacokinetics reflect the general pharmacokinetic properties of characteristic components in CF.
Animals ; Cornus/chemistry* ; Mice ; Metabolomics ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Myocardial Ischemia/metabolism* ; Humans ; Troponin I/metabolism* ; Myocardium/pathology* ; Disease Models, Animal ; Biomarkers/metabolism* ; Creatine Kinase, MB Form/metabolism*

The purpose of this study was to investigate the effect of aqueous extract of Corni Fructus on β-amyloid protein 25-35(Aβ_(25-35))-induced brain injury and neuroinflammation in Alzheimer's disease(AD) mice to provide an experimental basis for the treatment of AD by aqueous extract of Corni Fructus. Sixty C57BL/6J male mice were randomly divided into a sham group, a model group, a positive control group(huperizine A, 0.2 mg·kg~(-1)), a low-dose aqueous extract of Corni Fructus group(1.3 g·kg~(-1)), a medium-dose aqueous extract of Corni Fructus group(2.6 g·kg~(-1)), and a high-dose aqueous extract of Corni Fructus group(5.2 g·kg~(-1)). The AD model was induced by lateral ventricular injection of Aβ_(25-35) in mice except for those in the sham group, and AD model mice were treated with corresponding drugs by gavage for 24 days. The behavioral test was performed one week before animal dissection. Hematoxylin-eosin(HE) staining was performed to observe the morphology of neurons in the hippocampal region. Flow cytometry was used to detect the apoptosis level of primary hippocampal cells in mice. ELISA kits were used to detect the levels of β-amyloid protein 1-42(Aβ_(1-42)) and phosphorylated microtubule-associated protein Tau(p-Tau) in mouse brain tissues. Immunofluorescence and Western blot were used to detect the expression of related proteins in mouse brain tissues. MTT assay was used to detect the effect of compounds in aqueous extract of Corni Fructus on Aβ_(25-35)-induced N9 cell injury. Molecular docking was employed to analyze the interactions of caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-β-D-glucopyranoside, esculetin, and(+)-lyoniresinol with β-amyloid precursor protein(APP), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α). Aqueous extract of Corni Fructus could improve the learning and memory abilities of Aβ_(25-35)-induced mice by increasing the duration of the autonomous activity, the rate of autonomous alternation, the preference coefficient, and the discrimination coefficient, and reduce Aβ_(25-35)-induced brain injury and neuroinflammation in mice by increasing the expression levels of interleukin-10(IL-10) and B-cell lymphoma-2(Bcl-2) in brain tissues, decreasing the expression levels of Aβ_(1-42), p-Tau, IL-6, TNF-α, cysteine aspartate-specific protease 3(caspase-3), cysteine aspartate-specific protease 9(caspase-9), and Bcl-2-associated X protein(Bax), and decreasing the number of activated glial cells in brain tissues. The results of cell experiments showed that esculetin and(+)-lyoniresinol could improve Aβ_(25-35)-induced N9 cell injury. Molecular docking results showed that caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-β-D-glucopyranoside, esculetin, and(+)-lyoniresinol had good binding affinity with APP and weak binding affinity with IL-6 and TNF-α. Aqueous extract of Corni Fructus could ameliorate cognitive dysfunction and brain damage in Aβ_(25-35)-induced mice by reducing the number of apoptotic cells and activated glial cells in the brain and decreasing the expression level of inflammatory factors. Caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-β-D-glucopyranoside, esculetin, and(+)-lyoniresinol may be the material basis for the anti-AD effect of aqueous extract of Corni Fructus.
Mice ; Male ; Animals ; Alzheimer Disease/drug therapy* ; Amyloid beta-Peptides/metabolism* ; Cornus/metabolism* ; Neuroinflammatory Diseases ; Tumor Necrosis Factor-alpha/metabolism* ; Interleukin-6 ; Aspartic Acid ; Cysteine/therapeutic use* ; Molecular Docking Simulation ; Mice, Inbred C57BL ; Brain Injuries ; Peptide Hydrolases ; Disease Models, Animal ; Mice, Transgenic

