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Find video protocols related to scientific articles indexed in Pubmed.
An Anatomic Study to Determine the Optimal Entry Point, Medial Angles, and Effective Length for Safe Fixation using Posterior C1 Lateral Mass Screws.
Spine
PUBLISHED: 11-15-2014
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Study Design. Anatomic study of the C1 lateral mass using fine-cut computed tomographic (CT) scans and Mimics software.Objective. To investigate the optimal entry point, medial angles and effective length for safe fixation using posterior C1 lateral mass screws.Summary of Background Data. Placing posterior C1 lateral mass screws is technically demanding, and a misplaced screw can result in injury to the vertebral artery, spinal cord, or internal carotid artery. Although various insertion angles have been proposed for posterior C1 lateral mass screw, no clear consensus has been reached on the ideal medial angle of the C1 lateral mass.Methods. The C1 lateral masses were evaluated using CT scans and Mimics software in 70 patients. The effective width (EW) and effective screw length (ESL) of posterior C1 lateral mass screws were measured at different medial angulations relative to the midline sagittal plane. The height (H) for screw entry point on the posterior surface of C1 lateral mass and the distance (D) between screw entry point and the intersection of the midline sagittal plane and the posterior arch of the atlas were also measured.Results. The mean height (H) for screw entry on the posterior surface of the lateral mass was 4.25mm, the mean distance (D) between screw entry point and the intersection of the mid-sagittal plane and the posterior arch of the atlas was 27.62mm. The optimal medial angle was 20.86º with a corresponding effective width of 10.56mm and effective screw length of 21.87mm.Conclusion. This study helps to define the specific anatomy related to C1 posterior lateral mass screw placement in an effort to facilitate instrumentation. However, variation is seen in lateral mass anatomy, and this study must be combined with customized surgical planning that includes advanced imaging for safe and effective instrumentation.
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Low-intensity focused ultrasound mediated localized drug delivery for liver tumors in rabbits.
Drug Deliv
PUBLISHED: 11-05-2014
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Abstract Objective: To explore the antitumor effects of low-intensity focused ultrasound (LIFU) mediated localized drug delivery of adriamycin-microbubble-PLGA nanoparticle complexes on rabbits VX2 liver tumor. Methods: ADM-NMCs were prepared by covalent linking of ADM-PLGA nanoparticles (ADM-NPs) to the shell of the microbubbles. A fixed water bag filled with microbubbles was subjected to LIFU and non-focused ultrasound respectively, and the ultrasound images of which were recorded before and after ultrasonication. A total of 54 VX2 liver tumor-burdened rabbits were divided into six groups randomly, including control, ADM-NPs combined with LIFU, microbubbles combined with LIFU, ADM-NPs and microbubbles combined with LIFU, ADM-NMCs combined with LIFU and ADM-NMCs combined with Non-FUS. The tumor volume and volume inhibition rate (VIR) of tumor progression were calculated and compared. Apoptotic cells were labeled by terminal deoxyuridine nick end. Proliferating cell nuclear antigen was detected by immunohistochemistry. The median survival time of the animals were recorded and compared. Results: ADM-NMCs were successfully prepared with an average diameter of 1721?nm. The highest VIR and apoptotic index (AI) were found in the group of ADM-NMCs combined with LIFU while the lowest proliferating index (PI) was simultaneously observed in this group. The median survival time of the rabbits in the ADM-NMCs combined with LIFU group was the longest (71days) among all groups. Conclusions: ADM-NMCs combined with LIFU could inhibit the rabbits VX2 liver tumor progress by delaying the tumor proliferation and accelerating apoptosis, which presents a novel process for liver tumor targeting chemotherapy.
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KNOCKDOWN OF CS-SPOOK INDUCES DELAYED LARVAL MOLTING IN RICE STRIPED STEM BORER Chilo suppressalis.
Arch. Insect Biochem. Physiol.
PUBLISHED: 10-30-2014
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Spook has essential roles in the biogenesis of the molting hormone 20-hydroxyecdysone (20-E). The function of spook in the rice striped stem borer (SSB) Chilo suppressalis remains unclear, prompting our hypothesis that it exerts actions similar to those reported for other insect species. Here we amplified the full-length transcript of spook (Cs-Spook) in SSB by 5' and 3' rapid amplification of cDNA ends. Cs-Spook has conserved P450 motifs such as Helix-C, Helix-I, Helix-K, and PERF motif (PxxFxPxRF). It was highly expressed in late instar larvae but less so in newly molted larvae. Cs-Spook was highly expressed in prothoracic glands. Cs-Spook was knocked down by dsRNA treatments. Compared with controls, the gene expression level was reduced to 9% at 24 h post injection (PI), 33% at 48 h PI, and 24% at 72 h PI. The ecdysteroid titer decreased significantly in the dsRNA-treated group (P < 0.05), resulting in delayed larval development. The delayed development in dsRNA-treatment group was rescued by treating with 20-E. Our work demonstrates that Cs-Spook participates in the biogenesis of 20-E and regulates the molt of SSB, as seen in other species.
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Association of the plasminogen activator inhibitor-1 (PAI-1) Gene -675 4G/5G and -844 A/G promoter polymorphism with risk of keloid in a Chinese Han population.
Med. Sci. Monit.
PUBLISHED: 10-29-2014
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A keloid is pathological scar caused by aberrant response to skin injuries, characterized by excessive accumulation of histological extracellular matrix, and occurs in genetically susceptible individuals. Plasminogen activator inhibitor-1 (PAI-1) has been implicated in the pathogenesis of keloid. We investigated the association between PAI-1 polymorphisms and plasma PAI-1 level with keloid risk.
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The Relationship Between Colonoscopy Procedure Order and Adenoma Detection Rates: A Prospective Study.
J. Clin. Gastroenterol.
PUBLISHED: 10-17-2014
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The aim of this study was to prospectively assess the effects of the order of colonoscopic procedures and other possible factors on the adenoma detection rate (ADR).
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Hepatic fat, not visceral fat, is associated with gallbladder polyps - a study of 2643 healthy subjects.
J. Gastroenterol. Hepatol.
PUBLISHED: 10-05-2014
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Gallbladder polyps (GBPs) appear to be strongly associated with obesity and metabolic disease. To date, the relationship between GBPs and fatty liver has not been adequately evaluated. The aim of the present study was to investigate whether GBPs are associated with fatty liver, which is an ectopic regional fat deposit, independent of visceral adipose tissue (VAT).
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Modifying charge and hydrophilicity of simple Ru(II) polypyridyl complexes radically alters biological activities: old complexes, surprising new tricks.
Inorg Chem
PUBLISHED: 09-24-2014
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Compounds capable of light-triggered cytotoxicity are appealing potential therapeutics, because they can provide spatial and temporal control over cell killing to reduce side effects in cancer therapy. Two simple homoleptic Ru(II) polypyridyl complexes with almost-identical photophysical properties but radically different physiochemical properties were investigated as agents for photodynamic therapy (PDT). The two complexes were identical, except for the incorporation of six sulfonic acids into the ligands of one complex, resulting in a compound carrying an overall -4 charge. The negatively charged compound exhibited significant light-mediated cytotoxicity, and, importantly, the negative charges resulted in radical alterations of the biological activity, compared to the positively charged analogue, including complete abrogation of toxicity in the dark. The charges also altered the subcellular localization properties, mechanism of action, and even the mechanism of cell death. The incorporation of negative charged ligands provides a simple chemical approach to modify the biological properties of light-activated Ru(II) cytotoxic agents.
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Complete mitochondrial genome of the pink bollworm Pectinophora gossypiella (Lepidoptera: Gelechiidae).
Mitochondrial DNA
PUBLISHED: 09-19-2014
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Abstract Pectinophora gossypiella (Lepidoptera: Gelechiidae) is a key pest in many cotton-growing countries of the world. In this study, the complete mitochondrial (mt) genome of the pink bollworm P. gossypiella was determined, which is 15,202?bp in length (GenBank accession number: KM225795) containing 37 typical animal mitochondrial gene and an A?+?T-rich region. The gene order of P. gossypiella mtDNA was different from the insect ancestral gene order in the translocation of trnM, as shared by previously sequenced lepidopteran mtDNAs. The protein-coding genes (PCGs) have typical mitochondrial start codons ATN, with the exception of COI, Nad5, which uses the start codons CGA, GTT. Eight PCGs stop with complete termination codons (TAA), whereas five PCGs use incomplete stop codon T. All of the tRNA genes had typical cloverleaf secondary structures except for trnS1(AGN), in which the dihydrouridine (DHU) arm did not form a stable stem-loop structure. Like other insects, the control region is located between rrnS and trnM with a length of 309?bp and an A?+?T content of 94.8%, which is the most AT-rich region and comparatively simple, with little evidence of long tandem repeats, but harbors a conserved structure combining the motif ATAGA and a 18-bp poly-T stretch.
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Blood-brain barrier dysfunction in mice induced by lipopolysaccharide is attenuated by dapsone.
Biochem. Biophys. Res. Commun.
PUBLISHED: 09-18-2014
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Blood-brain barrier (BBB) dysfunction is a key event in the development of many central nervous system (CNS) diseases, such as septic encephalopathy and stroke. 4,4'-Diaminodiphenylsulfone (DDS, Dapsone) has displayed neuroprotective effect, but whether DDS has protective role on BBB integrity is not clear. This study was designed to examine the effect of DDS on lipopolysaccharide (LPS)-induced BBB disruption and oxidative stress in brain vessels. Using in vivo multiphoton imaging, we found that DDS administration significantly restored BBB integrity compromised by LPS. DDS also increased the expression of tight junction proteins occludin, zona occludens-1 (ZO-1) and claudin-5 in brain vessels. Level of reactive oxygen species (ROS) was reduced by DDS treatment, which may due to decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and NOX2 expression. Our results showed that LPS-induced BBB dysfunction could be attenuated by DDS, indicated that DDS has a therapeutic potential for treating CNS infection and other BBB related diseases.
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High-throughput Drug Screen Identifies Chelerythrine as a Selective Inducer of Death in a TSC2-null Setting.
