Genetic Modification of Dendritic Cells and Its Application for Cancer Immunotherapy

The Journal of Medical Investigation : JMI. Feb, 2002  |  Pubmed ID: 11901764

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs). DCs pulsed with peptides of tumor-associated antigens (TAA) and tumor lysate have been used in cancer immunotherapy. An early clinical study demonstrated the safety of the use of DCs, but the clinical response was not sufficient. The gene-modification of DCs with TAA and soluble factor genes such as cytokine and chemokine genes has been examined to enhance the antigen-presenting capacity of DCs. Viral vectors including retroviruses and adenoviruses have been reported to be useful to obtain a sufficient transduction efficiency into DCs. TAA gene-transduced DCs could have several advantages compared with TAA peptide-pulsed DCs as follows: 1) The use of TAA gene-modified DCs are not restricted by MHC haplotypes. 2) The gene transduction with TAA genes is likely to present the unknown TAA peptides on DCs. 3) The gene-modified DCs show the prolonged presentation of TAA peptides. The transduction of DCs with cytokine genes including IL-12 and GM-CSF have also been reported to argument the antitumor effects of DCs. Although the results in the experimental systems were promising, the clinical application of gene-modified DCs includes several problems such as the standardization of methods of manipulation and gene-transduction of DCs. Approaches to solve them require further studies.

Modulation of Drosophila Slowpoke Calcium-dependent Potassium Channel Activity by Bound Protein Kinase a Catalytic Subunit

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. May, 2002  |  Pubmed ID: 12019304

Drosophila Slowpoke (dSlo) calcium-dependent potassium channels bind directly to the catalytic subunit of cAMP-dependent protein kinase (PKAc). We demonstrate here that coexpression of PKAc with dSlo in mammalian cells results in a dramatic decrease of dSlo channel activity. This modulation requires catalytically active PKAc but is not mediated by phosphorylation of S942, the only PKA consensus site in the dSlo C-terminal domain. dSlo binds to free PKAc but not to the PKA holoenzyme that includes regulatory subunits and is inactive. Activators of endogenous PKA that stimulate dSlo phosphorylation, but do not produce detectable PKAc binding to dSlo, do not modulate channel function. Furthermore, the catalytically inactive PKAc mutant does bind to dSlo but does not modulate channel activity. These results are consistent with the hypothesis that both binding of active PKAc to dSlo and phosphorylation of dSlo or some other protein are necessary for channel modulation.

Calmodulin is an Auxiliary Subunit of KCNQ2/3 Potassium Channels

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Sep, 2002  |  Pubmed ID: 12223552

Calmodulin (CaM) was identified as a KCNQ2 and KCNQ3 potassium channel-binding protein, using a yeast two-hybrid screen. CaM is tethered constitutively to the channel, in the absence or presence of Ca2+, in transfected cells and also coimmunoprecipitates with KCNQ2/3 from mouse brain. The structural elements critical for CaM binding to KCNQ2 lie in two conserved motifs in the proximal half of the channel C-terminal domain. Truncations and point mutations in these two motifs disrupt the interaction. The first CaM-binding motif has a sequence that conforms partially to the consensus IQ motif, but both wild-type CaM and a Ca2+-insensitive CaM mutant bind to KCNQ2. The voltage-dependent activation of the KCNQ2/3 channel also shows no Ca2+ sensitivity, nor is it affected by overexpression of the Ca2+-insensitive CaM mutant. On the other hand, KCNQ2 mutants deficient in CaM binding are unable to generate detectable currents when coexpressed with KCNQ3 in CHO cells, although they are expressed and targeted to the cell membrane and retain the ability to assemble with KCNQ3. A fusion protein containing both of the KCNQ2 CaM-binding motifs competes with the full-length KCNQ2 channel for CaM binding and decreases KCNQ2/3 current density in CHO cells. The correlation of CaM binding with channel function suggests that CaM is an auxiliary subunit of the KCNQ2/3 channel.

