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1.
Front Pharmacol ; 15: 1344113, 2024.
Article in English | MEDLINE | ID: mdl-38567351

ABSTRACT

Introduction: Diabetic kidney disease (DKD) necessitates innovative therapeutic strategies. This study delves into the role of DNA damage-inducing transcription factor 4 (DDIT4) within the VDR-mTOR pathway, aiming to identify a novel target for DKD drug discovery. Methods: Transcriptome data from the Gene Expression Omnibus Database were analyzed to assess the expression of mTOR and VDR expression in human renal tissues. Clinical samples from DKD patients and minimal change disease (MCD) controls were examined, and a DKD animal model using 20-week-old db/db mice was established. DDIT4 plasmid transfection was employed to modulate the VDR-mTOR pathway, with its components evaluated using immunohistochemistry, real-time quantitative PCR (qRT-PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). Results: Changes in the expression of the VDR-mTOR pathway were observed in both DKD patients and the animal model. Overexpression of DDIT4 increased VDR expression and decreased levels of mTOR, p70s6k, and 4E-BP1. Furthermore, DDIT4 treatment regulated autophagy by upregulating LC3I expression and downregulating LC3II expression. Notably, DDIT4 alleviated oxidative stress by reducing the levels of lipid peroxidation product MDA, while simultaneously increasing the levels of superoxide dismutase (SOD) and glutathione (GSH), underscoring the role of DDIT4 in the pathological process of DKD and its potential as a therapeutic target. Conclusion: Unraveling DDIT4's involvement in the VDR-mTOR pathway provides insights for innovative DKD drug discovery, emphasizing its potential as a therapeutic target for future interventions.

2.
Br J Pharmacol ; 181(13): 2012-2032, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38112022

ABSTRACT

BACKGROUND AND PURPOSE: Neuropathic pain affects millions of patients, but there are currently few viable therapeutic options available. Microtubule affinity-regulating kinases (MARKs) regulate the dynamics of microtubules and participate in synaptic remodelling. It is unclear whether these changes are involved in the central sensitization of neuropathic pain. This study examined the role of MARK1 or MARK2 in regulating neurosynaptic plasticity induced by neuropathic pain. EXPERIMENTAL APPROACH: A rat spinal nerve ligation (SNL) model was established to induce neuropathic pain. The role of MARKs in nociceptive regulation was assessed by genetically knocking down MARK1 or MARK2 in amygdala and systemic administration of PCC0105003, a novel small molecule MARK inhibitor. Cognitive function, anxiety-like behaviours and motor coordination capability were also examined in SNL rats. Synaptic remodelling-associated signalling changes were detected with electrophysiological recording, Golgi-Cox staining, western blotting and qRT-PCR. KEY RESULTS: MARK1 and MARK2 expression levels in amygdala and spinal dorsal horn were elevated in SNL rats. MARK1 or MARK2 knockdown in amygdala and PCC0105003 treatment partially attenuated pain-like behaviours along with improving cognitive deficit, anxiogenic-like behaviours and motor coordination in SNL rats. Inhibition of MARKs signalling reversed synaptic plasticity at the functional and structural levels by suppressing NR2B/GluR1 and EB3/Drebrin signalling pathways both in amygdala and spinal dorsal horn. CONCLUSION AND IMPLICATIONS: These results suggest that MARKs-mediated synaptic remodelling plays a key role in the pathogenesis of neuropathic pain and that pharmacological inhibitors of MARKs such as PCC0105003 could represent a novel therapeutic strategy for the management of neuropathic pain.


Subject(s)
Neuralgia , Protein Serine-Threonine Kinases , Rats, Sprague-Dawley , Animals , Neuralgia/drug therapy , Neuralgia/metabolism , Male , Rats , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Amygdala/metabolism , Amygdala/drug effects , Neuronal Plasticity/drug effects , Spinal Nerves
3.
Acta Pharmacol Sin ; 43(2): 295-306, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34522005

ABSTRACT

Behavioral sensitization is a progressive increase in locomotor or stereotypic behaviours in response to drugs. It is believed to contribute to the reinforcing properties of drugs and to play an important role in relapse after cessation of drug abuse. However, the mechanism underlying this behaviour remains poorly understood. In this study, we showed that mTOR signaling was activated during the expression of behavioral sensitization to cocaine and that intraperitoneal or intra-nucleus accumbens (NAc) treatment with rapamycin, a specific mTOR inhibitor, attenuated cocaine-induced behavioural sensitization. Cocaine significantly modified brain lipid profiles in the NAc of cocaine-sensitized mice and markedly elevated the levels of phosphatidylinositol-4-monophosphates (PIPs), including PIP, PIP2, and PIP3. The behavioural effect of cocaine was attenuated by intra-NAc administration of LY294002, an AKT-specific inhibitor, suggesting that PIPs may contribute to mTOR activation in response to cocaine. An RNA-sequencing analysis of the downstream effectors of mTOR signalling revealed that cocaine significantly decreased the expression of SynDIG1, a known substrate of mTOR signalling, and decreased the surface expression of GluA2. In contrast, AAV-mediated SynDIG1 overexpression in NAc attenuated intracellular GluA2 internalization by promoting the SynDIG1-GluA2 interaction, thus maintaining GluA2 surface expression and repressing cocaine-induced behaviours. In conclusion, NAc SynDIG1 may play a negative regulatory role in cocaine-induced behavioural sensitization by regulating synaptic surface expression of GluA2.


