ABSTRACT
The c-Jun N-terminal kinase 3 (JNK3) signaling cascade is activated during cerebral ischemia leading to neuronal damage. The present study was carried out to identify and evaluate novel JNK3 inhibitors using in-silico and in-vitro approach. A total of 380 JNK3 inhibitors belonging to different organic groups was collected from the previously reported literature. These molecules were used to generate a pharmacophore model. This model was used to screen a chemical database (SPECS) to identify newer molecules with similar chemical features. The top 1000 hits molecules were then docked against the JNK3 enzyme coordinate following GLIDE rigid receptor docking (RRD) protocol. Best posed molecules of RRD were used during induced-fit docking (IFD), allowing receptor flexibility. Other computational predictions such as binding free energy, electronic configuration and ADME/tox were also calculated. Inferences from the best pharmacophore model suggested that, in order to have specific JNK3 inhibitory activity, the molecules must possess one H-bond donor, two hydrophobic and two ring features. Docking studies suggested that the main interaction between lead molecules and JNK3 enzyme consisted of hydrogen bond interaction with methionine 149 of the hinge region. It was also observed that the molecule with better MM-GBSA dG binding free energy, had greater correlation with JNK3 inhibition. Lead molecule (AJ-292-42151532) with the highest binding free energy (dG = 106.8 Kcal/mol) showed better efficacy than the SP600125 (reference JNK3 inhibitor) during cell-free JNK3 kinase assay (IC50 = 58.17 nM) and cell-based neuroprotective assay (EC50 = 7.5 µM).
Subject(s)
Mitogen-Activated Protein Kinase 10/chemistry , Neuroprotective Agents/chemistry , Organic Chemicals/chemistry , Protein Kinase Inhibitors/chemistry , Brain Ischemia/drug therapy , Brain Ischemia/enzymology , Brain Ischemia/pathology , Drug Evaluation, Preclinical , Humans , Mitogen-Activated Protein Kinase 10/antagonists & inhibitors , Neurons/drug effects , Neurons/enzymology , Neurons/pathology , Protein Binding/drug effects , Structure-Activity Relationship , User-Computer InterfaceABSTRACT
OBJECTIVES: In advanced stages, hepatocellular carcinoma (HCC) is often associated with major vascular involvement (cava, portal vein). The aim of the present study was to analyse the role of surgical resection (SR) and loco-regional therapy (LRT) in these advanced stage patients to determine if there was a survival benefit. METHODS: The study is a retrospective analysis from the Commission on Cancer's National Cancer Data Base (NCDB) from 1998 to 2011. In total, 148,882 patients with liver cancer were identified, of which 126,984 had HCC. Of these, 64,264 patients (1998-2006) had 5-year survival data available and 8825 patients had Stage 3A disease based on AJCC classification. Of these patients, 884 had SR, 771 had LRT and 7170 patients had neither intervention. Kaplan-Meier curves and log-rank tests were used for statistical analysis. RESULTS: Eight thousand eight hundred and twenty-five patients met analysis criteria. The mean age (years) in the SR, LRT and no intervention group were 62.5, 64.3 and 64.2, respectively. Most patients were males in all three groups (77.5%, 74.5% and 68.1%). The mean tumour size (cm) in the three groups was 9.8, 6.4 and 8.4, respectively. SR and LRT were primarily performed in major academic and comprehensive cancer programmes compared with community cancer programmes and other centres (SR: 93% versus 7%; LRT: 94.6% versus 5.4%). The median 5-year survival (months) was 26.6 in SR, 16.5 in LRT and 4.8 in the no intervention group (P < 0.0001). CONCLUSION: A SR and LRT offer a survival benefit in select patients diagnosed with Stage 3A HCC.