Differential Effects of IL-12 on the Generation of Alloreactive CTL Mediated by Murine and Human Dendritic Cells: a Critical Role for Nitric Oxide

Journal of Leukocyte Biology. May, 2003  |  Pubmed ID: 12714577

We examined the mechanisms involved in interleukin (IL)-12-mediated suppression of cellular immunity in mice using allogeneic mixed leukocyte reaction (MLR) stimulated by dendritic cells (DCs) in vitro and compared the effect of IL-12 on MLR in mice and humans. Although IL-12 stimulated human MLR, the addition of IL-12 or interferon-gamma (IFN-gamma) resulted in a dose-dependent suppression of MLR in mice. The treatment with N(G)-monomethyl-L-arginine (L-NMMA) completely abrogated IL-12- and IFN-gamma-mediated suppression of MLR in mice. Furthermore, IL-12 enhanced the alloreactive cytolytic T lymphocyte (CTL) induction in human MLR, whereas the addition of L-NMMA was required to generate alloreactive CTLs in the presence of IL-12 in mice. Nitric oxide (NO) was detected only in mouse MLR. Murine DCs could produce NO, but neither human CD34(+) cell- nor monocyte-derived DCs produced a detectable amount of NO. These results suggest that NO produced by DCs might play an important role in IL-12-mediated immune suppression in mice but not in humans.

Tethering Naturally Occurring Peptide Toxins for Cell-autonomous Modulation of Ion Channels and Receptors in Vivo

Neuron. Aug, 2004  |  Pubmed ID: 15294139

The physiologies of cells depend on electrochemical signals carried by ion channels and receptors. Venomous animals produce an enormous variety of peptide toxins with high affinity for specific ion channels and receptors. The mammalian prototoxin lynx1 shares with alpha-bungarotoxin the ability to bind and modulate nicotinic receptors (nAChRs); however, lynx1 is tethered to the membrane via a GPI anchor. We show here that several classes of neurotoxins, including bungarotoxins and cobratoxins, retain their selective antagonistic properties when tethered to the membrane. Targeted elimination of nAChR function in zebrafish can be achieved with tethered alpha-bungarotoxin, silencing synaptic transmission without perturbing synapse formation. These studies harness the pharmacological properties of peptide toxins for use in genetic experiments. When combined with specific methods of cell and temporal expression, the extension of this approach to hundreds of naturally occurring peptide toxins opens a new landscape for cell-autonomous regulation of cellular physiology in vivo.

Analysis of Protoberberine Alkaloids in Several Herbal Drugs and Related Medicinal Preparations by Non-aqueous Capillary Electrophoresis

Journal of Separation Science. Jan, 2005  |  Pubmed ID: 15688637

A simple, rapid, reproducible, and universal non-aqueous capillary electrophoresis method has been developed for the separation and determination of three major active protoberberine alkaloids including berberine, palmatine, and jatrorrhizine within 7 min. The effects of the concentrations of acetic acid and electrolyte, the ratio of organic solvent, and the applied voltage on the separation were investigated. The optimum running buffer was composed of 50 mM ammonium acetate, 0.5% (v/v) acetic acid, and 10% (v/v) acetonitrile in methanol. The applied voltage was 18 kV. The analytes were detected by UV at 214 nm. The linearities between peak areas and the concentrations of the analytes were also investigated, and they exhibit excellent linear behavior over the concentration ranges (correlation coefficients: 0.9975-0.9986). The method was successfully applied to determine the three alkaloids in several families of herbal drugs (Rhizoma Coptidis, Cortex Berberidis, Cortex Phellodendri, Herba Chelidonii, Caulis Mahoniae) and their relevant medicinal preparations for the first time, and the recoveries of the three constituents ranged between 95.6-103.2% for berberine, 97.5-103.3% for palmatine, and 96.1 -103.6% for jatrorrhizine.