Subject(s)
Carrier Proteins/metabolism , Cocaine/pharmacology , Nucleus Accumbens/drug effects , Receptors, AMPA/metabolism , TOR Serine-Threonine Kinases/metabolism , Animals , Biotinylation , Blotting, Western , Central Nervous System Sensitization/drug effects , Male , Mice , Mice, Inbred C57BL , Motor Activity/drug effects , Nucleus Accumbens/metabolism
4.
Biochem Pharmacol ; 177: 113926, 2020 07.
Article in English | MEDLINE | ID: mdl-32217098

ABSTRACT

BACKGROUND AND PURPOSE: Indoleamine 2, 3-dioxygenase 1 (IDO1) has been linked to neuropathic pain and IDO1 inhibitors have been shown to reduce pain in animals. Some studies have indicated that IDO1 expression increased after neuropathic pain in hippocampus and spinal cord, whether these changes existing in anterior cingulate cortex (ACC) and amygdala remains obscure and how IDO1 inhibition leads to analgesia is largely unknown. Here, we evaluated the antinociceptive effect of PCC0208009, an indirect IDO1 inhibitor, on neuropathic pain and examined the related neurobiological mechanisms. EXPERIMENTAL APPROACH: The effects of PCC0208009 on pain, cognition and anxiogenic behaviors were evaluated in a rat model of neuropathic pain. Motor disorder, sedation and somnolence were also assessed. Biochemical techniques were used to measure IDO1-mediated signaling changes in ACC and amygdala. KEY RESULTS: In rats receiving spinal nerve ligation (SNL), IDO1 expression level was increased in ACC and amygdala. PCC0208009 attenuated pain-related behaviors in the formalin test and SNL model and increased cognition and anxiogenic behaviors in SNL rats at doses that did not affect locomotor activity and sleeping. PCC0208009 inhibited IDO1 expression in ACC and amygdala by inhibiting the IL-6-JAK2/STAT3-IDO1-GCN2-IL-6 pathway. In addition, PCC0208009 reversed synaptic plasticity at the functional and structural levels by suppressing NMDA2B receptor and CDK5/MAP2 or CDK5/Tau pathway in ACC and amygdala. CONCLUSION AND IMPLICATIONS: These results support the role of IDO1-mediated molecular mechanisms in neuropathic pain and suggest that the IDO1 inhibitor PCC0208009 demonstrates selective pain suppression and could be a useful pharmacological therapy for neuropathic pain.


Subject(s)
Amygdala/metabolism , Analgesics/therapeutic use , Gyrus Cinguli/metabolism , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Neuralgia/drug therapy , Neuronal Plasticity/drug effects , Tetrazoles/therapeutic use , Analgesics/pharmacokinetics , Animals , Behavior, Animal/drug effects , Comorbidity , Disease Models, Animal , Formaldehyde/pharmacology , Hyperalgesia/drug therapy , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Inflammation/chemically induced , Inflammation/drug therapy , Male , Mice , Mice, Inbred C57BL , Neuralgia/metabolism , Pain Measurement , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Tetrazoles/pharmacokinetics
5.
Eur J Med Chem ; 161: 364-377, 2019 Jan 01.
Article in English | MEDLINE | ID: mdl-30384042

ABSTRACT

Hederagenin is a naturally occurring pentacyclic triterpenoids compound with multiple pharmacological activities. We recently showed that H6, a synthetic derivative of hederagenin, could enhance the anticancer activity of paclitaxel in drug-resistant cells in vitro and in vivo, but showed poor solubility. With the aim of improving the drug resistant reversal activity of H6, here we designed and synthesized a series of novel H6 analogues. Our results showed that compound 10 at the concentration of 5 µM significantly enhanced the cytotoxicity of paclitaxel to drug-resistant KBV cells and sensitized cells to paclitaxel in arresting cells in G2/M phase and inducing apoptosis. We found that compound 10 might block the drug efflux of P-gp via stimulating P-gp ATPase activity. Importantly, compound 10 enhanced the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors. Finally, we summarized a preliminary structure-activity relationship of hederagenin by the drug resistant reversal activity of H6 analogues in vitro and compound 10 and H6in vivo. This study highlights the importance of nitrogen-containing derivatives of hederagenin C-28 in the development of novel drug resistance reversal agents.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/drug effects , Oleanolic Acid/analogs & derivatives , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Oleanolic Acid/chemical synthesis , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , Structure-Activity Relationship , Tumor Cells, Cultured
6.
Clin Respir J ; 10(4): 477-85, 2016 Jul.
Article in English | MEDLINE | ID: mdl-25515647

ABSTRACT

BACKGROUND: Poor sleep is often associated with a series of health problems in patients with chronic obstructive pulmonary disease (COPD), but the relationship between sleep quality and functional exercise capacity has not been previously investigated. AIMS: To evaluate the relationship between quality of sleep and functional exercise capacity in clinically stable COPD. METHODS: One hundred three consecutive subjects with stable COPD were recruited. The subjects were assessed with the Pittsburgh Sleep Quality Index (PSQI) and divided into poor sleep group (PSQI >5) and good sleep group (PSQI ≤5). Subjects were also assessed with spirometry, 6-min walk distance (6MWD), oxygen saturation (SP O2 ), the Epworth Sleepiness Scale, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, COPD Assessment Test (CAT), Modified Medical Research Council dyspnea scale and quadriceps muscle function. RESULTS: Poor sleep was present in 43.69% of the patients with COPD. Subjects with poor sleep had shorter 6MWD (t = -3.588, P < 0.001), greater age (t = 2.519, P = 0.013), worse quality of life (t = 5.487, P < 0.001) and more depression (t = 6.576, P < 0.001) or anxiety (t = 4.245, P < 0.001) symptoms. 6MWD showed significant negative correlations with the PSQI global score (r = -0.373, P < 0.001). Multiple stepwise regresion analysis showed that PSQI global score was an independent psychological predictor of 6MWD, and 6MWD was the only physical predictor of PSQI total score in patients with COPD. CONCLUSION: There is a close relationship between sleep quality and functional exercise capacity in patients with COPD.


