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Molecular basis for the toxin insensitivity of scorpion voltage-gated potassium channel MmKv1. - The Biochemical journal
Scorpions are insensitive to own venoms, which contain various neurotoxins specific for mammalian or insect ion channels, whose molecular mechanism remains unsolved. Using MmKv1 potassium channel identified from the genome of scorpion Mesobuthus martensii, the channel kinetic experiments showed that MmKv1 was a classical voltage-gated potassium channel with a voltage-dependent fast activation and slow inactivation. Compared with human Kv1.3 channel (hKv1.3), MmKv1 channel exhibited a remarkable insensitivity to both scorpion venom and toxin. The chimeric channels of MmKv1 and hKv1.3 revealed that both turret and filter regions of MmKv1 channel were critical for the toxin insensitivity of MmKv1. Furthermore, mutagenesis of the chimeric channel indicated that two basic residues (Arg399 and Lys403) in the MmKv1 turret region and Arg425 in the MmKv1 filter region significantly affected its toxin insensitivity. Moreover, when these three basic residues of MmKv1 were simultaneously substituted with the corresponding residues from hKv1.3, the mutated MmKv1-R399T/K403S/R425H channel exhibited similar sensitivity to both scorpion venom and toxin as hKv1.3, which revealed the determining role of these three basic residues in the toxin insensitivity of MmKv1 channel. More strikingly, a similar triad sequence structure is present in all Shaker-like channels from venomous invertebrates, which suggested a possible convergent functional evolution of these channels to enable them to resist their own venoms. Together, these findings first illustrated the mechanism by which scorpions are insensitive to own venoms at the ion channel receptor level and enriched our knowledge of the insensitivity of scorpions and other venomous animals to their own venoms.Copyright 2016 The Author(s).
Sigma receptor-mediated targeted delivery of anti-angiogenic multifunctional nanodrugs for combination tumor therapy. - Journal of controlled release : official journal of the Controlled Release Society
The potential of low molecular weight heparin (LMWH) in anti-angiogenic therapy has been tempered by poor in vivo delivery to the tumor cell and potentially harmful side effects, such as the risk of bleeding due to heparin's anticoagulant activity. In order to overcome these limitations and further improve the therapeutic effect of LMWH, we designed a novel combination nanosystem of LMWH and ursolic acid (UA), which is also an angiogenesis inhibitor for tumor therapy. In this system, an amphiphilic LMWH-UA (LHU) conjugate was synthesized and self-assembled into core/shell nanodrugs with combined anti-angiogenic activity and significantly reduced anticoagulant activity. Furthermore, DSPE-PEG-AA-modified LHU nanodrugs (A-LHU) were developed to facilitate the delivery of nanodrugs to the tumor. The anti-angiogenic activity of A-LHU was investigated both in vitro and in vivo. It was found that A-LHU significantly inhibited the tubular formation of human umbilical vein endothelial cells (HUVECs) (p<0.01) and the angiogenesis induced by basic fibroblast growth factor (bFGF) in a Matrigel plug assay (p<0.001). More importantly, A-LHU displayed significant inhibition on the tumor growth in B16F10-bearing mice in vivo. The level of CD31 and p-VEGFR-2 expression has demonstrated that the excellent efficacy of antitumor was associated with a decrease in angiogenesis. In conclusion, A-LHU nanodrugs are a promising multifunctional antitumor drug delivery system.Copyright Â© 2015. Published by Elsevier B.V.
Selective potentiation of 2-APB-induced activation of TRPV1-3 channels by acid. - Scientific reports
Temperature-sensitive TRP channels are important for responses to pain and inflammation, to both of which tissue acidosis is a major contributing factor. However, except for TRPV1, acid-sensing by other ThermoTRP channels remains mysterious. We show here that unique among TRPV1-3 channels, TRPV3 is directly activated by protons from cytoplasmic side. This effect is very weak and involves key cytoplasmic residues L508, D512, S518, or A520. However, mutations of these residues did not affect a strong proton induced potentiation of TRPV3 currents elicited by the TRPV1-3 common agonist, 2-aminoethoxydiphenyl borate (2-APB), no matter if the ligand was applied from extracellular or cytoplasmic side. The acid potentiation was common among TRPV1-3 and only seen with 2-APB-related ligands. Using (1)H-nuclear magnetic resonance to examine the solution structures of 2-APB and its analogs, we observed striking structural differences of the boron-containing compounds at neutral/basic as compared to acidic pH, suggesting that a pH-dependent configuration switch of 2-APB-based drugs may underlie their functionality. Supporting this notion, protons also enhanced the inhibitory action of 2-APB on TRPM8. Collectively, our findings reveal novel insights into 2-APB action on TRP channels, which should facilitate the design of new drugs for these channels.
