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Cell Host & Microbe Jun 2018Natural products have long played a pivotal role in the development of therapeutics for a variety of diseases. Traditionally, soil and marine environments have provided... (Review)
Review
Natural products have long played a pivotal role in the development of therapeutics for a variety of diseases. Traditionally, soil and marine environments have provided a rich reservoir from which diverse chemical scaffolds could be discovered. Recently, the human microbiome has been recognized as a promising niche from which secondary metabolites with therapeutic potential have begun to be isolated. In this Review, we address how the expansive history of identifying bacterial natural products in other environments is informing the approaches being brought to bear on the study of the human microbiota. We also touch on how these tools can lead to insights about microbe-microbe and host-microbe interactions and help generate biological hypotheses that may lead to developments of new therapeutic modalities.
Topics: Anti-Bacterial Agents; Bacteria; Biological Products; Humans; Indoles; Metabolomics; Metagenomics; Microbial Interactions; Microbiota; Multigene Family; Peptides, Cyclic; Pyrrolidonecarboxylic Acid; Thiazolidines
PubMed: 29902438
DOI: 10.1016/j.chom.2018.05.013 -
Molecular Psychiatry Apr 2022One of the central aims in Alzheimer's disease (AD) research is the identification of clinically relevant drug targets. A plethora of potential molecular targets work... (Review)
Review
One of the central aims in Alzheimer's disease (AD) research is the identification of clinically relevant drug targets. A plethora of potential molecular targets work very well in preclinical model systems both in vitro and in vivo in AD mouse models. However, the lack of translation into clinical settings in the AD field is a challenging endeavor. Although it is long known that N-terminally truncated and pyroglutamate-modified Abeta (Aβ) peptides are abundantly present in the brain of AD patients, form stable and soluble low-molecular weight oligomers, and induce neurodegeneration in AD mouse models, their potential as drug target has not been generally accepted in the past. This situation has dramatically changed with the report that passive immunization with donanemab, an Aβ-specific antibody, cleared aymloid plaques and stabilized cognitive deficits in a group of patients with mild AD in a phase II trial. This review summarizes the current knowledge on the molecular mechanisms of generation of Aβ, its biochemical properties, and the intervention points as a drug target in AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Humans; Mice; Plaque, Amyloid; Pyrrolidonecarboxylic Acid
PubMed: 34880449
DOI: 10.1038/s41380-021-01409-2 -
The International Journal of... Feb 1996Hydra is an excellent model system for developmental biology, because pattern formation processes can be easily studied in regeneration, transplantation, and... (Review)
Review
Hydra is an excellent model system for developmental biology, because pattern formation processes can be easily studied in regeneration, transplantation, and reaggregation experiments. At the cellular level hydra has the advantage that it contains only a few basic cell types and that differentiation pathways are short. Two types of signals, produced and released by nerve cells, control the spatial and temporal patterns of differentiation. Positive signals induce specific local differentiation events, and negative signals inhibit the spread of such inductions to larger areas. Head-specific growth and differentiation are controlled by head activator and head inhibitor, food-specific processes are regulated by foot activator and foot inhibitor. The activators are peptides, the inhibitors are low-molecular-weight substances. The sequence of the head activator is known, and it is conserved throughout the animal kingdom. At the cellular level head activator exerts three types of effects in hydra. It stimulates cells to divide, and it is responsible for the determination and the final differentiation of nerve cells and head-specific epithelial cells. For nerve-cell differentiation the cAMP pathway is used as second messenger system. Components of this pathway were identified in hydra. In mammals head activator is produced by nerve and neuro-endocrine cells, and it acts as mitogen on cells of neural origin. It is present early in neural development and in abnormal neural development, such as brain and neuroendocrine tumours.