Mol. Cancer Res.
PUBLISHED: 09-03-2014
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Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome associated with tumors of the brain, heart, kidney, and lung. The TSC protein complex inhibits the mammalian or mechanistic target of Rapamycin complex 1 (mTORC1). Inhibitors of mTORC1, including Rapamycin, induce a cytostatic response in TSC tumors, resulting in temporary disease stabilization and prompt regrowth when treatment is stopped. The lack of TSC-specific cytotoxic therapies represents an important unmet clinical need. Using a high-throughput chemical screen in TSC2-deficient, patient-derived cells we identified a series of molecules antagonized by Rapamycin and therefore selective for cells with mTORC1 hyperactivity. In particular, the cell-permeable alkaloid chelerythrine induced reactive oxygen species (ROS) and depleted glutathione (GSH) selectively in TSC2-null cells based on metabolic profiling. N-acetylcysteine (NAC) or GSH co-treatment protected TSC2-null cells from chelerythrine's effects, indicating that chelerythrine-induced cell death is ROS-dependent. Induction of heme-oxygenase-1 (HMOX1/HO-1) with hemin also blocked chelerythrine-induced cell death. In vivo, chelerythrine inhibited the growth of TSC2-null xenograft tumors with no evidence of systemic toxicity with daily treatment over an extended period of time. This study reports the results of a bioactive compound screen and the identification of a potential lead candidate that acts via a novel oxidative stress-dependent mechanism to selectively induce necroptosis in TSC2-deficient tumors. Implications: This study demonstrates that TSC2-deficient tumor cells are hypersensitive to oxidative stress-dependent cell death, and provide critical proof-of-concept that TSC2-deficient cells can be therapeutically targeted without the use of a Rapalog to induce a cell death response.
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Characterization and plasmid elimination of NDM-1-producing Acinetobacter calcoaceticus from China.
PLoS ONE
PUBLISHED: 09-02-2014
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The presence of multidrug-resistant bacterial pathogens in the environment poses a serious threat to public health. The opportunistic Acinetobacter spp. are among the most prevalent causes of nosocomial infections. Here, we performed complete genome sequencing of the Acinetobacter calcoaceticus strain XM1570, which was originally cultivated from the sputum of a patient diagnosed with pneumonia in Xiamen in 2010. We identified carbapenem resistance associated gene bla(NDM-1) located on a 47.3-kb plasmid. Three methods--natural reproduction, sodium dodecyl sulfate treatment and nalidixic acid treatment--were used to eliminate the bla(NDM-1)-encoding plasmid, which achieved elimination rates of 3.32% (10/301), 83.78% (278/332), and 84.17% (298/354), respectively. Plasmid elimination dramatically increased antibiotic sensitivity, reducing the minimum bacteriostatic concentration of meropenem from 256 µg/ml in the clinical strain to 0.125 µg/ml in the plasmid-eliminated strain. Conjugation transfer assays showed that the bla(NDM-1)-containing plasmid could be transferred into Escherichia coli DH5?:pBR322 in vitro as well as in vivo in mice. The bla(NDM-1) genetic environment was in accordance with that of other bla(NDM-1) genes identified from India, Japan, and Hong-Kong. The multilocus sequence type of the isolate was identified as ST-70. Two novel genes encoding intrinsic OXA and ADC were identified and named as OXA-417 and ADC-72. The finding of bla(NDM-1) in species like A. calcoaceticus demonstrates the wide spread of this gene in gram-negative bacteria which is possible by conjugative plasmid transfer. The results of this study may help in the development of a treatment strategy for controlling NDM-1 bacterial infection and transmission.
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Design, synthesis, and evaluation of multitarget-directed selenium-containing clioquinol derivatives for the treatment of Alzheimer's disease.
ACS Chem Neurosci
PUBLISHED: 08-22-2014
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A series of selenium-containing clioquinol derivatives were designed, synthesized, and evaluated as multifunctional anti-Alzheimer's disease (AD) agents. In vitro examination showed that several target compounds exhibited activities such as inhibition of metal-induced A? aggregation, antioxidative properties, hydrogen peroxide scavenging, and the prevention of copper redox cycling. A parallel artificial membrane permeation assay indicated that selenium-containing clioquinol derivatives possessed significant blood-brain barrier (BBB) permeability. Compound 8a, with a propynylselanyl group linked to the oxine, demonstrated higher hydrogen peroxide scavenging and intracellular antioxidant activity than clioquinol. Furthermore, 8a exhibited significant inhibition of Cu(II)-induced A?1-42 aggregation and was capable of disassembling the preformed Cu(II)-induced A? aggregates. Therefore, 8a is an excellent multifunctional promising compound for development of novel drugs for AD.
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Factors that determine prolonged cecal intubation time during colonoscopy: impact of visceral adipose tissue.
Scand. J. Gastroenterol.
PUBLISHED: 08-21-2014
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Various factors including age, sex, body mass index (BMI) and history of operation have been linked to the colonoscopic intubation time. The aims of this study were to identify the factors predicting cecal intubation time (CIT) and to evaluate the effect of the visceral adipose tissue (VAT) area on CIT.
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Primary cilia signaling mediates intraocular pressure sensation.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 08-20-2014
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Lowe syndrome is a rare X-linked congenital disease that presents with congenital cataracts and glaucoma, as well as renal and cerebral dysfunction. OCRL, an inositol polyphosphate 5-phosphatase, is mutated in Lowe syndrome. We previously showed that OCRL is involved in vesicular trafficking to the primary cilium. Primary cilia are sensory organelles on the surface of eukaryotic cells that mediate mechanotransduction in the kidney, brain, and bone. However, their potential role in the trabecular meshwork (TM) in the eye, which regulates intraocular pressure, is unknown. Here, we show that TM cells, which are defective in glaucoma, have primary cilia that are critical for response to pressure changes. Primary cilia in TM cells shorten in response to fluid flow and elevated hydrostatic pressure, and promote increased transcription of TNF-?, TGF-?, and GLI1 genes. Furthermore, OCRL is found to be required for primary cilia to respond to pressure stimulation. The interaction of OCRL with transient receptor potential vanilloid 4 (TRPV4), a ciliary mechanosensory channel, suggests that OCRL may act through regulation of this channel. A novel disease-causing OCRL allele prevents TRPV4-mediated calcium signaling. In addition, TRPV4 agonist GSK 1016790A treatment reduced intraocular pressure in mice; TRPV4 knockout animals exhibited elevated intraocular pressure and shortened cilia. Thus, mechanotransduction by primary cilia in TM cells is implicated in how the eye senses pressure changes and highlights OCRL and TRPV4 as attractive therapeutic targets for the treatment of glaucoma. Implications of OCRL and TRPV4 in primary cilia function may also shed light on mechanosensation in other organ systems.
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A review of melatonin as a suitable antioxidant against myocardial ischemia-reperfusion injury and clinical heart diseases.
J. Pineal Res.
PUBLISHED: 08-16-2014
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Cardiac tissue loss is one of the most important factors leading to the unsatisfactory recovery even after treatment of ischemic heart disease. Melatonin, a circadian molecule with marked antioxidant properties, protects against ischemia-reperfusion (IR) injury. In particular, the myocardial protection of melatonin is substantial. We initially focus on the cardioprotective effects of melatonin in myocardial IR. These studies showed how melatonin preserves the microstructure of the cardiomyocyte and reduces myocardial IR injury. Thereafter, downstream signaling pathways of melatonin were summarized including Janus kinase 2/signal transducers and activators of transcription 3, nitric oxide-synthase, and nuclear factor erythroid 2 related factor 2. Herein, we propose the clinical applications of melatonin in several ischemic heart diseases. Collectively, the information summarized in this review (based on in vitro, animal, and human studies) should serve as a comprehensive reference for the action of melatonin in cardioprotection and hopefully will contribute to the design of future experimental research.
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Controlled nanodot fabrication by rippling polycarbonate surface using an AFM diamond tip.
Nanoscale Res Lett
PUBLISHED: 07-30-2014
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The single scratching test of polymer polycarbonate (PC) sample surface using an atomic force microscope (AFM) diamond tip for fabricating ripple patterns has been studied with the focus on the evaluation of the effect of the tip scratching angle on the pattern formation. The experimental results indicated that the different oriented ripples can be easily machined by controlling the scratching angles of the AFM. And, the effects of the normal load and the feed on the ripples formation and their periods were also studied. Based on the ripple pattern formation, we firstly proposed a two-step scratching method to fabricate controllable and oriented complex three-dimensional (3D) nanodot arrays. These typical ripple formations can be described via a stick-slip and crack formation process.
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The mediator subunit Med23 contributes to controlling T-cell activation and prevents autoimmunity.
Nat Commun
PUBLISHED: 07-24-2014
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T-cell activation is critical for successful immune responses and is controlled at multiple levels. Although many changes of T-cell receptor-associated signalling molecules affect T-cell activation, the transcriptional mechanisms that control this process remain largely unknown. Here we find that T cell-specific deletion of the mediator subunit Med23 leads to hyperactivation of T cells and aged Med23-deficient mice exhibit an autoimmune syndrome. Med23 specifically and consistently promotes the transcription of multiple negative regulators of T-cell activation. In the absence of Med23, the T-cell activation threshold is lower, which results in enhanced antitumour T-cell function. Cumulatively, our data suggest that Med23 contributes to controlling T-cell activation at the transcriptional level and prevents the development of autoimmunity.
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Why are some HIV/AIDS patients reluctant to receive antiviral therapy as soon as possible in China?