[Construction and Expression of the Major Outer Membrane Protein PI of Neisseria Gonorrhoeae in Escherichia Coli]

Sichuan Da Xue Xue Bao. Yi Xue Ban = Journal of Sichuan University. Medical Science Edition. Mar, 2005  |  Pubmed ID: 15807265

To construct Neisseria gonorrhoeae major outer membrane protein PI gene recombinants for expression of the target protein in E. coli.

Paired Motor Neuron-muscle Recordings in Zebrafish Test the Receptor Blockade Model for Shaping Synaptic Current

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Aug, 2005  |  Pubmed ID: 16135768

The transparent spinal cord and electrically compact fast muscle of zebrafish offer the first opportunity to perform simultaneous whole-cell patch-clamp recordings from both motor neuron and target skeletal muscle in situ. Our paired recordings reveal the fastest reported kinetics for both spontaneous and evoked synaptic currents at any synapse and a large quantal size that facilitates the resolution of spontaneous synaptic currents. We used this preparation to test the recent proposal that open channel block of the acetylcholine receptor by acetylcholine modulates the kinetics and timing of transmission between nerve and muscle in larval zebrafish (Legendre et al., 2000). Contrary to the predictions of this model, we find similar delay and onset kinetics of synaptic current at positive and negative muscle membrane potentials, even after inhibition of acetylcholinesterase. In contrast, blockade of motor neuron K channels by 4-aminopyridine prolonged the action potential and introduced a significant delay and slowing of evoked synaptic currents, demonstrating our ability to measured altered transmitter release with this system. We conclude that the kinetics of neuromuscular synaptic currents in zebrafish is not governed by receptor block.

Expression of a Calmodulin-binding KCNQ2 Potassium Channel Fragment Modulates Neuronal M-current and Membrane Excitability

Proceedings of the National Academy of Sciences of the United States of America. Nov, 2005  |  Pubmed ID: 16263935

KCNQ2 and KCNQ3 ion channel pore-forming subunits coassemble to form a heteromeric voltage-gated potassium channel that underlies the neuronal M-current. We and others showed that calmodulin (CaM) binds to specific sequence motifs in the C-terminal domain of KCNQ2 and KCNQ3. We also found that a fusion protein containing a KCNQ2 CaM-binding motif, coexpressed with KCNQ2 and KCNQ3, competes with the full-length KCNQ2 channel for CaM binding and thereby decreases KCNQ2/3 current density in heterologous cells. We have explored the importance of CaM binding for the generation of the native M-current and regulation of membrane excitability in rat hippocampal neurons in primary cell culture. M-current properties were studied in cultured neurons by using whole-cell patch clamp recording. The M-current density is lower in neurons expressing the CaM-binding motif fusion protein, as compared to control neurons transfected with vector alone. In contrast, no change in M-current density is observed in cells transfected with a mutant fusion protein that is unable to bind CaM. The CaM-binding fusion protein does not influence the rapidly inactivating A-current or the large conductance calcium-activated potassium channel-mediated fast spike afterhyperpolarization in neurons in which the M-current is suppressed. Furthermore, the CaM-binding fusion protein, but not the nonbinding mutant, increases both the number of action potentials evoked by membrane depolarization and the size of the spike afterdepolarization. These results suggest that CaM binding regulates M-channel function and membrane excitability in the native neuronal environment.

A Drosophila KCNQ Channel Essential for Early Embryonic Development

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Nov, 2005  |  Pubmed ID: 16267222

The mammalian voltage-dependent KCNQ channels are responsible for distinct types of native potassium currents and are associated with several human diseases. We cloned a novel Drosophila KCNQ channel (dKCNQ) based on its sequence homology to the mammalian genes. When expressed in Chinese hamster ovary cells, dKCNQ gives rise to a slowly activating and slowly deactivating current that activates in the subthreshold voltage range. Like the M-current produced by mammalian KCNQ channels, dKCNQ current is sensitive to the KCNQ-specific blocker linopirdine and is suppressed by activation of a muscarinic receptor. dKCNQ is also similar to the mammalian channels in that it binds calmodulin (CaM), and CaM binding is necessary to produce functional currents. In situ hybridization analysis demonstrates that dKCNQ mRNA is present in brain cortical neurons, the cardia (proventriculus), and the nurse cells and oocytes of the ovary. We generated mutant flies with deletions in the genomic sequence of dKCNQ. Embryos produced by homozygous deletion females exhibit disorganized nuclei and fail to hatch, suggesting strongly that a maternal contribution of dKCNQ protein and/or mRNA is essential for early embryonic development.