Subject(s)
Carcinoma, Hepatocellular/therapy , Hepatectomy/methods , Liver Neoplasms/therapy , Neoplasm Staging , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/mortality , Combined Modality Therapy , Databases, Factual , Disease Progression , Disease-Free Survival , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Liver Neoplasms/diagnosis , Liver Neoplasms/mortality , Male , Middle Aged , Neoplasm Recurrence, Local , Prognosis , Puerto Rico/epidemiology , Retrospective Studies , Survival Rate/trends , United States/epidemiologyABSTRACT
BACKGROUND AND PURPOSE: Visual impairments are frequent in multiple sclerosis (MS). Optic neuritis can directly reduce retinal nerve fiber layer (RNFL) thickness. Our objectives were to evaluate associations of the RNFL thickness (RNFLT) of MS patients with magnetic resonance imaging (MRI) measures of regional brain atrophy and tissue injury in the post-chiasmatic deep gray matter (GM) section of the visual pathway. METHODS: Retinal nerve fiber layer thickness was measured using optical coherence tomography (OCT) in 96 relapsing-remitting MS (RR-MS) patients and 46 controls. MRI was obtained within ±3 months of OCT. RNFLT associations with MRI measures from diffusion tensor imaging and regional and tissue specific atrophy were assessed. RESULTS: In RR-MS, lower RNFLT was associated with lower white matter volume and lower whole brain volume. Lower RNFLT was associated with lower total deep gray matter volume and lower thalamus volume. Lower RNFLT was associated with greater mean diffusivity (MD) in normal appearing (NA) brain tissue and NA gray matter. Trends were found for lower RNFLT with greater MD in NA white matter and thalamus. RNFLT in controls was not associated with MD. CONCLUSIONS: Lower RNFLT is associated with microscopic tissue injury in NA regions of the brain and with neurodegeneration of the deep gray matter and thalamus in RR-MS.
Subject(s)
Gray Matter/pathology , Multiple Sclerosis, Relapsing-Remitting/pathology , Nerve Fibers/pathology , Retinal Neurons/cytology , Thalamus/pathology , White Matter/pathology , Adult , Atrophy/pathology , Diffusion Tensor Imaging , Female , Humans , Male , Middle Aged , Tomography, Optical Coherence/methodsABSTRACT
Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and an aggressive malignancy with poor outcome. This tumor can co-express epithelial, neural, and mesenchymal markers. The molecular hallmark of DSRCT is the EWS-WT1 fusion protein. Despite the diversities in treatment modality, the best results have been seen with radical surgery and adjuvant or neoadjuvant chemotherapy.
Subject(s)
Abdominal Neoplasms/therapy , Desmoplastic Small Round Cell Tumor/therapy , Abdominal Neoplasms/genetics , Abdominal Neoplasms/mortality , Abdominal Neoplasms/pathology , Antibodies, Monoclonal/therapeutic use , Chemotherapy, Adjuvant , Chemotherapy, Cancer, Regional Perfusion , Desmoplastic Small Round Cell Tumor/genetics , Desmoplastic Small Round Cell Tumor/mortality , Desmoplastic Small Round Cell Tumor/pathology , Humans , Hyperthermia, Induced , Immunohistochemistry , Neoplasm Recurrence, Local , Neoplasm Staging , Oncogene Proteins, Fusion/genetics , Radiotherapy, Adjuvant , Tomography, X-Ray Computed , Translocation, GeneticABSTRACT
Perment, a polyherbal Ayurvedic formulation that contains equal parts of Clitoria ternatea Linn., Withania somnifera Dun., Asparagus racemosus Linn., Bacopa monniera Linn., is used clinically as mood elevators. The aim of the present study was to explore the behavioural effects and to understand possible mode of action of Perment in stress induced depressive model. Chronic unpredictable mild stress (CUMS) was used to induce depression in rats. Open field exploratory behaviour, elevated plus maze, social interaction and behavioural despair tests were used to assess behaviour. Using standard protocols plasma noradrenaline, serotonin, corticosterone and brain/adrenal corticosterone levels were measured to support the behavioural effects of Perment. Exposure to CUMS for 21 days caused anxiety and depression in rats, as indicated by significant decrease in locomotor activity in the open field exploratory behaviour test and increased immobility period in the behavioural despair test. Perment predominantly exhibited antidepressant action than anxiolytic activity. Further Perment increased the plasma noradrenaline and serotonin levels in stressed rats. No significant alteration in the brain corticosterone level in stressed rats was observed with Perment treatment. However the adrenal corticosterone level is decreased with Perment. It can be concluded that the Perment formulation exhibited synergistic activity, has a significant antidepressant and anxiolytic activity, which may be mediated through adrenergic and serotonergic system activation. Currently the formulation is clinically used as anxiolytic but the present results suggest that the formulation can also be indicated in patients affected with depression.
