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1.
The rapidly activating delayed rectifier potassium current (IKr) plays a critical role in cardiac repolarization. Although IKr is known to be regulated by both α1- and β1-adrenergic receptors (ARs), the cross-talk and feedback mechanisms that dictate its response to α1- and β1-AR activation are not known. In the present study, IKr was recorded using the whole-cell patch-clamp technique. IKr amplitude was measured before and after the sequential application of selective adrenergic agonists targeting α1- and β1-ARs. Stimulation of either receptor alone (α1-ARs using 1 μM phenylephrine (PE) or β1-ARs using 10 μM xamoterol (Xamo)) reduced IKr by 0.22 ± 0.03 and 0.28 ± 0.01, respectively. The voltage-dependent activation curve of IKr shifted in the negative direction. The half-maximal activation voltage (V0.5) was altered by −6.35 ± 1.53 and −1.95 ± 2.22 mV, respectively, with no major change in the slope factor (k). When myocytes were pretreated with Xamo, PE-induced reduction in IKr was markedly blunted and the corresponding change in V0.5 was significantly altered. Similarly, when cells were pretreated with PE, Xamo-induced reduction of IKr was significantly attenuated. The present results demonstrate that functional cross-talk between α1- and β1-AR signaling regulates IKr. Such non-linear regulation may form a protective mechanism under excessive adrenergic stimulation.  相似文献   

2.
Chiral separations of five β-adrenergic antagonists (propranolol, esmolol, atenolol, metoprolol, and bisoprolol) were studied by capillary electrophoresis using six cyclodextrins (CDs) as the chiral selectors. Carboxymethylated-β-cyclodextrin (CM-β-CD) exhibited a higher enantioselectivity power compared to the other tested CDs. The influences of the concentration of CM-β-CD, buffer pH, buffer concentration, temperature, and applied voltage were investigated. The good chiral separation of five β-adrenergic antagonists was achieved using 50 mM Tris buffer at pH 4.0 containing 8 mM CM-β-CD with an applied voltage of 24 kV at 20 °C. In order to understand possible chiral recognition mechanisms of these racemates with CM-β-CD, host-guest binding procedures of CM-β-CD and these racemates were studied using the molecular docking software Autodock. The binding free energy was calculated using the Autodock semi-empirical binding free energy function. The results showed that the phenyl or naphthyl ring inserted in the hydrophobic cavity of CM-β-CD and the side chain was found to point out of the cyclodextrin rim. Hydrogen bonding between CM-β-CD and these racemates played an important role in the process of enantionseparation and a model of the hydrogen bonding interaction positions was constructed. The difference in hydrogen bonding formed with the -OH next to the chiral center of the analytes may help to increase chiral discrimination and gave rise to a bigger separation factor. In addition, the longer side chain in the hydrophobic phenyl ring of the enantiomer was not beneficial for enantioseparation and the chiral selectivity factor was found to correspond to the difference in binding free energy.  相似文献   

3.
Proteasome malfunction parallels abnormal amyloid accumulation in Alzheimer's Disease (AD). Here we scrutinize a small library of pyrazolones by assaying their ability to enhance proteasome activity and protect neuronal cells from amyloid toxicity. Tube tests evidenced that aminopyrine and nifenazone behave as 20S proteasome activators. Enzyme assays carried out on an “open gate” mutant (α3ΔN) proteasome demonstrated that aminopyrine activates proteasome through binding the α-ring surfaces and influencing gating dynamics. Docking studies coupled with STD-NMR experiments showed that H-bonds and π-π stacking interactions between pyrazolones and the enzyme play a key role in bridging α1 to α2 and, alternatively, α5 to α6 subunits of the outer α-ring. Aminopyrine and nifenazone exhibit neurotrophic properties and protect differentiated human neuroblastoma SH-SY5Y cells from β-amyloid (Aβ) toxicity. ESI-MS studies confirmed that aminopyrine enhances Aβ degradation by proteasome in a dose-dependent manner. Our results suggest that some pyrazolones and, in particular, aminopyrine are promising compounds for the development of proteasome activators for AD treatment.  相似文献   