Biosci Trends
PUBLISHED: 07-18-2014
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In more than 20 years of medical practice, a surprising phenomenon has often occurred: some patients with acquired immunodeficiency syndrome (AIDS) decide not to go to the hospital and they do not let others know that they are suffering from the disease unless they believe that they are dieing. Zhang Shan (a pseudonym) is one such patient with human immunodeficiency virus (HIV)/AIDS who was reluctant to receive antiviral therapy as soon as possible, and this paper shares Zhang's story as he related it. Clearly, there are numerous views as to why patients in China behave as Zhang did. Presented here are several reasons, including society, history, morality and ideology, family, and education. Although all of these reasons do play a role, the patient's mindset and behavior is the most significant reason for a patient's reluctance to seek treatment or disclose his/her status. If the individual patient's mindset and behavior are not dealt with effectively, then HIV/AIDS can continue to spread and threaten additional lives and even the fabric of society. This paper analyzes the reasons why patients are hesitant to receive antiviral therapy, but this paper also suggests steps healthcare personnel can take to encourage patients to seek treatment. Such steps can save the lives of current patients with HIV/AIDS. In addition, sound public health measures and a rational approach to treatment are important to helping potential patients with HIV/AIDS.
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Relationship between T-SPOT.TB responses and numbers of circulating CD4+ T-cells in HIV infected patients with active tuberculosis.
Biosci Trends
PUBLISHED: 07-18-2014
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This study sought to evaluate the performance of the T-SPOT.TB assay for the diagnosis of active tuberculosis (TB) in human immunodeficiency virus (HIV) infected patients. One hundred confirmed HIV-infected patients with active TB and known T-SPOT.TB and CD4+ T-cell counts were enrolled in this clinical retrospective study. We found that patients with lower CD4+ T-cell counts (11-50 cells/?L) had the lowest T-SPOT.TB positive rates (50%), and patients with higher CD4+ T-cell counts (50-100 cells/?L) had the highest T-SPOT.TB positive rates (75%). However, there were no significant differences between the T-SPOT.TB positive rates of patients with different CD4+ T-cell counts (< 10, 11-50, 51-100 and > 100 cells/?L) (?(2) = 3.7747, p = 0.287). The patients with positive TB culture results had significantly higher T-SPOT.TB positive rates (78.9%) than patients that were culture-negative (44.3%) (?(2) = 12.8303, p < 0.001). Other variables, including gender, age, TB disease classification, HIV RNA level, and highly reactive antiretroviral therapy (HAART), had no significant effects on T-SPOT.TB positive rates. The number of spot-forming cells (SFCs) reactive with ESAT-6, CFP-10 and ESAT-6/CFP-10-specific T cells detected by T-SPOT.TB were positively is strongly related to the degree of immunodeficiency, while the T-SPOT.TB positive rates are less dependent on the level of CD4+ T-cell depletion in HIV infection and active TB.
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Application status of blood constituents during massive blood transfusion in some regions of China.
Int J Clin Exp Med
PUBLISHED: 07-15-2014
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This study aims to learn about the current situation of surgical massive blood transfusion in China's Class III general hospitals, which could provide the basis for the formulation of guidelines on massive blood transfusion.
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Recruitment of Gr1(+)CD11b (+)F4/80 (+) Population in the Bone Marrow and Spleen by Irradiation-Induced Pulmonary Damage.
Inflammation
PUBLISHED: 07-11-2014
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Radiation-induced lung injury is a kind of sterile inflammation, which may lead to morbidity and mortality. The mechanism by which ionizing radiation activate the immune system is not well understood. In the present study, we have investigated the immunological responses induced by local irradiation-induced damage in mouse lung. The left lungs of C57BL/6 mice were irradiated at a high dose of 100 Gy. The histology of the lungs and spleen showed evidences of alveolar inflammation and congestion at 2 weeks after X-ray treatment. Also, prominent increase in cells expressing the cell surface markers, Gr(+)CD11b(+)F4/80(+) and Ly6C(+) Ly6G(+) were observed 2 weeks after X-ray treatment (100 Gy). Gr1(+)CD11b(+)F4/80(+) cell depletion by clodronate treatment reversed the histological effects and also failed to recruit Gr(+)CD11b(+) cells or F4/80(+) cells caused by irradiation. The origin of recruited Gr1(+)CD11b(+) cells was found to be a mixed resident and recruited phenotype.
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New multi-target-directed small molecules against Alzheimer's disease: a combination of resveratrol and clioquinol.
Org. Biomol. Chem.
PUBLISHED: 07-03-2014
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Alzheimer's disease (AD) is currently one of the most difficult and challenging diseases to treat. Based on the ‘multi-target-directed ligands’ (MTDLs) strategy, we designed and synthesised a series of new compounds against AD by combining the pharmacophores of resveratrol and clioquinol. The results of biological activity tests showed that the hybrids exhibited excellent MTDL properties: a significant ability to inhibit self-induced ?-amyloid (A?) aggregation and copper(II)-induced A? aggregation, potential antioxidant behaviour (ORAC-FL value of 0.9–3.2 Trolox equivalents) and biometal chelation. Among these compounds, (E)-5-(4-hydroxystyryl)quinoline-8-ol (10c) showed the most potent ability to inhibit self-induced A? aggregation (IC50 = 8.50 ?M) and copper(II)-induced A? aggregation and to disassemble the well-structured A? fibrils generated by self- and copper(II)-induced A? aggregation. Note that 10c could also control Cu(I/II)-triggered hydroxyl radical (OH?) production by halting copper redox cycling via metal complexation, as confirmed by a Cu–ascorbate redox system assay. Importantly, 10c did not show acute toxicity in mice at doses of up to 2000 mg kg?1 and was able to cross the blood–brain barrier (BBB), according to a parallel artificial membrane permeation assay. These results indicate that compound 10c is a promising multifunctional compound for the development of novel drugs for AD.
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Neochromine S5 improves contact hypersensitivity through a selective effect on activated T lymphocytes.
Biochem. Pharmacol.
PUBLISHED: 07-02-2014
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Strategy on activated T cells is an effective treatment for T cell mediated diseases. By using a synthesized chromone derivative, we examined its effects on the activated T cells. This compound, (Z)-1,3-dihydroxy-9-methyl-13H-benzo[b]chromeno[3,2-f][1,4]oxazepin-13-one (neochromine S5), exhibited immunosuppressive activity in vitro and in vivo. Interestingly, neochromine S5 selectively inhibited proliferation and induced apoptosis in T lymphocytes activated by concanavalin A (Con A) in a dose-dependent manner but not in naïve T lymphocytes, distinct from quercetin. This compound triggered mitochondrial apoptotic pathway including cleavage of caspase 3, caspase 9 and PARP, downregulation of bcl-2 and release of cytochrome c in activated T cells, but did not affect ER stress or Fas signals. In addition, neochromine S5 downregulated the expression of CD25 and CD69 and the production of inflammatory cytokines, including TNF?, IFN? and IL-2, improved ear swelling in mice with contact hypersensitivity, reduced CD4(+) T cells infiltration, and increased apoptosis of isolated T lymphocytes from peripheral lymph nodes. Moreover, neochromine S5 showed no effect on the weight of mice and their immune organs, while dexamethasone caused a significant weight loss. Taken together, our results suggest that neochromine S5 exerts a unique anti-inflammatory activity mainly through a selective effect on activated T cells, which is different from the current immunosuppressant, dexamethasone.
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Inhibitory effect of emodin on migration, invasion and metastasis of human breast cancer MDA-MB-231 cells in vitro and in vivo.
Oncol. Rep.
PUBLISHED: 06-29-2014
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In breast cancer, metastasis is the main reason for patient mortality. In the present study, we used breast cancer MDA-MB-231 cells and a mouse xenograft model to demonstrate the effect of emodin on the migration, invasion and metastasis of human breast cancer MDA-MB-231 cells and the related mechanisms. In vitro, wound healing and Transwell assays showed that emodin dose-dependently inhibited the migration and invasion of MDA-MB-231 cells. Enzyme-linked immunosorbent assay (ELISA) showed that emodin decreased the secretion of MMP-2 and MMP-9. Western blot analysis showed that emodin downregulated the expression levels of MMP-2, MMP-9, uPA and uPAR as well as p38 inhibitor SB203580 and ERK inhibitor PD980559, even though TIMP-1 and TIMP-2 were not obviously changed in the MDA-MB-231 cells. Furthermore, emodin inhibited the activity of p38 and ERK1/2 in the MDA-MB-231 cells. In vivo, emodin inhibited lung metastasis in mice bearing the breast cancer MDA-MB-231 xenografts with no obvious changes in body weight, liver and kidney functions. These results indicated that emodin inhibited the lung metastasis of human breast cancer in a mouse xenograft model, and inhibited the invasion of MDA-MB-231 cells associated with the downregulation of MMP-2, MMP-9, uPA and uPAR expression as well as decreased activity of p38 and ERK.
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In vitro evaluation of the probiotic and functional potential of Lactobacillus strains isolated from fermented food and human intestine.
Anaerobe
PUBLISHED: 06-29-2014
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This study aims to evaluate the functional and probiotic characteristics of eight indigenous Lactobacillus strains in vitro. The selected lactobacilli include strains of Lactobacillus casei subsp. casei, Lactobacillus salivarius subsp. salicinius, Lactobacillus fermentum, Lactobacillus plantarum, Lactobacillus delbrueckii subsp. lactis, Lactobacillus delbrueckii subsp. bulgaricus, and Lactobacillus rhamnosus. All strains tolerated both pH 2 for 3 h and 1% bile salt for 24 h. The strains CICC 23174 and CGMCC 1.557 were the most adhesive strains producing the highest quantity of EPS. Although a wide variation in the ability of the eight strains to deplete cholesterol and nitrite, antagonize pathogens, scavenge free radical, and stimulate innate immune response were observed, the strains CICC 23174 and CGMCC 1.557 showed the widest range of these useful traits. Taken together, the strains CICC 23174 and CGMCC 1.557 exhibited the best probiotic properties with the potential for use in the production of probiotic fermented foods.
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Correction of blood coagulation dysfunction and anemia by supplementation of red blood cell suspension, fresh frozen plasma, and apheresis platelet: Results of in vitro hemodilution experiments.
J Crit Care
PUBLISHED: 06-27-2014
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This study aimed to determine the optimal composition and timing for the administration of blood supplements during in vivo blood transfusion with red blood cells suspension (pRBC), fresh frozen plasma (FFP), and apheresis platelet (PLT) administered for the correction of anemia and coagulation dysfunction caused by in vitro hemodilution.
