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Reviews in Medical Virology Mar 2016The mosquito-borne flavivirus, Japanese encephalitis virus (JEV), is the leading cause of virus-induced encephalitis globally and a major public health concern of... (Review)
Review
The mosquito-borne flavivirus, Japanese encephalitis virus (JEV), is the leading cause of virus-induced encephalitis globally and a major public health concern of several countries in Southeast Asia, with the potential to become a global pathogen. The virus is neurotropic, and the disease ranges from mild fever to severe hemorrhagic and encephalitic manifestations and death. The early steps of the virus life cycle, binding, and entry into the cell are crucial determinants of infection and are potential targets for the development of antiviral therapies. JEV can infect multiple cell types; however, the key receptor molecule(s) still remains elusive. JEV also has the capacity to utilize multiple endocytic pathways for entry into cells of different lineages. This review not only gives a comprehensive update on what is known about the virus attachment and receptor system (allies) and the endocytic pathways (alleys) exploited by the virus to gain entry into the cell and establish infection but also discusses crucial unresolved issues. We also highlight common themes and key differences between JEV and other flaviviruses in these contexts.
Topics: Encephalitis Virus, Japanese; Encephalitis, Japanese; Humans; Receptors, Virus; Viral Envelope Proteins; Virus Attachment; Virus Internalization; Virus Replication
PubMed: 26695690
DOI: 10.1002/rmv.1868 -
Progress in Molecular Biology and... 2016Recent technologies that aimed to elucidate cellular function have revealed essential roles for RNA molecules in living systems. Our knowledge concerning functional and... (Review)
Review
Recent technologies that aimed to elucidate cellular function have revealed essential roles for RNA molecules in living systems. Our knowledge concerning functional and structural information of naturally occurring RNA and RNA-protein (RNP) complexes is increasing rapidly. RNA and RNP interaction motifs are structural units that function as building blocks to constitute variety of complex structures. RNA-central synthetic biology and nanotechnology are constructive approaches that employ the accumulated information and build synthetic RNA (RNP)-based circuits and nanostructures. Here, we describe how to design and construct synthetic RNA (RNP)-based devices and structures at the nanometer-scale for biological and future therapeutic applications. RNA/RNP nanostructures can also be utilized as the molecular scaffold to control the localization or interactions of target molecule(s). Moreover, RNA motifs recognized by RNA-binding proteins can be applied to make protein-responsive translational "switches" that can turn gene expression "on" or "off" depending on the intracellular environment. This "synthetic RNA and RNP world" will expand tools for nanotechnology and synthetic biology. In addition, these reconstructive approaches would lead to a greater understanding of building principle in naturally occurring RNA/RNP molecules and systems.
Topics: Humans; Nanostructures; Nanotechnology; Nucleotide Motifs; Proteins; RNA; Ribonucleoproteins; Synthetic Biology
PubMed: 26970194
DOI: 10.1016/bs.pmbts.2015.12.004 -
Frontiers in Oncology 2019Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumour in humans and has a very poor prognosis. The existing treatments have had... (Review)
Review
Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumour in humans and has a very poor prognosis. The existing treatments have had limited success in increasing overall survival. Thus, identifying and understanding the key molecule(s) responsible for the malignant phenotype of GBM will yield new potential therapeutic targets. The treatment of brain tumours faces unique challenges, including the presence of the blood brain barrier (BBB), which limits the concentration of drugs that can reach the site of the tumour. Nevertheless, several promising treatments have been shown to cross the BBB and have shown promising pre-clinical results. This review will outline the status of several of these promising targeted therapies.
PubMed: 31616641
DOI: 10.3389/fonc.2019.00963 -
Biochemistry Apr 2020Messenger RNA degradation is an important component of overall gene expression. During the final step of eukaryotic mRNA degradation, exoribonuclease 1 (Xrn1) carries...