Topics: Amino Acid Sequence; Animals; Cell Differentiation; Cyclic AMP; Hydra; Mammals; Nervous System; Nervous System Physiological Phenomena; Neuropeptides; Pyrrolidonecarboxylic Acid; Signal Transduction
PubMed: 8735946
DOI: No ID Found -
Experimental Hematology Feb 2001The stem cells of the bone marrow have the capacity for both self-renewal and derivation of all the blood cell lineages. Consequently, toxicity to these cells can result... (Review)
Review
The stem cells of the bone marrow have the capacity for both self-renewal and derivation of all the blood cell lineages. Consequently, toxicity to these cells can result in neutropenia, agranulocytosis, thrombocytopenia, pancytopenia, or aplastic anemia. Many anticancer drugs adversely affect the bone marrow, and neutropenia is a common limiting factor in dose escalation. In this review, we discuss agents that appear to have potential as bone marrow sparing agents. Computerized catalogs of the National Library of Medicine and Medline were searched for reports on low-molecular-weight compounds that detailed effects on the hematopoietic progenitor cells. The most promising agents are the endogenous peptides p-glutamic acid-glutamic acid-aspartic acid-cysteine-lysine and acetyl-serine-aspartic acid-lysine-proline, and the exogenous compounds amifostine and ammonium trichloro[dioxoethylene-O,O']tellurate, but several others are also discussed. These compounds preserve stem cell function in the presence of antineoplastic drugs of diverse pharmacological classes, and they do so by various mechanisms of action. Their present status in clinical practice is also detailed. More needs to be learned about their mechanisms of action and therapeutic potential, but the results are encouraging for some of these compounds and more clinical trials should be expected.
Topics: Amifostine; Anemia, Aplastic; Antineoplastic Agents; Bone Marrow Cells; Ethylenes; Growth Inhibitors; Hematopoietic Stem Cells; Humans; Leukopenia; MEDLINE; Molecular Weight; Oligopeptides; Pyrrolidonecarboxylic Acid; Thrombocytopenia
PubMed: 11166451
DOI: 10.1016/s0301-472x(00)00621-4 -
The Journal of Nutrition Jan 2006Brain capillary endothelial cells form the blood-brain barrier (BBB). They are connected by extensive tight junctions, and are polarized into luminal (blood-facing) and... (Review)
Review
Brain capillary endothelial cells form the blood-brain barrier (BBB). They are connected by extensive tight junctions, and are polarized into luminal (blood-facing) and abluminal (brain-facing) plasma membrane domains. The polar distribution of transport proteins mediates amino acid (AA) homeostasis in the brain. The existence of two facilitative transporters for neutral amino acids (NAAs) on both membranes provides the brain access to essential AAs. Four Na(+)-dependent transporters of NAA exist in the abluminal membranes of the BBB. Together these systems have the capability to actively transfer every naturally occurring NAA from the extracellular fluid (ECF) to endothelial cells and from there into circulation. The presence of Na(+)-dependent carriers on the abluminal membrane provides a mechanism by which NAA concentrations in the ECF of brain are maintained at approximately 10% those of the plasma. Also present on the abluminal membrane are at least three Na(+)-dependent systems transporting acidic AAs (EAAT) and a Na(+)-dependent system transporting glutamine (N). Facilitative carriers for glutamine and glutamate are found only in the luminal membrane of the BBB. This organization promotes the net removal of acidic- and nitrogen-rich AAs from the brain and accounts for the low level of glutamate penetration into the central nervous system. The presence of a gamma-glutamyl cycle at the luminal membrane and Na(+)-dependent AA transporters at the abluminal membrane may serve to modulate movement of AAs from blood to the brain. The gamma-glutamyl cycle is expected to generate pyroglutamate (synonymous with oxyproline) within the endothelial cells. Pyroglutamate stimulates secondary active AA transporters at the abluminal membrane, thereby reducing the net influx of AAs to the brain. It is now clear that BBB participates in the active regulation of the AA content of the brain.