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Selective inhibition of unfolded protein response induces apoptosis in pancreatic cancer cells.
Oncotarget
PUBLISHED: 06-23-2014
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Endoplasmic reticulum stress from unfolded proteins is associated with the proliferation of pancreatic tumor cells, making the many regulatory molecules of this pathway appealing targets for therapy. The objective of our study was to assess potential therapeutic efficacy of inhibitors of unfolded protein response (UPR) in pancreatic cancers focusing on IRE1? inhibitors. IRE1?-mediated XBP-1 mRNA splicing encodes a transcription factor that enhances transcription of chaperone proteins in order to reverse UPR. Proliferation assays using a panel of 14 pancreatic cancer cell lines showed a dose- and time-dependent growth inhibition by IRE1?-specific inhibitors (STF-083010, 2-Hydroxy-1-naphthaldehyde, 3-Ethoxy-5,6-dibromosalicylaldehyde, toyocamycin). Growth inhibition was also noted using a clonogenic growth assay in soft agar, as well as a xenograft in vivo model of pancreatic cancer. Cell cycle analysis showed that these IRE1? inhibitors caused growth arrest at either the G1 or G2/M phases (SU8686, MiaPaCa2) and induced apoptosis (Panc0327, Panc0403). Western blot analysis showed cleavage of caspase 3 and PARP, and prominent induction of the apoptotic molecule BIM. In addition, synergistic effects were found between either STF-083010, 2-Hydroxy-1-naphthaldehyde, 3-Ethoxy-5,6-dibromosalicylaldehyde, or toyocamycin and either gemcitabine or bortezomib. Our data suggest that use of an IRE1? inhibitor is a novel therapeutic approach for treatment of pancreatic cancers.
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Genome Sequence of the ?-Poly-l-Lysine-Producing Strain Streptomyces albulus NK660, Isolated from Soil in Gutian, Fujian Province, China.
Genome Announc
PUBLISHED: 06-14-2014
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We determined the complete genome sequence of a soil bacterium, Streptomyces albulus NK660. It can produce ?-poly-l-lysine, which has antimicrobial activity against a spectrum of microorganisms. The genome of S. albulus NK660 contains a 9,360,281-bp linear chromosome and a 12,120-bp linear plasmid.
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Melatonin receptor-mediated protection against myocardial ischemia/reperfusion injury: role of SIRT1.
J. Pineal Res.
PUBLISHED: 06-10-2014
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Melatonin confers cardioprotective effect against myocardial ischemia/reperfusion (MI/R) injury by reducing oxidative stress. Activation of silent information regulator 1 (SIRT1) signaling also reduces MI/R injury. We hypothesize that melatonin may protect against MI/R injury by activating SIRT1 signaling. This study investigated the protective effect of melatonin treatment on MI/R heart and elucidated its potential mechanisms. Rats were exposed to melatonin treatment in the presence or the absence of the melatonin receptor antagonist luzindole or SIRT1 inhibitor EX527 and then subjected to MI/R operation. Melatonin conferred a cardioprotective effect by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase release, upregulating SIRT1, Bcl-2 expression and downregulating Bax, caspase-3 and cleaved caspase-3 expression. Melatonin treatment also resulted in reduced myocardium superoxide generation, gp91(phox) expression, malondialdehyde level, and increased myocardium superoxide dismutase (SOD) level, which indicate that the MI/R-induced oxidative stress was significantly attenuated. However, these protective effects were blocked by EX527 or luzindole, indicating that SIRT1 signaling and melatonin receptor may be specifically involved in these effects. In summary, our results demonstrate that melatonin treatment attenuates MI/R injury by reducing oxidative stress damage via activation of SIRT1 signaling in a receptor-dependent manner.
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SETDB1 accelerates tumorigenesis by regulating WNT signaling pathway.
J. Pathol.
PUBLISHED: 06-03-2014
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We investigated the oncogenic role of SETDB1 focusing on non-small cell lung cancer (NSCLC) having high expression of this protein. A total of 387 lung cancer cases were examined by immunohistochemistry, 72% of NSCLC samples were positive for SETDB1 staining, compared to 46% samples of normal bronchial epithelium (106 cases) (p?
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Disruption of chaperone-mediated autophagy-dependent degradation of MEF2A by oxidative stress-induced lysosome destabilization.
Autophagy
PUBLISHED: 06-01-2014
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Oxidative stress has been implicated in both normal aging and various neurodegenerative disorders and it may be a major cause of neuronal death. Chaperone-mediated autophagy (CMA) targets selective cytoplasmic proteins for degradation by lysosomes and protects neurons against various extracellular stimuli including oxidative stress. MEF2A (myocyte enhancer factor 2A), a key transcription factor, protects primary neurons from oxidative stress-induced cell damage. However, the precise mechanisms of how the protein stability and the transcriptional activity of MEF2A are regulated under oxidative stress remain unknown. In this study, we report that MEF2A is physiologically degraded through the CMA pathway. In pathological conditions, mild oxidative stress (200 ?M H 2O 2) enhances the degradation of MEF2A as well as its activity, whereas excessive oxidative stress (> 400 ?M H 2O 2) disrupts its degradation process and leads to the accumulation of nonfunctional MEF2A. Under excessive oxidative stress, an N-terminal HDAC4 (histone deacetylase 4) cleavage product (HDAC4-NT), is significantly induced by lysosomal serine proteases released from ruptured lysosomes in a PRKACA (protein kinase, cAMP-dependent, catalytic, ?)-independent manner. The production of HDAC4-NT, as a MEF2 repressor, may account for the reduced DNA-binding and transcriptional activity of MEF2A. Our work provides reliable evidence for the first time that MEF2A is targeted to lysosomes for CMA degradation; oxidative stress-induced lysosome destabilization leads to the disruption of MEF2A degradation as well as the dysregulation of its function. These findings may shed light on the underlying mechanisms of pathogenic processes of neuronal damage in various neurodegenerative-related diseases.
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Small molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition is responsible for the prevention of colitis-associated cancer.
Autophagy
PUBLISHED: 06-01-2014
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Nonresolving inflammation in the intestine predisposes individuals to the development of colitis-associated cancer (CAC). Inflammasomes are thought to mediate intestinal homeostasis, and their dysregulation contributes to inflammatory bowel diseases and CAC. However, few agents have been reported to reduce CAC by targeting inflammasomes. Here we show that the small molecule andrographolide (Andro) protects mice against azoxymethane/dextran sulfate sodium-induced colon carcinogenesis through inhibiting the NLRP3 inflammasome. Administration of Andro significantly attenuated colitis progression and tumor burden. Andro also inhibited NLRP3 inflammasome activation in macrophages both in vivo and in vitro, as indicated by reduced expression of cleaved CASP1, disruption of NLRP3-PYCARD-CASP1 complex assembly, and lower IL1B secretion. Importantly, Andro was found to trigger mitophagy in macrophages, leading to a reversed mitochondrial membrane potential collapse, which in turn inactivated the NLRP3 inflammasome. Moreover, downregulation of the PIK3CA-AKT1-MTOR-RPS6KB1 pathway accounted for Andro-induced autophagy. Finally, Andro-driven inhibition of the NLRP3 inflammasome and amelioration of murine models for colitis and CAC were significantly blocked by BECN1 knockdown, or by various autophagy inhibitors. Taken together, our findings demonstrate that mitophagy-mediated NLRP3 inflammasome inhibition by Andro is responsible for the prevention of CAC. Our data may help guide decisions regarding the use of Andro in patients with inflammatory bowel diseases, which ultimately reduces the risk of CAC.
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Rapamycin-resistant PARP1 overexpression is a potential therapeutic target in lymphangioleiomyomatosis (LAM).
Am. J. Respir. Cell Mol. Biol.
PUBLISHED: 05-31-2014
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Rationale: Lymphangioleiomyomatosis (LAM) is a female-predominant cystic lung disease that can lead to respiratory failure. LAM cells typically have inactivating TSC2 mutations and mTORC1 activation. Clinical response to the mTORC1 inhibitors has been limited, prompting a search for additional therapy for LAM. In this study, we investigate the impact of TSC2 on the expression of poly (ADP-ribose) polymerase-1 (PARP1) that initiates the DNA repair pathway and test the efficacy of PARP1 inhibitors in the survival of TSC2-deficient cells. Methods: We analyzed publicly available expression arrays of TSC2-deficient cells and validated the findings using real-time RT-PCR, immunoblotting, and immunohistochemistry. We examined the impact of rapamycin and Torin 1 on PARP1 expression. We also tested the effect of PARP1 inhibitors NU1025 and DPQ on the survival of TSC2-deficient cells. Results: We identified the upregulation of PARP1 in TSC2-deficient cells relative to TSC2-addback cells. The transcript levels of PARP1 in TSC2-deficient cells were not affected by rapamycin. PARP1 levels were increased in TSC2-deficient cells, xenograft tumors of rat-derived Tsc2-deficient cells, renal cystadenomas from Tsc2+/- mice, and human LAM nodules. RNA interference of mTOR failed to reduce PARP1 levels. Proliferation and survival of TSC2-deficient cells was reduced in response to PARP1 inhibitor treatment, more so than TSC2-addback cells. Conclusions: TSC2-deficient cells exhibit higher levels of PARP1 relative to TSC2-addback cells in an mTOR-insensitive manner. PARP1 inhibitors selectively suppress the growth and induce apoptosis of TSC2-deficient LAM patient-derived cells. Targeting PARP1 may be beneficial in the treatment of LAM and other neoplasms with mTORC1 activation.
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Inhibition of Beclin 1 expression enhances cisplatin-induced apoptosis through a mitochondrial-dependent pathway in human ovarian cancer SKOV3/DDP cells.
Oncol. Res.