4.
The molecular targets and the modes of action behind the cytotoxicity of two structurally established N,O- or N,N-hydrazone ruthenium(II)–arene complexes were explored in human breast adenocarcinoma cells (MCF-7) and paralleled in non-cancerous and cisplatin-resistant counterparts (MCF-10A and MCF-7CR respectively). Both complexes, [Ru(hmb)(L1)Cl] ( 1 , L1=4-((2-(2,4-dinitrophenyl)hydrazono)(phenyl)methyl)-3-methyl-1-phenyl-1H-pyrazol-5-olate) and [Ru(cym)(L2)Cl] ( 2 , L2=1-((3-methyl-5-oxo-1-phenyl-1H-pyrazol-4(5H)-ylidene)(phenyl)methyl)-2-(pyridin-2-yl)hydrazin-1-ide), reversibly interact with moderate-to-high affinity with a number of molecular targets in cell-free assays, namely serum albumin, DNA, the 20S proteasome and hydroxymethylglutaryl-CoA reductase. Most interestingly, only 2 readily crosses the cell membrane and preserves its binding/modulatory ability toward the targets of interest upon rapid cellular internalization. The resulting action at multiple levels of the cancer cascade is likely the cause for the selective sensitization of tumour cells to p27-mediated apoptotic death, and for the ability of 2 to overcome the drug resistance problem.  相似文献   

5.
Both α- and β-thalassaemia syndromes are public health problems in the multi-ethnic population of Malaysia. To molecularly characterise the α- and β-thalassaemia deletions and mutations among Malays from Penang, Gap-PCR and multiplexed amplification refractory mutation systems were used to study 13 α-thalassaemia determinants and 20 β-thalassaemia mutations in 28 and 40 unrelated Malays, respectively. Four α-thalassaemia deletions and mutations were demonstrated. −−SEA deletion and αCSα accounted for more than 70% of the α-thalassaemia alleles. Out of the 20 β-thalassaemia alleles studied, nine different β-thalassaemia mutations were identified of which βE accounted for more than 40%. We concluded that the highest prevalence of (α- and β-thalassaemia alleles in the Malays from Penang are −−SEA deletion and βE mutation, respectively.  相似文献   

6.
Currently, there is a lot of public interest in naturally occurring substances with medicinal properties that are minimally toxic, readily available and have an impact on health. Over the past decade, molecular hydrogen has gained the attention of both preclinical and clinical researchers. The death of pyramidal neurons in especially the CA1 area of the hippocampus, increased permeability of the blood-brain barrier, neuroinflammation, amyloid accumulation, tau protein dysfunction, brain atrophy, cognitive deficits and dementia are considered an integral part of the phenomena occurring during brain neurodegeneration after ischemia. This review focuses on assessing the current state of knowledge about the neuroprotective effects of molecular hydrogen following ischemic brain injury. Recent studies in animal models of focal or global cerebral ischemia and cerebral ischemia in humans suggest that hydrogen has pleiotropic neuroprotective properties. One potential mechanism explaining some of the general health benefits of using hydrogen is that it may prevent aging-related changes in cellular proteins such as amyloid and tau protein. We also present evidence that, following ischemia, hydrogen improves cognitive and neurological deficits and prevents or delays the onset of neurodegenerative changes in the brain. The available evidence suggests that molecular hydrogen has neuroprotective properties and may be a new therapeutic agent in the treatment of neurodegenerative diseases such as neurodegeneration following cerebral ischemia with progressive dementia. We also present the experimental and clinical evidence for the efficacy and safety of hydrogen use after cerebral ischemia. The therapeutic benefits of gas therapy open up new promising directions in breaking the translational barrier in the treatment of ischemic stroke.  相似文献   