Subject(s)
Exercise Tolerance/physiology , Pulmonary Disease, Chronic Obstructive/physiopathology , Sleep Wake Disorders/physiopathology , Aged , Aged, 80 and over , Cross-Sectional Studies , Exercise Test , Female , Forced Expiratory Volume , Humans , Male , Middle Aged , Prospective Studies , Pulmonary Disease, Chronic Obstructive/psychology , Quality of Life/psychology , Sleep Wake Disorders/prevention & control , Sleep Wake Disorders/psychology , Spirometry , Surveys and Questionnaires
7.
J Thorac Dis ; 7(7): 1142-50, 2015 Jul.
Article in English | MEDLINE | ID: mdl-26380729

ABSTRACT

BACKGROUND: Dynamic hyperinflation (DH) is a major contributor to exercise limitation in chronic obstructive pulmonary disease (COPD). Therefore, we aimed to elucidate the physiological factors responsible for DH development during the 6-minute walk test (6MWT) in COPD patients and compare ventilatory response to the 6MWT in hyperinflators and non-hyperinflators. METHODS: A total of 105 consecutive subjects with stable COPD underwent a 6MWT, and the Borg dyspnea scale, oxygen saturation (SpO2), breathing pattern, and inspiratory capacity (IC) were recorded before and immediately after walking. The change in IC was measured, and subjects were divided into hyperinflators (ΔIC >0.0 L) and non-hyperinflators (ΔIC ≤0.0 L). Spirometry, the Modified Medical Research Council (MMRC) dyspnea scale and St George's Respiratory Questionnaire (SGRQ) were also assessed. RESULTS: DH was present in 66.67% of subjects. ΔIC/IC was significantly and negatively correlated with the small airway function. On multiple stepwise regression analysis forced expiratory flow after exhaling 50% of the forced vital capacity (FEF50%) was the only predictor of ΔIC/IC. Non-hyperinflators had a higher post-walking VT (t=2.419, P=0.017) and post-walking VE (t=2.599, P=0.011) than the hyperinflators did. Age and resting IC were independent predictors of the 6-minute walk distance (6MWD) in hyperinflators. CONCLUSIONS: DH was considerably common in subjects with COPD. Small airway function may partly contribute to the DH severity during walking. The ventilator response to the 6MWT differed between hyperinflators and non-hyperinflators. Resting hyperinflation is an important predictor of functional exercise capacity in hyperinflators.

8.
Life Sci ; 124: 136-43, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-25640758

ABSTRACT

AIMS: The aim of the study is to evaluate the neuroprotective effects of continuous dopaminergic stimulation (CDS) by rotigotine-loaded microspheres (RoMS) in a mouse model of MPTP-induced Parkinson's disease (PD) and to elucidate the potential mechanism underlying these effects. MAIN METHODS: Male C57BL/6 mice were treated either intramuscularly once with RoMS or twice daily for two weeks with rotigotine, and from the 9th day, MPTP (30 mg/kg, i.p.) was injected for the last 5 days. Following treatment, Parkinsonism scores were calculated and oxidative stress-related indicators in the striatum were performed. Neuroinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) were detected in the striatum. Expression of apoptosis-related proteins B-cell leukemia/lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX) was measured in the striatum by Western blot. Nigral tyrosine hydroxylase (TH)-positive neurons and microglial cell markers, i.e., ionized calcium binding adaptor molecule-1 (Iba-1) and neuronal synaptosomes, were quantified to assess the neuroprotective efficacy of RoMS. KEY FINDINGS: The administration of rotigotine significantly improved the Parkinsonism score, protected dopaminergic neurons with antioxidants, reduced microglial cell activation and the release of neuroinflammatory cytokines, and balanced the expression of Bcl-2 and Bax in MPTP-treated mice. Interestingly, the neuroprotective properties of rotigotine were remarkably amplified by CDS treatment with RoMS. SIGNIFICANCE: These results suggest that CDS therapy can play a neuroprotective role in an MPTP mouse model. Neuroprotective disease-modifying therapy may have the potential benefits of early treatment by normalizing compensatory mechanisms and may also help to delay dyskinesia in the later stages of PD.