PUBLISHED: 05-24-2014
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The purpose of this study was to determine the influence of autophagy on cisplatin-induced ovarian cancer SKOV3/DDP cell line death through regulation of the expression of the autophagy gene, Beclin 1, and to explore the potential mechanism underlying the relationship between autophagy and apoptosis. When compared with a blank control group, the proportion of apoptotic cells undergoing Beclin 1 interfering increased significantly after cisplatin treatment, accompanied by reduction in mitochondrial membrane potential, increase in activities of caspase-9/3 and cytoplasmic cytochrome C, elevation of Bax expression, and reduction in Bcl-2 expression. However, the proportion of apoptotic cells with Beclin 1 overexpression reduced. These findings suggest that Beclin 1 plays an important role in the regulation of potent antitumor activity through a mitochondrial-dependent pathway in SKOV3/DDP cell line, and inhibition of Beclin 1 expression may become a new target for the sensitization therapy of ovarian cancer with cisplatin.
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Phenotypic variation and identification of Phenacoccus solenopsis Tinsley (Hemiptera: Pseudococcidae) in China.
Zootaxa
PUBLISHED: 05-22-2014
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Phenacoccus solenopsis Tinsley (Hemiptera: Pseudococcidae) is an invasive mealybug that seriously damages cotton and other important crops. In previous studies in China, the presence of two submedian longitudinal lines of pigmented spots on the dorsum of adult females frequently has been used to identify this species. However, the present study records the occasional absence of pigmented spots in a sample from Guangxi province, China. Specimens without pigmented spots showed all the molecular and morphological characters that separate P. solenopsis from the similar species P. solani Ferris, especially the distribution of multilocular disc pores. In different geographic populations of P. solenopsis in China, mitochondrial COI and nuclear 28SrDNA genes are very similar (99.8-100%), indicating that they are conspecific. For COI, the genetic distance between P. solenopsis and P. solani is more than 3%. A map of the distribution of P. solenopsis in China is given. To help identify both pigmented and non-pigmented P. solenopsis accurately, an identification key to the 16 species of Phenacoccus found in China is provided. The key also identifies five potentially invasive Phenacoccus species not yet established in China, in case they get introduced there.
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STAT6-mediated keratitis and blepharitis: a novel murine model of ocular atopic dermatitis.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 05-22-2014
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Atopic dermatitis (AD) is a common inflammatory disease that can affect the eye, resulting in ocular pathologies, including blepharitis, keratitis, and uveitis; however, the pathogenic mechanisms underlying the ocular manifestations of AD are not well understood.
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Acrolein induced both pulmonary inflammation and the death of lung epithelial cells.
Toxicol. Lett.
PUBLISHED: 05-18-2014
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Acrolein, a compound found in cigarette smoke, is a major risk factor for respiratory diseases. Previous research determined that both acrolein and cigarette smoke produced reactive oxygen species (ROS). As many types of pulmonary injuries are associated with inflammation, this study sought to ascertain the extent to which exposure to acrolein advanced inflammatory state in the lungs. Our results showed that intranasal exposure of mice to acrolein increased CD11c(+)F4/80(high) macrophages in the lungs and increased ROS formation via induction of NF-?B signaling. Treatment with acrolein activated macrophages and led to their increased production of ROS and expression of several key pro-inflammatory cytokines. In in vitro studies, acrolein treatment of bone marrow-derived GM-CSF-dependent immature macrophages (GM-IMs), activated the cells and led to their increased production of ROS and expression of several key pro-inflammatory cytokines. Acrolein treatment of macrophages induced apoptosis of lung epithelial cells. Inclusion of an inhibitor of ROS formation markedly decreased acrolein-mediated macrophage activation and reduced the extent of epithelial cell death. These results indicate that acrolein can cause lung damage, in great part by mediating the increased release of pro-inflammatory cytokines/factors by macrophages.
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Axitinib augments antitumor activity in renal cell carcinoma via STAT3-dependent reversal of myeloid-derived suppressor cell accumulation.
Biomed. Pharmacother.
PUBLISHED: 05-13-2014
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Axitinib, a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), is used as an anti-angiogenic agent for the treatment of metastatic renal cell carcinoma (RCC). However, the effect of axitinib on antitumor immunity has remained largely unexplored. In this study, we show that while axitinib (25mg/kg) significantly suppresses tumor growth and metastasis, thus prolonging life span in murine RCC xenografts, the treatment leads to a major decrease in the number of myeloid-derived suppressor cells (MDSCs) in the spleens and tumor beds of animals, which in turn promotes antitumor responses of CD8+ T-cells in vivo. Moreover, as one of the main transcription factors that regulate MDSC function, Signal transducer and activator of transcription 3 (STAT3) was also significantly inhibited in the Renca tumor-associated MDSC and tumor tissues. These results suggest that axitinib has the potential to modulate antitumor immunity by downregulating STAT3 expression and reversing MDSC-mediated tumor-induced immunosuppression. The study reveals the unique antitumor mechanism of axitinib and provided useful information for its clinical application.
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Suggestions to the media to help us cope with the A/H7N9 crisis in China.
Drug Discov Ther
PUBLISHED: 05-13-2014
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The A/H7N9 avian influenza virus sparked global concerns about public health. The media published numerous reports about emerging infectious diseases, including their clinical characteristics and genomic information. However, outbreaks of A/H7N9 posed a real challenge to China's emergency management and especially its dealing with the media. This study analyzes ways to deal with the media during A/H7N9 crises and it proposes a shift in public emergency management from an "Impact-Responsive" approach to a "Prevention-Active" approach. A "Prevention-Active" approach should be used when dealing with the media during subsequent outbreaks.
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Quaternary ammonium salt of U50488H, a new ?-opioid receptor agonist, protects rat heart against ischemia/reperfusion injury.
Eur. J. Pharmacol.
PUBLISHED: 05-04-2014
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To keep U50488H from going through the blood-brain barrier, U50488H, a selective ?-opioid receptor agonist, was structurally transformed into its quaternary ammonium salt (Q-U50488H). The effect of Q-U50488H on ischemic/reperfused myocardium and its underlying mechanisms were also investigated. U50488H was transformed into Q-U50488H, which was identified with mass spectrometry. The existences of U50488H and Q-U50488H in serum and brain tissue fluid were determined by high performance liquid chromatography (HPLC). SD rats' hearts were subjected to 30min of ischemia followed by 120min of reperfusion in vivo. After reperfusion, myocardial enzymes and free radicals in serum, area of myocardial infarction, cardiomyocyte apoptosis and the expression of Kir6.2 in rats' myocardium were determined. Molecular weight and solubility of Q-U50488H were higher than those of U50488H. Result of HPLC showed that Q-U50488H existed in serum but not in brain tissue after Q-U50488H intravenous injection. However, U50488H was detected in both serum and brain tissue. Compared with the I/R group, treatment with Q-U50488H significantly attenuated the activity of LDH, CK, AST/GOT and content of MDA in serum, upregulated the activity of SOD, and increased the expression of myocardial Kir6.2. It also reduced myocardial infarct size and cardiomyocyte apoptosis induced by I/R. Moreover, pretreatment with Nor-BNI (a selective ?-opioid receptor antagonist), 5-HD and glibenclamide (KATP antagonists) abolished the effects of Q-U50488H. It is suggested Q-U50488H, a new compound of ?-opioid receptor agonist, which is not able to pass the blood-brain barrier, elicits a protective effect against myocardial ischemia/reperfusion injury. The cardioprotective effect of Q-U50488H is associated with the opening of KATP.
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Progesterone and estradiol synergistically promote the lung metastasis of tuberin-deficient cells in a preclinical model of lymphangioleiomyomatosis.
Horm Cancer
PUBLISHED: 04-28-2014
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Lymphangioleiomyomatosis (LAM) is a female-predominant lung disease that can lead to respiratory failure. LAM cells typically have inactivating tuberous sclerosis 2 (TSC2) mutations, leading to mTORC1 hyperactivation. The gender specificity of LAM suggests that female hormones contribute to disease progression. Clinical findings indicate that estradiol exacerbates LAM behaviors and symptoms. Although hormonal therapy with progesterone has been employed, the benefit in LAM improvement has not been achieved. We have previously found that estradiol promotes the survival and lung metastasis of cells lacking tuberin in a preclinical model of LAM. In this study, we hypothesize that progesterone alone or in combination with estradiol promotes metastatic behaviors of TSC2-deficient cells. In cell culture models of TSC2-deficient LAM patient-derived and rat uterine leiomyoma-derived cells, we found that progesterone treatment or progesterone plus estradiol resulted in increased phosphorylation of Protein Kinase B (Akt) and Extracellular signal-regulated kinases1/2 (ERK1/2), induced the proliferation, and enhanced the migration and invasiveness. In addition, treatment of progesterone plus estradiol synergistically decreased the levels of reactive oxygen species and enhanced cell survival under oxidative stress. In a murine model of LAM, treatment of progesterone plus estradiol promoted the growth of xenograft tumors; however, progesterone treatment did not affect the development of xenograft tumors of Tsc2-deficient cells. Importantly, treatment of progesterone plus estradiol resulted in alteration of lung morphology and significantly increased the number of lung micrometastases of Tsc2-deficient cells compared with estradiol treatment alone. Collectively, these data indicate that progesterone increases the metastatic potential of Tsc2-deficient LAM patient-derived cells in vitro and lung metastasis in vivo. Thus, targeting progesterone-mediated signaling events may have therapeutic benefit for LAM and possibly other hormonally dependent cancers.
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Trichomide A, a Natural Cyclodepsipeptide, Exerts Immunosuppressive Activity against Activated T Lymphocytes by Upregulating SHP2 Activation to Overcome Contact Dermatitis.
J. Invest. Dermatol.
PUBLISHED: 04-24-2014
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Increasing numbers of people are suffering from allergic contact dermatitis. However, the immunosuppressive drug candidate with negligible toxicity is still deficient. In the present study, we identified a natural cyclodepsipeptide named trichomide A that effectively inhibited the proliferation of activated T cells and reduced the production of proinflammatory cytokines but had almost no toxic effect on naive T cells at 0.3-3??M. In addition, trichomide A caused G0/G1 phase arrest, suppressed the activation of AKT and STAT3, and increased the level of phosphorylated SHP2 in activated T cells in dose- and time-dependent manners. Furthermore, an in vivo experiment demonstrated that trichomide A significantly ameliorated picryl chloride (PCI)-induced contact hypersensitivity in mice. Such effects of trichomide A in the aforementioned experiments were significantly reversed by the inhibition of SHP2 activity using the SHP2-specific inhibitor PHPS1 or conditional SHP2 knockout mice in T cells, suggesting the SHP2-dependent action of trichomide A. Taken together, trichomide A showed an immunosuppressive activity against T cell-mediated immune responses both in vitro and in vivo, which has potential for the treatment of immune-related skin diseases.
