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1.
2.

Background

Few drugs are available for soil-transmitted helminthiasis (STH); the benzimidazoles albendazole and mebendazole are the only drugs being used for preventive chemotherapy as they can be given in one single dose with no weight adjustment. While generally safe and effective in reducing intensity of infection, they are contra-indicated in first-trimester pregnancy and have suboptimal efficacy against Trichuris trichiura. In addition, drug resistance is a threat. It is therefore important to find alternatives.

Methodology

We searched the literature and the animal health marketed products and pipeline for potential drug development candidates. Recently registered veterinary products offer advantages in that they have undergone extensive and rigorous animal testing, thus reducing the risk, cost and time to approval for human trials. For selected compounds, we retrieved and summarised publicly available information (through US Freedom of Information (FoI) statements, European Public Assessment Reports (EPAR) and published literature). Concomitantly, we developed a target product profile (TPP) against which the products were compared.

Principal Findings

The paper summarizes the general findings including various classes of compounds, and more specific information on two veterinary anthelmintics (monepantel, emodepside) and nitazoxanide, an antiprotozoal drug, compiled from the EMA EPAR and FDA registration files.

Conclusions/Significance

Few of the compounds already approved for use in human or animal medicine qualify for development track decision. Fast-tracking to approval for human studies may be possible for veterinary compounds like emodepside and monepantel, but additional information remains to be acquired before an informed decision can be made.  相似文献   

3.
Hypothermia improves resistance to ischemia in the cardioplegia-arrested heart. This adaptive process produces changes in specific signaling pathways for mitochondrial proteins and heat-shock response. To further test for hypothermic modulation of other signaling pathways such as apoptosis, we used various molecular techniques, including cDNA arrays. Isolated rabbit hearts were perfused and exposed to ischemic cardioplegic arrest for 2 h at 34 degrees C [ischemic group (I); n = 13] or at 30 degrees C before and during ischemia [hypothermic group (H); n = 12]. Developed pressure, the maximum first derivative of left ventricular pressure, oxygen consumption, and pressure-rate product (P < 0.05) recovery were superior in H compared with in I during reperfusion. mRNA expression for the mitochondrial proteins, adenine translocase and the beta-subunit of F1-ATPase, was preserved by hypothermia. cDNA arrays revealed that ischemia altered expression of 13 genes. Hypothermia modified this response to ischemia for eight genes, six related to apoptosis. A marked, near fivefold increase in transformation-related protein 53 in I was virtually abrogated in H. Hypothermia also increased expression for the anti-apoptotic Bcl-2 homologue Bcl-x relative to I but decreased expression for the proapoptotic Bcl-2 homologue bak. These data imply that hypothermia modifies signaling pathways for apoptosis and suggest possible mechanisms for hypothermia-induced myocardial protection.  相似文献   

4.
Amplification, deletion, and loss of heterozygosity of genomic DNA are hallmarks of cancer. In recent years a variety of studies have emerged measuring total chromosomal copy number at increasingly high resolution. Similarly, loss-of-heterozygosity events have been finely mapped using high-throughput genotyping technologies. We have developed a probe-level allele-specific quantitation procedure that extracts both copy number and allelotype information from single nucleotide polymorphism (SNP) array data to arrive at allele-specific copy number across the genome. Our approach applies an expectation-maximization algorithm to a model derived from a novel classification of SNP array probes. This method is the first to our knowledge that is able to (a) determine the generalized genotype of aberrant samples at each SNP site (e.g., CCCCT at an amplified site), and (b) infer the copy number of each parental chromosome across the genome. With this method, we are able to determine not just where amplifications and deletions occur, but also the haplotype of the region being amplified or deleted. The merit of our model and general approach is demonstrated by very precise genotyping of normal samples, and our allele-specific copy number inferences are validated using PCR experiments. Applying our method to a collection of lung cancer samples, we are able to conclude that amplification is essentially monoallelic, as would be expected under the mechanisms currently believed responsible for gene amplification. This suggests that a specific parental chromosome may be targeted for amplification, whether because of germ line or somatic variation. An R software package containing the methods described in this paper is freely available at http://genome.dfci.harvard.edu/~tlaframb/PLASQ.  相似文献   