Subject(s)
Dopamine Agonists/pharmacology , MPTP Poisoning/prevention & control , Neuroprotective Agents/pharmacology , Parkinsonian Disorders/drug therapy , Tetrahydronaphthalenes/pharmacology , Thiophenes/pharmacology , Animals , Antioxidants/metabolism , Blotting, Western , Corpus Striatum/drug effects , Corpus Striatum/pathology , Cytokines/metabolism , Disease Models, Animal , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/pathology , Gene Expression Regulation/drug effects , Male , Mice , Mice, Inbred C57BL , Microspheres , Oxidative Stress/drug effects , Parkinsonian Disorders/physiopathology
9.
Respir Care ; 59(5): 654-66, 2014 May.
Article in English | MEDLINE | ID: mdl-24170916

ABSTRACT

OBJECTIVE: This meta-analysis was performed to evaluate the efficacy and safety of the addition of tiotropium to standard treatment regimens for inadequately controlled asthma. METHODS: A systematic search was made of PubMed, EMBASE, MEDLINE, and CENTRAL databases, and ClinicalTrials.gov, and a hand search of leading respiratory journals. Randomized, double-blind clinical trials on the treatment of inadequately controlled asthma for ≥ 4 weeks with the addition of tiotropium, compared with placebo, were reviewed. Studies were pooled to odds ratio (OR) and weighted mean differences (WMDs), with 95% CI. RESULTS: Six trials met the inclusion criteria. The addition of tiotropium, compared with placebo, significantly improved all spirometric indices, including morning and evening peak expiratory flow (WMD 20.59 L/min, 95% CI 15.36-25.81 L/min, P < .001; and WMD 24.95 L/min, 95% CI 19.22-30.69 L/min, P < .001, respectively), trough and peak FEV1 (WMD 0.13 L, 95% CI 0.09-0.18 L, P < .001; and WMD 0.10 L, 95% CI 0.06-0.14 L, P < .001, respectively), the area under the curve of the first 3 h of FEV1 (WMD 0.13 L, 95% CI 0.08-0.18 L, P < .001), trough and peak FVC (WMD 0.1 L, 95% CI 0.05-0.15 L, P < .001; and WMD 0.08 L, 95% CI 0.04-0.13 L, P < .001, respectively), the area under the curve of the first 3 h of FVC (WMD 0.11 L, 95% CI 0.06-0.15 L, P < .001). The mean change in the 7-point Asthma Control Questionnaire score (WMD -0.12, 95% CI -0.21 to -0.03, P = .01) was markedly lower in tiotropium group, but not clinically important. There were no significant differences in Asthma Quality of Life Questionnaire score (WMD 0.09, 95% CI -0.01 to 0.20, P = .09), night awakenings (WMD 0.00, 95% CI -0.05 to 0.05, P = .99) or rescue medication use (WMD -0.18, 95% CI -0.36 to 0.00, P = .06). No significant increase was noticed in adverse events in the tiotropium group (OR 0.80, 95% CI 0.62-1.03, P = .08). CONCLUSIONS: The addition of tiotropium to standard treatment regimens has significantly improved lung function without increasing adverse events in patients with inadequately controlled asthma. Long-term trials are required to assess the effects of the addition of tiotropium on asthma exacerbations and mortality.


Subject(s)
Asthma/drug therapy , Bronchodilator Agents/therapeutic use , Scopolamine Derivatives/therapeutic use , Asthma/physiopathology , Bronchodilator Agents/adverse effects , Drug Therapy, Combination , Forced Expiratory Volume/drug effects , Humans , Placebos/therapeutic use , Quality of Life , Randomized Controlled Trials as Topic , Scopolamine Derivatives/adverse effects , Severity of Illness Index , Spirometry , Tiotropium Bromide , Vital Capacity/drug effects
10.
Article in English | MEDLINE | ID: mdl-23125868

ABSTRACT

Doxorubicin (DOX) is considered as one of the best antineoplastic agents. However, its clinical use is restricted by its associated cardiotoxicity, which is mediated by the production of reactive oxygen species. In this study, 20(S)-ginsenoside Rh2 (Rh2) was explored whether it had protective effects against DOX-induced cardiotoxicity. In vitro study on H9C2 cell line, as well as in vivo investigation in one mouse and one rat model of DOX-induced cardiomyopathy, was carried out. The results showed that pretreatment with Rh2 significantly increased the viability of DOX-injured H9C2 cells. In the mouse model, Rh2 could suppress the DOX-induced release of the cardiac enzymes into serum and improved the occurred pathological changes through ameliorating the decreased antioxidant biomolecules and the cumulated lipid peroxidation malondialdehyde in heart tissues. In the rat model, Rh2 could attenuate the change of ECG resulting from DOX administration. Furthermore, Rh2 enhanced the antitumor activity of DOX in A549 cells. Our findings thus demonstrated that Rh2 pretreatment could effectively alleviate heart injury induced by DOX, and Rh2 might act as a novel protective agent in the clinical usefulness of DOX.