Subject(s)
Behavior, Animal/drug effects , Depression/drug therapy , Phytotherapy , Plant Preparations/pharmacology , Animals , Chronic Disease , Corticosterone/blood , Depression/etiology , Depression/psychology , Disease Models, Animal , Exploratory Behavior/drug effects , Male , Maze Learning/drug effects , Medicine, Ayurvedic , Neurotransmitter Agents/blood , Rats , Rats, Wistar , Social Behavior , Stress, PhysiologicalABSTRACT
Evaluations of molecular mechanisms of dietary plants with their active molecules are essential for the complete exploration of their nutritive and therapeutic value. In the present study, we investigated the effect of chicory (Cichorium intybus) salad leaves in inhibiting protein tyrosine phosphatase 1B (PTP1B), and evaluated their role in modulating the key markers involved in insulin cell signalling and adipogenesis using 3T3-L1 adipocytes. Bioactivity-directed purification studies enlightened the additive effects of chlorogenic acid (CGA) along with other caffeic acid derivatives present in methanolic extract of C. intybus (CME). Incubation of CME and CGA with 3T3-L1 adipocytes significantly enhanced the 2-deoxy-d-3[H]-glucose uptake and inhibited adipogenesis through altering the expressions of insulin signalling and adipogenesis markers. Extending to an in vivo model, the effect of CME was also investigated on insulin sensitivity in high-fat diet with low streptozotocin-induced diabetic rats. Supplementation of CME for 2 weeks reinstated the insulin sensitivity along with plasma metabolic profile. The present results demonstrate that the caffeoyl derivatives of chicory salad leaves show promising pharmacological effect on energy homoeostasis via PTP1B inhibition both in vitro and in vivo.
Subject(s)
Caffeic Acids/pharmacology , Cichorium intybus/chemistry , Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/pharmacology , Insulin/metabolism , Plant Extracts/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , 3T3-L1 Cells , Adipocytes/drug effects , Adipogenesis/drug effects , Animals , Caffeic Acids/therapeutic use , Chlorogenic Acid/pharmacology , Chlorogenic Acid/therapeutic use , Diabetes Mellitus, Experimental/metabolism , Dietary Fats/administration & dosage , Glucose/metabolism , Hypoglycemic Agents/therapeutic use , Insulin Resistance/physiology , Male , Mice , Phytotherapy , Plant Extracts/therapeutic use , Plant Leaves , Rats , Rats, Wistar , Signal Transduction/drug effectsABSTRACT
Lipid lowering effect of 50% ethanolic extract of the leaves of A. marmelos (Linn.) was evaluated in triton and diet induced hyperlipidaemic models of Wistar albino rats. The extract at 125 and 250 mg/kg dose levels inhibited the elevation in serum cholesterol and triglycerides levels on Triton WR 1339 administration in rats. The extract at the same dose levels significantly attenuated the elevated serum total cholesterol and triglycerides with an increase in the high-density lipoprotein cholesterol in high-fat diet- induced hyperlipidaemic rats. The standard drugs atorvastatin in the former and gemfibrozil in the latter studies showed slightly better effects.