Comparison of the influence on renal function between cefepime and cefpirome. - Biomedical reports
Although known for their broad spectrum and curative efficacy on drug-resistant pathogens and as nephrotoxicity-free, impairments were observed on renal function during clinical treatment of the two most commonly used fourth-generation cephalosporins: Cefpirome and cefepime. The present study aimed to further explore the exact influences of them on renal function. In vitro, the cell viability of renal cells cultured in drug-combined medium was tested for six dilutions. In vivo, a clinical cohort study was carried out to detect the influence of cefpirome and cefepime on the serum creatinine (SCr) level of patients. Cefpirome had an inhibition rate with half maximal inhibitory concentration (IC50) of 143.5 Âµmol/l on renal mesangial cells, which was greater compared to the IC50 of 7.702 Âµmol/l for cefepime. The clinical cohort study data revealed that cefpirome treatment could lead to a greater increase of the average SCr level compared to cefepime on days 3 and 7 during therapy, and in addition, a greater incidence of SCr >445 Âµmol/l, an indicator of clinical renal failure. Furthermore, patients with an average age >65 years were observed as more susceptible to an SCr rise caused by either cefpirome or cefepime, with a larger augment in the average SCr, as well as a higher incidence of SCr >445 Âµmol/l compared to patients aged <65 years. In conclusion, cefpirome may have more potential to cause renal impairment compared to cefepime, therefore, more caution and comprehensive analysis of patient conditions is required during the clinical choice of fourth-generation cephalosporins.
One-step generation of triple gene-targeted pigs using CRISPR/Cas9 system. - Scientific reports
Pig shows multiple superior characteristics in anatomy, physiology, and genome that have made this species to be more suitable models for human diseases, especially for neurodegenerative diseases, because they have similar cerebral convolutions compared with human neocortex. Recently, CRISPR/Cas9 system shows enormous potential for engineering the pig genome. In this study, we expect to generate human Parkinson's disease pig model using CRISPR/Cas9 system by simultaneously targeting three distinct genomic loci, parkin/DJ-1/PINK1, in Bama miniature pigs. By co-injection of Cas9 mRNA and multiplexing single guide RNAs (sgRNAs) targeting parkin, DJ-1, and PINK1 genes, respectively, into in vivo derived pronuclear embryos, we simultaneously targeted three distinct genomic loci. The gene modified piglets remain healthy and display normal behavior at the age of 10 months. In addition, despite the high number of sgRNAs were employed in the present study, our trio-based whole-genome sequencing analysis suggested that the incidence of off-target events is low. Our results demonstrate that the simplicity, efficiency, and power of the CRISPR/Cas9 system to allow for the modification of multiple genes in pigs and yield results of high medical value.
Increasing prevalence of membranous nephropathy in patients with primary glomerular diseases: a cross-sectional study in china. - Nephrology (Carlton, Vic.)
