Abiraterone acetate is approved for the treatment of castration-resistant prostate cancer (CRPC); however, its effects vary. An accurate prediction model to identify patient groups that will benefit from abiraterone treatment is therefore urgently required. The Chi model exhibits a good profile for risk classification, although its utility for the chemotherapy-naive group is unclear. This study aimed to externally validate the Chi model and develop a new nomogram to predict overall survival (OS). We retrospectively analyzed a cohort of 110 patients. Patients were distributed among good-, intermediate-, and poor-risk groups, according to the Chi model. The good-, intermediate-, and poor-risk groups had a sample size of 59 (53.6%), 34 (30.9%), and 17 (15.5%) in our dataset, and a median OS of 48.4, 29.1, and 10.5 months, respectively. The C-index of external validation of Chi model was 0.726. Univariate and multivariate analyses identified low hemoglobin concentrations (<110 g l^-1), liver metastasis, and a short time interval from androgen deprivation therapy to abiraterone initiation (<36 months) as predictors of OS. Accordingly, a new nomogram was developed with a C-index equal to 0.757 (95% CI, 0.678-0.836). In conclusion, the Chi model predicted the prognosis of abiraterone-treated, chemotherapy-naive patients with mCRPC, and we developed a new nomogram to predict the overall survival of this group of patients with less parameters.
Abiraterone Acetate/therapeutic use* ; Adenocarcinoma/secondary* ; Aged ; Aged, 80 and over ; Alkaline Phosphatase/blood* ; Androgen Antagonists/therapeutic use* ; Antineoplastic Agents/therapeutic use* ; Bone Neoplasms/secondary* ; Cohort Studies ; Humans ; Kaplan-Meier Estimate ; L-Lactate Dehydrogenase/blood* ; Liver Neoplasms/secondary* ; Male ; Middle Aged ; Multivariate Analysis ; Neoplasm Metastasis ; Nomograms ; Prognosis ; Proportional Hazards Models ; Prostatic Neoplasms, Castration-Resistant/pathology* ; Retrospective Studies ; Serum Albumin/metabolism* ; Survival Rate ; Time Factors

OBJECTIVE: To evaluate whether dexmedetomidine hydrochloride, an α(2)-adrenergic receptor agonist, can prevent H(2)O(2)-induced oxidative stress and inflammatory response in Kupffer cells.
 METHODS: H(2)O(2)-induced oxidative damage model of Kupffer cell was established. Kupffer cells were pre-conditioned by dexmedetomidine hydrochloride or Yohimbine for 24 h. MTT colorimetry was used to demonstrate the survival rate of Kupffer cells. The levels of lactate dehydrogenase (LDH), malonaldehyde (MDA) and TNF-α in the culture medium were assessed by corresponding kits.
 RESULTS: Dexmedetomidine hydrochloride protected Kupffer cells from H(2)O(2)-induced oxidative damage, showing an increase in the cell survival rate while a decrease in LDH, MDA and TNF-α release in the culture supernatant. Yohimbine, an α(2)-adrenergic receptor antagonist, completely neutralized the protective effect of Dexmedetomidine hydrochloride on Kupffer cells. Yohimbine itself had no effect on H(2)O(2)-induced oxidative damage and inflammatory response.
 CONCLUSION Dexmedetomidine hydrochloride can prevent H(2)O(2)-induced oxidative stress and inflammatory response in Kupffer cells through activation of α(2)-adrenergic receptors.
Adrenergic alpha-2 Receptor Antagonists ; pharmacology ; Cell Survival ; Cells, Cultured ; Dexmedetomidine ; pharmacology ; Humans ; Hydrogen Peroxide ; pharmacology ; Kupffer Cells ; cytology ; drug effects ; L-Lactate Dehydrogenase ; metabolism ; Malondialdehyde ; metabolism ; Oxidative Stress ; drug effects ; Receptors, Adrenergic, alpha-2 ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism ; Yohimbine ; pharmacology