7.
Six hull-less barley cultivars widely grown in China were roller-milled to produce bran, shorts and flour fractions. The distribution and molecular characteristics of β-glucans from the three roller-milled fractions were investigated. The β-glucan contents in the six hull-less barley cultivars varied from 4.96% to 7.62%. For all the six cultivars, the shorts fraction contained the highest concentration of β-glucan (8.12-13.01%), followed by bran (6.15-7.58%) and flour (2.48-2.95%). Crude β-glucans were prepared from the three roller-milled fractions using aqueous sodium carbonate (pH 10). These preparations contained 45.38-71.41% β-glucan, 10.81-17.26% arabinoxylan, 2.6-9.6% protein, 2.7-9.0% starch, and 5.23-9.68% ash. Purification using α-amylase and β-xylanase in combination with pH adjustment and dialysis produced high purity β-glucan preparations (91-95%). The molecular weight (Mw) of β-glucan preparations from roller-milled fractions ranged from 117,600 to 852,400 g/mol. β-Glucan from flour had higher Mw than those from shorts and bran within the same cultivar, and β-glucan preparations from bran had the lowest Mw.  相似文献   

8.
The ability of strontium ion to inhibit the abnormally high bone resorption, which occurs in pathologies characterized by loss of bone substance, has stimulated a number of research on strontium substituted/doped calcium phosphates. However, no information was available up to now on strontium substitution to calcium in the structure of α-CaHPO4, monetite, in spite of the involvement of this phosphate in the composition of biomaterials for hard tissue substitution/repair and although it is isomorphous with α-SrHPO4. Herein, we investigated the substitution of strontium to calcium in the structure of α-CaHPO4, as well as the replacement of calcium for strontium in the structure of a further polymorph of SrHPO4, namely β-SrHPO4. To this purpose, monetite at increasing degree of strontium substitution for calcium was synthesized by means of direct synthesis in aqueous solution, as well as through thermal treatment of strontium-substituted brushite; whereas the synthesis of β-SrHPO4 was carried out at low temperature. The results of structural refinements, spectroscopic analysis and electron microscopy investigation indicate that the method of synthesis has a great influence on the range of strontium incorporation into α-CaHPO4, which can reach 100 at%. The morphology of the synthesized materials is also remarkably dependent on composition. The analysis of the products synthesized at low temperature shows that the upper limit of possible substitution of calcium to strontium in the structure of β-SrHPO4 is much more limited, just up to about 20 at%. Moreover, powder X-ray analysis of β-SrHPO4 states that it crystallizes with a monoclinic cell in the space group P21/c.  相似文献   

9.
The α(1A)-adrenergic receptor (α(1A)-AR) antagonist is useful in treating benign prostatic hyperplasia, lower urinary tract symptoms, and cardiac arrhythmia. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed on a set of α(1A)-AR antagonists of N-aryl and N-nitrogen class. Statistically significant models constructed from comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were established based on a training set of 32 ligands using pharmacophore-based molecular alignment. The leave-oneout cross-validation correlation coefficients were q(2) (CoMFA) = 0.840 and q(2) (CoMSIA) = 0.840. The high correlation between the cross-validated/predicted and experimental activities of a test set of 12 ligands revealed that the CoMFA and CoMSIA models were robust (r(2) (pred) (/CoMFA) = 0.694; r(2) (pred) (/CoMSIA) = 0.671). The generated models suggested that electrostatic, hydrophobic, and hydrogen bonding interactions play important roles between ligands and receptors in the active site. Our study serves as a guide for further experimental investigations on the synthesis of new compounds. Structural modifications based on the present 3D-QSAR results may lead to the discovery of other α(1A)-AR antagonists.  相似文献   

10.
Amyloid β-protein(Aβ) and Tau, two common pathogenic proteins associated with Alzheimer’s disease(AD), cross-interact, and thus co-assemble into hybrid aggregates. However, molecular mechanism of the cross-interactions remains unclear. To explore the issue, docking and molecular dynamics(MD) simulations were coupled to study the cross-interactions between Aβ pentamer and Tau pentamer. Four stable hybrid decamer conformations including double layer, single layer, block, and part-in were obtained ...  相似文献   