Subject(s)
Aegle/chemistry , Cholesterol/blood , Hyperlipidemias/drug therapy , Hypolipidemic Agents/therapeutic use , Lipoproteins, HDL/blood , Triglycerides/blood , Animals , Atherosclerosis/prevention & control , Diet, Atherogenic , Disease Models, Animal , Ethanol , Hyperlipidemias/blood , Hypolipidemic Agents/administration & dosage , Hypolipidemic Agents/pharmacology , Male , Plant Extracts/administration & dosage , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Plant Leaves/chemistry , Rats , Rats, WistarABSTRACT
The effect of chloroform: methanolic (80:20) extract of C. asiatica (CA; 100 and 200 mg/kg), was evaluated on the course of free radical generation and excitotoxicity in monosodiumglutamate (MSG) treated female Sprague Dawley rats. The extract showed significant improvement in catalase, super oxide desmutase and lipid peroxides levels in hippocampus and striatum regions. Glutathione level was not altered with CA treatment. Similar observation was made with dextromethorphan. The general behavior, locomotor activity and CAl a region of the hippocampus was significantly protected by CA indicating neuroprotective effect of CA in MSG induced excitotoxic condition. Hence it can be concluded that CA protected MSG induced neurodegeneration attributed to its antioxidant and behavioural properties. This activity of CA can be explored in epilepsy, stroke and other degenerative conditions in which the role of glutamate is known to play vital role in the pathogenesis.
Subject(s)
Centella , Neurodegenerative Diseases/chemically induced , Neurodegenerative Diseases/prevention & control , Neuroprotective Agents/therapeutic use , Phytotherapy , Plant Extracts/therapeutic use , Sodium Glutamate , Animals , Behavior, Animal/drug effects , Catalase/analysis , Centella/chemistry , Corpus Striatum/chemistry , Corpus Striatum/drug effects , Corpus Striatum/enzymology , Corpus Striatum/pathology , Female , Glutathione/analysis , Hippocampus/chemistry , Hippocampus/drug effects , Hippocampus/enzymology , Hippocampus/pathology , Neurodegenerative Diseases/pathology , Rats , Rats, Sprague-Dawley , Superoxide Dismutase/analysis , Thiobarbituric Acid Reactive Substances/analysisABSTRACT
The ethanolic extract of leaves of Nymphaea stellata given by oral route to diabetic rats at dose of 100 and 200 mg/kg/day for seven days reduced significantly by 31.6 and 42.6 % the plasma glucose level increased by intraperitoneal injection of 120 mg/day of alloxan. Moreover, the treatment significantly affected the plasma level of cholesterol and triglyceride.
Subject(s)
Blood Glucose/drug effects , Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/pharmacology , Nymphaea , Phytotherapy , Plant Extracts/pharmacology , Administration, Oral , Alloxan , Animals , Cholesterol/metabolism , Diabetes Mellitus, Experimental/chemically induced , Dose-Response Relationship, Drug , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Plant Extracts/administration & dosage , Plant Extracts/therapeutic use , Plant Leaves , Rats , Rats, Wistar , Triglycerides/metabolismABSTRACT
The antidiabetic activity of various subfractions of the alcohol extract of the bark of Pterocarpus marsupium Roxb. was evaluated in alloxan-induced diabetic rats. The effect of these extracts on lipid profile and liver function tests were also assessed to evaluate their activity in controlling diabetes related metabolic alterations. The parameters measured were plasma glucose, total protein, cholesterol, triglycerides, alkaline phosphatase, SGOT and SGPT. The results indicate the effective role of Pterocarpus marsupium on the above mentioned parameters indicating that Pterocarpus marsupium can also control the diabetes related metabolic alterations apart from controlling the glucose levels. Among the fractions tested the butanol subfraction was found to be more active in comparison with other subfractions. It can be concluded that the butanol subfraction of the alcohol extract of Pterocarpus marsupium exhibits significant antidiabetic activity and corrects the metabolic alterations in diabetic rats and this activity may resemble insulin-like properties.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/therapeutic use , Phytotherapy , Plant Extracts/therapeutic use , Pterocarpus , Animals , Blood Glucose/drug effects , Blood Glucose/metabolism , Blood Proteins/drug effects , Hypoglycemic Agents/pharmacology , Lipids/blood , Liver/drug effects , Liver/physiopathology , Liver Function Tests , Plant Bark/chemistry , Plant Extracts/pharmacology , Rats , SolventsABSTRACT
The antihyperglycemic effect of ethanolic extract of flowers of Musa sapientum (Musaceae), a herb (used in Indian folklore medicine for the treatment of diabetes mellitus) in alloxan induced diabetic rats. Oral administration of the ethanolic extract showed significant (p < 0.001) blood glucose lowering effect at 200 mg/kg in alloxan induced diabetic rats (120 mg/kg, i.p.) and the extract was also found to significantly (p < 0.001) scavenge oxygen free radicals, viz., superoxide dismutase (SOD), catalase (CAT) and also protein, malondialdehyde and ascorbic acid in vivo. Musa sapientum induced blood sugar reduction may be due to possible inhibition of free radicals and subsequent inhibition of tissue damage induced by alloxan. The antidiabetic activity observed in this plant may be attributed to the presence of flavonoids, alkaloids, steroid and glycoside principles.