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Evaluation of superparamagnetic iron oxide-polymer composite microcapsules for magnetic resonance-guided high-intensity focused ultrasound cancer surgery.
BMC Cancer
PUBLISHED: 04-11-2014
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Superparamagnetic poly (lactic-co-glycolic acid) (PLGA)-coated Fe3O4 microcapsules are receiving increased attention as potential diagnostic and therapeutic modalities in the field of oncology. In this study, PLGA-coated Fe3O4 microcapsules were combined with a magnetic resonance imaging-guided high-intensity focused ultrasound (MR-guided HIFU) platform, with the objective of investigating the effects of these composite microcapsules regarding MR-guided HIFU liver cancer surgery in vivo.
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Epigallocatechin-3-gallate sensitizes IFN-?-stimulated CD4(+) T cells to apoptosis via alternative activation of STAT1.
Int. Immunopharmacol.
PUBLISHED: 04-11-2014
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Epigallocatechin-3-gallate (EGCG) exerts anti-inflammatory properties on immune cells and binds to CD4 molecules. However, the effects of EGCG on CD4(+) T cells remain largely unknown. Here, we found that EGCG enhanced IFN-?-induced signal transducer and activator of transcription 1 (STAT1) activation in primary CD4(+) T cells from C57BL/6 mice and in a human leukemic CD4(+) T-cell line of Hut 78 cells, while it inhibited the classical pathway of IFN-? signaling including activating phosphorylations of Janus kinase (JAK) 1, JAK2 and STAT3, forming interferon-? activated sequence (GAS)-binding STAT1 homodimers, and producing pro-inflammatory chemokine (C-X-C motif) ligand 9 (CXCL9). CD4 blockade did not suppress the increase in IFN-?-induced STAT1 activation in CD4(+) T cells by EGCG. Furthermore, activation of Src kinase was also triggered by IFN-? plus EGCG in both Hut 78 and primary CD4(+) T cells. Interestingly, EGCG promoted apoptosis of CD4(+) T cells treated with IFN-?. The increases in STAT1 activation and apoptosis induced by EGCG in IFN-?-activated CD4(+) T cells were almost completely abolished by a selective Src family kinase inhibitor, SU6656. Moreover, EGCG alleviates CD4(+) CD45RB(hi) CD25(-) T cell transfer induced colitis with less accumulation of CD4(+) T cells in the colon. In conclusion, the present study reports an alternative activation of STAT1 via Src by EGCG in IFN-?-activated CD4(+) T cells, which promotes the apoptosis of IFN-?-activated CD4(+) T cells and contributes to the improvement of T cell-mediated colitis. Our findings suggest a novel role of EGCG in regulating IFN-? signaling and controlling inflammation.
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Paris saponin VII from trillium tschonoskii reverses multidrug resistance of adriamycin-resistant MCF-7/ADR cells via P-glycoprotein inhibition and apoptosis augmentation.
J Ethnopharmacol
PUBLISHED: 04-10-2014
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Saponins of several herbs are known to induce apoptosis in some cancer cells and are proposed to be promising modulators of drug resistance. In the present study, we extracted Paris saponin VII (PS VII), a kind of saponin, from Trillium tschonoskii Maxim. and observed its effect on adriamycin-resistant breast cancer cells.
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Erlotinib promotes endoplasmic reticulum stress-mediated injury in the intestinal epithelium.
Toxicol. Appl. Pharmacol.
PUBLISHED: 04-10-2014
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Erlotinib, a popular drug for treating non-small cell lung cancer (NSCLC), causes diarrhea in approximately 55% of patients receiving this drug. In the present study, we found that erlotinib induced barrier dysfunction in rat small intestine epithelial cells (IEC-6) by increasing epithelial permeability and down-regulating E-cadherin. The mRNA levels of various pro-inflammatory cytokines (Il-6, Il-25 and Il-17f) were increased after erlotinib treatment in IEC-6 cells. Erlotinib concentration- and time-dependently induced apoptosis and endoplasmic reticulum (ER) stress in both IEC-6 and human colon epithelial cells (CCD 841 CoN). Intestinal epithelial injury was also observed in male C57BL/6J mice administrated with erlotinib. Knockdown of C/EBP homologous protein (CHOP) with small interference RNA partially reversed erlotinib-induced apoptosis, production of IL-6 and down-regulation of E-cadherin in cultured intestinal epithelial cells. In conclusion, erlotinib caused ER stress-mediated injury in the intestinal epithelium, contributing to its side effects of diarrhea in patients.
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Metabolic engineering of Bacillus amyloliquefaciens for poly-gamma-glutamic acid (?-PGA) overproduction.
Microb Biotechnol
PUBLISHED: 03-30-2014
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We constructed a metabolically engineered glutamate-independent Bacillus amyloliquefaciens strain with considerable ?-PGA production. It was carried out by double-deletion of the cwlO gene and epsA-O cluster, as well as insertion of the vgb gene in the bacteria chromosome. The final generated strain NK-PV elicited the highest production of ?-PGA (5.12 g l(-1)), which was 63.2% higher than that of the wild-type NK-1 strain (3.14 g l(-1)). The ?-PGA purity also improved in the NK-PV strain of 80.4% compared with 76.8% for the control. Experiments on bacterial biofilm formation experiment showed that NK-1 and NK-c (?cwlO) strains can form biofilm; the epsA-O deletion NK-7 and NK-PV strains could only form an incomplete biofilm.
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CXCL12/CXCR4 axis confers adriamycin resistance to human chronic myelogenous leukemia and oroxylin A improves the sensitivity of K562/ADM cells.
Biochem. Pharmacol.
PUBLISHED: 03-28-2014
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This study was aimed at investigating the reversal effect of oroxylin A, a naturally bioactive monoflavonoid separated and purified from Scutellaria baicalensis Georgi, in human chronic myeloid leukemia (CML) and the underlying mechanisms. The results showed that CXCL12 could enhance the resistance of K562 cells to adriamycin (ADM) by increasing the expression of CXCR4, up-regulating the downstream PI3K/Akt pathway, and promoting translocation of NF-?B dimers into nucleus and subsequently decreasing the expression of apoptosis-related proteins in K562 cells. And we found that ADM resistance was partially reversed by CXCR4 siRNA transfection. Moreover, the sensitivity enhancement of oroxylin A was demonstrated by decreasing the expression of CXCR4 at both protein and mRNA levels, via PI3K/Akt/NF-?B pathway and triggering the apoptosis pathway in vitro. In addition, the in vivo study showed that oroxylin A increased apoptosis of leukemic cells with low systemic toxicity, and the mechanism was the same as in vitro study. In conclusion, all these results showed that oroxylin A improved the sensitivity of K562/ADM cells by increasing apoptosis in leukemic cells and decreasing the expression of CXCR4 and PI3K/Akt/NF-?B pathway, and probably served as a most promising agent for CML treatment.
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Angiopoietin-like 4 promotes melanoma cell invasion and survival through aldolase A.
Oncol Lett
PUBLISHED: 03-20-2014
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In the present study, the association between angiopoietin-like 4 (ANGPTL4) and aldolase A (ALDOA) in human melanoma cell invasion and survival was investigated. Overexpression and knockdown of ANGPTL4 were respectively performed in WM-115 and WM-266-4 cells. ALDOA expression at both the mRNA and the protein levels as well as the ALDOA gene promoter activities were increased and decreased in parallel with overexpression and knockdown of ANGPTL4 in the melanoma cells, which was blocked by selective protein kinase C (PKC) inhibitor and restored by PKC agonist, respectively. ANGPTL4 overexpression significantly increased cell invasion and matrix metalloproteinase-2 (MMP-2) expression and decreased cell apoptosis against cisplatin in WM-115 cells, which was reversed by knocking down ALDOA. In WM-266-4 cells, knockdown of ANGPTL4 decreased cell invasion and MMP-2 expression and increased cell apoptosis against cisplatin, which was reversed by overexpression of ALDOA. In conclusion, this study demonstrates that ANGPTL4 upregulates ALDOA expression in human melanoma cells at the ALDOA gene promoter/transcriptional level through a PKC-dependent mechanism, and that ALDOA is a critical mediator of the promoting effect of ANGPTL4 on melanoma cell invasion, likely through upregulating the MMP-2 expression. Additionally, our results suggest that ALDOA plays an important role in ANGPTL4-enhanced melanoma cell survival against apoptotic stress, which implicates ANGPTL4 and ALDOA in the development of melanoma chemoresistance.
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A markerless gene replacement method for B. amyloliquefaciens LL3 and its use in genome reduction and improvement of poly-?-glutamic acid production.
Appl. Microbiol. Biotechnol.
PUBLISHED: 03-19-2014
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We herein adapted a markerless gene replacement method by combining a temperature-sensitive plasmid pKSV7 with a counterselectable marker, the upp gene encoding uracil phosphoribosyltransferase (UPRTase), for the poly-?-glutamic acid (?-PGA)-producing strain Bacillus amyloliquefaciens LL3. Deletion of the upp gene conferred LL3 5-fluorouracil (5-FU) resistance. Sensitivity to 5-FU was restored when LL3 ?upp was transformed with pKSV7-based deletion plasmid which carries a functional allele of the upp gene of Bacillus subtilis 168. These observations allowed us to adapt a two-step plasmid integration and excision strategy to perform markerless deletion of genes of interest. Deletion plasmid harboring a mutant allele of the target gene was first integrated in the genome by culturing cells under nonpermissive conditions for pKSV7 replication. Single-crossover recombinants were then grown without antibiotics to aid the second recombinational event. 5-FU was used to select for double-crossover recombinants with plasmid evicted from the chromosome. The resulting recombinants either harbored the wild-type or mutated allele of the target gene and could be identified by PCR and DNA sequencing. Using this method, we successively removed the amyA gene and a 47-kb fragment of the bae cluster from the genome of LL3, with higher efficiency compared with previous reports. We also investigated the effects of a transcriptional regulator, RocR, on ?-PGA production and cell growth. Specific ?-PGA production of the rocR mutant was increased by 1.9-fold, which represents a new way to improve ?-PGA production.