Messenger RNA degradation is an important component of overall gene expression. During the final step of eukaryotic mRNA degradation, exoribonuclease 1 (Xrn1) carries out 5' → 3' processive, hydrolytic degradation of RNA molecules using divalent metal ion catalysis. To initiate studies of the 5' → 3' RNA decay machinery in our lab, we expressed a C-terminally truncated version of Xrn1 and explored its enzymology using a second-generation, time-resolved fluorescence RNA degradation assay. Using this system, we quantitatively explored Xrn1's preference for 5'-monophosphorylated RNA substrates, its pH dependence, and the importance of active site mutations in the molecule's conserved catalytic core. Furthermore, we explore Xrn1's preference for RNAs containing a 5' single-stranded region both in an intermolecular hairpin structure and in an RNA-DNA hybrid duplex system. These results both expand and solidify our understanding of Xrn1, a centrally important enzyme whose biochemical properties have implications in numerous RNA degradation and processing pathways.
Topics: Exoribonucleases; Hydrogen-Ion Concentration; Models, Molecular; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 32251580
DOI: 10.1021/acs.biochem.9b01035 -
Nature Jan 2016A thorough understanding of the pharmacokinetic and pharmacodynamic properties of a drug in animal models is a critical component of drug discovery and development. Such...
A thorough understanding of the pharmacokinetic and pharmacodynamic properties of a drug in animal models is a critical component of drug discovery and development. Such studies are performed in vivo and in vitro at various stages of the development process--ranging from preclinical absorption, distribution, metabolism and excretion (ADME) studies to late-stage human clinical trials--to elucidate a drug molecule's metabolic profile and to assess its toxicity. Radiolabelled compounds, typically those that contain (14)C or (3)H isotopes, are one of the most powerful and widely deployed diagnostics for these studies. The introduction of radiolabels using synthetic chemistry enables the direct tracing of the drug molecule without substantially altering its structure or function. The ubiquity of C-H bonds in drugs and the relative ease and low cost associated with tritium ((3)H) make it an ideal radioisotope with which to conduct ADME studies early in the drug development process. Here we describe an iron-catalysed method for the direct (3)H labelling of pharmaceuticals by hydrogen isotope exchange, using tritium gas as the source of the radioisotope. The site selectivity of the iron catalyst is orthogonal to currently used iridium catalysts and allows isotopic labelling of complementary positions in drug molecules, providing a new diagnostic tool in drug development.
Topics: Catalysis; Deuterium; Drug Discovery; Iridium; Iron; Isotope Labeling; Pharmaceutical Preparations; Tritium
PubMed: 26762456
DOI: 10.1038/nature16464 -
Frontiers in Pharmacology 2015The use of herbal therapies for treatment and management of cardiovascular diseases (CVDs) is increasing. Plants contain a bounty of phytochemicals that have proven to... (Review)
Review
The use of herbal therapies for treatment and management of cardiovascular diseases (CVDs) is increasing. Plants contain a bounty of phytochemicals that have proven to be protective by reducing the risk of various ailments and diseases. Indeed, accumulating literature provides the scientific evidence and hence reason d'etre for the application of herbal therapy in relation to CVDs. Slowly, but absolutely, herbal remedies are being entrenched into evidence-based medical practice. This is partly due to the supporting clinical trials and epidemiological studies. The rationale for this expanding interest and use of plant based treatments being that a significant proportion of hypertensive patients do not respond to Modern therapeutic medication. Other elements to this equation are the cost of medication, side-effects, accessibility, and availability of drugs. Therefore, we believe it is pertinent to review the literature on the beneficial effects of herbs and their isolated compounds as medication for treatment of hypertension, a prevalent risk factor for CVDs. Our search utilized the PubMed and ScienceDirect databases, and the criterion for inclusion was based on the following keywords and phrases: hypertension, high blood pressure, herbal medicine, complementary and alternative medicine (CAM), nitric oxide, vascular smooth muscle cell (VSMC) proliferation, hydrogen sulfide, nuclear factor kappa-B, oxidative stress, and epigenetics/epigenomics. Each of the aforementioned keywords was co-joined with herb in question, and where possible with its constituent molecule(s). In this first of a two-part review, we provide a brief introduction of hypertension, followed by a discussion of the molecular and cellular mechanisms. We then present and discuss the plants that are most commonly used in the treatment and management of hypertension.
