scholarly journals Molecular aspects of creating vaccines for the prevention of poisoning ribosome-inactivating proteins of plant origin: current situation, problems of vaccine development

2021 ◽  
Vol 23 (2) ◽  
pp. 219-228
Author(s):  
Vadim A. Myasnikov ◽  
Alexander V. Stepanov ◽  
Olga A. Miteva ◽  
Alexander S. Nikishin ◽  
Alexander S. Gogolevsky ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Vaccine Development ◽  
Genetically Engineered ◽  
Targeted Mutagenesis ◽  
Clinical Effects ◽  
Ribosome Inactivating Proteins ◽  
Ricin Toxin ◽  
Unique Nature ◽  
Molecular Aspects ◽  
Toxic Plant

This article reviews the current understanding of the mechanism of action of the toxin, the clinical effects of ricin and abrin intoxication and how these relate to current and continuing prospects for vaccine development. The threat of bioterrorism worldwide has accelerated the demand for the development of therapies and vaccines against the ribosome-inactivating proteins. The diverse and unique nature of these toxins poses a challenge to vaccinologists. This paper will review the mechanism of toxicity and vaccines development to protect against the highly toxic plant-derived ribosomal toxins. Vaccine development is further complicated by the fact that as bioterrorism agents, abrin and ricin would most likely be disseminated as aerosols supplies. Our understanding of the mechanisms by which these toxins cross mucosal surfaces, and importance of mucosal immunity in preventing toxin uptake is only rudimentary. Research is now aimed at developing recombinant, attenuated vaccines based on a detailed understanding of the molecular mechanisms by which these toxins function. The evolution of the development of specific immunoprophylaxis of acute ricin poisoning from native toxoid to genetically engineered subunit vaccines based on the method of targeted mutagenesis is traced. The past several years have seen major advances in the development of a safe and efficacious ricin toxin vaccine. These vaccines are discussed in the context of the toxicity and structure of ricin. In this review we summarize ongoing efforts to leverage recent advances in the design and use of vaccines.

scholarly journals Ribavirin and Alpha Interferon Enhance Death Receptor-Mediated Apoptosis and Caspase Activation in Human Hepatoma Cells

2003 ◽  
Vol 47 (6) ◽  
pp. 1912-1921 ◽  
Author(s):  
Stephan F. Schlosser ◽  
Markus Schuler ◽  
Christoph P. Berg ◽  
Kirsten Lauber ◽  
Klaus Schulze-Osthoff ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Death Receptor ◽  
Alpha Interferon ◽  
Target Cells ◽  
Clinical Effects ◽  
Caspase Activation ◽  
Human Hepatoma Cells ◽  
Promoting Effect

ABSTRACT The molecular mechanisms underlying the clinical effects of alpha interferon (IFN) and ribavirin are not understood. Elimination of infected cells occurs in part by cytotoxic T lymphocytes (CTLs) expressing CD95 ligand and thereby attacking target cells which are positive for the death receptor CD95. Since many viruses have evolved mechanisms to inhibit apoptosis, the opposite, namely, promotion of apoptosis, could be a strategy to strengthen the host antiviral response. In the present study, we have asked whether the antiviral substances IFN and ribavirin could support CD95-mediated apoptosis by interfering with the activation of caspases, a family of proteases known for their essential role in apoptosis. HepG2 cells, stimulated with the agonistic anti-CD95 antibody, served as a minimal model to mimic the CD95 stimulation ocurring during a CTL attack of target cells in vivo. Apoptosis was quantitated by flow cytometric detection of hypodiploid nuclei. Caspase activity was measured by cytofluorometry, immunocytochemistry, and immunoblot analysis. IFN and ribavirin sensitized HepG2 cells for CD95-mediated apoptosis. This effect was correlated with an increase in CD95-mediated caspase activation and enhanced cleavage of the caspase substrate poly(ADP-ribose) polymerase. Furthermore, the positive effect on CD95-mediated caspase activation by IFN and ribavirin was confirmed by immunocytochemistry for activated caspase-3 and by immunoblot detection of activated caspase-3, caspase-7, and caspase-8. Our data demonstrate that the antiviral substances IFN and ribavirin are able to sensitize for CD95-mediated apoptosis. IFN and ribavirin also enhance CD95-mediated caspase activation, which might in part be responsible for the apoptosis-promoting effect of these antiviral compounds.

scholarly journals miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice

2011 ◽  
Vol 208 (6) ◽  
pp. 1189-1201 ◽  
Author(s):  
Mark P. Boldin ◽  
Konstantin D. Taganov ◽  
Dinesh S. Rao ◽  
Lili Yang ◽  
Jimmy L. Zhao ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Immune Cell ◽  
Myeloid Cell ◽  
Genetically Engineered ◽  
Biological Processes ◽  
Targeted Deletion ◽  
Genetically Engineered Mice ◽  
Immune Defects ◽  
Molecular Brake

Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs (miRNAs), ∼22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse biological processes, including responses to non-self. In this study, we examine the biological role of miR-146a using genetically engineered mice and show that targeted deletion of this gene, whose expression is strongly up-regulated after immune cell maturation and/or activation, results in several immune defects. Collectively, our findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation.

scholarly journals Molecular Aspects of Varicella-Zoster Virus Latency

2018 ◽  
Author(s):  
Daniel P. Depledge ◽  
Tomohiko Sadaoka ◽  
Werner J. D. Ouwendijk
Keyword(s):  
Varicella Zoster Virus ◽  
Molecular Mechanisms ◽  
Neurological Complications ◽  
In Vitro Models ◽  
New Era ◽  
Varicella Zoster ◽  
Virus Latency ◽  
Technological Advances ◽  
Molecular Aspects

Primary varicella-zoster virus (VZV) infection causes varicella (chickenpox) and the establishment of a lifelong latent infection in ganglionic neurons. VZV reactivates in about one-third of infected individuals to cause herpes zoster, often accompanied by neurological complications. The restricted host range of VZV and, until recently, the lack of suitable in vitro models to study VZV latency have seriously hampered molecular studies of viral latency. Nevertheless, recent technological advances facilitated a series of exciting studies that resulted in the discovery of a VZV latency-associated transcript (VLT) and have redefined our understanding of VZV latency and factors that initiate reactivation. Together, these findings pave the way for a new era of research that may finally unravel the precise molecular mechanisms that govern latency. In this review, we will summarize the implications of recent discoveries in the VZV latency field from both a virus and host perspective and provide a roadmap for future studies.

scholarly journals The Use of Non-Canonical Amino Acids as a Novel Biocontainment Strategy

2018 ◽  
Vol 5 (1) ◽  
Author(s):  
Jourdan Witt
Keyword(s):  
Oral Delivery ◽  
Genetically Modified Organisms ◽  
Vaccine Development ◽  
Open Systems ◽  
Genetically Modified ◽  
Environmental Safety ◽  
Genetically Engineered ◽  
Natural Environments ◽  
Delivery Vector ◽  
The Impact

Advancements in synthetic biology have led to the use of genetically modified organisms in research and industrial fields. Bacteria were one of the first organisms to be genetically engineered due to their fast growth and simple genetics, and have emerged as a major scientific and commercial interest. For instance, modified commensal bacteria can be used as an oral delivery vector of therapeutics, or as probiotics to target specific pathogens in the gastrointestinal tract. The impact of the release of pathogens used in research or vaccine development could be catastrophic to the environment and public health. In addition, there is growing concern about using genetically modified organisms in open systems, as there is a possibility for unintentional proliferation into natural environments. Therefore, is imperative that the environmental safety of genetically modified organisms are addressed, and that adequate biocontainment mechanisms are developed.

scholarly journals Heterogeneity of the mechanisms of action of antidepressants

2021 ◽  
pp. 11-17
Author(s):  
V. L. Kozlovskii ◽  
M. Yu. Popov ◽  
D. N. Kosterin ◽  
O. V. Lepik
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Response ◽  
Pathological Process ◽  
Clinical Activity ◽  
Clinical Effects ◽  
Drug Induced ◽  
Neuronal Interactions ◽  
Neurophysiological Studies ◽  
The Central Nervous System ◽  
Monoamine Receptors

The article discusses the heterogeneous mechanisms of the pharmacodynamics of antidepressants that underlie the therapeutic response. Sharing the similar clinical activity, antidepressants determine the development of drug-induced homeostasis by means of different molecular mechanisms (selective or nonselective blockade of monoamine reuptake, inhibition of monoamine oxidase, blockade of certain monoamine receptors). However, an increase of serotonin and other monoamines concentrations in the synapses of the central nervous system is only the initiating factor in the development of specific clinical effects. The latter are probably determined by other neurochemical effects, including changes in the density of postsynaptic receptors and an increase in the synthesis of neurotrophic factors. However, the primary mechanisms that increase monoamine concentrations in the synapses might not always “work properly”, leading to the lack of efficacy of the initial antidepressant, while the probability of the therapeutic response to the subsequent antidepressant remains rather high. Thus, the efficacy of an antidepressant may depend on the baseline differences in the neurochemical state contributing to the pathological “depressive” homeostasis. The heterogeneous neurochemical effects of antidepressants can determine the dissociation of existing neuronal interactions, leading to the development of the new — druginduced — homeostasis. At the same time, it is possible that stimulation of general neurotrophic processes by antidepressants may contribute to the progression and chronicity of pathology due to the ambiguous influence on certain stages of the pathological process. This determines the significance of neurophysiological studies of central disturbances in depression and search of fundamentally new neurochemical targets for the treatment of depressive states associated with various mental disorders.