11.
Eur J Pharmacol ; 640(1-3): 75-81, 2010 Aug 25.
Article in English | MEDLINE | ID: mdl-20470770

ABSTRACT

The present study was to investigate the neuroprotective efficacy and mechanism of Forsythoside B. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion for 1 h followed by reperfusion for 23 h. Rats received an intravenous bolus injection of Forsythoside B at 15 min after reperfusion. The results showed that Forsythoside B at doses higher than 8 mg/kg produced a significant neuroprotective potential in cerebral ischemia and reperfusion rats. Forsythoside B (20 mg/kg) demonstrated significant neuroprotective activity even after delayed administration at 1 h, 3 h and 5 h after cerebral ischemia and reperfusion. Forsythoside B 20 mg/kg attenuated histopathological damage as demonstrated by smaller brain infarct size and brain edema, decreased cerebral Evans blue extravasation and myeloperoxidase (MPO) activity, inhibited cerebral phosphor-IkappaB-alpha and nuclear transcription factors kappaB (NF-kappaB) expression. Meanwhile, NF-kappaB expression with immunohistochemical staining was reduced, while circulating polymorphonuclear leukocytes was increased. All of these findings suggested that Forsythoside B exerted potent neuroprotective effects with a favorable therapeutic time-window, reduce of cerebral ischemia and reperfusion injury degree, attenuating blood-brain barrier (BBB) breakdown, and its protective effects may be due to inhibition of inflammatory response.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Brain Ischemia/drug therapy , Caffeic Acids/pharmacology , Glucosides/pharmacology , Glycosides/pharmacology , Neuroprotective Agents/pharmacology , Reperfusion Injury/drug therapy , Animals , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/toxicity , Antigens, Nuclear/metabolism , Brain Infarction/complications , Brain Infarction/drug therapy , Brain Infarction/metabolism , Brain Infarction/pathology , Brain Ischemia/complications , Brain Ischemia/metabolism , Brain Ischemia/pathology , Caffeic Acids/therapeutic use , Caffeic Acids/toxicity , Disease Models, Animal , Evans Blue/metabolism , Extravasation of Diagnostic and Therapeutic Materials , Glucosides/therapeutic use , Glucosides/toxicity , Glycosides/therapeutic use , Glycosides/toxicity , Leukocytes/drug effects , Male , NF-kappa B/metabolism , Nerve Tissue Proteins/metabolism , Neurons/drug effects , Neurons/immunology , Neurons/metabolism , Neuroprotective Agents/therapeutic use , Neuroprotective Agents/toxicity , Peroxidase/metabolism , Rats , Rats, Sprague-Dawley , Reperfusion Injury/complications , Reperfusion Injury/metabolism , Reperfusion Injury/pathology
12.
Phytomedicine ; 17(3-4): 282-8, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19524418

ABSTRACT

This study was carried out to investigate whether rosmarinic acid (RA) has antifibrotic effect on experimental liver fibrosis in vitro and in vivo and its possible mechanism. Culture of hepatic stellate cells (HSCs) determine proliferation and expression of transforming growth factor-beta1 (TGF-beta1), connective transforming growth factor (CTGF) and alpha-smooth muscle actin (alpha-SMA). In carbon tetrachloride (CCL(4))-induced rat liver fibrosis model, determined biochemical indicator, liver fibrosis grade and histopathological changes, immunohistochemical detected liver TGF-beta1 and CTGF expression. The results indicated that RA could inhibit HSCs proliferation, inhibit TGF-beta1, CTGF and alpha-SMA expression in cultured HSCs. It has marked evident in reducing fibrosis grade, ameliorating biochemical indicator and histopathological morphology, reducing liver TGF-beta1 and CTGF expression in CCL(4)-induced liver fibrosis. These findings suggest that RA has potentially conferring antifibrogenic effects.


Subject(s)
Antioxidants/therapeutic use , Carbon Tetrachloride Poisoning/drug therapy , Cinnamates/therapeutic use , Depsides/therapeutic use , Hepatic Stellate Cells/drug effects , Liver Cirrhosis/drug therapy , Liver/drug effects , Plant Extracts/therapeutic use , Actins/metabolism , Animals , Antioxidants/pharmacology , Carbon Tetrachloride Poisoning/complications , Cell Proliferation/drug effects , Cells, Cultured , Cinnamates/pharmacology , Connective Tissue Growth Factor/antagonists & inhibitors , Depsides/pharmacology , Disease Models, Animal , Liver/metabolism , Liver/pathology , Liver Cirrhosis/etiology , Liver Cirrhosis/metabolism , Male , Phytotherapy , Plant Extracts/pharmacology , Rats , Rats, Sprague-Dawley , Transforming Growth Factor beta1/antagonists & inhibitors , Rosmarinic Acid
13.
Phytother Res ; 24(4): 547-52, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20041427

ABSTRACT

This study was conducted to investigate the efficacy of cornin, an iridoid glycoside, in an experimental cerebral ischemia induced by middle cerebral artery occlusion (MCAO) and reperfusion (I/R), and to elucidate the potential mechanism. Adult male Sprague-Dawley rats were subjected to MCAO for 1 h, then reperfusion for 23 h. Behavioral tests were used to evaluate the damage to central nervous system. The cerebral infarct volume and histopathological damage were assessed to evaluate the brain pathophysiological changes. Spectrophotometric assay methods were used to determine the activities of superoxide dismutase (SOD) and glutathione-peroxidase (GPx). Contents of malondialdehyde (MDA), the generation of reactive oxygen species (ROS) as well as respiratory control ratio and respiratory enzymes of the brain mitochondria were also determined. The results showed that cornin significantly decreased neurological deficit scores, and reduced cerebral infarct volume and degenerative neurons. Meanwhile, cornin significantly increased the brain ATP content, improved mitochondrial energy metabolism, inhibited the elevation of MDA content and ROS generation, and attenuated the decrease of SOD and GPx activities in brain mitochondria. These findings indicate that cornin has protective potential against cerebral ischemia injury and its protective effects may be due to amelioration of cerebral mitochondrial function and its antioxidant property.