[The Analysis of Risk Factors Correlated to Pulmonary Hypertension in Obstructive Sleep Apnea Syndrome Patients During Awake State]

Zhonghua Nei Ke Za Zhi [Chinese Journal of Internal Medicine]. May, 2006  |  Pubmed ID: 16780740

To investigate the development of pulmonary hypertension in obstructive sleep apnea syndrome (OSAS) patients and to analyze the correlated factors.

Seasonality Effects on Pharmaceuticals and S-triazine Herbicides in Wastewater Effluent and Surface Water from the Canadian Side of the Upper Detroit River

Environmental Toxicology and Chemistry / SETAC. Sep, 2006  |  Pubmed ID: 16986790

The influence of seasonal changes in water conditions and parameters on several major pharmacologically active compounds (PhACs) and s-triazine herbicides was assessed in the wastewater and sewage treatment plant (WSTP) effluent as well as the downstream surface water from sites on the Canadian side of the upper Detroit River, between the Little River WSTP and near the water intake of a major drinking water treatment facility for the City of Windsor (ON, Canada). The assessed PhACs were of neutral (carbamazepine, cotinine, caffeine, cyclophosphamide, fluoxetine, norfluoxetine, pentoxifylline, and trimethoprim) and acidic (ibuprofen, bezafibrate, clofibric acid, diclofenac, fenoprofen, gemfibrozil, indomethacin, naproxen, and ketoprofen) varieties. The major assessed s-triazine herbicides were atrazine, simazine, propazine, prometon, ametryn, prometryn, and terbutryn. At sampling times from September 2002 to June 2003, 15 PhACs were detected in the WSTP effluent at concentrations ranging from 1.7 to 1244 ng/L. The PhAC concentrations decreased by as much 92 to 100% at the Little River/Detroit River confluence because of the river dilution effect, with further continual decreases at sites downstream from the WSTP. The only quantifiable s-triazine in WSTP effluent, atrazine, ranged from 6.7 to 200 ng/L and was higher in Detroit River surface waters than in WSTP effluent. Only carbamazepine, cotinine, and atrazine were detectable at the low-nanogram and subnanogram levels in surface waters near a drinking water intake site. Unlike the PhACs, atrazine in the Detroit River is not attributable to point sources, and it is heavily influenced by seasonal agricultural usage and runoff. Detroit River surface water concentrations of carbamazepine, cotinine, and atrazine may present a health concern to aquatic wildlife and to humans via the consumption of drinking water.

[Responses of Shenyang Urban Tree Phrenology to Climate Warming]

Ying Yong Sheng Tai Xue Bao = The Journal of Applied Ecology / Zhongguo Sheng Tai Xue Xue Hui, Zhongguo Ke Xue Yuan Shenyang Ying Yong Sheng Tai Yan Jiu Suo Zhu Ban. Oct, 2006  |  Pubmed ID: 17209369

By using statistic and linear regression methods, this paper studied the last 40 years responses of Shenyang urban tree phenology to climate warming. The results showed that there was a significant correlation between the duration of tree dormancy and the mean air temperature in winter. Appropriate cold condition was beneficial to bud break, and a significant negative correlation was observed between the outset of sprouting and the mean air temperature in winter and early spring. Leaf expansion started 15 days after sprouting, which was mainly affected by the mean air temperature in spring but had no correlation with the temperature in winter. The air temperature within 20-80 days and especially 20-40 days before flowering had a significant effect on the outset of flowering, i. e. , an increasing temperature in spring could advance the outset of flowering. Both sprouting and leaf expansion were negatively correlated with cold index (CI) , but no significant correlation was observed between the outset of flowering and CI. An increase of mean annual air temperature by 1 degree C would advance the outset of sprouting by 9 days, leaf expansion by 10 days, and outset of flowering by 5 days.