BACKGROUND AND PURPOSE: Atrophy of the hippocampus is an important clinical diagnostic marker of Alzheimer's disease (AD), and so assessments of hippocampal activity and its subdivisions might provide invaluable information. This study compared the glucose metabolism of hippocampal subdivisions in mild-AD patients and healthy controls. METHODS: High-resolution T2*-weighted gradient-echo magnetic resonance imaging (MRI) images and ¹⁸F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) images were acquired using 7.0-T MRI and high-resolution research tomograph FDG-PET, respectively, in 9 early-stage AD patients and 10 healthy subjects. The hippocampal body was divided into three equal parts (anterior, middle, and posterior), and in each part a region of interest (ROI) was drawn over the cornus ammonis (CA)1, CA2/3, CA4/dentate gyrus (DG), and subiculum. The standardized uptake values of the hippocampal subdivisions were calculated for each ROI as ratios relative to the pons standardized uptake value. Statistical analysis was conducted using the Mann-Whitney U test. RESULTS: Patients with early-stage AD patients showed significantly less metabolic activity than healthy controls focally in the middle (p=0.050) and posterior (p=0.034) CA2/3 regions of the right hippocampus, and significantly less activity throughout the left hippocampal body in the anterior CA2/3 (p=0.027) and CA4/DG (p=0.027) regions, the middle CA1 region (p=0.011), and the posterior CA1 (p=0.034), CA2/3 (p=0.007), and CA4/DG (p=0.014) regions. CONCLUSIONS: It was possible to use high-resolution PET-MRI fusion images to identify hippocampus subdivisions and assess glucose metabolism in the subfields. Reductions in metabolic activity were found to vary along the hippocampal axis in early-stage AD patients.
Alzheimer Disease* ; Atrophy ; Cornus ; Glucose* ; Healthy Volunteers ; Hippocampus ; Humans ; Magnetic Resonance Imaging* ; Metabolism ; Pilot Projects* ; Pons ; Positron-Emission Tomography

5-Hydroxymethylfurfural (5-HMF), a water-soluble compound extracted from wine-processed Fructus corni, is a novel hepatic protectant for treating acute liver injury. The present study was designed to investigate the protective effect of 5-HMF in human L02 hepatocytes injured by D-galactosamine (GalN) and tumor necrosis factor-α (TNF-α) in vitro and to explore the underlying mechanisms of action. Our results showed that 5-HMF caused significant increase in the viability of L02 cells injured by GalN/TNF-α, in accordance with a dose-dependent decrease in apoptotic cell death confirmed by morphological and flow cytometric analyses. Based on immunofluorescence and Western blot assays, we found that GalN/TNF-α induced ER stress in the cells, as indicated by the disturbance of intracellular Ca(2+) concentration, the activation of protein kinase RNA (PKR)-like ER kinase (PERK), phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α), and expression of ATF4 and CHOP proteins, which was reversed by 5-HMF pre-treatment in a dose-dependent manner. The anti-apoptotic effect of 5-HMF was further evidenced by balancing the expression of Bcl-2 family members. In addition, the knockdown of PERK suppressed the expression of phospho-PERK, phospho-eIF2α, ATF4, and CHOP, resulting in a significant decrease in cell apoptosis after the treatment with GalN/TNF-α. 5-HMF could enhance the effects of PERK knockdown, protecting the cells against the GalN/TNF-α insult. In conclusion, these findings demonstrate that 5-HMF can effectively protect GalN/TNF-α-injured L02 hepatocytes against ER stress-induced apoptosis through the regulation of the PERK-eIF2α signaling pathway, suggesting that it is a possible candidate for liver disease therapy.
Apoptosis ; drug effects ; Cornus ; chemistry ; Endoplasmic Reticulum Stress ; drug effects ; Eukaryotic Initiation Factor-2 ; genetics ; metabolism ; Furaldehyde ; analogs & derivatives ; pharmacology ; Galactosamine ; metabolism ; Hepatocytes ; cytology ; drug effects ; metabolism ; Humans ; Liver ; cytology ; drug effects ; metabolism ; Plant Extracts ; pharmacology ; Protective Agents ; pharmacology ; Signal Transduction ; drug effects ; Tumor Necrosis Factor-alpha ; genetics ; metabolism ; eIF-2 Kinase ; genetics ; metabolism

OBJECTIVETo investigate whether total triterpene acids (TTAs), isolated from Cornus Fructus, attenuates renal function by reducing oxidative stress and down-regulating the expression of transforming growth factor β1 (TGF-β1).

METHODSDiabetes was induced by an injection of streptozotocin (40 mg/kg intravenously). Thirty rats were randomly divided into three groups: control group, diabetic model group and TTAs treatment group (50 mg/kg, intragastrically) administrated for 8 weeks from 5th to 12th week. All rats were anaesthetized and then were killed to remove kidneys. The renal function and redox enzyme system parameters were tested. Glomerular morphology was observed by a light microscopy. Immunohistochemistry and Western blot assays were employed to determine the protein levels of TGF-β1.

RESULTSTTAs attenuated the levels of urinary protein, serum creatinine and blood urea nitrogen, although it did not significantly reduce the level of glucose. In addition, TTAs decreased the malondialdehyde while increased superoxide dismutase, catalase and glutathione peroxide activities in diabetic rats. The renal pathological changes in TTAs treatment group were ameliorated. Furthermore, TTAs also ameliorated the expression of TGF-β1.