Subject(s)
Infarction, Middle Cerebral Artery/drug therapy , Iridoids/therapeutic use , Phytotherapy , Verbena , Animals , Brain/metabolism , Brain/pathology , Calcium/metabolism , Cell Respiration/drug effects , Electron Transport/drug effects , Glutathione Peroxidase/metabolism , Infarction, Middle Cerebral Artery/metabolism , Infarction, Middle Cerebral Artery/pathology , Iridoid Glycosides , Male , Malondialdehyde/metabolism , Membrane Fluidity/drug effects , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondrial Membranes/metabolism , Neuroprotective Agents/therapeutic use , Phospholipids/metabolism , Plant Extracts/therapeutic use , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Reperfusion Injury/drug therapy , Superoxide Dismutase/metabolism , Water/metabolism
14.
Pharmacology ; 84(3): 162-70, 2009.
Article in English | MEDLINE | ID: mdl-19696522

ABSTRACT

Cornuside, a secoiridoid glucoside compound, was isolated from the fruit of Cornus officinalis Sieb. et Zucc. The present study elucidates the effects of cornuside on cultured rat cortical neuron damage induced by oxygen-glucose deprivation. The results show that cornuside treatment obviously attenuates apoptosis and ameliorates mitochondrial energy metabolism in rat cortical neurons by increasing the cell survival rate, mitochondrial antioxidant enzyme activities, mitochondrial respiratory enzyme activity, mitochondrial respiratory control ratio and the ATP content, and by decreasing the mitochondrial malondialdehyde content, lactate dehydrogenase leakage rate, intracellular Ca(2+) level and caspase-3 activity in a concentration-dependent manner. These findings indicate that cornuside has protective potential against cerebral ischemic injury, and its protective effects may be due to the suppression of intracellular Ca(2+) elevation and caspase-3 activity, and improvements in mitochondrial energy metabolism and antioxidant properties.


Subject(s)
Apoptosis/drug effects , Cornus/chemistry , Energy Metabolism/drug effects , Glucosides/pharmacology , Pyrans/pharmacology , Animals , Antioxidants/administration & dosage , Antioxidants/isolation & purification , Antioxidants/pharmacology , Brain Ischemia/prevention & control , Calcium/metabolism , Caspase 3/metabolism , Cell Survival/drug effects , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Dose-Response Relationship, Drug , Fruit , Glucosides/administration & dosage , Glucosides/isolation & purification , In Vitro Techniques , L-Lactate Dehydrogenase/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Pyrans/administration & dosage , Pyrans/isolation & purification , Rats , Rats, Sprague-Dawley
15.
Planta Med ; 75(14): 1470-5, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19644810

ABSTRACT

Astilbin, a flavonoid compound, was isolated from the rhizome of Smilax glabra Roxb. This study was conducted to investigate the efficacy of astilbin on experimental diabetic nephropathy (DN) in vivo and in vitro and its possible mechanisms. Astilbin was added in high glucose stimulated HK-2 cells, streptozotocin-induced experimental DN, randomized to receive intragastric ( I. G.) astilbin to observe its anti-renal lesion effect. Results showed that astilbin inhibited high glucose stimulated HK-2 cell production of transforming growth factor-beta1 (TGF-beta1) and connective tissue growth factor (CTGF) in vitro, especially CTGF; analogic results was also found in vivo. I. G. of astilbin 2.5 mg/kg or 5 mg/kg significantly ameliorated renal function, reduced kidney index, while it increased body weight and survival time in animals. In addition there was no significant difference in blood glucose level between the STZ-treated group and the astilbin groups. Furthermore, astilbin ameliorated the pathological progress of renal morphology. Astilbin can exert an early renal protective role to DN, inhibit production of TGF-beta1 and especially of CTGF. We suggest that astilbin inhibition of CTGF may be a potential target in DN therapy. This work provides the first evidence for astilbin as a new candidate of DN therapeutic medicine.


Subject(s)
Antioxidants/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Diabetic Nephropathies/drug therapy , Flavonols/therapeutic use , Kidney/drug effects , Plant Extracts/therapeutic use , Smilax/chemistry , Animals , Antioxidants/pharmacology , Body Weight/drug effects , Cell Line , Connective Tissue Growth Factor/antagonists & inhibitors , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/physiopathology , Diabetic Nephropathies/pathology , Diabetic Nephropathies/physiopathology , Flavonols/isolation & purification , Flavonols/pharmacology , Glucose/metabolism , Humans , Kidney/pathology , Kidney/physiopathology , Longevity/drug effects , Male , Models, Animal , Phytotherapy , Plant Extracts/chemistry , Plant Extracts/pharmacology , Random Allocation , Rats , Rats, Sprague-Dawley , Rhizome , Transforming Growth Factor beta1/antagonists & inhibitors
16.
Basic Clin Pharmacol Toxicol ; 105(1): 64-71, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19371254