[Morphological-ecological Characters and Growth Patterns of Main Tree Species Leaves in Urban Forest of Shenyang]

Ying Yong Sheng Tai Xue Bao = The Journal of Applied Ecology / Zhongguo Sheng Tai Xue Xue Hui, Zhongguo Ke Xue Yuan Shenyang Ying Yong Sheng Tai Yan Jiu Suo Zhu Ban. Nov, 2006  |  Pubmed ID: 17269315

The study with statistic and multivariate analyses showed that the main meteorological factors affecting the growth and development rhythms of main tree species leaves in urban forest of Shenyang were > or = 5 degrees C accumulated temperature, accumulated sunshine hours, and mean temperature in the middle ten days of each phenological period. The meteorological factors needed by the tree species varied with their phenological period. Necessary low temperature and CI were required in germination period, and suitable WI and HI were needed in the growth period. The major quantitative morphological characters of 10 tree species in Shenyang urban forest were displayed in their leaf morphology and size, which decreased in the sequence of Lespedeza cyrtobotrya > Syringa oblata > Sophora japonica > Populus alba > Cornus alba > Lonicera maackii > Ligustrum obtusifolium > Fraxinus mandshurica > Prunus padus > Phellodondron amurense. As for the leaf area, it was decreased in the order of S. oblata > P. alba > P. amurense > P. padus > F. mandshurica > C. alba > L. cyrtobotrya > L. maackii > S. japonica > L. obtusifolium. The relationships of leaf length with leaf width, perimeter and area accorded with the model of y = ax(k), and the growth trend belonged to allometic type. The k value between leaf length and width of all test tree species except P. alba was lower than 1, and that between leaf length and perimeter was > 1 for P. amuresne, approximately 1 for P. alba, and < 1 for other tree species. As for the k value between leaf length and area, it was > 1 for all the tree species, with that of P. alba being 2. 1028. The increasing rate of leaf area was about 2 times higher than that of leaf length. An optimum regression assessment model of the 10 tree species leaf area was built and tested.

[Stereotactic Multi-target Operation for Patients with Affective Disorder]

Zhonghua Wai Ke Za Zhi [Chinese Journal of Surgery]. Dec, 2007  |  Pubmed ID: 18476524

To explore the efficacy and complication of bilateral multi-target radiofrequency lesion operation in patients with affective disorder.

Function of Neuromuscular Synapses in the Zebrafish Choline-acetyltransferase Mutant Bajan

Journal of Neurophysiology. Oct, 2008  |  Pubmed ID: 18684905

We have identified a zebrafish mutant line, bajan, in which compromised motility and fatigue result from a point mutation in the gene coding choline acetyltransferase (ChAT), the enzyme responsible for acetylcholine (ACh) synthesis. Although the mutation predicts loss of ChAT function, bajan inexplicably retains low levels of neuromuscular transmission. We exploited this residual activity and determined the consequences for synaptic function. The attenuated synaptic responses were a direct consequence of a decrease in both resting mean quantal size and quantal content. To replicate behavioral fatigue in swimming, motorneurons were stimulated at high frequencies. A prominent reduction in quantal content, reflecting vesicle depletion, was coincident with a small additional reduction in quantal size. In humans, defective ChAT leads to episodic apnea, a form of congenital myasthenic syndrome characterized by use-dependent fatigue. In contrast to bajan, however, afflicted individuals exhibit a normal resting quantal size and quantal content. The fatigue in humans results from a pronounced long-lasting drop in quantal size with little or no change in quantal content. These differences have important implications for interpreting fatigue as well as on understanding the impact of ACh availability on vesicle filling and recycling.