Subject(s)
Antioxidants/pharmacology , Blood Glucose/drug effects , Diabetes Mellitus, Experimental/drug therapy , Hyperglycemia/drug therapy , Hypoglycemic Agents/pharmacology , Musa , Phytotherapy , Administration, Oral , Alloxan , Animals , Antioxidants/administration & dosage , Blood Glucose/analysis , Diabetes Mellitus, Experimental/chemically induced , Hemoglobins/analysis , Hemoglobins/drug effects , Hyperglycemia/chemically induced , Hypoglycemic Agents/administration & dosage , Lipid Peroxidation/drug effects , Male , Plant Extracts/pharmacology , Rats , Rats, WistarABSTRACT
Glycowithanolides, consisting of equimolar concentrations of sitoindosides VII-X and withaferin A, isolated from the roots of Withania somnifera Dunal, have been reported to have an antioxidant effect in the rat brain frontal cortex and striatum. In the present study, the effect of 10 days of oral administration of these active principles, in graded doses (10, 20 and 50 mg/kg), was noted on iron overload (FeSo(4), 30 mg/kg, i.p.) induced hepatotoxicity in rats. Apart from hepatic lipid peroxidation (LPO), the serum enzymes, alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase, were assessed as indices of hepatotoxicity. Silymarin (20 mg/kg, p.o.) was used for comparison. Iron overload induced marked increase in hepatic LPO and serum levels of the enzymes, which was attenuated by WSG in a dose-related manner, and by silymarin. The results indicate that the reported use of WS in Ayurveda for hepatoprotection against heavy metals and other environmental toxins, may be due the antioxidant action of WSG.
Subject(s)
Chemical and Drug Induced Liver Injury/prevention & control , Ergosterol/pharmacology , Phytotherapy , Protective Agents/pharmacology , Sitosterols/pharmacology , Solanaceae/therapeutic use , Administration, Oral , Animals , Ergosterol/administration & dosage , Ergosterol/analogs & derivatives , Ergosterol/therapeutic use , Ferrous Compounds/toxicity , Hepatocytes/drug effects , Lipid Peroxidation/drug effects , Male , Plant Extracts/administration & dosage , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Protective Agents/administration & dosage , Protective Agents/therapeutic use , Rats , Rats, Inbred Strains , Sitosterols/administration & dosage , Sitosterols/therapeutic use , WithanolidesABSTRACT
Organophosphorus insecticides are widely used in agriculture. Despite their biodegradable nature, some are highly toxic and their residues are found in the environment. Reports on the mineralization of a spectrum of these insecticides by a single potential strain are scarce. We have isolated a soil isolate, Pseudomonas sp. A3, through enrichment technique, able to degrade methylparathion (MP), malathion, monocrotophos, and Diazinon. The potential of this strain to mineralize MP as a carbon and/or phosphorus source has been evaluated. On hydrolysis of MP, the aromatic portion (p-nitrophenol) was used as a carbon and energy source whereas the alkyl moiety (dithiomethylphosphorothioate) was broken down for the phosphorus source. The results from the experiments involving [U-14C]p-nitrophenol provided the evidence for incorporation of carbon into the cellular constituents and release of CO2 from this insecticide. During the breakdown of MP, nitrite was released as a catabolic by-product.