ABSTRACT

The present study was carried out to investigate the effects of paeoniflorin in cultured RAW264.7 cell line as well as in an experimental model of sepsis induced by cecal ligation and puncture, and intraperitoneal injection (i.p.) of lipopolysaccharide in rats. Results showed that paeoniflorin concentration-dependently down-regulated the levels of TNF-alpha, IL-6 and high-mobility group-box 1 protein in lipopolysaccharide-induced RAW264.7 cell, inhibited the IkappaB kinase pathway and modulated NF-kappaB. Intravenous injection (i.v.) of paeoniflorin alone or in combination with imipenem reduced i.p. of lipopolysaccharide or cecal ligation and puncture-induced lethality in rats. In addition, serum levels of TNF-alpha, IL-6, high-mobility group-box 1 protein, triggering receptor expressed on myeloid cells and endotoxin were down-regulated; by contrast, serum levels of IL-10 were up-regulated. Amelioration of hemodynamics, decrease of enzyme levels, decrease of myeloperoxidase in lung, liver, and small intestine were also found after paeoniflorin injection. These data indicate that the anti-sepsis effect of paeoniflorin was mediated by decreasing local and systemic levels of a wide spectrum of inflammatory mediators. This work provides the first evidence that paeoniflorin has the capacity to inactivate inflammatory response in sepsis and the anti-inflammatory mechanism of paeoniflorin may inhibit activation of the NF-kappaB pathway by inhibiting IkappaB kinase activity.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzoates/pharmacology , Bridged-Ring Compounds/pharmacology , Glucosides/pharmacology , Inflammation/pathology , Shock, Septic/mortality , Animals , Anti-Bacterial Agents/pharmacology , Blood Urea Nitrogen , Cecum/injuries , Cecum/surgery , Cell Line , Clinical Enzyme Tests , DNA-Binding Proteins/analysis , Endotoxins/blood , Endotoxins/toxicity , Hemodynamics/physiology , Imipenem/pharmacology , Inflammation Mediators/blood , Inflammation Mediators/physiology , Intestine, Small/drug effects , Intestine, Small/enzymology , Lactic Acid/blood , Liver/drug effects , Liver/enzymology , Lung/drug effects , Lung/enzymology , Macrophages/chemistry , Macrophages/drug effects , Male , Membrane Glycoproteins/blood , Mice , Monoterpenes , Peroxidase/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Immunologic/blood , Shock, Septic/chemically induced , Triggering Receptor Expressed on Myeloid Cells-1
17.
Planta Med ; 75(6): 614-9, 2009 May.
Article in English | MEDLINE | ID: mdl-19263342

ABSTRACT

This study was conducted to investigate the efficacy of cornuside, a secoiridoid glucoside compound, in cultured macrophages as well as in an experimental model of sepsis induced by cecal ligation and puncture (CLP) in rats. Cornuside was added to cultured macrophages at different concentrations, and all CLP rats were randomized to receive an intravenous injection of the corresponding drug followed by observation of its antisepsis effect. Our results showed that cornuside downregulated the levels of TNF- alpha, IL-6, and NO production in a dose-dependent manner in activated macrophages, while it upregulated the level of IL-10. Intravenous injection of cornuside or imipenem alone or in combination reduced CLP-induced lethality in rats after CLP. In addition, serum levels of TNF- alpha, IL-6, triggering receptor expressed on myeloid cells, and endotoxin were downregulated. On the other hand, the serum levels of IL-10 were upregulated. Decreased bacterial counts in blood, peritoneum, spleen, liver, and mesenteric lymph nodes and decreased myeloperoxidase in lung, liver, and small intestine also were found after cornuside injection. These data indicate that the antisepsis therapeutic effect of cornuside is mediated by decreased local and systemic levels of a wide spectrum of inflammatory mediators. This work provides first evidence for the clinic use of cornuside as a new immunomodulatory drug that has the capacity to inhibit the inflammatory response in sepsis.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Cornus/chemistry , Glucosides/therapeutic use , Immunologic Factors/therapeutic use , Inflammation Mediators/blood , Plant Extracts/therapeutic use , Pyrans/therapeutic use , Sepsis/drug therapy , Animals , Anti-Bacterial Agents/pharmacology , Colony Count, Microbial , Cytokines/blood , Disease Models, Animal , Dose-Response Relationship, Drug , Down-Regulation , Drug Therapy, Combination , Endotoxins/blood , Fruit , Glucosides/isolation & purification , Glucosides/pharmacology , Imipenem/pharmacology , Imipenem/therapeutic use , Immunologic Factors/pharmacology , Macrophages/drug effects , Male , Myeloid Cells/drug effects , Nitric Oxide/blood , Peroxidase/metabolism , Phytotherapy , Plant Extracts/chemistry , Plant Extracts/pharmacology , Pyrans/isolation & purification , Pyrans/pharmacology , Random Allocation , Rats , Rats, Sprague-Dawley , Sepsis/blood , Up-Regulation
18.
Shock ; 32(6): 608-13, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19295475

ABSTRACT

The present study was to investigate the effects of rosmarinic acid (RA) in cultured RAW264.7 cells and experimental model of sepsis induced by cecal ligation and puncture in rats and the potential mechanism. Results showed that RA concentration dependently down-regulated the levels of TNF-alpha, IL-6, and high-mobility group box 1 protein in LPS-induced RAW264.7 cells, inhibited the IkappaB kinase pathway, and modulated nuclear factor-kappaB. Intravenous injection of RA alone or in combination with imipenem reduced cecal ligation and puncture-induced lethality in rats. In addition, serum levels of TNF-alpha, IL-6, high-mobility group box 1 protein, triggering receptor expressed on myeloid cells, and endotoxin were down-regulated; in contrast, serum level of IL-10 was up-regulated. Amelioration of hemodynamics and decrease in serum enzyme activities and myeloperoxidase in lung, liver, and small intestine were also observed after RA injection. These data indicate that the antisepsis effect of RA was mediated by decreasing local and systemic levels of a wide spectrum of inflammatory mediators. This article provides the first evidence that RA has the capacity to inactivate inflammatory response in sepsis. The anti-inflammatory mechanism of RA may inhibit activation of the nuclear factor- kappaB pathway by inhibiting IkappaB kinase activity.


