scholarly journals Targeted and non-targeted effects of radiation in mammalian cells: An overview

2021 ◽  
Vol 5 (1) ◽  
pp. 013-019
Author(s):  
Ghosh Rita ◽  
Hansda Surajit

Radiation of different wavelengths can kill living organisms, although, the mechanism of interactions differs depending on their energies. Understanding the interaction of radiation with living cells is important to assess their harmful effects and also to identify their therapeutic potential. Temporally, this interaction can be broadly divided in three stages – physical, chemical and biological. While radiation can affect all the important macromolecules of the cells, particularly important is the damage to its genetic material, the DNA. The consequences of irradiation include- DNA damage, mutation, cross-linkages with other molecules, chromosomal aberrations and DNA repair leading to altered gene expression and/or cell death. Mutations in DNA can lead to heritable changes and is important for the induction of cancer. While some of these effects are through direct interaction of radiation with the target, radiation can interact with the surrounding environment to result in its indirect actions. The effects of radiation depend not only on the total dose but also on the dose rate, LET etc. and also on the cell types. However, action of radiation on organisms is not restricted to interactions with irradiated cells, i.e. target cells alone; it also exerts non-targeted effects on neighboring unexposed cells to produce productive responses; this is known as bystander effect. The bystander effects of ionizing radiations are well documented and contribute largely to the relapse of cancer and secondary tumors after radiotherapy. Irradiation of cells with non-ionizing Ultra-Violet light also exhibits bystander responses, but such responses are very distinct from that produced by ionizing radiations.

2003 ◽  
Vol 2003 (2) ◽  
pp. 79-91 ◽  
Author(s):  
Lindsay J. Stanbridge ◽  
Vincent Dussupt ◽  
Norman J. Maitland

Current curative strategies for prostate cancer are restricted to the primary tumour, and the effect of treatments to control metastatic disease is not sustained. Therefore, the application of gene therapy to prostate cancer is an attractive alternative. Baculoviruses are highly restricted insect viruses, which can enter, but not replicate in mammalian cells. Baculoviruses can incorporate large amounts of extra genetic material, and will express transgenes in mammalian cells when under the control of a mammalian or strong viral promoter. Successful gene delivery has been achieved both in vitro and in vivo and into both dividing and nondividing cells, which is important since prostate cancers divide relatively slowly. In addition, the envelope protein gp64 is sufficiently mutable to allow targeted transduction of particular cell types. In this review, the advantages of using baculoviruses for prostate cancer gene therapy are explored, and the mechanisms of viral entry and transgene expression are described.


2020 ◽  
Vol 21 (23) ◽  
pp. 9092
Author(s):  
Waheed Ur Rahman ◽  
Adriana Osickova ◽  
Nela Klimova ◽  
Jinery Lora ◽  
Nataliya Balashova ◽  
...  

The Gram-negative coccobacillus Kingella kingae is increasingly recognized as an important invasive pediatric pathogen that causes mostly bacteremia and skeletal system infections. K. kingae secretes an RtxA toxin that belongs to a broad family of the RTX (Repeats in ToXin) cytotoxins produced by bacterial pathogens. Recently, we demonstrated that membrane cholesterol facilitates interaction of RtxA with target cells, but other cell surface structures potentially involved in toxin binding to cells remain unknown. We show that deglycosylation of cell surface structures by glycosidase treatment, or inhibition of protein N- and O-glycosylation by chemical inhibitors substantially reduces RtxA binding to target cells. Consequently, the deglycosylated cells were more resistant to cytotoxic activity of RtxA. Moreover, experiments on cells expressing or lacking cell surface integrins of the β2 family revealed that, unlike some other cytotoxins of the RTX family, K. kingae RtxA does not bind target cells via the β2 integrins. Our results, hence, show that RtxA binds cell surface oligosaccharides present on all mammalian cells but not the leukocyte-restricted β2 integrins. This explains the previously observed interaction of the toxin with a broad range of cell types of various mammalian species and reveals that RtxA belongs to the group of broadly cytolytic RTX hemolysins.