In this study, the effects of catalase (CAT) inhibitor aminotriazole (ATZ) on alcohol-induced acute liver injury were investigated to explore the potential roles of CAT in alcoholic liver injury. Acute liver injury was induced by intraperitoneal injection of alcohol in Sprague Dawley (SD) rats, and various doses of ATZ (100-400 mg/kg) or vehicle were administered intraperitoneally at 30 min before alcohol exposure. After 24 h of alcohol exposure, the levels of aspartate transaminase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH) in plasma were determined. The degree of hepatic histopathological abnormality was observed by HE staining. The activity of hepatic CAT, hydrogen peroxide (H₂O₂) level and malondialdehyde (MDA) content in liver tissue were measured by corresponding kits. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in plasma were determined by ELISA method. The results showed that treatment with ATZ dose-dependently suppressed the elevation of ALT, AST and LDH levels induced by alcohol exposure, and that ATZ alleviated alcohol-induced histopathological alterations. Furthermore, ATZ inhibited the activity of CAT, reduced hepatic levels of H₂O₂and MDA in alcohol exposed rats. ATZ also decreased the levels of plasma TNF-α and IL-6 in rats with alcohol exposure. These results indicated that ATZ attenuated alcohol-induced acute liver injury in rats, suggesting that CAT might play important pathological roles in the pathogenesis of alcoholic liver injury.
Alanine Transaminase ; metabolism ; Amitrole ; pharmacology ; Animals ; Aspartate Aminotransferases ; metabolism ; Catalase ; antagonists & inhibitors ; Ethanol ; Hydrogen Peroxide ; metabolism ; Interleukin-6 ; blood ; L-Lactate Dehydrogenase ; metabolism ; Liver ; enzymology ; Liver Diseases, Alcoholic ; drug therapy ; Malondialdehyde ; metabolism ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha ; blood

OBJECTIVE: To investigate the protective effect of a non-specific NMDA receptor antagonist memantine on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. METHODS: Healthy male mice were divided into 4 groups: a normal group, a memantine group, an ALI group and a memantine+ALI group. The ALI group was induced by intraperitoneal injection of LPS (10 mg/kg). Memantine (10 mg/kg) was injected intraperitoneally before the injection of LPS to determine the effect of blockade of NMDA receptor in the memantine+ALI group. The lung wet/dry ratio was detected. HE staining was preformed to show the morphological changes in the lung tissue. Myeloperoxidase enzyme (MPO) activity and malondialdehyde (MDA) content in the lung tissue were detected. ELISA was used to detect the tumor necrosis factor-α (TNF-α) content and lactate dehydrogenase (LDH) activity in the bronchoalveolar lavage fluid (BALF). RESULTS: Memantine pretreatment improved the LPS-induced ALI lung tissue morphological changes, reduced their lung wet/dry ratio, the levels of TNF-α and LDH activity in BALF, and also reduced the MPO and MDA content in the lung tissue. CONCLUSION Blockade of NMDA receptors can ameliorate LPS-induced mice ALI.
Acute Lung Injury ; drug therapy ; Animals ; Bronchoalveolar Lavage Fluid ; L-Lactate Dehydrogenase ; metabolism ; Lipopolysaccharides ; Lung ; metabolism ; Male ; Malondialdehyde ; metabolism ; Memantine ; pharmacology ; Mice ; Peroxidase ; metabolism ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; Tumor Necrosis Factor-alpha ; metabolism