CONCLUSIONTTAs improved renal function via reducing oxidative stress and down-regulation the expression of TGF-β1 in diabetic rats.

Animals ; Blood Glucose ; metabolism ; Blood Urea Nitrogen ; Blotting, Western ; Body Weight ; drug effects ; Catalase ; metabolism ; Cornus ; chemistry ; Creatinine ; metabolism ; Diabetes Mellitus, Experimental ; blood ; drug therapy ; pathology ; physiopathology ; Disease Progression ; Glutathione Peroxidase ; metabolism ; Hypertrophy ; Kidney ; drug effects ; pathology ; physiopathology ; Kidney Function Tests ; Male ; Malondialdehyde ; metabolism ; Rats, Sprague-Dawley ; Streptozocin ; Superoxide Dismutase ; metabolism ; Transforming Growth Factor beta1 ; metabolism ; Triterpenes ; isolation & purification ; pharmacology ; therapeutic use

To compare and study the decoction and dissolution of active constituents in crude and processed Corni Fructus. HPLC, the traditional Chinese medicine (TCM) decoction method and the dissolution methods were adopted to compare and study the decoction yield and dissolution rate of loganin and morroniside, active constituents in crude and processed Corni Fructus. The results showed that the content of active constituents loganin and morroniside in crude and processed Corni Fructus did not change significantly; compared with crude Corni Fructus, processed Corni Fructus (decoction) contained much higher loganin, with no obvious change in morroniside; compared with crude Corni Fructus, processed Corni Fructus (extracts) showed no significant difference in loganin dissolution, but notable increase in morroniside dissolution in intestinal fluid; in gastric fluid, processed Corni Fructus showed significant increase in loganin and morroniside dissolutions. However, in comprehensive consideration of the decoction dose in clinical administration, and calculated on the basis of the formula of the decoction yield x dissolution rate = decoction-dissolution product, it showed increase in the decoction-dissolution products of both of the active constituents loganin and morroniside, with significant difference. This suggested that processed Corni Fructus is superior to crude Corni Fructus in clinical application. In this article, we proposed to compare the changes in decoction and dissolution of active constituents in crude and processed Corni Fructus, study the decoction-dissolution product, and then apply it in the quality evaluation of crude and processed Corni Fructus.
Chromatography, High Pressure Liquid ; Cornus ; chemistry ; Drug Compounding ; methods ; Drugs, Chinese Herbal ; chemistry ; isolation & purification ; pharmacokinetics ; Humans ; Intestines ; metabolism ; Models, Biological ; Solubility

OBJECTIVETo investigate the protective effects of terpenes from fructus corni (TFC) on diabetic cardiomyopathy (DCM).

METHODSDiabetes was produced by a single injection of alloxan (220 mg/kg, i.p.) in mice. The fasting blood glucose of mice were tested 15 days later and that greater than 13.9 mmol/L were regarded as the diabetic mice which were divided randomly into the model and TFC groups. TFC dissolved by physiological saline (P.O, 80 mg/kg) was administrated to the TFC group for successive 8 weeks since the 15th day.

RESULTSCompared to the control group, the weight index increased significantly. The level of superoxide dismutase (SOD) was markedly decreased and malondialdehyde(MDA), the inflammatory factors (TNF-alpha, IL-6) were obviously increased in myocardium. The histopathological examination suggested that myocardial cells disarranged, swelling and the intercellular space increased in model group. It also showed the infiltration of inflammatory cells and fibroblasts in TFC group. The above change was improved significantly.

CONCLUSIONTFC ameliorated the alterations of cardiomyopathy in diabetic mice induced by alloxan. the mechanism might be related to decrease blood glucose, antioxidative stress and inflammatory factors.

Alloxan ; adverse effects ; Animals ; Cornus ; chemistry ; Diabetic Cardiomyopathies ; chemically induced ; metabolism ; prevention & control ; Interleukin-6 ; metabolism ; Male ; Malondialdehyde ; metabolism ; Mice ; Mice, Inbred Strains ; Oxidative Stress ; drug effects ; Superoxide Dismutase ; metabolism ; Terpenes ; pharmacology ; therapeutic use ; Tumor Necrosis Factor-alpha ; metabolism

