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Background: Postoperative cognitive dysfunction (POCD) are a common complication of the central nervous system following surgery and anesthesia. The specific pathogenesis and effective therapeutics of POCD need to be further studied. Ginkgolide B (GB), a platelet-activating factor receptor-specific antagonist, has been suggested to have strong anti-inflammatory effects. Here we tested the effects and mechanism of GB on POCD of aged rats. Methods: Neurobehavioral tests were used to investigate the effect of GB pretreatment on POCD. The hippocampus were harvested to test the expression of proinflammatory cytokines by ELISA. The expression of the microglial marker ionized calcium-binding adaptor molecule-1 (Iba-1) in the hippocampus was evaluated by western blot assay and immunohistochemistry. A Nissl staining experiment was used to detect the neuronal numbers in the hippocampus. Results: Surgery might result in the overexpression of platelet activating factor (PAF) in the plasma and hippocampus and might cause hippocampus-dependent memory impairment. GB pretreatment, inhibited the activation of microglia, reduced the levels of IL-1β and TNF-α, decreased the loss of neurons after surgery, and prevented POCD in aged rats. Conclusion: Our findings suggested that PAF was involved in the development of POCD. Improvement of POCD by PAF antagonist GB was associated with the inhibition of microgliosis-mediated neuroinflammation and neuronal apoptosis in aged rats. [ABSTRACT FROM AUTHOR]

Mitochondria are organelles responsible for vital cell functions. p53 is a transcription factor that regulates the DNA stability and cell growth normality. Recent studies revealed that p53 can influence mitochondrial function changing from normal condition to abnormal condition under different stress levels. In normal state, p53 can maintain mitochondrial respiration through transactivation of SCO2. When stress stimuli presents, SCO2 overexpresses and leads to ROS generation. ROS promotes p53 inducing MALM (Mieap-induced accumulation of lysosome-like organelles within mitochondria) to repair dysfunctional mitochondria and MIV (Mieap-induced vacuole) to accomplish damaged mitochondria degradation. If stress or damage is irreversible, p53 will translocate to mitochondria, leading into apoptosis or necrosis. Neurodegenerative diseases including Parkinson's disease, Huntington's disease and Alzheimer's disease are still lack of clear explanations of mechanisms, but more studies have revealed the functional relationship between mitochondria and p53 towards the pathological development of these diseases. In this review, we discuss that p53 plays the vital role in the function of mitochondria in the aspect of pathological change metabolism. We also analyze these diseases with novel targeted treating molecules which are related to p53 and mitochondria, hoping to present novel therapies in future clinic. [ABSTRACT FROM AUTHOR]

In 2008, CLAs received a no-objection letter from the FDA on its generally recognized as safe (GRAS) status for certain foods. However, aside from the mixture of c9, t11-CLA and t10, c12-CLA, other CLA mixtures are still not used in food production. The effects of different concentrations (25, 50, 100, and 200 µmol/L) of CLA mixture (c9, t11-CLA and t9, t11-CLA) on the human colorectal carcinoma cell line Caco-2 cells after various treatment times (1, 2, 3, and 4 days) and the induced apoptosis were examined in the study. The mRNA expression level and activities of caspase-3, -8, and -9 were determined via quantitative real-time PCR and caspase-3, -8, and -9 assay kits. The results indicated that the CLA mixture inhibited the proliferation of the Caco-2 cells, and the antiproliferative effects were closely related to treatment time and concentration. Meanwhile, the CLA mixture increased the mRNA expression level and activities of caspase-3, -8, and -9 compared with control which suggested apoptosis induced by CLA mixture was related to the caspase pathway. In conclusion, the CLA mixture can inhibit Caco-2 cell proliferation and induce its apoptosis through increasing caspase 3, 8, and 9 expression and activities. Practical applications: In the food industry, lactic acid bacteria (LAB) are generally recognized as safe and important for the production of fermented food and may be used as probiotic bacteria in the human gastrointestinal tract, contributing to pathogen inhibition and immunomodulation. C9, t11-CLA and t9, t11-CLA isomers used for the present study were obtained from the conversion of linoleic acid by Lactobacillus helveticus L7 (used as a probiotic bacterial in our laboratory). Here, the mixture of c9, t11-CLA and t9, t11-CLA had a synergistic antiproliferation effect on the Caco-2 cells which suggested that the CLA mixture has potential health value, and can be a beneficial supplement in the food industry. [ABSTRACT FROM AUTHOR]