11.
Fritsche K 《Lipids》2007,42(11):961-979
Omega-3 polyunsaturated fatty acids (n-3 PUFA) are noted for their ability to diminish inflammatory and immune responses in vitro and in a variety of animal-based models of autoimmunity and inflammation. Yet, recent systematic reviews suggest that the evidence for these fatty acids having beneficial effects on inflammation or autoimmunity in humans is equivocal. A possible explanation for these disappointing and somewhat paradoxical findings emerged from the analyses described in this review. The available data on the changes in immune cell fatty acid profiles in mice, rats and humans, fed various forms and amounts of n-3 PUFA are summarized and displayed graphically. The dose–response curves generated provide new insights into the relationship between dietary n-3 PUFA and immune cell fatty acid profiles. The author suggests that the poor predictive value of most in vitro as well as many animal trials may, in part, be a consequence of the frequent adoption of experimental conditions that create differences in immune cell fatty acid profiles that far exceed what is possible in free-living humans through dietary intervention. Recommendations for improving the preclinical value of future in vitro and animal-based studies with n-3 PUFA are provided.  相似文献   

12.
Over expression of proteins in E. coli frequently results in the production of inclusion bodies. Although β(2) -microglobulin frequently forms fibrillar structures, our studies reveal significant differences between the protein in fibrils and inclusion bodies. This suggests that the formation of fibrils in inclusion bodies is dependent on the propensity of the protein to form fibrillar structures.  相似文献   

13.
To evaluate the antioxidant and immune effects of low molecular yeast β-glucan on mice, three sulfated glucans from Saccharomyces cerevisiae (sGSCs) with different molecular weight (MW) and degrees of sulfation (DS) were prepared. The structures of the sGSCs were analyzed through high performance liquid chromatography-gel permeation chromatography (HPLC-GPC) and Fourier transform infrared spectroscopy (FTIR). sGSC1, sGSC2, and sGSC3 had MW of 12.9, 16.5 and 19.2 kDa, respectively, and DS of 0.16, 0.24 and 0.27, respectively. In vitro and in vivo experiments were conducted to evaluate the antioxidant and immunological activities of the sGSCs. In vitro experiment, the reactive oxygen species (ROS) scavenging activities were determined. In vivo experiment, 50 male BALB/c mice were divided into five groups. The sGSC1, sGSC2 and sGSC3 treatment groups received the corresponding sGSCs at 50 mg/kg/day each. The GSC (glucans from Saccharomyces cerevisiae) treatment group received 50 mg/kg/day GSC. The normal control group received equal volume of physiological saline solution. All treatments were administered intragastrically for 14 day. Results showed that sGSC1, sGSC2 and sGSC3 can scavenge 1,1-diphenyl-2-picryl-hydrazyl (DPPH), superoxide, and hydroxyl radicals in vitro. The strength of the radical scavenging effects of the sGSCs was in the order of sGSC1 > sGSC2 > sGSC3. Oral administration of sGSC1 significantly improved serum catalase (CAT) and glutathione peroxidase (GSH-Px) activities and decreased malondialdehyde (MDA) level in mice. sGSC1 significantly improved the spleen and thymus indexes and the lymphocyte proliferation, effectively enhanced the percentage of CD4+ T cells, decreased the percentage of CD8+ T cells, and elevated the CD4+/CD8+ ratio. sGSC1 significantly promoted the secretion of IL-2 and IFN-γ. These results indicate that sGSC1 with low MW and DS has better antioxidant and immunological activities than the other sGSCs, and sGSC1 could be used as a new antioxidant and immune-enhancing agent.  相似文献   