Primary glomerular diseases (PGD) remain the most common renal disease in China. A limited number of single center studies show that the frequency of membranous nephropathy (MN) has increased; however, IgA nephropathy (IgAN) is still the most common PGD. To the best of our knowledge, there has been no multi-centre study in China that has explored the changes in PGD spectrum. To further investigate the changes in renal histopathological spectrum, we performed the cross-sectional study.From June 2010 to May 2015, 5935 patients from 37 hospitals in Shandong Province were involved in this retrospective study. The study was divided into 5 periods according to 1-year intervals. The patients were divided into 4 age groups (â‰¤18 years, 19-44 years, 45-59 years and â‰¥60 years).Among the 5935 qualified specimens, 4855 (81.8%) were diagnosed with PGD. MN (43.3%) became the most common PGD instead of IgA (34.1%) (P<0.001). The frequency of MN was increased from 30.7% in period 1 to 53.5% in period 5 (P<0.001). The prevalence of MN tended to increase in every age section. IgA was the main cause of PGD in periods 1 and 2; however, its proportion decreased significantly from 41.8% in period 2 to 25.2% in period 5 (p<0.001).PGD remains the most common renal disease in our study. For the first time, this cross-sectional study suggests that MN, in place of IgAN, has grown to be the first leading pathological type of PGD. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.
Knockdown of NADPH-cytochrome P450 reductase results in reduced resistance to buprofezin in the small brown planthopper, Laodelphax striatellus (fallÃ©n). - Pesticide biochemistry and physiology
NADPH-cytochrome P450 reductase (CPR) plays an important role in cytochrome P450 function, and CPR knockdown in several insects leads to increased susceptibility to insecticides. However, a putative CPR gene has not yet been fully characterized in the small brown planthopper Laodelphax striatellus, a notorious agricultural pest in rice that causes serious damage by transmitting rice stripe and rice black-streaked dwarf viruses. The objective of this study was to clone the cDNA and to knock down the expression of the gene that encodes L. striatellus CPR (LsCPR) to further determine whether P450s are involved in the resistance of L. striatellus to buprofezin. First, the full-length cDNA of LsCPR was cloned and found to contain an open reading frame (ORF) encoding a polypeptide of 679 amino acids with a calculated molecular mass and isoelectric point of 76.92kDa and 5.37, respectively. The deduced amino acid sequence shares high identity with the CPRs of other insects (98%, 97%, 75% and 68% for Sogatella furcifera, Nilaparvata lugens, Cimex lectularius and Anopheles gambiae, respectively) and possesses the characteristic features of classical CPRs, such as an N-terminal membrane anchor and conserved domains for flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide phosphate (NADPH) binding. Phylogenetic analysis revealed that LsCPR is located in a branch along with the CPRs of other hemipteran insects. LsCPR mRNA was detectable in all examined body parts and developmental stages of L. striatellus, as determined by real-time quantitative PCR (qPCR), and transcripts were most abundant in the adult abdomen and in first-instar nymphs and adults. Ingestion of 200Î¼g/mL of LsCPR double-stranded RNA (dsLsCPR) by the planthopper for 5days significantly reduced the transcription level of LsCPR. Moreover, silencing of LsCPR caused increased susceptibility to buprofezin in a buprofezin-resistant (YN-BPF) strain but not in a susceptible (YN) strain. These data further suggested that the P450-mediated metabolic detoxification of xenobiotics might be an important mechanism for buprofezin resistance in L. striatellus.Copyright Â© 2015 Elsevier B.V. All rights reserved.
The role of speckle tracking echocardiography in assessment of lipopolysaccharide-induced myocardial dysfunction in mice. - Journal of thoracic disease
Sepsis-induced myocardial dysfunction is a common and severe complication of septic shock. Conventional echocardiography often fails to reveal myocardial depression in severe sepsis due to hemodynamic changes; in contrast, decline of strain measurements by speckle tracking echocardiography (STE) may indicate impaired cardiac function. This study investigates the role of STE in detecting lipopolysaccharide (LPS)-induced cardiac dysfunction with mouse models.We evaluated cardiac function in 20 mice at baseline, 6 h (n=10) and 20 h (n=10) after LPS injection to monitor the development of heart failure induced by severe sepsis using 2-D and M-mode echocardiography. Ejection fraction (EF) and fractional shortening (FS) were measured with standard M-mode tracings, whereas circumferential and radial strain was derived from STE. Serum biochemical and cardiac histopathological examinations were performed to determine sepsis-induced myocardial injury.Left ventricular (LV) myocardial function was significantly reduced at 6 h after LPS treatment assessed by circumferential strain (-14.65%Â±3.00% to -8.48%Â±1.72%, P=0.006), whereas there were no significant differences between 6 and 20 h group. Conversely, EF and FS were significantly increased at 20 h when comparing to 6 h (P<0.05) accompanied with marked decreases in EF and FS 6 h following LPS administration. Consistent with strain echocardiographic results, we showed that LPS injection leaded to elevated serum level of cardiac Troponin-T (cTnT), CK-MB and rising leucocytes infiltration into myocardium within 20 h.Altogether, these results demonstrate that, circumferential strain by STE is a specific and reliable value for evaluating LPS-induced cardiac dysfunction in mice.