Microarray data reported elsewhere indicated that herpes simplex virus I induces the up-regulation of nuclear factor &key;B (NF-&key;B)regulated genes, including that of its inhibitor, I&key;Bα, consistent with the reports that wild-type virus induces the activation of NF-&key;B. In this report we show that activation of NF-&key;B in infected cells is linked to the activation of protein kinase R (PKR). Specifically: (i) PKR is activated in infected cells although the effects of the activated enzyme on protein synthesis are negated by the viral gene 1,134.5, which encodes a protein phosphatase la accessory factor that enables the dephosphorylation of the a subunit of eukaryotic translation initiation factor 2. NF-&key;B is activated in wild-type murine embryonic fibroblasts but not in related PKR-null cells. (ii) In cells infected with a replication-competent δγ134.5 mutant (R5104), but carrying a Us11 gene expressed early in infection, eukaryotic translation initiation factor 2α is not phosphorylated, and in in vitro assays, PKR bound to the Us11 protein is not phosphorylated on subsequent addition of double-stranded RNA. Here we report that this mutant does not activate PKR, has no effect on the accumulation of I&key;Bα, and does not cause the translocation of NF-&key;B in infected cells. (iii) One hypothesis advanced for the activation of NF-&key;B is that it blocks apoptosis induced by viral gene products. The replication-competent R5104 mutant does not induce the programmed cell's death. We conclude that in herpes simplex virus 1-infected cells, activation of NF-&key;B depends on activation of PKR and that NF-&key;B is not required to block apoptosis in productively infected cells. [ABSTRACT FROM AUTHOR]

Perioperative neurocognitive dysfunction (PND) is a prevalent neurological complication after anesthesia and surgery. Ginkgolide B (GB) has been suggested to improve lipopolysaccharide-induced learning and memory impairment. The present study aimed to investigate whether GB serves a protective role against PND by inhibiting inducible nitric oxide synthase (iNOS) and nitric oxide (NO). Abdominal surgery was performed on 10- to 12-week-old male C57BL/6 mice under isoflurane anesthesia. Prior to surgery, 1400W (a specific iNOS inhibitor) and GB were administered via intraperitoneal injection. Open field and fear conditioning tests were conducted to assess cognitive function on postoperative days 1 and 3. Biochemical assays were performed to evaluate alterations in NO, malondialdehyde (MDA) and superoxide dismutase (SOD) levels. Western blotting was performed to measure iNOS expression in the hippocampus on postoperative day 1. In addition, hematoxylin and eosin staining was performed to detect the neuronal morphology in the hippocampus. Following treatment with 1400W or GB, surgery-induced cognitive dysfunction was improved. Compared with the control group, the surgery group exhibited significant overproduction of iNOS and MDA in the hippocampus on postoperative day 1. Higher levels of NO were also detected in the hippocampus and prefrontal cortex of the surgery group on postoperative day 1. Furthermore, pretreatment with 1400W or GB significantly inhibited the surgery-induced elevation of NO and MDA in brain tissues. Moreover, GB pretreatment significantly inhibited surgery-induced downregulation of SOD and upregulation of iNOS. Surgery-induced increases in neuronal loss and the Bax/Bcl-2 ratio in the hippocampus were significantly inhibited by pretreatment with GB. Collectively, the results of the present study demonstrated that the therapeutic effects of GB on PND were associated with inhibition of iNOS-induced NO production, increased SOD, and the alleviation of neuronal loss and apoptosis. [ABSTRACT FROM AUTHOR]