14.
The effects of dietary Cinnamomum camphora seed kernel oil (CCSKO) containing medium‐chain triacylglycerols on lipid metabolism and mRNA and protein expression of β‐3 adrenergic receptor in adipose tissue were studied in diet‐induced obese rats. High fat food‐induced obese rats were randomly divided into CCSKO group, Lard group, Soybean oil (SOY) group and naturally restoring group (n = 10). Rats fed with low fat food were used as a normal control group. Significant decreases in body mass and abdominal fat mass/body mass after 12 weeks were found in CCSKO group as compared with Lard and SOY groups (p < 0.05). Levels of blood total cholesterol (TC), triglyceride, free fatty acid, fasting insulin and insulin resistance in the CCSKO group were decreased significantly, and noradrenaline level and insulin sensitivity index in the CCSKO group were significantly higher than other groups. Meanwhile liver TC and triglyceride levels in the CCSKO group were also decreased markedly. Expression levels of β3‐adrenergic receptor mRNA and protein were higher in CCSKO group than in Lard and SOY groups. These results suggest that CCSKO may contribute to reduction of the body fat mass, promote lipid metabolism and up‐regulate β3‐adrenergic receptor expression in high fat diet‐induced obese rats.  相似文献   

15.
Enzyme inhibitors play a crucial role in diagnosis of a wide spectrum of diseases related to bacterial infections. We report here the effect of a water-soluble self-assembled PdII8 molecular cage towards β-galactosidase enzyme activity. The molecular cage is composed of a tetrapyridyl donor ( L ) and cis-[(en)Pd(NO3)2] (en=ethane-1,2-diamine) acceptor and it has a hydrophobic internal cavity. We have observed that the acceptor moiety mainly possesses the ability to inactivate the β-galactosidase enzyme activity. Kinetic investigation revealed the mixed mode of inhibition. This inhibition strategy was extended to control the growth of methicillin-resistant Staphylococcus aureus. The internalization of the Pd(II) cage inside the bacteria was confirmed when bacterial solutions were incubated with curcumin loaded cage. The intrinsic green fluorescence of curcumin made the bacteria glow when put under an optical microscope. Furthermore, this curcumin loaded molecular cage shows an enhanced antibacterial activity. Thus, PdII8 molecular cage is quite attractive due to its dual role as enzyme inhibitor and drug carrier.  相似文献   

16.
The structure–activity relationship between the molecular structure of Gemini surfactants and foam properties has not yet been deeply revealed. In this study, we clarified for the first time the structure–activity relationship between foam properties and molecular structure of Gemini surfactant by discussing the variation characteristics of parameters such as free energy of interface formation, radial distribution function, and mean square displacement calculated by molecular simulation method. The research results show that (1) the Gemini surfactant with the sulfonic acid head group has the most excellent foam properties; (2) the foam properties increase monotonously with the increase of the hydrophobic tail chain length; (3) the foam properties decrease monotonously with the increase of the spacer group length. It is hoped that this article can further broaden the application range of surfactants as foaming agents in industrial fields such as oil and gas exploitation.  相似文献   

17.
pH-responsive amphiphilic H-shaped copolymer was prepared by the supramolecular self-assembly between β-cyclodextrin-graft-poly(2-(N,N-diethylamino)ethyl methacrylate) (β-CD-(PDEAEMA)2) and bi-adamantyl terminated poly(ε-caprolactone) (Ad-PCL-Ad). β-CD-(PDEAEMA)2 was synthesized by click reaction of alkynyl-modified β-CD with azide PDEAEMA (PDEAEMA-N3). Ad-PCL-Ad was synthesized by the DCC reaction of bi-hydroxyl terminated PCL (HO-PCL-OH) with adamantaneacetic acid. The supramolecular copolymer can self-assemble into micelles in water at room temperature. The micellization and pH-responsivity of the amphiphilic copolymer solution were investigated by transmittance, dynamic light scattering spectrophotometer, and transmission electron microscopy in water. Investigation shows that the micelles’ sizes can be adjusted through the alteration of the pH values of solutions and the supramolecular copolymer will have the potential applications in biomedical field.  相似文献   