5.
Anxiety is a normal reaction to threatening situations, and serves a physiological protective function. Pathological anxiety is characterized by a bias to interpret ambiguous situations as threatening, by avoidance of situations that are perceived to be harmful, and/or by exaggerated reactions to threat. Although much evidence indicates the involvement of the gamma-aminobutyric acid, serotonin, norepinephrine, dopamine, and neuropeptide transmitter systems in the pathophysiology of anxiety, little is known about how anxiety develops and what genetic/environmental factors underlie susceptibility to anxiety. Recently, inactivation of several genes, associated with either chemical communication between neurons or signaling within neurons, has been shown to give rise to anxiety-related behavior in knockout mice. Apart from confirming the involvement of serotonin, gamma-aminobutyric acid, and corticotrophin-releasing hormone as major mediators of anxiety and stress related behaviors, two novel groups of anxiety-relevant molecules have been revealed. The first group consists of neurotrophic-type molecules, such as interferon gamma, neural cell adhesion molecule, and midkine, which play important roles in neuronal development and cell-to-cell communication. The second group comprises regulators of intracellular signaling and gene expression, which emphasizes the importance of gene regulation in anxiety-related behaviors. Defects in these molecules are likely to contribute to the abnormal development and/or function of neuronal networks, which leads to the manifestation of anxiety disorders.  相似文献   

6.
A variety of experimental evidence suggests that rapid, long-range propagation of conformational changes through the core of proteins plays a vital role in allosteric communication. Here, we describe a non-equilibrium molecular dynamics simulation method, anisotropic thermal diffusion (ATD), which allowed us to observe a dominant intramolecular signaling pathway in PSD-95, a member of the PDZ domain protein family. The observed pathway is in good accordance with a pathway previously inferred using a multiple sequence analysis of 276 PDZ domain proteins. In comparison with conventional solution molecular dynamics methods, the ATD method provides greatly enhanced signal-to-noise, allowing long-distance correlations to be observed clearly. The ATD method requires neither a large number of homologous proteins, nor extremely long simulation times to obtain a complete signaling pathway within a protein. Therefore, the ATD method should prove to be a powerful and general complement to experimental efforts to understand the physical basis of intramolecular signaling.  相似文献   

7.
Pharmacokinetic studies play an important role in all stages of drug discovery and development. Recent advancements in the tools for discovery and optimization of therapeutic proteins have created an abundance of candidates that may fulfill target product profile criteria. Implementing a set of in silico, small scale in vitro and in vivo tools can help to identify a clinical lead molecule with promising properties at the early stages of drug discovery, thus reducing the labor and cost in advancing multiple candidates toward clinical development. In this review, we describe tools that should be considered during drug discovery, and discuss approaches that could be included in the pharmacokinetic screening part of the lead candidate generation process to de-risk unexpected pharmacokinetic behaviors of Fc-based therapeutic proteins, with an emphasis on monoclonal antibodies.  相似文献   

8.
以抗体阻断血管生成信号来治疗实体肿瘤显示了很好的前景,但鼠源抗体首先必须经人源化改造以降低其免疫原性才能应用于人体。本研究以同源模建预测了一体人血管内皮生长因子(VEGF)特异性鼠源单链抗体E11的三维结构,以结构数据为基础并采取单个最相似框架区替代法对其进行人源化设计;合成并组装了人源化单链抗体基因并在大肠杆菌中表达,包含体形式的产物以凝胶柱色谱法复性,经ELISA检测表明,人源化后的单链抗体保持了与天然VEGF结合的活性,表明采取的人源化路线具有可行性。  相似文献   

9.
Vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS) play critical roles in vascular physiology and pathophysiology. We have demonstrated previously that NADPH oxidase-derived ROS are required for VEGF-mediated migration and proliferation of endothelial cells. The goal of this study was to determine the extent to which VEGF signaling is coupled to NADPH oxidase activity. Human umbilical vein endothelial cells and/or human coronary artery endothelial cells were transfected with short interfering RNA against the p47(phox) subunit of NADPH oxidase, treated in the absence or presence of VEGF, and assayed for signaling, gene expression, and function. We show that NADPH oxidase activity is required for VEGF activation of phosphoinositide 3-kinase-Akt-forkhead, and p38 MAPK, but not ERK1/2 or JNK. The permissive role of NADPH oxidase on phosphoinositide 3-kinase-Akt-forkhead signaling is mediated at post-VEGF receptor levels and involves the nonreceptor tyrosine kinase Src. DNA microarrays revealed the existence of two distinct classes of VEGF-responsive genes, one that is ROS-dependent and another that is independent of ROS levels. VEGF-induced, thrombomodulin-dependent activation of protein C was dependent on NADPH oxidase activity, whereas VEGF-induced decay-accelerating factor-mediated protection of endothelial cells against complement-mediated lysis was not. Taken together, these findings suggest that NADPH oxidase-derived ROS selectively modulate some but not all the effects of VEGF on endothelial cell phenotypes.  相似文献   