Retaining or improving periodontal ligament (PDL) function is crucial for restoring periodontal defects. The aim of this study was to evaluate the physiological effects of low-power laser irradiation (LPLI) on the proliferation and osteogenic differentiation of human PDL (hPDL) cells. Cultured hPDL cells were irradiated (660 nm) daily with doses of 0, 1, 2 or 4 J⋅cm(-2). Cell proliferation was evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, and the effect of LPLI on osteogenic differentiation was assessed by Alizarin Red S staining and alkaline phosphatase (ALP) activity. Additionally, osteogenic marker gene expression was confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR). Our data showed that LPLI at a dose of 2 J⋅cm(-2) significantly promoted hPDL cell proliferation at days 3 and 5. In addition, LPLI at energy doses of 2 and 4 J⋅cm(-2) showed potential osteogenic capacity, as it stimulated ALP activity, calcium deposition, and osteogenic gene expression. We also showed that cyclic adenosine monophosphate (cAMP) is a critical regulator of the LPLI-mediated effects on hPDL cells. This study shows that LPLI can promote the proliferation and osteogenic differentiation of hPDL cells. These results suggest the potential use of LPLI in clinical applications for periodontal tissue regeneration.
Adenine ; analogs & derivatives ; pharmacology ; Adenylyl Cyclase Inhibitors ; Alkaline Phosphatase ; analysis ; genetics ; radiation effects ; Anthraquinones ; Bone Morphogenetic Protein 2 ; genetics ; Calcium ; metabolism ; radiation effects ; Cell Culture Techniques ; Cell Differentiation ; radiation effects ; Cell Line ; Cell Proliferation ; radiation effects ; Coloring Agents ; Core Binding Factor Alpha 1 Subunit ; genetics ; Cyclic AMP ; antagonists & inhibitors ; radiation effects ; Gene Expression ; radiation effects ; Humans ; L-Lactate Dehydrogenase ; analysis ; Lasers, Semiconductor ; Low-Level Light Therapy ; instrumentation ; Osteocalcin ; genetics ; Osteogenesis ; genetics ; radiation effects ; Periodontal Ligament ; cytology ; radiation effects ; Radiation Dosage ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Tetrazolium Salts ; Thiazoles

OBJECTIVE: To study the effects of norcantharidin (NCTD) on lipopolysaccharide (LPS)-induced hepatocyte injury and the expression of TNF-α and IL-6 in vitro. METHODS: Hepatocytes were isolated from male Sprague-Dawley rats by collagenase perfusion. LPS at concentration of 40 mg/L was used to induce injury to the cultured cells, and NCTD (0.5, 1.0, 2.5 μg/mL) was added at the same time. After 24 h of incubation, the cell proliferation rates were detected by MTT. LDH, TNF-α and IL-6 were measured by appropriate reagent kits.NF-κB DNA binding activity was measured. RESULTS: 40 mg/L LPS caused a 27% growth inhibition in primary hepatocytes. LDH leakage was 20- fold higher in NCTD-treated hepatocytes than in normal ones. TNF-α and IL-6 expression significantly increased. In cells treated with NCTD at doses of 0.5, 1.0 and 2.5 μg/mL, LDH leakage, TNF-α and IL-6 expression, and NF-κB DNA binding activity were attenuated in a dose dependent manner. CONCLUSION NCTD protects hepatocytes from injury induced by LPS; the protection is associated with suppression of the inflammatory cytokine TNF-α and IL-6.
Animals ; Bridged Bicyclo Compounds, Heterocyclic ; pharmacology ; Cell Proliferation ; Chick Embryo ; DNA-Binding Proteins ; metabolism ; Hepatocytes ; cytology ; metabolism ; pathology ; Interleukin-6 ; genetics ; metabolism ; L-Lactate Dehydrogenase ; genetics ; metabolism ; Lipopolysaccharides ; antagonists & inhibitors ; Male ; NF-kappa B ; metabolism ; Primary Cell Culture ; Protective Agents ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha ; genetics ; metabolism

OBJECTIVETo investigate the effect of mitochondrial permeability transition pore inhibitor cyclosporine A (CsA) on lipopolysaccharide (LPS)-induced acute lung injury in mice.

METHODSAll male ICR mice were randomly divided into five groups (n = 24): control group, LPS group, dexamethasone group, cyclosporine A(CsA) group and CsA + atractyloside(Atr) group. Six hours after treatment with LPS, the activity of lactate dehydrogenlase (LDH) in bronchoalveolar lavage fluid (BALF) and level of tumor necrosis factor-alpha (TNF-alpha) in lung tissue were detected. The lung wet weight/dry weight ratio and the pulmonary capillary permeability index were also detected.

RESULTSIn contrast to LPS group, the mitochondrial permeability transition pore inhibitor CsA induced a decrease in LDH activity in the BALF and TNF-alpha level in lung tissue, lung wet weight/dry weight ratio and the pulmonary capillary permeability index were declined. Atractyloside, the activator of mitochondrial permeability transition pore, almost abolished the role of CsA on LPS-induced lung injury.

