摘要 :
MRP4 transports multiple endogenous and exogenous substances and is critical not only for detoxification but also in the homeostasis of several signaling molecules. Its dysregulation has been reported in numerous pathological diso...
展开
MRP4 transports multiple endogenous and exogenous substances and is critical not only for detoxification but also in the homeostasis of several signaling molecules. Its dysregulation has been reported in numerous pathological disorders, thus MRP4 appears as an attractive therapeutic target. However, the efficacy of MRP4 inhibitors is still controversial. The design of specific pharmacological agents with the ability to selectively modulate the activity of this transporter or modify its affinity to certain substrates represents a challenge in current medicine and chemical biology. The first step in the long process of drug rational design is to identify the therapeutic target and characterize the mechanism by which it affects the given pathology. In order to develop a pharmacological agent with high specific activity, the second step is to systematically study the structure of the target and identify all the possible binding sites. Using available homology models and mutagenesis assays, in this review we recapitulate the up-to-date knowledge about MRP structure and aligned amino acid sequences to identify the candidate MRP4 residues where cyclic nucleotides bind. We have also listed the most relevant MRP inhibitors studied to date, considering drug safety and specificity for MRP4 in particular. This meta-analysis platform may serve as a basis for the future development of inhibitors of MRP4 cAMP specific transport. ? 2019 Bentham Science Publishers.
收起
摘要 :
The mammalian hippocampal formation contains several distinct populations of neurons involved in representing self-position and orientation. These neurons, which include place, grid, head direction, and boundary cells, are thought...
展开
The mammalian hippocampal formation contains several distinct populations of neurons involved in representing self-position and orientation. These neurons, which include place, grid, head direction, and boundary cells, are thought to collectively instantiate cognitive maps supporting flexible navigation. However, to flexibly navigate, it is necessary to also maintain internal representations of goal locations, such that goal-directed routes can be planned and executed. Although it has remained unclear how the mammalian brain represents goal locations, multiple neural candidates have recently been uncovered during different phases of navigation. For example, during planning, sequential activation of spatial cells may enable simulation of future routes toward the goal. During travel, modulation of spatial cells by the prospective route, or by distance and direction to the goal, may allow maintenance of route and goal-location information, supporting navigation on an ongoing basis. As the goal is approached, an increased activation of spatial cells may enable the goal location to become distinctly represented within cognitive maps, aiding goal localization. Lastly, after arrival at the goal, sequential activation of spatial cells may represent the just-taken route, enabling route learning and evaluation. Here, we review and synthesize these and other evidence for goal coding in mammalian brains, relate the experimental findings to predictions from computational models, and discuss outstanding questions and future challenges.
收起
摘要 :
Chemicals with estrogenic activity are derived from many different natural and synthetic processes and products, including endogenous production (e.g., estradiol, conjugated estrogens), drugs (e.g., ethinyl estradiol, conjugated e...
展开
Chemicals with estrogenic activity are derived from many different natural and synthetic processes and products, including endogenous production (e.g., estradiol, conjugated estrogens), drugs (e.g., ethinyl estradiol, conjugated estrogens), plants used as foods (phytoestrogens such as genistein, daidzein, S-equol), and man-made chemicals (xenoestrogens such as bisphenol A). Human exposure to low doses of endogenous estrogens, estrogenic drugs, phytoestrogens, and xenoestrogens has the potential to improve health or disrupt normal endocrine activity, as well as impact the diverse systems with which estrogens interact, including the cardiovascular system, and lipid and carbohydrate metabolism. Mechanisms of action and diversity of adverse and non-adverse effects following human exposure to low doses of estrogen active chemicals (EACs, defined as chemicals which interact with an estrogen receptor [ER]) are poorly understood. This review summarizes our current understanding of the pharmacological action with a focus on pharmacokinetics (PK) and toxicokinetics (TK) of several representative EACs in both physiological and pathological processes. The goal of this review is to assess the current state-of-the-science on: (i) the potential for EACs to interfere with endocrine activity, (ii) factors which contribute to endocrine-related clinical outcomes, and (iii) existing knowledge gaps. While classical PK approaches (compartmental or non-compartmental) can be used to characterize absorption, distribution, metabolism, and elimination of EACs, many of the detailed pharmacological characteristics necessary to understand benefit-risk balance have not yet been clarified. Pharmacological complexities mirror the complexity of determining whether and under what conditions exposure to estrogens in drugs, foods or to xenoestrogenic chemicals are beneficial or harmful to human health.
收起
摘要 :
Biomaterials science encompasses elements of medicine, biology, chemistry, materials, and tissue engineering. They are engineered to interact with biological systems to treat, augment, repair, or replace lost tissue function. The ...