Subject(s)
Insecticides/metabolism , Methyl Parathion/metabolism , Pseudomonas/metabolism , Biodegradation, Environmental , Carbon/metabolism , Carbon Dioxide/metabolism , Insecticides/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Methyl Parathion/chemistry , Models, Chemical , Nitrites/metabolism , Phosphorus/metabolism , Pseudomonas/isolation & purification , Soil Microbiology , Spectrophotometry, InfraredABSTRACT
Rodent models of clinical depression are extensively used for the evaluation of putative antidepressants. In the present review, the available experimental methods which can be utilized by most laboratories involved in preclinical screening of antidepressants, have been discussed. The methods have been categorized on the basis of induction of the depressive state or on the assumption that monoamine deficiency leads to depression. These methods have been critically validated in terms of efficacy of standard antidepressants in these tests and, in some cases, by the neurochemical basis of depression, namely, the deficient monoaminergic theory of clinical depression.
Subject(s)
Antidepressive Agents/pharmacology , Animals , Behavior, Animal/drug effects , Depression/chemically induced , Depression/drug therapy , Depression/etiology , Disease Models, Animal , Drug Evaluation, Preclinical/methods , Female , Humans , Male , Mice , RatsABSTRACT
Glucose levels in rats with hyperglycemia induced by streptozotocin were determined after i.p. administration of marsupsin (1), pterosupin (2), and pterostilbene (3), three important phenolic constituents of the heartwood of Pterocarpus marsupium. Marsupsin and pterostilbene significantly lowered the blood glucose level of hyperglycemic rats, and the effect was comparable to that of 1,1-dimethylbiguanide (metformin).
Subject(s)
Benzofurans/isolation & purification , Cresols/isolation & purification , Glucosides/isolation & purification , Hypoglycemic Agents/isolation & purification , Phenols/isolation & purification , Plants, Medicinal/chemistry , Stilbenes/isolation & purification , Animals , Benzofurans/pharmacology , Blood Glucose/metabolism , Body Weight/drug effects , Cresols/pharmacology , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/drug therapy , Female , Glucosides/pharmacology , Hypoglycemic Agents/pharmacology , Male , Metformin/pharmacology , Phenols/pharmacology , Rats , Stilbenes/pharmacology , WoodABSTRACT
Exercise capacity is significantly impaired in postpneumonectomy patients who have relatively normal remaining lungs. Our objectives are to determine (1) the nature and extent of mechanical ventilatory abnormalities and oxygen cost of breathing in such patients, and (2) the efficacy of a selective respiratory muscle training program in improving ventilatory and exercise performance. A group of eight postpneumonectomy and eight normal subjects (mean ages 59 and 50 yr, respectively) were studied during steady-state exercise and resting voluntary hyperventilation. Ventilation, work of breathing, cardiac output, and oxygen costs of breathing were determined. Four postpneumonectomy and five normal subjects were studied before and after a respiratory muscle training program. In patients after pneumonectomy compared with normal control subjects, maximal oxygen uptake (VO2) was 56% lower (p < 0.001). Work of breathing was significantly higher at a given ventilation. Mechanical efficiency of ventilation was lower by 44% (p < 0.05). Near maximal VO2, 48% of any additional increment of total-body VO2 was required to sustain the associated increment in ventilatory work, compared with 28% in normal subjects (p < 0.05), suggesting that competition between respiratory and nonrespiratory muscles for oxygen delivery is a significant factor limiting exercise after pneumonectomy. After respiratory muscle training, maximal respiratory pressures improved but maximal sustained ventilation and maximal VO2 did not improve significantly, suggesting that selective respiratory muscle training is of limited utility in postpneumonectomy patients.