CONCLUSIONThese results suggested that CsA plays the protective effect on LPS-induced lung injury in mice, it is likely through inhibiting the opening of mitochondrial permeability transition pore.

Acute Lung Injury ; chemically induced ; physiopathology ; prevention & control ; Animals ; Cyclosporine ; pharmacology ; L-Lactate Dehydrogenase ; metabolism ; Lipopolysaccharides ; Male ; Mice ; Mice, Inbred ICR ; Mitochondrial Membrane Transport Proteins ; antagonists & inhibitors ; Protective Agents ; pharmacology ; Tumor Necrosis Factor-alpha ; metabolism

BACKGROUNDNeuregulin-1 (NRG-1), the ligand of the myocardial ErbB receptor, is a protein mediator with regulatory actions in the heart. This study investigated whether NRG-1 preconditioning has protective effects on myocardial ischemia/reperfusion (I/R) injury and its potential mechanism.

METHODSWe worked with an in vivo rat model with induced myocardial ischemia (45 minutes) followed by reperfusion (3 hours). NRG-1 message was detected in the heart using RT-PCR and the protein levels of NRG-1 and ErbB4 were detected by Western blotting analysis. Infarct size was assessed using the staining agent triphenyltetrazolium chloride and cardiac function was continuously monitored. The levels of creatine kinase and lactate dehydrogenase in plasma were analyzed to assess the degree of cardiac injury. The extent of cardiac apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and by Western blotting analysis of cleaved caspase-3. We examined the phosphorylation of Akt in the myocardium and the effect of PI3K/Akt inhibition on NRG-1-induced cardioprotection.

RESULTSTranscription and expression of NRG-1 and phosphorylation of its ErbB4 receptor were significantly upregulated in the I/R hearts. NRG-1 pretreatment reduced the infarct size following cardiac I/R in a concentration-dependent manner with an optimal concentration of 4 µg/kg in vivo. NRG-1 pretreatment with 4 µg/kg, i.v. markedly reduced the plasma creatine kinase and lactate dehydrogenase levels. Pretreatment with NRG-1 also significantly reduced the percentage of TUNEL positive myocytes and the level of cleaved caspase-3 in the I/R hearts. Pretreatment with NRG-1 significantly increased phosphorylation of Akt following I/R. Furthermore, the cardioprotective effect limiting the infarct size that was induced by NRG-1 was abolished by co-administration of the PI3K inhibitor LY294002.

CONCLUSIONSThe concentration of NRG-1, a new autacoid, was rapidly upregulated after myocardial I/R. NRG-1 preconditioning has cardioprotective effects against I/R injury through a PI3K/Akt-dependent mechanism in vivo.

Animals ; Apoptosis ; drug effects ; Caspase 3 ; metabolism ; Dose-Response Relationship, Drug ; Ischemic Preconditioning, Myocardial ; L-Lactate Dehydrogenase ; blood ; Male ; Myocardial Reperfusion Injury ; prevention & control ; Neuregulin-1 ; analysis ; pharmacology ; Phosphatidylinositol 3-Kinases ; antagonists & inhibitors ; physiology ; Phosphorylation ; Proto-Oncogene Proteins c-akt ; physiology ; Rats ; Rats, Sprague-Dawley ; Receptor, Epidermal Growth Factor ; analysis ; Receptor, ErbB-4