Chrysin alleviates allergic inflammation and airway remodeling in a murine model of chronic asthma. - International immunopharmacology
Asthma is a chronic airway inflammatory disorder and progresses mainly due to airway remodeling. Chrysin, a natural flavonoid, has been reported to possess multiple biologic activities, including anti-inflammation, anti-oxidation and anti-proliferation. The present study aimed to investigate whether chrysin could relieve allergic airway inflammation and remodeling in a murine model of chronic asthma and the mechanism involved. The female BALB/c mice sensitized and challenged with ovalbumin (OVA) successfully developed airway hyperresponsiveness (AHR), inflammation and remodeling. The experimental data showed that chrysin could alleviate OVA-induced AHR. Chrysin could also reduce OVA-induced increases in the number of inflammatory cells, especially eosinophils, interleukin (IL) -4, and IL-13 in bronchoalveolar lavage fluid (BALF) and total IgE in serum. The decreased interferon-Î³ (IFN-Î³) level in BALF was also upregulated by chrysin. In addition, inflammatory cell infiltration, goblet cell hyperplasia and the expression of Î±-smooth muscle actin (Î±-SMA) around bronchioles were suppressed by chrysin. Furthermore, the phosphorylation levels of Akt and extracellular signal-regulated kinase (ERK) could be decreased by chrysin, which are associated with airway smooth muscle cell (ASMC) proliferation. These results indicate the promising therapeutic effect of chrysin on chronic asthma, especially the progression of airway remodeling.Copyright Â© 2016 Elsevier B.V. All rights reserved.
The residue I257 at S4-S5 linker in KCNQ1 determines KCNQ1/KCNE1 channel sensitivity to 1-alkanols. - Acta pharmacologica Sinica
KCNQ1 and KCNE1 form a complex in human ventricular cardiomyocytes, which are important in maintaining a normal heart rhythm. In the present study we investigated the effects of a homologous series of 1-alkanols on KCNQ1/KCNE1 channels expressed in Xenopus oocytes.ECG recording was made in rats injected with ethanol-containing solution (0.3 mL, ip). Human KCNQ1 channel and its auxiliary subunit KCNE1 were heterologously coexpressed in Xenopus oocytes, which were superfused with ND96 solution; 1-alkanols (ethanol, 1-butanol and 1-hexanol) were delivered through a gravity-driven perfusion device. The slow-delayed rectifier potassium currents IKs (KCNQ1/KCNE1 currents) were recorded using a two-electrode voltage clamp method. Site-directed mutations (I257A) were made in KCNQ1.In ECG recordings, a low concentration of ethanol (3%, v/v) slightly increased the heart rate of rats, whereas the higher concentrations of ethanol (10%, 50%, v/v) markedly reduced it. In oocytes coexpressing KCNQ1/KCNE1 channels, ethanol, 1-butanol and 1-hexanol dose-dependently inhibited IKs currents with IC50 values of 80, 11 and 2.7 mmol/L, respectively. Furthermore, the 1-alkanols blocked the KCNQ1 channel in both open and closed states, and a four-state model could adequately explain the effects of 1-alkanols on the closed-state channel block. Moreover, the mutation of I257A at the intracellular loop between S4 and S5 in KCNQ1 greatly decreased the sensitivity to 1-alkanols; and the IC50 values of ethanol, 1-butanol and 1-hexanol were increased to 634, 414 and 7.4 mmol/L, respectively. The mutation also caused the ablation of closed-state channel block.These findings provide new insight into the intricate mechanisms of the blocking effects of ethanol on the KCNQ1 channel.
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629 D Lowther Road Lewisberry, PA 17339
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