18.
Chitosan ultrathin films have been formed on polycrystalline Au substrates using the LbL technique with the purpose of studying its interaction with bovine β-lactoglobulin (β-LG) at the solid-liquid interface. The immobilization of chitosan was followed by Quartz Crystal Microbalance with energy dissipation (QCM-D), Cyclic Voltammetry (CV) and Electrochemical Impedance Spectroscopy (EIS). The behavior of the chitosan films in the presence of β-LG solutions with different bulk concentrations ([β-LG]), ionic strength (I), and pH has been investigated using the same techniques plus Atomic Force Microscopy (AFM). The results showed that for pHs lower than protein's pI, weak intermolecular forces (H bonding, Van der Waals, hydrophobic, etc.) are established between β-LG and chitosan (especially close to the pI) leading to low coverage nonspecific adsorption. On the contrary when pH > pI, strong ionic bonding through attractive electrostatic interactions lead to high coverage adsorbed phases composed of large β-LG aggregates. The adsorption process was shown to consist of a relatively fast step (in which these interactions are predominant) which is followed, once the β-LG monolayer is exceeded, by the slow formation of thicker and increasingly viscoelastic films through β-LG self-aggregation. QCM-D and AFM experiments unveiled the role of [β-LG] and I on the formation of these aggregates. The adsorption isotherm built from impedance data in the medium-low [β-LG] range (0.001-0.3 mg mL−1), showed good fitting to the Langmuir model confirming that the formation of one β-LG monolayer is achieved in this concentration range.  相似文献   

19.
Human pluripotent stem cells, including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), hold promise as novel therapeutic tools for diabetes treatment because of their self-renewal capacity and ability to differentiate into beta (β)-cells. Small and large molecules play important roles in each stage of β-cell differentiation from both hESCs and hiPSCs. The small and large molecules that are described in this review have significantly advanced efforts to cure diabetic disease. Lately, effective protocols have been implemented to induce hESCs and human mesenchymal stem cells (hMSCs) to differentiate into functional β-cells. Several small molecules, proteins, and growth factors promote pancreatic differentiation from hESCs and hMSCs. These small molecules (e.g., cyclopamine, wortmannin, retinoic acid, and sodium butyrate) and large molecules (e.g. activin A, betacellulin, bone morphogentic protein (BMP4), epidermal growth factor (EGF), fibroblast growth factor (FGF), keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), noggin, transforming growth factor (TGF-α), and WNT3A) are thought to contribute from the initial stages of definitive endoderm formation to the final stages of maturation of functional endocrine cells. We discuss the importance of such small and large molecules in uniquely optimized protocols of β-cell differentiation from stem cells. A global understanding of various small and large molecules and their functions will help to establish an efficient protocol for β-cell differentiation.  相似文献   

20.
Mesenchymal stem cells, also called medicinal signaling cells (MSC), have been studied regarding their potential to facilitate tissue repair for >30 years. Such cells, derived from multiple tissues and species, are capable of differentiation to a number of lineages (chondrocytes, adipocytes, bone cells). However, MSC are believed to be quite heterogeneous with regard to several characteristics, and the large number of studies performed thus far have met with limited or restricted success. Thus, there is more to understand about these cells, including the molecular recognition systems that are used by these cells to perform their functions, to enhance the realization of their potential to effect tissue repair. This perspective article reviews what is known regarding the recognition systems available to MSC, the possible systems that could be looked for, and alternatives to enhance their localization to specific injury sites and increase their subsequent facilitation of tissue repair. MSC are reported to express recognition molecules of the integrin family. However, there are a number of other recognition molecules that also could be involved such as lectins, inducible lectins, or even a MSC-specific family of molecules unique to these cells. Finally, it may be possible to engineer expression of recognition molecules on the surface of MSC to enhance their function in vivo artificially. Thus, improved understanding of recognition molecules on MSC could further their success in fostering tissue repair.  相似文献   

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