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International Journal of Physiology,... 2019Membrane fusion is a universal event in all living organism. It is at the heart of intracellular organelle biogenesis and membrane traffic processes such as endocytosis... (Review)
Review
Membrane fusion is a universal event in all living organism. It is at the heart of intracellular organelle biogenesis and membrane traffic processes such as endocytosis and exocytosis, and is also used by enveloped viruses to enter hosting cells. Regarding the cellular mechanisms underlying membrane fusion, pioneering studies by Randy Schekman, James Rothman, Thomas C. Südhof and their colleagues have demonstrated the function of specific proteins and protein-protein interactions as essential fusogenic factor to initiate membrane fusion. Since then, function of lipids and protein-lipid interaction has also been identified as important players in membrane fusion. Based on that NSF (NEM-sensitive factor where NEM stands for -ethyl-maleimide) and acyl-CoA are required for the membrane fusion of transporting vesicles with Golgi cisternae, it is further suggested that the transfer of the acyl chain to a molecule(s) is essential for membrane fusion. Among the previously identified fusogens, phosphatidic acid (PA) is found as an acyl chain recipient. Functionally, acylation of PA is required for tethering the membranes of Rab5a vesicles and early endosomes together during membrane fusion. As certain threshold of proximity between the donor and acceptor membrane is required to initiate membrane fusion, fusogenic factors beyond protein-protein and protein-lipid interaction need to be identified.
PubMed: 31993099
DOI: No ID Found -
Nature Communications Feb 2024Liver failure causes breakdown of the Blood CNS Barrier (BCB) leading to damages of the Central-Nervous-System (CNS), however the mechanisms whereby the liver influences...
Liver failure causes breakdown of the Blood CNS Barrier (BCB) leading to damages of the Central-Nervous-System (CNS), however the mechanisms whereby the liver influences BCB-integrity remain elusive. One possibility is that the liver secretes an as-yet to be identified molecule(s) that circulate in the serum to directly promote BCB-integrity. To study BCB-integrity, we developed light-sheet imaging for three-dimensional analysis. We show that liver- or muscle-specific knockout of Hfe2/Rgmc induces BCB-breakdown, leading to accumulation of toxic-blood-derived fibrinogen in the brain, lower cortical neuron numbers, and behavioral deficits in mice. Soluble HFE2 competes with its homologue RGMa for binding to Neogenin, thereby blocking RGMa-induced downregulation of PDGF-B and Claudin-5 in endothelial cells, triggering BCB-disruption. HFE2 administration in female mice with experimental autoimmune encephalomyelitis, a model for multiple sclerosis, prevented paralysis and immune cell infiltration by inhibiting RGMa-mediated BCB alteration. This study has implications for the pathogenesis and potential treatment of diseases associated with BCB-dysfunction.
Topics: Animals; Female; Mice; Blood-Brain Barrier; Central Nervous System; Encephalomyelitis, Autoimmune, Experimental; Endothelial Cells; Liver; Muscles
PubMed: 38310100
DOI: 10.1038/s41467-024-45303-1 -
PloS One 2019Dextranol, a reduced dextran, prevents damage to stored dry protein samples that unmodified dextran would otherwise cause. Desiccation protectants (xeroprotectants) like...
Dextranol, a reduced dextran, prevents damage to stored dry protein samples that unmodified dextran would otherwise cause. Desiccation protectants (xeroprotectants) like the polysaccharide dextran are critical for preserving dried protein samples by forming a rigid glass that protects entrapped protein molecules. Stably dried proteins are important for maintaining critical information in clinical samples like blood serum as well as maintaining activity of biologic drug compounds. However, we found that dextran reacts with both dried serum proteins and lyophilized purified proteins during storage, producing high-molecular weight Amadori-product conjugates. These conjugates appeared in a matter of days or weeks when stored at elevated temperatures (37° or 45°C), but also appeared on a timescale of months when stored at room temperature. We synthesized a less reactive dextranol by reducing dextran's anomeric carbon from an aldehyde to an alcohol. Serum samples dried in a dextranol-based matrix protected the serum proteins from forming high-molecular weight conjugates. The levels of four cancer-related serum biomarkers (prostate specific antigen, neuropilin-1, osteopontin, and matrix-metalloproteinase 7) decreased, as measured by immunoassay, when serum samples were stored for one to two weeks in dextran-based matrix. Switching to a dextranol-based xeroprotection matrix slightly reduced the damage to osteopontin and completely stopped any detectable damage during storage in the other three biomarkers when stored for a period of two weeks at 45°C. We also found that switching from dextran to dextranol in a lyophilization formulation eliminates this unwanted reaction, even at elevated temperatures. Dextranol offers a small and easy modification to dextran that significantly improves the molecule's function as a xeroprotectant by eliminating the potential for damaging protein-polysaccharide conjugation.