PURPOSE: Diabetes is the leading cause of end-stage renal failure. The present study was undertaken to characterize the effects of Corni Fructus on diabetic nephropathy in streptozotocin-induced diabetic rats and their mechanisms. MATERIALS AND METHODS: Streptozotocin-diabetic rats were orally administrated with Corni Fructus at a dose of 100, 200 or 400 mg/kg body mass for 40 days. RESULTS: Corni Fructus-treated diabetic rats showed significant decreases of blood glucose, urinary protein levels and water consumption. Corni Fructus also reduced serum total cholesterol, total triglyceride and low-density lipoprotein cholesterol levels, and showed a tendency of enhancing high-density lipoprotein cholesterol level. Levels of serum albumin and creatinine in diabetic rats were also significantly reduced by Corni Fructus administration at a dose of 200 and 400 mg/kg body mass compared with non-treated diabetic rats. Corni Fructus increased catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidose (GSH-px) activities in the kidneys of diabetic rats. Furthermore, Corni Fructus treatment enhanced renal peroxisome proliferator-activated receptor-gamma (PPARgamma) expression in diabetic rats. CONCLUSION: These results demonstrated that Corni Fructus may have the potential to protect the animals from diabetic nephropathy by amelioration of oxidative stress and stimulation of PPARgamma expression.
Animals ; Blotting, Western ; Body Weight/drug effects ; Catalase/metabolism ; Cornus/*chemistry ; Diabetes Mellitus, Experimental/*drug therapy ; Glucose Tolerance Test ; Glutathione/metabolism ; Hypoglycemic Agents/*therapeutic use ; Male ; Malondialdehyde/metabolism ; Plant Extracts/*therapeutic use ; Rats ; Rats, Wistar ; Reverse Transcriptase Polymerase Chain Reaction ; Superoxide Dismutase/metabolism

OBJECTIVETo study the urinary protein patterns of nephropathy mice induced by dextran and the effects of aquesous extract of Fructus Corni (AEFC) and Radix Astragali (AERA).

METHODNephropathy model was established by administrated with dextran to mice. Some of the dextran treated mice were given AERA (20 g x kg(-1) x d(-1)) as AERA group, other mice were given AEFC (10 g x kg(-1) x d(-1)) as AEFC group. Some of the dextran treated mice were given water as model group, some normal mice as normal control group. After a 12 weeks' treatment, 24 hour urine of four groups was collected, respectively. Each urinary sample was divided into two parts, one was non-concentrated urine sample, another was used as concentrated urine sample. Two kinds of urinary sample of four groups were analyzed with microfluidic chips on Agilent 2100 Bioanalyzer instrument.

RESULTEach group's urinary protein patterns were obtained, more than 20 proteins were were detected. Compared with normal group, about five kinds of protein were found in urinary sample of model group, among which M > 43 x 10(3) proteins were increased. Compared with model group, significant treated-related protein's kind and quantitative changes in AERA treated group and AEFC group were found. Urinary protein kinds were reduced, especially certain the proteins (M > 50 x 10(3)) were significantly decreased approach to normal patterns. Non-concentrated urine samples' protein pattern mainly included were proteins (M=29, 32, 43, 52, 68, 76 x 10(3) and concentrated urine samples mainly included the proteins (M=22, 24, 32, 46 x 10(3)).

CONCLUSIONAERA and AEFC could reduce the urinary protein and made protein pattern different, which showed that radix astragali and fructus corni could play an important role in protecting renal function of nephropathy mice and finding the target protein markers related to AERA and AEFC effects on nephropathy mice.

Animals ; Astragalus membranaceus ; chemistry ; Cornus ; chemistry ; Dextrans ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; Female ; Kidney ; drug effects ; physiopathology ; Male ; Mice ; Microfluidic Analytical Techniques ; methods ; Nephritis ; chemically induced ; metabolism ; urine ; Plants, Medicinal ; chemistry ; Proteinuria ; urine ; Proteomics ; methods

OBJECTIVETo observe the change of nitric oxide (NO) and expression of nuclear factor-kappa B (NF-kappaB) in the cortex of cerebral infarction rat induced by photochemical reaction, and study the effect of extract from Cornus officinalis (whose main ingredient is iridoid glycoside) in the course of disease.

METHODAfter rats were fed with experimental drugs for 7 days, the model of cerebral infarction was induced. Spectrophotography and immunohistochemistry were used to detect the change of the content of NO, NOS and the expression of NF-kappaB in the cortex.

RESULTCompared with control group, distinct infarction was visible in the model group, and the content of NO, the activity of NOS and the positive cell number of NF-kappaB were increased obviously. Compared with model group, the extract of C. officeinalis decreased the area of infarction, the content of NO, the activity of NOS and the positive cell number of NF-kappaB.

CONCLUSIONThe iridoid glycoside of C. officinalis may have therapeutical effect on cerebral infarction through regulating the content of NO and NF-kappaB.

Animals ; Cerebral Cortex ; metabolism ; pathology ; Cerebral Infarction ; metabolism ; pathology ; Cornus ; chemistry ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; Male ; NF-kappa B ; metabolism ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase ; metabolism ; Plants, Medicinal ; chemistry ; Random Allocation ; Rats ; Rats, Sprague-Dawley