展开
Biomaterials science encompasses elements of medicine, biology, chemistry, materials, and tissue engineering. They are engineered to interact with biological systems to treat, augment, repair, or replace lost tissue function. The choice of biomaterial depends on the procedure being performed, the severity of the patients condition, and the surgeons preference. Prostheses made from natural-derived biomaterials are often derived from decellularized extracellular matrix (ECM) of animal (xenograft) or human (allograft) origin. Advantages of using ECM include their resemblance in morphology and three-dimensional structures with that of tissue to be replaced. Due to this, scientists all over are now focusing on naturally derived biomaterials which have been shown to possess several advantages compared to synthetic ones, owing to their biocompatibility, biodegradability, and remodeling properties. Advantages of a naturally derived biomaterial enhance their application for replacement or restoration of damaged organs/tissues. They adequately support cell adhesion, migration, proliferation, and differentiation. Naturally derived biomaterials can induce extracellular matrix formation and tissue repair when implanted into a defect by enhancing attachment and migration of cells from surrounding environment. In the current chapter, we will focus on the natural and synthetic dermal matrix development and all of the progress in this field.
收起
摘要 :
ABSTRACT: Our understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α-synuclein and LRRK2 pathogenic mutat...
展开
ABSTRACT: Our understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α-synuclein and LRRK2 pathogenic mutations. While α-synuclein protein composes the aggregates that can spread through much of the brain in disease, LRRK2 encodes a multidomain dual-enzyme distinct from any other protein linked to neurodegeneration. In this review, we discuss emergent datasets from multiple model systems that suggest these unlikely partners do interact in important ways in disease, both within cells that express both LRRK2 and α-synuclein as well as through more indirect pathways that might involve neuroinflammation. Although the link between LRRK2 and disease can be understood in part through LRRK2 kinase activity (phosphotransferase activity), α-synuclein toxicity is multilayered and plausibly interacts with LRRK2 kinase activity in several ways. We discuss common protein interactors like 14-3-3s that may regulate α-synuclein and LRRK2 in disease. Finally, we examine cellular pathways and outcomes common to both mutant α-synuclein expression and LRRK2 activity and points of intersection. Understanding the interplay between these two unlikely partners in disease may provide new therapeutic avenues for PD. ? 2018 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
收起
摘要 :
AP@LZ is an electronic organiser that was designed to support the day-to-day activities of persons with Alzheimer's disease. To assess the potential of this technology, three participants (NI, JB, RD) were approached to take part ...
展开
AP@LZ is an electronic organiser that was designed to support the day-to-day activities of persons with Alzheimer's disease. To assess the potential of this technology, three participants (NI, JB, RD) were approached to take part in the study. They benefited from a structured cognitive intervention to learn how to operate AP@LZ; the intervention included the following learning stages: Acquisition, Application and Adaptation. Pre- and post-intervention measures were collected. NI, for whom a longitudinal study was conducted, still continued to use AP@LZ 24 months post-intervention. JB and RD also showed a gradual improvement in their performance throughout the intervention phase (sessions 1 to 19 for JB: performance increased from 50 to 100%; sessions 1 to 25 for RD: from 56 to 89%). The results of the use of AP@LZ in activities of daily living suggest that the application was beneficial for three persons with Alzheimer's disease whose profiles differed notably (age, cognitive and social profiles). Thus, results indicate that they were all able to learn how to operate AP@LZ's functions and to use them in their activities of daily living. Cognitive intervention appears to play an important role for the promotion of learning and adoption of such technology.
收起
摘要 :
The adult zebrafish is considered a useful model for studying mechanisms involved in tissue growth and regeneration. We have characterized cytotoxic damage to the retina of adult zebrafish caused by the injection of cobalt chlorid...
展开
The adult zebrafish is considered a useful model for studying mechanisms involved in tissue growth and regeneration. We have characterized cytotoxic damage to the retina of adult zebrafish caused by the injection of cobalt chloride (CoCl2) into the vitreous cavity. The CoCl2 concentration we used primarily caused injury to photoreceptors. We observed the complete disappearance of cones, followed by rods, across the retina surface from 28 to 96 hr after CoCl2 injury. The loss of 30% of bipolar cells was also observed by 50 hr after lesion (hpl). CoCl2 injury provoked a strong induction of the proliferative activity of multipotent M黮ler glia and derived progenitors. The effect of CoCl2 on retina cells was significantly reduced by treatment with glutamate ionotropic receptor antagonists. Cone photoreceptor regeneration occurred 25 days after injury. Moreover, a single dose of CoCl2 induced vascular damage and regeneration, whereas three injections of CoCl2 administered weekly provoked neovascular-like changes 20 days after injury. CoCl2 injury also caused microglial reactivity in the optic disc, retina periphery and fibre layer. CoCl2-induced damage enhanced pluripotency and proneural transcription factor gene expression in the mature retina 72 hpl. Tumour necrosis factor alpha, vascular endothelial growth factor (VEGF) and VEGF receptor mRNA levels were also significantly enhanced by 72 hpl. The injury paradigm we have described in this work may be useful for the discovery of signalling molecules and pathways that participate in the regenerative response and it may serve as a model to screen for compounds that could potentially treat aberrant angiogenesis.