Molecule which changed the view on skin treatment

2021 ◽  
pp. 44-55
Author(s):  
L.Ya. Fedorich
Keyword(s):  
Retinoic Acid ◽  
Nuclear Receptors ◽  
Mechanism Of Action ◽  
Molecular Mechanisms ◽  
Local Treatment ◽  
Mechanisms Of Action ◽  
Clinical Effects ◽  
Topical Retinoids ◽  
Acne Therapy ◽  
Universal Mechanism

Objective — to study the modern classification, mechanisms of action and clinical effects of vitamin A derivatives, to analyze retinoid for local treatment of various dermatoses with a universal mechanism of action at the epidermis and dermis levels. Materials and methods. A review of the literature and an analysis of the results of international clinical trials of drugs based on the natural retinoid of the first generation — tretinoin (retinoic acid) is presented. The works of dozens of authors since 1980s to the present day are analyzed. Most sources provide detailed information on the results of topical retinoids in acne therapy, which are the base of clinical guidelines. Long-term (6 months or more) studies of retinoic acid-based preparations carried out in recent decades have discovered the unique clinical effects of tretinoin in the treatment of skin photoaging, actinic keratosis, etc. They are achieved due to the effect of tretinoid on the nuclear receptors of keratinocytes and fibroblasts. Results and discussion. The molecular mechanisms of action of retinoic acid, realizing the cellular and tissue effects of the most studied retinoid, are systematized and grouped in a single review. It has been proven that a unique feature of tretinin is its ability to activate directly all subtypes of RARs- and, indirectly, RARs-nuclear receptors of skin cells. A new modern drug for external use is presented — AltrenoТМ lotion containing micronized 0.05 % tretinoin in combination with sodium hyaluronate, soluble collagen and glycerin. This combination exhibits the expected clinical efficacy in acne therapy and prevents side effects such as dryness, redness and exfoliation. AltrenoТМ is approved for use in children of 9 years of age and older. Conclusions. Tretinoin (retinoic acid) is a modern powerful retinoid with a universal mechanism of action, recommended for the treatment of acne.

Analysis of the molecular mechanisms by flavonoids with potential use for osteoporosis prevention or therapy

2021 ◽  
Vol 28 ◽  
Author(s):  
Valeria Rodríguez ◽  
María Rivoira ◽  
Gabriela Picotto ◽  
Gabriela Díaz de Barboza ◽  
Alejandro Collin ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Osteoporosis Treatment ◽  
Epidemiological Studies ◽  
Common Mechanism ◽  
Osteoporotic Bone ◽  
Osteoporosis Prevention ◽  
Mineral Density ◽  
Pubmed Database ◽  
Molecular Aspects ◽  
Potential Use

Background: Osteoporosis is the most common skeletal disorder worldwide. Flavonoids have the potential to alleviate bone alterations in osteoporotic patients with the advantage of being safer and less expensive than the conventional therapies. Objective: The main objective is to analyze the molecular mechanisms triggered in bone by different subclasses of flavonoids. In addition, this review provides an up-to-date overview on the cellular and molecular aspects of osteoporotic bones versus healthy bones, and a brief description of some epidemiological studies indicating that flavonoids could be useful for osteoporosis treatment. Methods: The PubMed database was searched in the range of years 2001- 2021 using the keywords osteoporosis, flavonoids, and their subclasses such as flavones, flavonols, flavanols, isoflavones, flavanones and anthocyanins, focusing the data on the molecular mechanisms triggered in bone. Results: Although flavonoids comprise many compounds that differ in structure, their effects on bone loss in postmenopausal women or in ovariectomized-induced osteoporotic animals are quite similar. Most of them increase bone mineral density and bone strength, which occur through enhancement of osteoblastogenesis and osteoclast apoptosis, decrease in osteoclastogenesis as well as increase in neovascularization on the site of the osteoporotic fracture. Conclusion: Several molecules of signaling pathways are involved in the effect of flavonoids on osteoporotic bone. Whether all flavonoids have a common mechanism or they act as ligands of estrogen receptors remain to be established. More clinical trials are necessary to know better their safety, efficacy, delivery and bioavailability in humans, as well as comparative studies with conventional therapies.