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Biodegradable polymer scaffolds loaded with low-dose BMP-2 stimulate periodontal ligament cell differentiation.
J Biomed Mater Res A
PUBLISHED: 03-14-2014
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Poly(l-lactide)-co-(epsilon-caprolactone) [poly(LLA-co-CL)] and poly(l-lactide)-co-(1,5-dioxepan-2-one) [poly(LLA-co-DXO)] are being considered candidate scaffolds for bone tissue engineering. We evaluated the bioactive potential of poly(LLA-co-CL) and poly(LLA-co-DXO) scaffolds loaded with low-dose bone morphogenetic protein-2 (BMP-2). Periodontal ligament (PDL) cells were cultured onto the various scaffolds loaded with 1 µg BMP-2 or without BMP-2 (control). Cell viability, attachment, and proliferation were determined using a methylthiazol tetrazolium (MTT) colorimetric assay at day 1, 3, and 7. Scanning electron microscopy was used to analyze cell morphology at day 7. Cell differentiation was evaluated assaying alkaline phosphatase (ALP) activity at day 7, 14, and 21. Real-time PCR was used to evaluate the mRNA expression of periostin, ALP, type I collagen, bone sialoprotein and BMP-2. A commercially available enzyme-linked immunosorbent assay was used to assess BMP-2 production. Surface analysis disclosed excellent cell attachment, spread, and penetration into the porous scaffolds. The MTT assay indicated that scaffolds loaded with low concentration of BMP-2 did not influence the viability of cells. Cells grown on the modified scaffolds expressed higher levels of osteogenic markers than the nonmodified scaffolds (p?
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Catabolite control protein A is an important regulator of metabolism in Streptococcus suis type 2.
Biomed Rep
PUBLISHED: 03-12-2014
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Streptococcus suis (S. suis) type 2 is an extremely important Gram-positive bacterial pathogen that can cause human or swine endocarditis, meningitis, bronchopneumonia, arthritis and sepsis. Catabolite control protein A (CcpA) is a major transcriptional regulator in S. suis type 2 that functions in catabolite control, specifically during growth on glucose or galactose. The regulation of central metabolism can affect the virulence of bacteria. In the present study, a metabolomics approach was used along with principal components analysis (PCA) and partial least-squares-discriminant analysis (PLS-DA) models and 37 metabolites were found that differed substantially between native S. suis and a mutant lacking CcpA. These results showed that CcpA is an important protein in S. suis type 2 for studying bacterial protein function.
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Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections.
Nat Commun
PUBLISHED: 03-07-2014
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The potential for avian influenza H5N1 outbreaks has increased in recent years. Thus, it is paramount to develop novel strategies to alleviate death rates. Here we show that avian influenza A H5N1-infected patients exhibit markedly increased serum levels of angiotensin II. High serum levels of angiotensin II appear to be linked to the severity and lethality of infection, at least in some patients. In experimental mouse models, infection with highly pathogenic avian influenza A H5N1 virus results in downregulation of angiotensin-converting enzyme 2 (ACE2) expression in the lung and increased serum angiotensin II levels. Genetic inactivation of ACE2 causes severe lung injury in H5N1-challenged mice, confirming a role of ACE2 in H5N1-induced lung pathologies. Administration of recombinant human ACE2 ameliorates avian influenza H5N1 virus-induced lung injury in mice. Our data link H5N1 virus-induced acute lung failure to ACE2 and provide a potential treatment strategy to address future flu pandemics.
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Discovery of indanone derivatives as multi-target-directed ligands against Alzheimer's disease.
Eur J Med Chem
PUBLISHED: 03-04-2014
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A series of indanone derivatives were designed, synthesized, and tested using a variety of assays to assess their potential as anti-Alzheimer's disease (AD) agents. The investigations assessed the activities of the agents for the inhibition of cholinesterases (AChE and BuChE), the inhibition of amyloid beta (A?) self-assembly, and the catalysis of the disassembly of preformed A? oligomers and measured their antioxidant activities. Our results demonstrate that most of the synthesized compounds demonstrated good inhibitory activity against AChE with IC50 values in the nanomolar range. In particular, compounds 9 (IC50 = 14.8 nM) and 14 (IC50 = 18.6 nM) exhibited markedly higher inhibitory activities than tacrine and similar activities to donepezil. In addition, 9 and 14 significantly inhibited A? aggregation (inhibition rates of 85.5% and 83.8%, respectively), catalysed the disaggregation of A? fibrils generated by self-induced A? aggregation, and exhibited antioxidant activity. Furthermore, these two compounds can cross the blood-brain barrier (BBB) in vitro. These properties highlight the potential of these new compounds to be developed as multi-functional drugs for the treatment of Alzheimer's disease.
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The role of leptin in gastric cancer: clinicopathologic features and molecular mechanisms.
Biochem. Biophys. Res. Commun.
PUBLISHED: 02-12-2014
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Obesity is associated with certain types of cancer, including gastric cancer. However, it is still unclear whether obesity-related cytokine, leptin, is implicated in gastric cancer. Therefore, we aimed to investigate the role of leptin in gastric cancer. The expression of leptin and its receptor, Ob-R, was assessed by immunohistochemical staining and was compared in patients with gastric adenoma (n=38), early gastric cancer (EGC) (n=38), and advanced gastric cancer (AGC) (n=38), as a function of their clinicopathological characteristics. Gastric cancer cell lines were studied to investigate the effects of leptin on the signal transducer and activator of transcription-3 (STAT3) and extracellular receptor kinase 1/2 (ERK1/2) signaling pathways using MTT assays, immunoblotting, and inhibition studies. Leptin was expressed in gastric adenomas (42.1%), EGCs (47.4%), and AGCs (43.4%). Ob-R expression tended to increase from gastric adenoma (2%), through EGC (8%), to AGC (18%). Leptin induced the proliferation of gastric cancer cells by activating STAT3 and ERK1/2 and up-regulating the expression of vascular endothelial growth factor (VEGF). Blocking Ob-R with pharmacological inhibitors and by RNAi decreased both the leptin-induced activation of STAT3 and ERK1/2 and the leptin-induced expression of VEGF. Leptin plays a role in gastric cancer by stimulating the proliferation of gastric cancer cells via activating the STAT3 and ERK1/2 pathways.
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Sublethal effects of the chitin synthesis inhibitor, hexaflumuron, in the cotton mirid bug, Apolygus lucorum (Meyer-Dür).
Pestic Biochem Physiol
PUBLISHED: 02-11-2014
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Hexaflumuron is a type of benzoylphenylurea insecticide which is highly toxic for many insects. Sublethal doses of hexaflumuron have been shown to significantly affect insect growth and development. However, the action mechanism of hexaflumuron is not well understood. In the present study, first instar Apolygus lucorum nymphs were exposed to sublethal doses of hexaflumuron based on the estimated 120h acute LC50 valve of 20.53mg/ml. We found that exposure to sublethal hexaflumuron doses resulted in a significant increase in development time and reduced the weights of fifth instar A. lucorum nymphs. We also measured trehalose, which is a primary blood sugar in insects, and the enzyme trehalase that is involved in energy metabolism. Trehalose content in first instar nymphs significantly increased following hexaflumuron treatment while the glucose content, soluble trehalase activity and expression levels of ALTre-1 mRNA decreased significantly. However, no significant changes in membrane-bound trehalase activity and ALTre-2 mRNA expression were observed. In addition, these decreases or increases could be correlated to increases in treatment time or concentration of hexaflumuron, respectively. The present findings indicated that sublethal doses of hexaflumuron could interfere the normal carbohydrate metabolism by depressing the expression of ALTre-1 in A. lucorum, which provide valuable information on the physiology and molecular mechanisms for the toxicity of hexaflumuron.
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Expression and clinical significance of tyrosine phosphatase SHP-2 in colon cancer.
Biomed. Pharmacother.
PUBLISHED: 01-21-2014
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Protein-tyrosine phosphatase SHP-2, encoded by gene PTPN11, has been identified as a tumor-promoting factor in several types of leukemia and is hyper-activated by other mechanisms in some solid tumors including gastric cancer, breast cancer, non-small cell lung cancer (NSCLC), etc. But few were reported on the expression and significances of SHP-2 in colon cancer. Here, we detect SHP-2 expression in colon cancer cells, colon cancer-induced by AOM+DSS in mice and 232 human colon cancer specimens, including 58 groups of self-matched adjacent peritumor tissues and normal tissues. We found that compared to the normal colon tissues, SHP-2 significantly decreased in tumor tissues (P<0.001). The same results were got in colon tumor cells as well as mice colon tumors. And in humans samples, low SHP-2 expression showed a significantly correlation with poor tumor differentiation (P<0.05), late TNM stage (P=0.1666) and lymph node metastasis (P<0.05).
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The large-conductance calcium-activated potassium channel holds the key to the conundrum of familial hypokalemic periodic paralysis.
Korean J Pediatr
PUBLISHED: 01-17-2014
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Familial hypokalemic periodic paralysis (HOKPP) is an autosomal dominant channelopathy characterized by episodic attacks of muscle weakness and hypokalemia. Mutations in the calcium channel gene, CACNA1S, or the sodium channel gene, SCN4A, have been found to be responsible for HOKPP; however, the mechanism that causes hypokalemia remains to be determined. The aim of this study was to improve the understanding of this mechanism by investigating the expression of calcium-activated potassium (KCa) channel genes in HOKPP patients.
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Should GLP-1 receptor agonists be used with caution in high risk population for colorectal cancer?