10.
The unique contributions of connexin (Cx)37 and Cx40, gap junction-forming proteins that are coexpressed in vascular endothelium, to the recovery of tissues from ischemic injury are unknown. We recently reported that Cx37-deficient (Cx37(-/-)) animals recovered ischemic hindlimb function more quickly and to a greater extent than wild-type (WT) or Cx40(-/-) animals, suggesting that Cx37 limits recovery in the WT animal. Here, we tested the hypothesis that enhanced angiogenesis, arteriogenesis, and vasculogenesis contribute to improved postischemic hindlimb recovery in Cx37(-/-) animals. Ischemia was induced unilaterally in the hindlimbs of WT or Cx37(-/-) mice (isoflurane anesthesia). Postsurgical limb appearance, use, and perfusion were documented during recovery, and the number (and size) of large and small vessels was determined. Native collateral number, predominantly established during embryonic development (vasculogenesis), was also determined in the pial circulation. Both microvascular density in the gastrocnemius of the ischemic limb (an angiogenic field) and the number and tortuosity of larger vessels in the gracilis vasculature (an arteriogenic field) were increased in Cx37(-/-) animals compared with WT animals. Cx37(-/-) mice also had an increased (vs. WT) number of collateral vessels in the pial circulation. These findings suggest that in Cx37(-/-) animals, improved recovery of the ischemic hindlimb involves enhanced vasculogenesis, resulting in increased numbers of collaterals in the hindlimb (and pial circulations) and more extensive collateral remodeling and angiogenesis. These results are consistent with Cx37 exerting a growth-suppressive effect in the vasculature that limits embryonic vasculogenesis as well as arteriogenic and angiogenic responses to ischemic injury in the adult animal.  相似文献   

11.
Oral squamous cellular carcinoma is a malignant tumor with poor prognosis. Discovery of early markers to discriminate between malignant and normal cells is of high importance in clinical diagnosis. Subcellular fractions from 10 oral squamous cell carcinoma and corresponding control samples, enriched in mitochondrial and cytosolic proteins, as well as blood from the tumor were analyzed by proteomics, two-dimensional gel electrophoresis, followed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Three-hundred and fifty different gene products were identified. Twenty proteins showed deranged levels in oral squamous cell carcinoma in comparison with the control samples and are potentially involved in tumor growth and metastasis. Of these, 16 proteins were upregulated. By applying pathway analysis, we found 8 of the upregulated gene products to be linked to three main locus genes, p53, MYC, and MYCN, and could be candidate biomarkers for OSCC. The findings of this pilot study show that OSCC gene ontology combined with proteomic analysis is a powerful tool in systems biology for the elucidation of the complexity of expression profiles in cellular processes. Application of such pathway analysis has the potential to generate new insights into complex molecular mechanisms underlying disease related processes and could therefore significantly contribute to the efficient performance of the entire discovery process.  相似文献   

12.
A recent study of experimental results for flavodoxin-like folds suggests that proteins from this family may exhibit a similar, signature pattern of folding intermediates. We study the folding landscapes of three proteins from the flavodoxin family (CheY, apoflavodoxin, and cutinase) using a simple nucleation and growth model that accurately describes both experimental and simulation results for the transition state structure, and the structure of on-pathway and misfolded intermediates for CheY. Although the landscape features of these proteins agree in basic ways with the results of the study, the simulations exhibit a range of folding behaviours consistent with two alternate folding routes corresponding to nucleation and growth from either side of the central beta-strand.  相似文献   