收起
摘要 :
Tris-bipyridine ferrous complexes having β-lactosides, β-maltosides or α-mannosides with serinol spacers were prepared as molecular mimics of densely packed carbohydrate clusters on cell surfaces. Conformational analysis on the...
展开
Tris-bipyridine ferrous complexes having β-lactosides, β-maltosides or α-mannosides with serinol spacers were prepared as molecular mimics of densely packed carbohydrate clusters on cell surfaces. Conformational analysis on these glycosylated complexes were conducted by UV–vis and circular dichroism spectroscopy measurements, which disclosed that the chloride, nitrate and sulfate salts induced the conformational changes of the glycosylated complexes in the anion- and carbohydrate-dependent manners. ? 2019, ? 2019 Taylor & Francis Group, LLC.
收起
摘要 :
Thrombosis is one of the major causes of morbidity and mortality in a wide range of vessels diseases. Due to the high prevalence of thromboembolic disorders investigations are being carried out on new antithrombotic agents with li...
展开
Thrombosis is one of the major causes of morbidity and mortality in a wide range of vessels diseases. Due to the high prevalence of thromboembolic disorders investigations are being carried out on new antithrombotic agents with limited adverse side effects in which herbal medicines are considered as alternative remedies. Persian medicine (PM) as a traditional medicine has a good potential for pharmacotherapy based on its own principles and development of drugs via investigating PM literature. In PM manuscripts there are some concepts that express the management of blood clots and antithrombotic properties. This study reviewed the pharmacological effects of medicinal plants mentioned in PM literature for blood clot management in light of current knowledge. Plants mentioned in PM for management of blood clot belong to 12 families in which Apiaceae, Lamiaceae and Compositae were the most repeated ones. Among the proposed plants Allium sativum, Rosmarinus officinalis, Boswellia serrata, Sesamum indicum, Matricaria chamomilla and Carthamus tinctorius have been the most researched plants in modern antithrombotic studies while for some plants such as Helichrysum stoechas, Dracocephalum kotschi, Carum carvi, Bunium persicum and Lagoecia cuminoides no evidence could be found. One of the interesting notes in clot management in PM texts was introducing the target organ for some of the recommended herbs like Carum carvi and Bunium persicum for dissolving blood clot in stomach and Commiphora mukul for thrombosed hemorrhoid. It seems review of PM recommendations can help to design future researches for antithrombotic drugs discovering with more effectiveness and safety. ? 2017, Springer Science+Business Media, LLC.
收起
摘要 :
Histone deacetylase 6 (HDAC6) has been shown to be involved in various pathological conditions, including cancer, neurodegenerative disorders and inflammatory diseases. Nonetheless, its specific role in drug-induced nephrotoxicity...
展开
Histone deacetylase 6 (HDAC6) has been shown to be involved in various pathological conditions, including cancer, neurodegenerative disorders and inflammatory diseases. Nonetheless, its specific role in drug-induced nephrotoxicity is poorly understood. Cisplatin (dichlorodiamino platinum) belongs to an inorganic platinum - fundamental chemotherapeutic drug utilized in the therapy of various solid malignant tumors. However, the use of cisplatin is extremely limited by obvious side effects, for instance bone marrow suppression and nephrotoxicity. In the present study, we utilized a murine model of cisplatin-induced acute kidney injury (AKI) and a highly selective inhibitor of HDAC6, tubastatin A (TA), to assess the role of HDAC6 in nephrotoxicity and its associated mechanisms. Cisplatin-induced AKI was accompanied by increased expression and activation of HDAC6; blocking HDAC6 with TA lessened renal dysfunction, attenuated renal pathological changes, reduced expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule 1, and decreased tubular cell apoptosis. In cultured human epithelial cells, TA or HDAC6 siRNA treatment also inhibited cisplatin-induced apoptosis. Mechanistic studies demonstrated that cisplatin treatment induced phosphorylation of AKT and loss of E-cadherin in the nephrotoxic kidney, and administration of TA enhanced AKT phosphorylation and preserved E-cadherin expression. HDAC6 inhibition also potentiated autophagy as evidenced by increased expression of autophagy-related gene (Atg) 7 (Atg7), Beclin-1, and decreased renal oxidative stress as demonstrated by up-regulation of superoxide dismutase (SOD) activity and down-regulation of malondialdehyde levels. Moreover, TAwas effective in inhibiting nuclear factor-?B (NF-築) phosphorylation and suppressing the expression of tumor necrosis factor-?(TNF-? and interleukin-6 (IL-6). Collectively, these data provide strong evidence that HDAC6 inhibition is protective against cisplatin-induced AKI and suggest that HDAC6 may be a potential therapeutic target for AKI treatment.
收起
原文获取