Topics: Blood Proteins; Desiccation; Dextrans; Drug Compounding; Oxidation-Reduction; Preservation, Biological; Protein Stability; Temperature
PubMed: 31490977
DOI: 10.1371/journal.pone.0222006 -
The Indian Journal of Medical Research Sep 2018A young physician starting a fresh career in medicine in this millennium would hardly stop to think about the genesis of a particular biological drug that he/she will be... (Review)
Review
A young physician starting a fresh career in medicine in this millennium would hardly stop to think about the genesis of a particular biological drug that he/she will be prescribing for a patient evaluated in the morning outpatient department. For him/her, this is now routine, and the question of 'Who', 'How' and 'When' about these biologicals would be the last thing on their mind. However, for those who came to the medical profession in the 1950s, 1960s and 1970s, these targeted drugs are nothing short of 'miracles'. It would be a fascinating story for the young doctor to learn about the long journey that the dedicated biomedical scientists of yesteryears took to reach the final destination of producing such wonder drugs. The story is much like an interesting novel, full of twists and turns, heart-breaking failures and glorious successes. The biologicals acting as 'targeted therapy' have not only changed the natural history of a large number of incurable/uncontrollable diseases but have also transformed the whole approach towards drug development. From the classical empirical process, there is now a complete shift towards understanding the disease pathobiology focusing on the dysregulated molecule(s), targeting them with greater precision and aiming for better results. Seminal advances in understanding the disease mechanism, development of remarkably effective new technologies, greater knowledge of the human genome and genetic medicine have all made it possible to reach the stage where artificially developed 'targeted' drugs are now therapeutically used in routine clinical medicine.
Topics: Biological Products; Drug Development; History, 20th Century; History, 21st Century; Humans; Molecular Targeted Therapy
PubMed: 30425216
DOI: 10.4103/ijmr.IJMR_1471_18 -
Phytotherapy Research : PTR May 2022Thrombotic complications occur in many cardiovascular pathologies and have been demonstrated in COVID-19. The currently used antithrombotic drugs are not free of adverse... (Review)
Review
Thrombotic complications occur in many cardiovascular pathologies and have been demonstrated in COVID-19. The currently used antithrombotic drugs are not free of adverse reactions, and COVID-19 patients in particular, when treated with a therapeutic dose of an anticoagulant do not receive mortality benefits. The clinical management of COVID-19 is one of the most difficult tasks for clinicians, and the search for safe, potent, and effective antithrombotic drugs may benefit from exploring naturally bioactive molecules from plant sources. This review describes recent advances in understanding the antithrombotic potential of herbal drug prototypes and points to their future clinical use as potent antithrombotic drugs. Although natural products are perceived to be safe, their clinical and therapeutic applications are not always apparent or accepted. More in-depth studies are necessary to demonstrate the clinical usefulness of plant-derived, bioactive compounds. In addition, holistic approaches in systematic investigations and the identification of antithrombotic mechanisms of the herbal bioactive molecule(s) need to be conducted in pre-clinical studies. Moreover, rigorous studies are needed to compare the potency of herbal drugs to that of competitor chemical antithrombotic drugs, and to examine their interactions with Western antithrombotic medicines. We have also proposed a road map to improve the commercialization of phytopharmaceuticals.
Topics: Anticoagulants; Fibrinolytic Agents; Humans; Thrombosis; COVID-19 Drug Treatment
PubMed: 35147268
DOI: 10.1002/ptr.7408 -
Frontiers in Microbiology 2021Understanding the mechanism behind probiotic action will enable a rational selection of probiotics, increase the chances of success in clinical studies and make it easy... (Review)
Review
Understanding the mechanism behind probiotic action will enable a rational selection of probiotics, increase the chances of success in clinical studies and make it easy to substantiate health claims. However, most probiotic studies over the years have rather focused on the effects of probiotics in health and disease, whereas little is known about the specific molecules that trigger effects in hosts. This makes it difficult to describe the detailed mechanism by which a given probiotic functions. Probiotics communicate with their hosts through molecular signaling. Meanwhile, since the molecules produced by probiotics under conditions may differ from those produced , mechanistic studies would have to be conducted under conditions that mimic gastrointestinal conditions as much as possible. The ideal situation would, however, be to carry out well-designed clinical trials in humans (or the target animal) using adequate quantities of the suspected probiotic molecule(s) or adequate quantities of isogenic knock-out or knock-in probiotic mutants. In this review, we discuss our current knowledge about probiotic bacteria and yeast molecules that are involved in molecular signaling with the host. We also discuss the challenges and future perspectives in the search for probiotic effector molecules.