13.
An antigen from meconium was revealed by monoclonal antibody D 12 (IgM). This antigen was heat liable substance with relative m. m. about 400-600 kD. Reactions on histological slides with MAb D 12 were blocked up after processing tissues by neuraminidase and become stronger after processing tissues by NaIO4. Antigen D 12 was found in goblet cells of fetal and definitive colon and in analogous cells of trachea and bronchi.  相似文献   

14.
Inosine monophosphate dehydrogenase (IMPDH) catalyzes an essential step in the biosynthesis of guanine nucleotides. This reaction involves two different chemical transformations, an NAD-linked redox reaction and a hydrolase reaction, that utilize mutually exclusive protein conformations with distinct catalytic residues. How did Nature construct such a complicated catalyst? Here we employ a “Wang-Landau” metadynamics algorithm in hybrid quantum mechanical/molecular mechanical (QM/MM) simulations to investigate the mechanism of the hydrolase reaction. These simulations show that the lowest energy pathway utilizes Arg418 as the base that activates water, in remarkable agreement with previous experiments. Surprisingly, the simulations also reveal a second pathway for water activation involving a proton relay from Thr321 to Glu431. The energy barrier for the Thr321 pathway is similar to the barrier observed experimentally when Arg418 is removed by mutation. The Thr321 pathway dominates at low pH when Arg418 is protonated, which predicts that the substitution of Glu431 with Gln will shift the pH-rate profile to the right. This prediction is confirmed in subsequent experiments. Phylogenetic analysis suggests that the Thr321 pathway was present in the ancestral enzyme, but was lost when the eukaryotic lineage diverged. We propose that the primordial IMPDH utilized the Thr321 pathway exclusively, and that this mechanism became obsolete when the more sophisticated catalytic machinery of the Arg418 pathway was installed. Thus, our simulations provide an unanticipated window into the evolution of a complex enzyme.  相似文献   

15.
Monoclonal antibodies and derived fragments are used extensively both experimentally and therapeutically. Thorough characterization of such antibodies is necessary and includes assessment of their thermal and storage stabilities. Thus, assessment of the underlying conformational stabilities of the antibodies is also important. We recently documented that non-reducing SDS-PAGE can be used to assess both monoclonal and polyclonal IgG domain thermal unfolding in SDS. Utilizing this same h2E2 anti-cocaine mAb, in this study we generated and analyzed various mAb antibody fragments to delineate the structural domains of the antibody responsible for the observed discrete bands following various heating protocols and analysis by non-reducing SDS-PAGE. Previously, these domain unfolding transitions and gel bands were hypothesized to stem from known mAb structural domains based on the relative thermal stability of those CH2, CH3, and Fab domains in the absence of SDS, as measured by differential scanning calorimetry. In this study, we generated and analyzed F(ab’)2, Fab, and Fc fragments, as well as a mAb consisting of only heavy chains, and examined the thermally induced domain unfolding in each of these fragments by non-reducing SDS-PAGE. The results were interpreted and integrated to generate an improved model of thermal unfolding for the mAb IgG in SDS. These results and the model presented should be generally applicable to many monoclonal and polyclonal antibodies and allow novel comparisons of conformational stabilities between chemically or genetically modified versions of a given antibody. Such modified antibodies and antibody drug conjugates are commonly utilized and important for experimental and therapeutic applications.  相似文献   

16.
In this study we have investigated the molecular mechanisms of insulin and insulin-like growth factor-I (IGF-I) action on vascular endothelial growth factor (VEGF) gene expression. Treatment with insulin or IGF-I for 4 h increased the abundance of VEGF mRNA in NIH3T3 fibroblasts expressing either the human insulin receptor (NIH-IR) or the human IGF-I receptor (NIH-IGFR) by 6- and 8-fold, respectively. The same elevated levels of mRNA were maintained after 24 h of stimulation with insulin, whereas IGF-I treatment further increased VEGF mRNA expression to 12-fold after 24 h. Pre-incubation with the phosphatidylinositol 3-kinase inhibitor wortmannin abolished the effect of insulin on VEGF mRNA expression in NIH-IR cells but did not modify the IGF-I-induced VEGF mRNA expression in NIH-IGFR cells. Blocking mitogen-activated protein kinase activation with the MEK inhibitor PD98059 abolished the effect of IGF-I on VEGF mRNA expression in NIH-IGFR cells but had no effect on insulin-induced VEGF mRNA expression in NIH-IR cells. Expression of a constitutively active PKB in NIH-IR cells induced the expression of VEGF mRNA, which was not further modified by insulin treatment. We conclude that VEGF induction by insulin and IGF-I occurs via different signaling pathways, the former involving phosphatidylinositol 3-kinase/protein kinase B and the latter involving MEK/mitogen-activated protein kinase.  相似文献   