Subject(s)
Cinnamates/pharmacology , Depsides/pharmacology , Gene Expression Regulation , Hemodynamics , Inflammation/pathology , Sepsis/drug therapy , Animals , Anti-Bacterial Agents/pharmacology , Disease Models, Animal , Endotoxins/metabolism , Humans , Imipenem/pharmacology , Male , Mice , Myeloid Cells/cytology , Rats , Rats, Sprague-Dawley , Sepsis/prevention & control , Tretinoin , Rosmarinic Acid
19.
Biol Pharm Bull ; 30(1): 44-7, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17202657

ABSTRACT

Previous research has shown that salvianic acid A [2-(3,4-dihydroxyphenyl)-2-hydroxy-propanoic acid, SA] extracted from Salvia miltiorrhiza BGE (Danshen) markedly inhibits lipid peroxidation of mitochondrial membrane of hepatic cells in vitro. The present study was conducted to examine protective effect of SA on liver injury induced by carbon tetrachloride (CCl4) and its possible mechanism in vivo. Male Sprague-Dawley rats weighing 180-200 g were used in the experiments. Five mmol/kg CCl4 in olive oil was given to rats i.p. Spectrophotometrical method was used to measure activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum, activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) as well as malondialdehyde (MDA) level in hepatic tissue and the rate of superoxide anion (O2*-) generation in hepatic submitochondrial particles. Hepatic histological structure was observed under light microscopy. CCl4 caused significant changes of activities of the enzymes, MDA level, and the rate of O2*- generation and histopathological changes of acute hepatic injury were noted. SA reversed the significant changes induced by CCl4. These results demonstrate that SA produces protective action on acute hepatic injury induced by CCl4 via an antioxidative mechanism.


Subject(s)
Antioxidants/pharmacology , Caffeic Acids/pharmacology , Carbon Tetrachloride , Lactates/pharmacology , Liver Diseases/prevention & control , Liver/drug effects , Alanine Transaminase/blood , Animals , Antioxidants/isolation & purification , Antioxidants/therapeutic use , Aspartate Aminotransferases/blood , Caffeic Acids/isolation & purification , Caffeic Acids/therapeutic use , Catalase/metabolism , Chemical and Drug Induced Liver Injury , Dose-Response Relationship, Drug , Drugs, Chinese Herbal/chemistry , Glutathione Peroxidase/metabolism , Lactates/isolation & purification , Lactates/therapeutic use , Liver/metabolism , Liver/pathology , Liver Diseases/blood , Liver Diseases/metabolism , Liver Diseases/pathology , Male , Malondialdehyde/metabolism , Necrosis , Plant Extracts , Rats , Rats, Sprague-Dawley , Salvia miltiorrhiza , Superoxide Dismutase/metabolism , Superoxides/metabolism
20.
J Asian Nat Prod Res ; 7(4): 607-13, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16087635

ABSTRACT

The therapeutic effects of hydroxysafflor yellow A (HSYA), extracted from Carthamus tinctorius. L, on focal cerebral ischemic injury in rats and its related mechanisms have been investigated. Focal cerebral ischemia in rats were made by inserting a monofilament suture into internal carotid artery to block the origin of the middle cerebral artery and administrated by HSYA via sublingular vein injection in doses of 1.5, 3.0, 6.0 mg kg(-1) at 30 min after the onset of ischemia, in comparison with the potency of nimodipine at a dose of 0.2 mg kg(-1). Then, 24 h later, the evaluation for neurological deficit scores of the rats were recorded and postmortem infarct areas determined by quantitative image analysis. At the end of the experiment, blood samples were taken to determine plasma 6-Keto-PGF1alpha/TXB2 by radioimmunoassays and blood rheological parameters. The effects exerted by HSYA on thrombosis formation by artery vein by-pass method and ADP-induced platelet aggregation in vivo and in vitro were investigated, respectively. The results indicated that more than 30% of the area of ischemic cerebrum was observed in the ischemic model group. HSYA dose-dependently improved the neurological deficit scores and reduced the cerebral infarct area, and HSYA bore a similarity in potency of the therapeutic effects on focal cerebral ischemia to nimodipine. The inhibition rates of thrombosis formation by HSYA at the designated doses were 20.3%, 43.6% and 54.2%, respectively, compared with saline-treated group. Inhibitory activities of HSYA were observed on ADP-induced platelets aggregation in a dose-dependent manner, and the maximum inhibitory aggregation rate of HSYA was 41.8%. HSYA provided a suppressive effect on production of TXA2 without significant effect on plasma PGI2 concentrations. Blood rheological parameters were markedly improved by HSYA, such as whole blood viscosity (from 21.71 +/- 4.77 to 11.61 +/- 0.90 mPa.s), plasma viscosity (from 2.73 +/- 0.53 to 1.42 +/- 0.07 mPa.s), deformability (from 0.66 +/- 0.26 to 0.77 +/- 0.33) and aggregation of erythrocyte (from 3.24 +/- 0.41 to 2.57 +/- 0.30), but no significant effect of HSYA on homatocrit was found (from 51.38 +/- 4.68% to 49.91 +/- 2.32%). HSYA appears to be a good potential agent to treat focal cerebral ischemia, and the underlying mechanisms exerted by HSYA might be involved in its inhibitory effects on thrombosis formation and platelet aggregation as well as its beneficial action on regulation of PGI2/TXA2 and blood rheological changes in rats.


Subject(s)
Brain Ischemia/drug therapy , Chalcone/analogs & derivatives , Infarction, Middle Cerebral Artery/complications , Quinones/pharmacology , Animals , Brain Ischemia/veterinary , Chalcone/pharmacology , Dose-Response Relationship, Drug , Epoprostenol/blood , Infarction, Middle Cerebral Artery/veterinary , Rats , Stroke/drug therapy , Stroke/veterinary
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