[The Expression of ERCC1, DNA-PKcs Protein and the Relation to Prognosis in Non-small Cell Lung Cancer.]

Zhongguo Fei Ai Za Zhi = Chinese Journal of Lung Cancer. Apr, 2008  |  Pubmed ID: 20731906

The results of many studies have proven that excision repair crosscomplementation group 1 (ERCC1) and DNA-dependent protein kinase catalytic subunit(DNA-PKcs),as the key genes in the repairment of DNA damage, are related to carcinogenesis and tumor progression. The aim of this study is to investigate the expression and clinical significance of ERCC1 and DNA-PKcs in patients with NSCLC,and analyze the relationship between their expression and the prognosis.

[Anatomic Study of the Facial Artery Using Multislice Spiral CT Angiography]

Nan Fang Yi Ke Da Xue Xue Bao = Journal of Southern Medical University. Mar, 2008  |  Pubmed ID: 18359713

To study the anatomy of the facial artery using 16-slice spiral CT angiography (CTA).

Effect of Dietary Chromium Picolinate on Growth Performance and Blood Parameters in Grass Carp Fingerling, Ctenopharyngodon Idellus

Fish Physiology and Biochemistry. Sep, 2010  |  Pubmed ID: 19459058

An experiment was conducted to investigate the effect of dietary chromium picolinate supplement on growth and haematology parameters of grass carp, Ctenopharyngodon idellus. Six diets with increasing dietary chromium picolinate levels 0, 0.2, 0.4, 0.8, 1.6 and 3.2 mg kg(-1) were fed to triplicate groups of 20 fish (initial weight of 12.78 +/- 1.16 g, mean +/- SD) in a flow water system for 10 weeks. Fish fed the diet supplemented with 0.8 mg Cr kg(-1) had significantly improved weight gain (WG), feed efficiency ratio (FER), protein efficiency ratio (PER) and protein retention (PR). Fish fed high-chromium diets exhibited lower whole-body crude lipid contents than fish fed low-chromium diets. Liver glycogen concentrations for fish fed the diet with 0.2 mg Cr kg(-1) was the highest (77.67 mg g(-1)). Fish fed the diet supplemented with 1.6 and 3.2 mg Cr kg(-1) had significantly lower liver glycogen concentrations than other groups (P < 0.05). The highest serum insulin concentrations were observed in fish fed the diet supplemented with 0.8 mg Cr kg(-1), but serum insulin concentrations decreased (P < 0.05) when dietary supplementation of chromium was higher than 0.8 mg Cr kg(-1). Cholesterol concentrations decreased in direct proportion to dietary chromium level and achieved the lowest level when the fish were fed the 0.8 mg Cr kg(-1) diet, but increased when the fish were fed the diet with more than 0.8 mg Cr kg(-1) (P < 0.05). Fish fed the diet supplemented with 0.8 mg Cr kg(-1) had higher triglyceride and high-density lipoprotein cholesterol (HDL-C) concentrations compared to other treatments. The results of the present study suggested that chromium picolinate could modify serum carbohydrate and lipid metabolism profile, and that the optimal dietary chromium level was 0.8 mg kg(-1) for grass carp according to growth.

Distinct Roles for Two Synaptotagmin Isoforms in Synchronous and Asynchronous Transmitter Release at Zebrafish Neuromuscular Junction

Proceedings of the National Academy of Sciences of the United States of America. Aug, 2010  |  Pubmed ID: 20643933

An obligatory role for the calcium sensor synaptotagmins in stimulus-coupled release of neurotransmitter is well established, but a role for synaptotagmin isoform involvement in asynchronous release remains conjecture. We show, at the zebrafish neuromuscular synapse, that two separate synaptotagmins underlie these processes. Specifically, knockdown of synaptotagmin 2 (syt2) reduces synchronous release, whereas knockdown of synaptotagmin 7 (syt7) reduces the asynchronous component of release. The zebrafish neuromuscular junction is unique in having a very small quantal content and a high release probability under conditions of either low-frequency stimulation or high-frequency augmentation. Through these features, we further determined that during the height of shared synchronous and asynchronous transmission these two modes compete for the same release sites.