Topics: Amino Acids; Ammonia; Animals; Biological Transport; Blood-Brain Barrier; Glutamic Acid; Glutamine; Humans; Pyrrolidonecarboxylic Acid; Sodium; gamma-Glutamyltransferase
PubMed: 16365086
DOI: 10.1093/jn/136.1.218S -
Computational and Mathematical Methods... 2020The current emergence of coronavirus (SARS-CoV-2) puts the world in threat. The structural research on the receptor recognition by SARS-CoV-2 has identified the key...
The current emergence of coronavirus (SARS-CoV-2) puts the world in threat. The structural research on the receptor recognition by SARS-CoV-2 has identified the key interactions between SARS-CoV-2 spike protein and its host (epithelial cell) receptor, also known as angiotensin-converting enzyme 2 (ACE2). It controls both the cross-species and human-to-human transmissions of SARS-CoV-2. In view of this, we propose and analyze a mathematical model for investigating the effect of CTL responses over the viral mutation to control the viral infection when a postinfection immunostimulant drug (pidotimod) is administered at regular intervals. Dynamics of the system with and without impulses have been analyzed using the basic reproduction number. This study shows that the proper dosing interval and drug dose both are important to eradicate the viral infection.
Topics: Adjuvants, Immunologic; Angiotensin-Converting Enzyme 2; Basic Reproduction Number; Betacoronavirus; COVID-19; Computer Simulation; Coronavirus Infections; Dose-Response Relationship, Drug; Host Microbial Interactions; Humans; Mathematical Concepts; Models, Biological; Mutation; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Pyrrolidonecarboxylic Acid; Receptors, Virus; SARS-CoV-2; Spike Glycoprotein, Coronavirus; T-Lymphocytes, Cytotoxic; Thiazolidines; COVID-19 Drug Treatment
PubMed: 32908574
DOI: 10.1155/2020/1352982 -
The Journal of Reproduction and... Feb 2005When released into an appropriate environment, mammalian spermatozoa begin to capacitate and then continue until fully capacitated and able to fertilize. During... (Review)
Review
When released into an appropriate environment, mammalian spermatozoa begin to capacitate and then continue until fully capacitated and able to fertilize. During capacitation in vitro, some cells 'over-capacitate' and undergo spontaneous acrosome reactions; this would be highly undesirable in vivo since already acrosome-reacted spermatozoa are non-fertilizing. Recent studies have revealed that seminal plasma contains several small molecules that bind to specific receptors on the sperm plasma membrane and act as 'first messengers', causing biologically important changes in availability of the 'second messenger' cAMP. Fertilization promoting peptide (FPP), calcitonin and adenosine all regulate cAMP production, stimulating it in uncapacitated spermatozoa and then inhibiting it in capacitated cells; in contrast, angiotensin II stimulates cAMP throughout capacitation. The molecules that regulate cAMP appear to do so via G protein-modulated changes in membrane associated adenylyl cyclases (mACs). Both mouse and human spermatozoa have been shown to have Galphas and Galphai2, as well as several isoforms of mAC, located in the same regions as the specific receptors. Thus spermatozoa possess the required elements for several separate signal transduction pathways, many of which regulate mAC/cAMP and so maintain sperm fertilizing ability. In vivo, such responses could increase the chances of successful fertilization.
Topics: Adenylyl Cyclases; Angiotensin II; Animals; Calcitonin; Cyclic AMP; Female; Humans; Male; Mice; Models, Biological; Pyrrolidonecarboxylic Acid; Signal Transduction; Sperm Capacitation; Spermatozoa; Thyrotropin-Releasing Hormone
PubMed: 15750295
DOI: 10.1262/jrd.51.37 -
Scientific Reports Jan 2023Pyroglutamate amyloid-β (Aβ) is an N-terminally truncated and pyroglutamate-modified Aβ peptide retaining highly hydrophobic, amyloidogenic, and neurotoxic...