PubMed: 33746935
DOI: 10.3389/fmicb.2021.655705 -
Microbiology and Molecular Biology... Dec 2015Why some viruses are enveloped while others lack an outer lipid bilayer is a major question in viral evolution but one that has received relatively little attention. The... (Review)
Review
Why some viruses are enveloped while others lack an outer lipid bilayer is a major question in viral evolution but one that has received relatively little attention. The viral envelope serves several functions, including protecting the RNA or DNA molecule(s), evading recognition by the immune system, and facilitating virus entry. Despite these commonalities, viral envelopes come in a wide variety of shapes and configurations. The evolution of the viral envelope is made more puzzling by the fact that nonenveloped viruses are able to infect a diverse range of hosts across the tree of life. We reviewed the entry, transmission, and exit pathways of all (101) viral families on the 2013 International Committee on Taxonomy of Viruses (ICTV) list. By doing this, we revealed a strong association between the lack of a viral envelope and the presence of a cell wall in the hosts these viruses infect. We were able to propose a new hypothesis for the existence of enveloped and nonenveloped viruses, in which the latter represent an adaptation to cells surrounded by a cell wall, while the former are an adaptation to animal cells where cell walls are absent. In particular, cell walls inhibit viral entry and exit, as well as viral transport within an organism, all of which are critical waypoints for successful infection and spread. Finally, we discuss how this new model for the origin of the viral envelope impacts our overall understanding of virus evolution.
Topics: Animals; Cell Wall; Evolution, Molecular; Virus Internalization; Virus Physiological Phenomena; Virus Release; Viruses
PubMed: 26378223
DOI: 10.1128/MMBR.00017-15 -
International Journal of Molecular... May 2019Small airways were historically considered to be almost irrelevant in the development and control of pulmonary chronic diseases but, as a matter of fact, in the past few... (Review)
Review
Small airways were historically considered to be almost irrelevant in the development and control of pulmonary chronic diseases but, as a matter of fact, in the past few years we have learned that they are not so "silent". Asthma is still a worldwide health issue due to the great share of patients being far from optimal management. Several studies have shown that the deeper lung inflammation plays a critical role in asthma pathogenesis, mostly in these not well-controlled subjects. Therefore, assessing the degree of small airways inflammation and impairment appears to be a pivotal step in the asthmatic patient's management. It is now possible to evaluate them through direct and indirect measurements, even if some obstacles still affect their clinical application. The success of any treatment obviously depends on several factors but reaching the deeper lung has become a priority and, for inhaled drugs, this is strictly connected to the molecule's size. The aim of the present review is to summarize the recent evidence concerning the small airway involvement in asthma, its physiopathological characteristics and how it can be evaluated in order to undertake a personalized pharmacological treatment and achieve a better disease control.
Topics: Administration, Inhalation; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchioles; Humans
PubMed: 31141956
DOI: 10.3390/ijms20112617 -
Journal of Chemical Information and... Mar 2023Cytochrome P450 enzymes aid in the elimination of a preponderance of small molecule drugs, but can generate reactive metabolites that may adversely react with protein...
Cytochrome P450 enzymes aid in the elimination of a preponderance of small molecule drugs, but can generate reactive metabolites that may adversely react with protein and DNA and prompt drug candidate attrition or market withdrawal. Previously developed models help understand how these enzymes modify molecule structure by predicting sites of metabolism or characterizing formation of metabolite-biomolecule adducts. However, the majority of reactive metabolites are formed by multiple metabolic steps, and understanding the progenitor molecule's network-level behavior necessitates an integrative approach that blends multiple site of metabolism and structure inference models. Our previously developed tool, XenoNet 1.0, generates metabolic networks, where nodes are molecules and weighted edges are metabolic transformations. We extend XenoNet with a bidirectional message passing neural network that integrates edge feature information and local network structure using edge-conditioned graph convolutions and jumping knowledge to predict the authenticity of inferred Phase I metabolite structures. Our model significantly outperformed prior work and algorithmic baselines on a data set of 311 networks and 6606 intermediates annotated using a chemically diverse set of 20 736 individual in vitro and in vivo reaction records accounting for 92.3% of all human Phase I metabolism in the Accelrys Metabolite Database. Cross-validated predictions resulted in area under the receiver operating characteristic curves of 88.5% and 87.6% for separating experimentally observed and unobserved metabolites at global and network levels, respectively. Further analysis verified robustness to networks of varying depth and breadth, accurate detection of metabolites, such as d,l-methamphetamine, that are experimentally observed or unobserved in different network contexts, extraction of important metabolic subnetworks, and identification of known bioactivation pathways, such as for nimesulide and terbinafine. By exploiting network structures, our approach accurately suggests unreported metabolites for experimental study and may rationalize modifications for avoiding deleterious pathways antecedent to reactive metabolite formation.
Topics: Humans; Neural Networks, Computer; Molecular Structure; Metabolic Networks and Pathways; Terbinafine
PubMed: 36926871
DOI: 10.1021/acs.jcim.2c01383