PubMed: 26834637
DOI: 10.3389/fphar.2015.00323 -
Science (New York, N.Y.) Aug 2023Ergodicity, the central tenet of statistical mechanics, requires an isolated system to explore all available phase space constrained by energy and symmetry. Mechanisms...
Ergodicity, the central tenet of statistical mechanics, requires an isolated system to explore all available phase space constrained by energy and symmetry. Mechanisms for violating ergodicity are of interest for probing nonequilibrium matter and protecting quantum coherence in complex systems. Polyatomic molecules have long served as a platform for probing ergodicity breaking in vibrational energy transport. Here, we report the observation of rotational ergodicity breaking in an unprecedentedly large molecule, C, determined from its icosahedral rovibrational fine structure. The ergodicity breaking occurs well below the vibrational ergodicity threshold and exhibits multiple transitions between ergodic and nonergodic regimes with increasing angular momentum. These peculiar dynamics result from the molecule's distinctive combination of symmetry, size, and rigidity, highlighting its relevance to emergent phenomena in mesoscopic quantum systems.
PubMed: 37590361
DOI: 10.1126/science.adi6354 -
The Journal of Physical Chemistry. A Mar 2023Charge migration (CM) is a coherent attosecond process that involves the movement of localized holes across a molecule. To determine the relationship between a...
Charge migration (CM) is a coherent attosecond process that involves the movement of localized holes across a molecule. To determine the relationship between a molecule's structure and the CM dynamics it exhibits, we perform systematic studies of para-functionalized bromobenzene molecules (X-CH-R) using real-time time-dependent density functional theory. We initiate valence-electron dynamics by emulating rapid strong-field ionization leading to a localized hole on the bromine atom. The resulting CM, which takes on the order of 1 fs, occurs via an X localized → CH delocalized → R localized mechanism. Interestingly, the hole contrast on the acceptor functional group increases with increasing electron-donating strength. This trend is well-described by the Hammett σ value of the group, which is a commonly used metric for quantifying the effect of functionalization on the chemical reactivity of benzene derivatives. These results suggest that simple attochemistry principles and a density-based picture can be used to predict and understand CM.
PubMed: 36791088
DOI: 10.1021/acs.jpca.3c00568 -
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 -
Current Drug Metabolism 2018Nitidine is a bioactive plant benzophenanthridine alkaloid isolated from the root of Zanthoxylum nitidum. Since its discovery in 1959, literature revealed marked... (Review)
Review
BACKGROUND
Nitidine is a bioactive plant benzophenanthridine alkaloid isolated from the root of Zanthoxylum nitidum. Since its discovery in 1959, literature revealed marked anticancer, neuroprotective, antimalarial, anti-HIV, analgesic, anti-inflammatory and antifungal activities. However, its clinical status is not defined yet.
METHODS
Various scientific search engines were used for the available literature All the peer-reviewed journals were considered in this review. MOE (molecular operating environment) ligand-based pharmacophores features of nitidine were also studied to determine the various targeted sites in the molecule.
RESULTS
The search revealed an outstanding therapeutic potential in terms of various pharmacological effects of the molecule. MOE (Molecular Operating Environment) ligand-based pharmacophores features of nitidine showed that it has got multiple bioactive functional sites that implicate its sensitivity towards several receptors protein and therefore could be a useful lead compound. Despite having an outstanding therapeutic potential, it is not subjected to clinical trial yet, probably, due to host toxicity and being a quaternary salt, charged at all body pH values, and therefore, absorption through the gastro-intestinal-tract could be an issue.
CONCLUSION
The issues can be resolved while applying latest pharmaceutical technologies, synthesizing its derivatives and subsequent clinical studies and thus could lead to the discovery of new clinically effective molecule(s).
Topics: Analgesics; Animals; Anti-HIV Agents; Anti-Inflammatory Agents; Antimalarials; Antineoplastic Agents; Benzophenanthridines; Drug Discovery; Humans; Neuroprotective Agents; Osteogenesis
PubMed: 29956622
DOI: 10.2174/1389200219666180628165643