Diabetic patients are more sensitive to ischemic injury than non-diabetics. Endoplasmic reticulum (ER) stress has been reported to be closely associated with the pathophysiology of ischemic injury in diabetes. The aim of the present study was to investigate the mechanisms involved in the progression of diabetes complicated by myocardial infarction (MI) and further verify the role of CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP) using an in vitro model of diabetes/MI. The rats were exposed to 65 mg/kg streptozotocin (STZ) and left anterior descending (LAD) coronary artery ligation. ST-segment elevation, heart rate, left ventricular systolic pressure (LVSP) and LV end-diastolic pressure (LVEDP) were measured. Serum creatinine kinase-MB (CK-MB) and cardiac troponin T (cTnT) levels were examined by ELISA. Infarct size and apoptosis were measured by triphenyltetrazolium chloride staining and terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling assay. Pathological changes were evaluated by hematoxylin and eosin staining. H9c2 cells were used to establish an in vitro model of diabetes complicated by MI. Following CHOP knockdown, cell viability, cell cycle distribution and apoptosis were examined by Cell Counting Kit-8 assay, flow cytometry and Hoechst staining. Glucose-regulated protein 78 (GRP78), CHOP, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), endoplasmic reticulum oxidoreductase 1 (Ero1)-α, Ero1β and protein disulfide isomerase (PDI) levels in both myocardial tissues and H9c2 cells were determined by western blotting. In the present study, diabetes complicated by MI promoted ST-segment elevation and myocardial apoptosis, increased infarct size, induced pathological changes and elevated LVEDP, CK-MB, cTnT, GRP78, CHOP, Bax, Ero1α, Ero1β and PDI; however, it decreased heart rate, LVSP and Bcl-2. Additionally, high glucose combined with hypoxic treatment reduced cell viability, induced cell cycle arrest at G1 phase, promoted cell apoptosis, and activated the GRP78/CHOP and Ero1/PDI signaling pathways, which were reversed by CHOP knockdown. Thus, CHOP may be an effective therapeutic target for the treatment of diabetes complicated by MI. [ABSTRACT FROM AUTHOR]

Postcontrast acute kidney injury (PC-AKI) is directly caused by the use of contrast, indicating a clear causal relationship between the contrast and the injury. Salvianolic acid B (Sal B), a water-soluble compound of Salvia miltiorrhiza, has a potent anti-inflammatory effect. We conducted a study to explore whether the protective effect of Sal B on iopromide-induced injury in human proximal tubular epithelial cells (HK-2 cells) is related to inhibition of the TLR4/NF-κB/NLRP3 signal pathway. The results showed that 100 μmol/L Sal B counteracted the decrease in cell viability, the increase of ROS and the number of apoptotic cells, and the decrease of mitochondrial membrane potential (ΔΨm) induced by iopromide. Molecular docking analysis showed that Sal B binds TLR4 and NLRP3 proteins. Moreover, 100 μmol/L Sal B also decreased the expression of TLR4, NLRP3, ASC, Caspase-1, IL-18, IL-1β, TNF-α, p-NF-κB, cleaved caspase-3, and the ratio of Bax/Bcl-2 induced by iopromide. TAK-242, a TLR4 antagonist, was added to further explore the mechanism of Sal B. However, the cotreatment group with TAK-242 and Sal B had no significant difference in cell viability and apoptosis rate compared to the treatment group with TAK-242 or Sal B alone. These results indicated that Sal B can inhibit the TLR4/NF-κB/NLRP3 signal pathway, resulting in the alleviation of iopromide-induced HK-2 cell injury. [ABSTRACT FROM AUTHOR]

Actinomycin D (Act D) is a general transcriptional inhibitor that is approved for the treatment of sarcomas, and Wilms, germ cell and trophoblastic tumors. Little is known about the molecular mechanisms that dictate the sensitivity of cancer cells to Act D. In this study, we investigated the effects of Act D on heat shock proteins ( HSPs) and the expression and roles of HSP27 in Act D-induced cancer cell apoptosis. We show that Act D upregulates HSP27 and HSP70 expression in cancer cells, whereas it inhibits HSP90 expression. The upregulation of HSP27 by Act D is not attributable to changes in HSP27 transcription or HSP27 synthesis. HSP27 knockdown leads to an increase in Act D-induced caspase 3 and caspase 7 cleavage, and sensitizes rhabdosarcoma cells and breast cancer cells to Act D-induced apoptosis. We conclude that upregulation of HSP27 represents an adaptive response that compromises the anticancer activity of Act D. [ABSTRACT FROM AUTHOR]