The present study was aimed to investigate whether calreticulin (CRT) was involved in the protective effect of hypoxic preconditioning (HPC) against oxidative stress injury in rat cardiomyocytes. Neonatal cardiomyocytes were prepared from Sprague-Dawley rats aged 24 h, and cultured in DMEM medium containing 10% fetal bovine serum. The cultured cardiomyocytes were randomly divided into 8 groups as follows: (1) hydrogen peroxide stress (H(2)O(2) group); (2) brief hypoxic exposure for 20 min to simulate HPC (HPC group); (3) hypoxic exposure for 20 min followed by normoxic reoxygenation for 24 h before hydrogen peroxide stress (HPC + H(2)O(2) group); (4) SB203580 (a specific inhibitor of p38 MAPK) + HPC + H(2)O(2) group; (5) CRT antisense oligonucleotide transfection (AS group); (6) AS + H(2)O(2) group; (7) AS + HPC + H(2)O(2) group; (8) control group. Morphological observation, lactate dehydrogenase (LDH) leakage and flow cytometry were employed to assess cell apoptosis and necrosis. RT-PCR and Western blot were used to detect CRT expression and activity of p38 MAPK. All experiments were repeated at least four separate times. The results obtained were as follows: (1) HPC relieved cell injury caused by H(2)O(2). Compared with that in H(2)O(2) group, the cell survival rate increased by 18.0% (P<0.05), apoptotic rate and LDH leakage in culture medium decreased by 19.4% and 53.0%, respectively (P<0.05) in HPC + H(2)O(2) group. (2) H(2)O(2) induced CRT over-expression (7.1-fold increase compared with control, P<0.05), while HPC resulted in mild CRT up-regulation (2.4-fold increase compared with control, P<0.05), suggesting that HPC can relieve the over-expression of CRT induced by H(2)O(2). (3) CRT AS transfection weakened the protection of HPC. Compared with that in HPC + H(2)O(2) group, the cell survival rate decreased by 4% (P<0.05), and apoptotic rate and LDH leakage in culture medium increased by 2.6% and 39.0%, respectively (P< 0.05) in AS + HPC + H(2)O(2) group. (4) The protection of HPC and HPC-induced upregulation of CRT were almost eliminated when SB203580 was administered before HPC. These results suggest that HPC up-regulates CRT expression through the p38 MAPK signaling pathway and protects cardiomyocytes from oxidative stress injury.
Animals ; Apoptosis ; Calreticulin ; metabolism ; Cell Hypoxia ; Cell Survival ; Cells, Cultured ; Hydrogen Peroxide ; Imidazoles ; pharmacology ; Ischemic Preconditioning, Myocardial ; L-Lactate Dehydrogenase ; metabolism ; Myocytes, Cardiac ; pathology ; Oxidative Stress ; Pyridines ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Up-Regulation ; p38 Mitogen-Activated Protein Kinases ; antagonists & inhibitors

This study is to investigate the protective effect of (-) clausenamide against the neurotoxicity of okadaic acid in SH-SY5Y cell line, and injection beta-amyloid peptide25-35 (Abeta25-35) to the cerebral ventricle in ovariectomy (OVX) rats. MTT assay, LDH assay, and Hoechst 33258 staining were used to detect the effect of (-) clausenamide on the toxicity of okadaic acid in SH-SY5Y cell line. The animal model was induced by ovariectomized and injection of Abeta25-35 in the cerebroventricle of rats. The effect of (-) clausenamide on learning and memory deficiency was observed by step-through test. Electron microscope, Nissl body staining, and HE staining were used to examine the morphological changes in hippocampus and cerebral cortex neurons. Pretreatment of (-) clausenamide and LiCl decreased the rate of cell death from MTT, LDH release, and apoptosis from Hoechst 33258 staining in SH-SY5Y cell line. The step-through tests showed (-) clausenamide could improve the ability of learning and memory. The Nissl body staining and HE staining experiments also showed the neuroprotective effects of (-) clausenamide on the neurons of hippocampus and cerebral cortex. (-) Clausenamide has the protective effects against the neurotoxicity induced by okadaic acid and Abeta25-35.
Amyloid beta-Peptides ; antagonists & inhibitors ; toxicity ; Animals ; Apoptosis ; drug effects ; Cell Line, Tumor ; Cell Survival ; drug effects ; Cerebral Cortex ; cytology ; Clausena ; chemistry ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; Female ; Hippocampus ; cytology ; Humans ; L-Lactate Dehydrogenase ; metabolism ; Lactams ; isolation & purification ; pharmacology ; Learning ; drug effects ; Lignans ; isolation & purification ; pharmacology ; Memory Disorders ; physiopathology ; Neuroblastoma ; metabolism ; pathology ; Neurons ; drug effects ; Neuroprotective Agents ; isolation & purification ; pharmacology ; Okadaic Acid ; antagonists & inhibitors ; toxicity ; Ovariectomy ; Peptide Fragments ; antagonists & inhibitors ; toxicity ; Plants, Medicinal ; chemistry ; Rats ; Rats, Sprague-Dawley