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Over the last decade, hydrogen sulfide (H2S) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide,H2S is p...
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Over the last decade, hydrogen sulfide (H2S) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide,H2S is produced by various enzymatic reactions and regulates a host of physiologic and pathophysiological processes in various cells and tissues. H2S levels are decreased in a number of conditions (e.g., diabetes mellitus, ischemia, and aging) and are increased in other states (e.g., inflammation, critical illness, and cancer). Over the last decades, multiple approaches have been identified for the therapeutic exploitation of H2S, either based on H2S donation or inhibition ofH2S biosynthesis.H2S donation can be achieved through the inhalation of H2S gas and/or the parenteral or enteral administration of so-called fast-releasing H2S donors (salts of H2S such as NaHS and Na2S) or slow-releasingH2S donors (GYY4137 being the prototypical compound used in hundreds of studies in vitro and in vivo). Recent work also identifies various donors with regulated H2S release profiles, including oxidant-triggered donors, pH-dependent donors, esterase-activated donors, and organelle-targeted (e.g., mitochondrial) compounds. There are also approaches where existing, clinically approved drugs of various classes (e.g., nonsteroidal anti-inflammatories) are coupled with H2S-donating groups (the most advanced compound in clinical trials is ATB-346, anH2S-donating derivative of the non-steroidal anti-inflammatory compound naproxen). For pharmacological inhibition ofH2S synthesis, there are now several small molecule compounds targeting each of the three H2S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase. Although many of these compounds have their limitations (potency, selectivity), thesemolecules, especially in combination with genetic approaches, can be instrumental for the delineation of the biologic processes involving endogenous H2S production. Moreover, some of these compounds (e.g., cell-permeable prodrugs of the CBS inhibitor aminooxyacetate, or benserazide, a potentially repurposable CBS inhibitor) may serve as starting points for future clinical translation. The present article overviews the currently known H2S donors and H2S biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.
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Introduction: Minimal change disease (MCD) and Focal and segmental glomerulosclerosis (FSGS) are two of the major causes of nephrotic syndrome (NS) in children and adults. According to KDIGO (Kidney Disease: Improving Global Outco...
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Introduction: Minimal change disease (MCD) and Focal and segmental glomerulosclerosis (FSGS) are two of the major causes of nephrotic syndrome (NS) in children and adults. According to KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, the treatment of adult primary MCD and FSGS should be based on immunosuppressants and antiproteinuric drugs. Recently, Rituximab, a humanized monoclonal antibody (mAb) has emerged as a potential treatment for steroid or calcineurin inhibitor-dependent patients; it has however demonstrated lower efficacy in those with nephrotic syndrome that is resistant to the above indicated drugs. Area covered: Analysis of ongoing and already completed clinical trials, retrieved from clinicaltrials.gov, clinicaltrialsregister.eu and PubMed involving new therapies for nephrotic syndrome secondary to MCD and FSGS. Expert opinion: The most promising drugs under investigation for MCD and FSGS are mAbs. We are hopeful that new therapeutic options to treat multi-drug resistant MCD and FSGS will emerge from currently ongoing studies. What appears certain is the difficulty in enrolling patients affected by orphan renal diseases and the selection of valid endpoints in clinical trials, such as kidney failure.
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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...
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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.
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L-arabinose is found in biopolymers such as hemicellulose, pectin, arabinogalactan-protein complexes, and polysaccharides of exudate plant gums. Recent studies have revealed many possible applications of L-arabinose in the fields ...
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L-arabinose is found in biopolymers such as hemicellulose, pectin, arabinogalactan-protein complexes, and polysaccharides of exudate plant gums. Recent studies have revealed many possible applications of L-arabinose in the fields of pharmaceutical, food and chemical industries. Novel approaches to obtain L-arabinose are focused on the utilization of lignocellulosic by-products, purified polysaccharides, and residual hydrolysates containing a mixture of sugars. L-arabinose can be released from lignocellulosic biomasses by acid-catalysed or enzymatic hydrolysis. L-arabinose-enriched solutions can be obtained from residual hydrolysates by yeast-mediated biopurification. The most promising, novel processes to obtain L-arabinose have combined the advantages of different methods but technological barriers still exist impeding the industrial implementation.
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Several studies have shown the immunomodulatory effects of extracellular vesicles (EVs) released by pathogenic fungi. Herein, we discuss the data regarding the immunomodulatory properties of fungal EVs, but also of EVs produced by...
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Several studies have shown the immunomodulatory effects of extracellular vesicles (EVs) released by pathogenic fungi. Herein, we discuss the data regarding the immunomodulatory properties of fungal EVs, but also of EVs produced by infected leukocytes. This characterizes a two-way path, in which both host and fungal EVs could coexist and play crucial roles in disease progression or protection in fungal infections. We suggest that EVs can dictate the progress of fungal diseases, and their potential as therapeutic targets.
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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...
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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.
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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...
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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.
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