Genetically-engineered protein prodrug-like nanoconjugates for tumor-targeting biomimetic delivery via a SHEATH strategy

Nanoscale ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 611-621 ◽  
Author(s):  
Ya Chang ◽  
Shuo Yao ◽  
Yifang Chen ◽  
Jingjing Huang ◽  
Aihua Wu ◽  
...  
Keyword(s):  
Drug Development ◽  
Clinical Application ◽  
Tumor Targeting ◽  
Genetically Engineered ◽  
Ribosome Inactivating Proteins

A SHEATH strategy was developed to overcome the delivery barrier against drug development and the clinical application of the cytoplasmic active proteins (e.g., ribosome-inactivating proteins, RIPs).

Crkl is constitutively tyrosine phosphorylated in platelets from chronic myelogenous leukemia patients and inducibly phosphorylated in normal platelets stimulated by thrombopoietin

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4304-4313 ◽  
Author(s):  
A Oda ◽  
Y Miyakawa ◽  
BJ Druker ◽  
A Ishida ◽  
K Ozaki ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Tyrosine Phosphorylation ◽  
Molecular Mechanisms ◽  
Genetically Engineered ◽  
Myelogenous Leukemia ◽  
Insoluble Residue ◽  
Consistent Difference ◽  
Clot Retraction ◽  
Phosphorylated Protein ◽  
Tyrosine Phosphorylated Protein

Abstract Platelet functions such as aggregation and clot retraction are often abnormal in chronic mylogenous leukemia (CML) patients. However, the molecular mechanisms of these altered functions are unknown. As expression of the p210bcr-abl oncogene product, a constitutively active tyrosine kinase, is known to have an essential role in the pathogenesis of CML and tyrosine phosphorylation is intimately involved in various aspects of platelet activation, we examined the pattern of protein tyrosine phosphorylation in platelets from 15 CML patients by immunoblotting with a monoclonal antiphosphotyrosine antibody (4G10). Before and after stimulation with thrombin, the only consistent difference between normal and CML platelets was the presence of a tyrosine phosphorylated protein with a relative molecular weight of 39 kD. This tyrosine phosphorylated protein was identified as crid, an SH2, SH3 containing adapter protein. Thus, as previously demonstrated for neutrophils from CML patients, tyrosine phosphorylation of p39crkl persists in mature platelets. No tyrosine phosphorylation of crid was detected following stimulation with thrombin in normal platelets. However, crkl became incorporated into the Triton X-100 insoluble residue following thrombin stimulation in a manner dependent on platelet aggregation. Further, we found that crkl is an endogenous substrate for calpain, a protease that may be involved in postaggregation signaling processes. This suggests that crkl may be involved in the reorganization of the cytoskeleton during normal platelet aggregation and its tyrosine phosphorylation in CML platelets may contribute to the abnormal platelet function in CML patients. Finally, we found that thrombopoietin induces tyrosine phosphorylation of crk1 in normal platelets and FDCP cells genetically engineered to express human c-Mpl. This suggests that crk1 can be phosphorylated by a kinase other than p210bcr-abl and that crk1 may have a role in signaling by thrombopoietin.

scholarly journals A Compass To Boost Navigation: Cell Biology of Bacterial Magnetotaxis

2020 ◽  
Vol 202 (21) ◽  
Author(s):  
Frank D. Müller ◽  
Dirk Schüler ◽  
Daniel Pfeiffer
Keyword(s):  
Magnetic Field ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Magnetotactic Bacteria ◽  
Genetically Engineered ◽  
Model Organisms ◽  
Complex Cell ◽  
Magnetite Biomineralization ◽  
Directed Motility ◽  
The Impact

ABSTRACT Magnetotactic bacteria are aquatic or sediment-dwelling microorganisms able to take advantage of the Earth’s magnetic field for directed motility. The source of this amazing trait is magnetosomes, unique organelles used to synthesize single nanometer-sized crystals of magnetic iron minerals that are queued up to build an intracellular compass. Most of these microorganisms cannot be cultivated under controlled conditions, much less genetically engineered, with only few exceptions. However, two of the genetically amenable Magnetospirillum species have emerged as tractable model organisms to study magnetosome formation and magnetotaxis. Recently, much has been revealed about the process of magnetosome biogenesis and dedicated structures for magnetosome dynamics and positioning, which suggest an unexpected cellular intricacy of these organisms. In this minireview, we summarize new insights and place the molecular mechanisms of magnetosome formation in the context of the complex cell biology of Magnetospirillum spp. First, we provide an overview on magnetosome vesicle synthesis and magnetite biomineralization, followed by a discussion of the perceptions of dynamic organelle positioning and its biological implications, which highlight that magnetotactic bacteria have evolved sophisticated mechanisms to construct, incorporate, and inherit a unique navigational device. Finally, we discuss the impact of magnetotaxis on motility and its interconnection with chemotaxis, showing that magnetotactic bacteria are outstandingly adapted to lifestyle and habitat.

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