17.
Cell growth and differentiation in developing tissues are, at first impression, quite different endeavors from readjusting synaptic strength during activity-dependent synaptic plasticity in mature neurons. Nevertheless, it is becoming increasingly clear that these two distinct processes share multiple intracellular signaling events. How these common pathways result in cell division (during proliferation), large-scale cellular remodeling (during differentiation) or synapse-specific changes (during synaptic plasticity) is only starting to be elucidated. Here we review the latest findings on two prototypical examples of these shared mechanisms: the Ras-PI3K pathway and the intracellular signaling elicited by neural cell adhesion molecules interacting with growth factor receptors.  相似文献   

18.
Summary Tyrosine hydroxylase (TH)- and peptide-immunoreactivity of postganglionic neurons and of nerve fibres in guinea pig lumbar paravertebral sympathetic ganglia 2–4 after transection of the communicating rami and the visceral branches, respectively, were investigated by single-and double-labelling techniques. Six subpopulations of postganglionic neurons were discriminated immunohistochemically: two cell types, which were immunoreactive to only one of the applied antisera — TH, and vasoactive intestinal polypeptide (VIP); and four cell types in which immunoreactivity was colocalized — TH/neuropeptide Y (NPY), NPY/VIP, dynorphin/α-neoendorphin and dynorphin (α-neoendorphin)/NPY. Small intensely fluorescent (SIF) cells dependent on their location exhibited differential immunobehaviour to NPY-/dynorphin-(α-neoendorphin-) and TH-antisera. Immunoreactivity to substance P (SP), calcitonin gene-related peptide (CGRP), met-enkephalin-arg-phe (MEAP) and leu-enkephalin was present in nerve fibres but not in postganglionic neurons with frequent colocalization of SP/CGRP- and MEAP/leu-enkephalin- and, sometimes leu-enkephalin/SP- and dynorphin/SP-immunoreactivity. TH-immunoreactive intraganglionic nerve fibres were numerically more increased after cutting the visceral branches, than after transection of the communicating rami. Vice versa, NPY-, VIP-, dynorphin- and α-neoendorphin-immunoreactive nerve fibres were particularly increased in number after cutting the communicating rami. Many but not all of the nerve fibres exhibited colocalization of two of these peptides. SP-, CGRP-, and enkephalin-immunoreactive nerve fibres were not visibly affected by cutting the visceral branches but virtually disappeared after lesioning the communicating rami.  相似文献   

19.
We describe here a new method, based on fluorescent techniques, for the determination of the orientation of membrane protein molecules present in vesicles. The method consists of: (a) attachment of a fluorescein derivative to sugar residues of glycoproteins and glycolipids in the cell membrane, and (b) the use of anti-fluorescein antibody, a highly efficient quencher of fluorescein fluorescence, for the quantitative evaluation of sidedness of transmembrane orientation of protein molecules in vesicles. Since antibody molecules do not permeate membranes, quenching is limited exclusively to sites exposed at the external surface of the vesicles. Addition of antibody to a fluorescently-labeled cell suspension results in a full and immediate quenching of the fluorescent signal. The method is highly sensitive (pM protein concentration), rapid and readily applicable to various vesicle preparations. With this method we assessed the orientation of vesicles derived from red blood cell membranes (ghosts) in isotonic medium and followed their inversion from right-side-out to inside-out orientation upon incubation in alkaline, low ionic strength medium.  相似文献   

20.
Monoclonal antibodies with affinity for Thy-1.2 on thymocytes also can bind to actin within marsupial, murine, and human cells. A similar cross-reactivity between Thy-1.1 and vimentin was revealed by Dulbecco and co-workers employing monoclonals. A computer-assisted analysis of the amino acid composition provided suggestive evidence for the occurrence of sequence homology between Thy-1.1 or Thy-1.2, actin, and vimentin that likely accounts for the serologic relatedness detected by hybridoma antibodies.  相似文献   

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