A series of novel benzothiazole-2-thiol derivatives were synthesized and their structures determined by 1H-NMR, 13C-NMR and HRMS (ESI). The effects of all compounds on a panel of different types of human cancer cell lines were investigated. Among them, pyridinyl-2-amine linked benzothiazole-2-thiol compounds 7d, 7e, 7f and 7i exhibited potent and broad-spectrum inhibitory activities. Compound 7e displayed the most potent anticancer activity on SKRB-3 (IC50 = 1.2 nM), SW620 (IC50 = 4.3 nM), A549 (IC50 = 44 nM) and HepG2 (IC50 = 48 nM) and was found to induce apoptosis in HepG2 cancer cells. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma is one of the most common cancers in worldwide. We previously reported a novel thienopyridine derivative 3-amino-6-(3,4-dichlorophenyl) thieno[2,3-b]pyridine-2-carboxamide (SKLB70359) which possesses anticancer activity against hepatocellular carcinoma. In present study, we further investigated its anticancer activity and possible mechanism. The SKLB70359 treatment decreased the viability of a panel of hepatocellular carcinoma cell lines in a concentration- and time-dependent manner with IC50 0.4ñ2.5 μM. The mechanism study showed that SKLB70359 induced G0/G1 cell cycle arrest and then led to apoptotic cell death of HepG2 cell. The SKLB70359 induced G0/G1 cell cycle arrest was characterized by down-regulation of cyclin-dependent kinase 2 (CDK2), CDK4, CDK6 expression and up-regulation of p53, p21WAF1. Activating of caspase-3 and caspase-9 was also observed. Meanwhile, proliferation inhibitory effect of SKLB70359 was associated with decreased level of phosphorylated p44/42 mitogen activated protein kinase (p44/42 MAPK) and phosphorylated retinoblastoma protein (Rb). Moreover, SKLB70359 exhibit less toxicity to non-cancer cells than tumor cells. In conclusion, the findings in this study suggested that SKLB70359 have potential anticancer efficacy via G0/G1 cell cycle arrest and apoptosis induction. Its potential to be a candidate of anticancer agent is worth being further investigated. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Inducing apoptosis is a promising therapeutic approach to overcome cancer. Here we described that a novel synthesized compound, 3-amino-N-(4-chlorobenzyl)-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide (SKLB703), exhibits antitumor activity via inducing apoptosis both in vitro and in vivo. Our results showed that SKLB703 inhibited the proliferation of a panel of human cancer cell lines, and human hepatocellular carcinoma cell line HepG2 was the most sensitive. The proliferation inhibitory effect of SKLB703 was associated with its apoptosis-inducing effect by activating caspase-3 and caspase-9 rather than caspase 8. Exposure of HepG2 to SKLB703 also resulted in Bax upregulation, Bcl-2 downregulation, cytochrome c release and mitochondrial transmembrane potential change in mitochondrial apoptotic pathway. Moreover, the decrease of phosphorylated p 44/42 mitogen-activated protein kinase and phosphorylated Akt was observed. SKLB703 suppressed the growth of established tumors in xenograft models in mice, whereas no toxicity was exhibited. TUNAL analysis showed that SKLB703 induced HepG2 tumor apoptosis. Taken together, the present study demonstrates that SKLB730 exhibits its antitumor activity through inducing apoptosis via mitochondrial apoptotic pathway. Its potential to be a candidate of anticancer agent is worth being further investigated. [Copyright &y& Elsevier]

In a cell-based screen of novel anticancer agents, the hit compound 1a which bears a pyrazolo[3,4-d]pyrimidine scaffold exhibited high inhibitory activity against a panel of four different types of tumor cell lines. In particular, the IC50 for A549 cells was 2.24 μM, compared with an IC50 of 9.20 μM for doxorubicin, the positive control. Four synthetic routes of the key intermediate 3 of 1a were explored and 1a was prepared via route D on the gram scale for further research. Two analogs of 1a were synthesized and their preliminary structure-activity relationships were studied. Flow cytometric analysis revealed that compound 1a could significantly induce apoptosis in A549 cells in vitro at low micromolar concentrations. These results suggest that the target compound 1a and its analogs with the pyrazolo[3,4-d]pyrimidine scaffold might potentially constitute a novel class of anticancer agents, which requires further studies. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel benzothiazole-2-thiol derivatives were synthesized, and their anti-proliferative activities on HepG2 and MCF-7 cells were investigated. Most compounds had inhibitory effects on cell growth, and some of them were more effective than cisplatin. Compounds 6m and 6t displayed good inhibitory activities against a panel of different types of human cancer cell lines, with IC50 values in the low micromolar range. Further biological evaluation indicated that 6m induced apoptosis in HepG2 cancer cells. Structure–activity relationships were also proposed. [Copyright &y& Elsevier]