[DCX and GFAP Time-course Expression in Dentate Gyrus of Hippocampus Following Kainic Acid-induced Seizures on C57/BL6 Mice]

Zhongguo Ying Yong Sheng Li Xue Za Zhi = Zhongguo Yingyong Shenglixue Zazhi = Chinese Journal of Applied Physiology. Feb, 2011  |  Pubmed ID: 21560329

The Role of OATP1B1 and BCRP in Pharmacokinetics and DDI of Novel Statins

Cardiovascular Therapeutics. May, 2011  |  Pubmed ID: 21884024

The aim of this review is to provide useful information not only for studying the effect of OATP1B1 and/or BCRP gene mutation on pharmacokinetics of novle statins of pitavastatin and rosuvastatin but also for studying drug-drug interactions (DDI) between the novle statins and other substrates of OATP1B1 and/or BCRP. Intra- and inter-ethnic differences in pharmacokinetic profiles of clinically relevant drugs are important issues reported in many papers not only for scenes of appropriate drug used in clinical settings but also for those of the drug development. Pharmacogenomics is extremely useful for understanding these racial differences. Recent pharmacogenetics study have disclosed important roles of drug transporters in the pharmacokinetic (PK) profiles of some clinically relevant drugs. In this presentation, we introduce single nucleotide polymorphisms (SNPs) of OATP1B1 and BCRP and review the contribution of genetic polymorphisms of the transporters to the pharmacokinetics of dual substrates as pitavastatin and rosuvastatin from recent study. At the same time, the DDIs between pitavastatin or rosuvastatin and other drug have been extensively concerned because of inhibiting OATP1B1-mediated hepatic uptake or BCRP-mediated hepatic efflux of pitavastatin and rosuvastatin. This review summarized the current studies about the role of OATP1B1 and BCRP in DDIs between pitavastatin or rosuvastatin and other clinically relevant drugs. The role of OATP1B1 and BCRP gene mutation can affect the PK profiles of pitavastatin and rosuvastatin. The DDIs between the novle statins and other substrates of OATP1B1 or BCRP may occur and cause change in the pharmacokinetic of the novle statins.

Connexin 39.9 Protein is Necessary for Coordinated Activation of Slow-twitch Muscle and Normal Behavior in Zebrafish

The Journal of Biological Chemistry. Jan, 2012  |  Pubmed ID: 22075003

In many tissues and organs, connexin proteins assemble between neighboring cells to form gap junctions. These gap junctions facilitate direct intercellular communication between adjoining cells, allowing for the transmission of both chemical and electrical signals. In rodents, gap junctions are found in differentiating myoblasts and are important for myogenesis. Although gap junctions were once believed to be absent from differentiated skeletal muscle in mammals, recent studies in teleosts revealed that differentiated muscle does express connexins and is electrically coupled, at least at the larval stage. These findings raised questions regarding the functional significance of gap junctions in differentiated muscle. Our analysis of gap junctions in muscle began with the isolation of a zebrafish motor mutant that displayed weak coiling at day 1 of development, a behavior known to be driven by slow-twitch muscle (slow muscle). We identified a missense mutation in the gene encoding Connexin 39.9. In situ hybridization found connexin 39.9 to be expressed by slow muscle. Paired muscle recordings uncovered that wild-type slow muscles are electrically coupled, whereas mutant slow muscles are not. The further examination of cellular activity revealed aberrant, arrhythmic touch-evoked Ca(2+) transients in mutant slow muscle and a reduction in the number of muscle fibers contracting in response to touch in mutants. These results indicate that Connexin 39.9 facilitates the spreading of neuronal inputs, which is irregular during motor development, beyond the muscle cells and that gap junctions play an essential role in the efficient recruitment of slow muscle fibers.