Med. Hypotheses
PUBLISHED: 01-16-2014
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Glucagon-like peptide-1 (GLP-1) receptor agonists, with few reported side effects, are a kind of very promising anti-diabetes drugs. They are thus being paid high hopes on by both doctors and patients. GLP-1 receptor agonists, however, have not been used in clinic for a long time. Some unknown potential adverse effects may exist. Because GLP-1 receptor agonists enhance ? cells proliferation in pancreas via influencing Wnt/?-catenin pathway, a pathway which is associated with tumorigenesis in colon, we then assume that GLP-1 receptor agonists may increase the risk for colorectal cancer.
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Paris saponin ? inhibits metastasis by modulating matrix metalloproteinases in colorectal cancer cells.
Mol Med Rep
PUBLISHED: 01-08-2014
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Metastasis is the main cause of mortality of patients with cancer?related disease. Targeting the process of metastasis has been proposed as a potential strategy in cancer treatment. Trillium tschonoskii Maxim., a traditional Chinese medicine, is used for the treatment of numerous diseases, including cancer. The current study aimed to determine the anti?metastatic effect of Paris saponin VII (PS ?), which was extracted from T. tschonoskii Maxim., using SW620 and LoVo cells, two human metastatic colorectal cancer (CRC) cell lines. The present study conducted cell attachment, wound healing and migration assays to detect the anti?metastatic effects of PS VII on colorectal cells. In addition, gelatin zymography assay and western blot analysis were used to detect the possible mechanisms involved. The results of this study demonstrated that PS ? significantly suppresses the viability, attachment, migration and invasive abilities of CRC cells in a concentration?dependent manner. In addition, PS ? reduced the expression levels and activity of matrix metalloproteinase (MMP)?2 and MMP?9. These data indicate that PS ? reduces the metastatic capability of CRC cells, possibly via the downregulation of the expression and activity of MMP?2 and MMP?9. These results demonstrate a novel therapeutic potential for PS ? in anti?metastatic therapy.
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Follistatin is a novel biomarker for lung adenocarcinoma in humans.
PLoS ONE
PUBLISHED: 01-01-2014
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Follistatin (FST), a single chain glycoprotein, is originally isolated from follicular fluid of ovary. Previous studies have revealed that serum FST served as a biomarker for pregnancy and ovarian mucinous tumor. However, whether FST can serve as a biomarker for diagnosis in lung adenocarcinoma of humans remains unclear.
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Rapamycin-insensitive up-regulation of adipocyte phospholipase A2 in tuberous sclerosis and lymphangioleiomyomatosis.
PLoS ONE
PUBLISHED: 01-01-2014
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Tuberous sclerosis syndrome (TSC) is an autosomal dominant tumor suppressor gene syndrome affecting multiple organs, including renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM). LAM is a female-predominant interstitial lung disease characterized by the progressive cyst formation and respiratory failure, which is also seen in sporadic patients without TSC. Mutations in TSC1 or TSC2 cause TSC, result in hyperactivation of mammalian target of rapamycin (mTOR), and are also seen in LAM cells in sporadic LAM. We recently reported that prostaglandin biosynthesis and cyclooxygenase-2 were deregulated in TSC and LAM. Phospholipase A2 (PLA2) is the rate-limiting enzyme that catalyzes the conversion of plasma membrane phospholipids into prostaglandins. In this study, we identified upregulation of adipocyte AdPLA2 (PLA2G16) in LAM nodule cells using publicly available expression data. We showed that the levels of AdPLA2 transcript and protein were higher in LAM lungs compared with control lungs. We then showed that TSC2 negatively regulates the expression of AdPLA2, and loss of TSC2 is associated with elevated production of prostaglandin E2 (PGE2) and prostacyclin (PGI2) in cell culture models. Mouse model studies also showed increased expression of AdPLA2 in xenograft tumors, estrogen-induced lung metastatic lesions of Tsc2 null leiomyoma-derived cells, and spontaneous renal cystadenomas from Tsc2+/- mice. Importantly, rapamycin treatment did not affect the expression of AdPLA2 and the production of PGE2 by TSC2-deficient mouse embryonic fibroblast (Tsc2-/-MEFs), rat uterine leiomyoma-derived ELT3 cells, and LAM patient-associated renal angiomyolipoma-derived "mesenchymal" cells. Furthermore, methyl arachidonyl fluorophosphate (MAFP), a potent irreversible PLA2 inhibitor, selectively suppressed the growth and induced apoptosis of TSC2-deficient LAM patient-derived cells relative to TSC2-addback cells. Our findings suggest that AdPLA2 plays an important role in promoting tumorigenesis and disease progression by modulating the production of prostaglandins and may serve as a potential therapeutic target in TSC and LAM.
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[Repair of defects in lower extremities with peroneal perforator-based sural neurofasciocutaneous flaps].
Zhonghua Shao Shang Za Zhi
PUBLISHED: 12-24-2013
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To explore the operative technique and clinical results of using peroneal perforator-based sural neurofasciocutaneous flaps to repair skin and soft tissue defects in lower extremities.
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[Correlation between ABCC11 gene single nucleotide polymorphism and the incidence of axillary osmidrosis in Chinese Han population].
Zhong Nan Da Xue Xue Bao Yi Xue Ban
PUBLISHED: 12-10-2013
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Objective: To explore the relationship between ABCC11 gene single nucleotide polymorphism (SNP) and the incidence of axillary osmidrosis in Chinese Han population. Methods: The genotype of ABCC11 gene SNP at rs17822931 in 40 patients with axillary osmidrosis and 5 normal Han people was detected and analyzed by high resolution melt and gene sequencing. Results: The detection of the genotype of ABCC11 gene SNP at rs17822931 showed that: 37 of the 40 patients were GA genotype and the other 3 were GG genotype, while the 5 normal subjects were AA genotype. Conclusion: SNP in ABCC11 is the genetic cause of axillary osmidrosis. GG or GA leads to axillary osmidrosis, while AA allele presents the absence of axillary osmidrosis.
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Resveratrol prevents rapamycin-induced upregulation of autophagy and selectively induces apoptosis in TSC2-deficient cells.
Cell Cycle
PUBLISHED: 12-04-2013
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The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is hyperactivated in a variety of cancers and disorders, including lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC), which are characterized by mutations in tumor suppressors TSC1 or TSC2. The concern with the use of mTORC1 inhibitors, such as rapamycin or its analogs (rapalogs), is that they cause upregulation of autophagy and suppress the negative feedback loop to Akt, which promotes cell survival, causing the therapy to be only partially effective, and relapse occurs upon cessation of treatment. In this study, we investigate the use of rapamycin in combination with resveratrol, a naturally occurring polyphenol, in TSC2-deficient cells. We tested whether such combination would prevent rapamycin-induced upregulation of autophagy and shift the cell fate toward apoptosis. We found that this combination treatment blocked rapamycin-induced upregulation of autophagy and restored inhibition of Akt. Interestingly, the combination of rapamycin and resveratrol selectively promoted apoptosis of TSC2-deficient cells. Thus, the addition of resveratrol to rapamycin treatment may be a promising option for selective and targeted therapy for diseases with TSC loss and mTORC1 hyperactivation.
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An apple oligogalactan potentiates the growth inhibitory effect of celecoxib on colorectal cancer.
Nutr Cancer
PUBLISHED: 11-25-2013
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Multiple studies have indicated that selective cyclooxygenase-2 (COX-2) inhibitors possess clinically chemopreventive and preclinically anticancer activities. Their long-term use, however, may be limited by the cardiovascular toxicity. This study tried to investigate whether an apple oligogalactan (AOG) could enhance the growth inhibitory effect of celecoxib on colorectal cancer. Caco-2 and HT-29 cell lines were exposed to different concentrations of AOG (0-1 g/L), celecoxib (0-25 ?mol/L), and their combination. COX-2 levels were assessed by reverse transcription PCR and Western blot. COX-2 activity was evaluated by measuring prostaglandin E2 concentration. A colitis-associated colorectal cancer (CACC) mouse model was used to determine the effect of the combination in vivo. AOG (0.1-0.5 g/L) could potentiate the inhibitory effect of physiologic doses of celecoxib (5 ?mol/L) on cell growth and decrease COX-2 expressions both at RNA and protein levels. In vivo, the combination (2.5% AOG plus 0.04% celecoxib, w/w) prevented against CACC in mice effectively. Our data indicate that AOG could potentiate the growth inhibitory effect of celecoxib on colorectal cancer both in vitro and in vivo through influencing the expression and function of COX-2 and phosphorylation of MAPKs, which suggests a new possible combinatorial strategy in colorectal cancer therapy.
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[MiR-150-5p inhibits the proliferation and promoted apoptosis of pancreatic cancer cells].
Zhonghua Bing Li Xue Za Zhi
PUBLISHED: 11-20-2013
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To investigate the role of miR-150-5p in cell proliferation and apoptosis in human pancreatic cancer cell lines.
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Synthesis and Evaluation of Multi-Target-Directed Ligands against Alzheimers Disease Based on the Fusion of Donepezil and Ebselen.
J. Med. Chem.
PUBLISHED: 11-12-2013
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A novel series of compounds obtained by fusing the cholinesterase inhibitor donepezil and the antioxidant ebselen were designed as multi-target-directed ligands against Alzheimers disease. An in vitro assay showed that some of these molecules did not exhibit highly potent cholinesterase inhibitory activity but did have various other ebselen-related pharmacological effects. Among the molecules, compound 7d, one of the most potent acetylcholinesterase inhibitors (IC50 values of 0.042 ?M for Electrophorus electricus acetylcholinesterase and 0.097 ?M for human acetylcholinesterase), was found to be a strong butyrylcholinesterase inhibitor (IC50 = 1.586 ?M), to possess rapid H2O2 and peroxynitrite scavenging activity and glutathione peroxidase-like activity (?0 = 123.5 ?M min(-1)), and to be a substrate of mammalian TrxR. A toxicity test in mice showed no acute toxicity at doses of up to 2000 mg/kg. According to an in vitro blood-brain barrier model, 7d is able to penetrate the central nervous system.
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