Abstract: Novel thienopyridine derivatives 1b–1r were synthesized, based on a hit compound 1a that was found in a previous cell-based screening of anticancer drugs. Compounds 1a–1r have the following features: (1) their anticancer activity in vitro was first reported by our group. (2) The most potent analog 1g possesses hepatocellular carcinoma (HCC)-specific anticancer activity. It can specifically inhibit the proliferation of the human hepatoma HepG2 cells with an IC50 value of 0.016μM (compared with doxorubicin as a positive control, whose IC50 was 0.37μM). It is inactive toward a panel of five different types of human cancer cell lines. (3) Compound 1g remarkably induces G0/G1 arrest and apoptosis in HepG2 cells in vitro at low micromolar concentrations. These results, especially the HCC-specific anticancer activity of 1g, suggest their potential in targeted chemotherapy for HCC. [ABSTRACT FROM AUTHOR]

• WNY1613 was a potent and selective PI3Kδ inhibitor with piperazinone-containing purine scaffold. • WNY1613 could induce cancer cell apoptosis and inhibit the phosphorylation of PI3K downstream components in NHL cell lines. • WNY1613 exhibited anti-NHL activity in vitro and in vivo. PI3Kδ has proved to be an effective target for anti-lymphoma drugs. However, the application of current approved PI3Kδ inhibitors has been greatly limited due to their specific immune-mediated toxicity and increased risk of infection, it is necessary to develop more PI3Kδ inhibitors with new scaffold. In this study, SAR study with respect to piperazinone-containing purine derivatives led to the discovery of a potent and selective PI3Kδ inhibitor, 4-(cyclobutanecarbonyl)-1-((2-(2-ethyl-1 H -benzo d imidazol-1-yl)-9-methyl-6-morpholino-9 H -purin-8-yl)methyl)piperazin-2-one (WNY1613). WNY1613 exhibits good antiproliferative activity against a panel of non-Hodgkin's lymphoma (NHL) cell lines by inducing cancer cell apoptosis and inhibiting the phosphorylation of PI3K and MAPK downstream components. In addition, it can also prevent the tumor growth in both SU-DHL-6 and JEKO-1 xenograft models without observable toxicity. WNY1613 thus could be developed as a promising candidate for the treatment of NHL after subsequent extensive pharmacodynamics and pharmacokinetics investigation. [ABSTRACT FROM AUTHOR]

• Ethanol extract of Pycnoporus sanguineus (PSE) relieves inflammatory signs of colitis. • PSE enhances tight junction and adherens junction to recover mucosal integrity. • PSE inhibits the helper T cells (Th)-mediated immune response. • PSE suppresses T cells and the Th subset upon stimulation by inducing apoptosis. Inflammatory bowel disease (IBD) is a chronic relapsing inflammation involving the gut system, and disequilibrium of T helper (Th) cell paradigm has been recognized as critical pathogenesis. Pycnoporus sanguineus (L.) Murrill is a species of the white-rot basidiomycetes listed as food- and cosmetic-grade microorganisms. In this study, anti-inflammatory activity of the ethanol extract from P. sanguineus (PSE) was investigated in dextran sulfate sodium (DSS)-induced experimental colitis model. PSE recovered the DSS-caused weight loss, reversed the colon shortening, and ameliorated the histopathological lesion in colon, resulting in lower disease activity index (DAI). Levels of serumal lipopolysaccharide (LPS), colonic myeloperoxidase (MPO) in the colitis-suffering mice were declined by PSE treatment. PSE also improved the mucosal integrity by enhancing the expression of tight junction and adherens junction proteins in the colon, including ZO-1, occludin, claudin-1, and E-cadherin. Besides, PSE reduced helper T cells (Th) in the colon, together with an evident decrease of several Th cell-related cytokines. Moreover, it was found that in vitro , PSE suppressed T cells and the Th subset upon Concanavalin A (ConA)-stimulation by inducing apoptosis. In summary, PSE displayed a remission on the colitis-related inflammation, which would possibly rely on the epithelial barrier restoration by suppressing Th cells via apoptosis induction, highlighting a promising potential in the treatment for IBD. [ABSTRACT FROM AUTHOR]