Pyroglutamate amyloid-β (Aβ) is an N-terminally truncated and pyroglutamate-modified Aβ peptide retaining highly hydrophobic, amyloidogenic, and neurotoxic properties. In Alzheimer's disease (AD) patients, Aβ peptides accumulate into oligomers and induce cellular toxicity and synaptic dysfunction. Aβ aggregates further seed the formation of amyloid plaques, which are the pathological hallmarks of AD. Given that Aβ peptides play critical roles in the development of neurodegeneration, a reliable and reproducible synthetic access to these peptides may support pathological and medicinal studies of AD. Here, we synthesized Aβ peptides through the microwave-assisted solid-phase peptide synthesis (SPPS). Utilizing thioflavin T fluorescence assay and dot blotting analysis with anti-amyloid oligomer antibody, the amyloidogenic activity of synthesized Aβ peptides was confirmed. We further observed the cytotoxicity of Aβ aggregates in cell viability test. To examine the cognitive deficits induced by synthetic Aβ peptides, Aβ oligomers were intracerebroventricularly injected into imprinting control region mice and Y-maze and Morris water maze tests were performed. We found that Aβ aggregates altered the expression level of postsynaptic density protein 95 in cortical lysates. Collectively, we produced Aβ peptides in the microwave-assisted SPPS and evaluated the amyloidogenic and pathological function of the synthesized peptides.
Topics: Animals; Mice; Pyrrolidonecarboxylic Acid; Solid-Phase Synthesis Techniques; Peptide Fragments; Amyloid beta-Peptides; Alzheimer Disease
PubMed: 36627316
DOI: 10.1038/s41598-022-26616-x -
International Journal of Molecular... Oct 2015Insects, like other organisms, must deal with a wide variety of potentially challenging environmental factors during the course of their life. An important example of... (Review)
Review
Insects, like other organisms, must deal with a wide variety of potentially challenging environmental factors during the course of their life. An important example of such a challenge is the phenomenon of oxidative stress. This review summarizes the current knowledge on the role of adipokinetic hormones (AKH) as principal stress responsive hormones in insects involved in activation of anti-oxidative stress response pathways. Emphasis is placed on an analysis of oxidative stress experimentally induced by various stressors and monitored by suitable biomarkers, and on detailed characterization of AKH's role in the anti-stress reactions. These reactions are characterized by a significant increase of AKH levels in the insect body, and by effective reversal of the markers-disturbed by the stressors-after co-application of the stressor with AKH. A plausible mechanism of AKH action in the anti-oxidative stress response is discussed as well: this probably involves simultaneous employment of both protein kinase C and cyclic adenosine 3',5'-monophosphate pathways in the presence of extra and intra-cellular Ca(2+) stores, with the possible involvement of the FoxO transcription factors. The role of other insect hormones in the anti-oxidative defense reactions is also discussed.
Topics: Animals; Insect Hormones; Insecta; Oligopeptides; Oxidative Stress; Pyrrolidonecarboxylic Acid; Signal Transduction
PubMed: 26516847
DOI: 10.3390/ijms161025788 -
MAbs 2014Tremendous knowledge has been gained in the understanding of various modifications of IgG antibodies, driven mainly by the fact that antibodies are one of the most... (Review)
Review
Tremendous knowledge has been gained in the understanding of various modifications of IgG antibodies, driven mainly by the fact that antibodies are one of the most important groups of therapeutic molecules and because of the development of advanced analytical techniques. Recombinant monoclonal antibody (mAb) therapeutics expressed in mammalian cell lines and endogenous IgG molecules secreted by B cells in the human body share some modifications, but each have some unique modifications. Modifications that are common to recombinant mAb and endogenous IgG molecules are considered to pose a lower risk of immunogenicity. On the other hand, modifications that are unique to recombinant mAbs could potentially pose higher risk. The focus of this review is the comparison of frequently observed modifications of recombinant monoclonal antibodies to those of endogenous IgG molecules.
Topics: Animals; Antibodies; Antibodies, Monoclonal; Cell Line; Glycosylation; Humans; Immunoglobulin G; Protein Sorting Signals; Pyrrolidonecarboxylic Acid; Recombinant Proteins
PubMed: 25517300
DOI: 10.4161/mabs.29883