Materials ◽  
2019 ◽  
Vol 12 (17) ◽  
pp. 2671 ◽  
Author(s):  
Jana Váňová ◽  
Alžběta Hejtmánková ◽  
Marie Hubálek Kalbáčová ◽  
Hana Španielová

Viral particles (VPs) have evolved so as to efficiently enter target cells and to deliver their genetic material. The current state of knowledge allows us to use VPs in the field of biomedicine as nanoparticles that are safe, easy to manipulate, inherently biocompatible, biodegradable, and capable of transporting various cargoes into specific cells. Despite the fact that these virus-based nanoparticles constitute the most common vectors used in clinical practice, the need remains for further improvement in this area. The aim of this review is to discuss the potential for enhancing the efficiency and versatility of VPs via their functionalization with cell-penetrating peptides (CPPs), short peptides that are able to translocate across cellular membranes and to transport various substances with them. The review provides and describes various examples of and means of exploitation of CPPs in order to enhance the delivery of VPs into permissive cells and/or to allow them to enter a broad range of cell types. Moreover, it is possible that CPPs are capable of changing the immunogenic properties of VPs, which could lead to an improvement in their clinical application. The review also discusses strategies aimed at the modification of VPs by CPPs so as to create a useful cargo delivery tool.


Viruses ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 1103 ◽  
Author(s):  
Luis Apolonia

Lentiviral vectors have been developed and used in multiple gene and cell therapy applications. One of their main advantages over other vectors is the ability to integrate the genetic material into the genome of the host. However, this can also be a disadvantage as it may lead to insertional mutagenesis. To address this, non-integrating lentiviral vectors (NILVs) were developed. To generate NILVs, it is possible to introduce mutations in the viral enzyme integrase and/or mutations on the viral DNA recognised by integrase (the attachment sites). NILVs are able to stably express transgenes from episomal DNA in non-dividing cells or transiently if the target cells divide. It has been shown that these vectors are able to transduce multiple cell types and tissues. These characteristics make NILVs ideal vectors to use in vaccination and immunotherapies, among other applications. They also open future prospects for NILVs as tools for the delivery of CRISPR/Cas9 components, a recent revolutionary technology now widely used for gene editing and repair.


2013 ◽  
Vol 42 (4) ◽  
pp. e28-e28 ◽  
Author(s):  
Yujia Cai ◽  
Rasmus O. Bak ◽  
Louise Bechmann Krogh ◽  
Nicklas H. Staunstrup ◽  
Brian Moldt ◽  
...  

Abstract DNA transposon-based vectors have emerged as gene vehicles with a wide biomedical and therapeutic potential. So far, genomic insertion of such vectors has relied on the co-delivery of genetic material encoding the gene-inserting transposase protein, raising concerns related to persistent expression, insertional mutagenesis and cytotoxicity. This report describes potent DNA transposition achieved by direct delivery of transposase protein. By adapting integrase-deficient lentiviral particles (LPs) as carriers of the hyperactive piggyBac transposase protein (hyPBase), we demonstrate rates of DNA transposition that are comparable with the efficiency of a conventional plasmid-based strategy. Embedded in the Gag polypeptide, hyPBase is robustly incorporated into LPs and liberated from the viral proteins by the viral protease during particle maturation. We demonstrate lentiviral co-delivery of the transposase protein and vector RNA carrying the transposon sequence, allowing robust DNA transposition in a variety of cell types. Importantly, this novel delivery method facilitates a balanced cellular uptake of hyPBase, as shown by confocal microscopy, and allows high-efficiency production of clones harboring a single transposon insertion. Our findings establish engineered LPs as a new tool for transposase delivery. We believe that protein transduction methods will increase applicability and safety of DNA transposon-based vector technologies.


2020 ◽  
Author(s):  
Ekapot Singsuksawat ◽  
Suppachoke Onnome ◽  
Pratsaneeyaporn Posiri ◽  
Amporn Suphatrakul ◽  
Nittaya Srisuk ◽  
...  

SummaryWith sequencing as a standard frontline protocol to identify emerging viruses such zika virus and SARS-CoV2, direct utilization of sequence data to program antivirals against the viruses could accelerate drug development to treat their infections. CRISPR-Cas effectors are promising candidates that could be programmed to inactivate viral genetic material based on sequence data but several challenges such as delivery and design of effective crRNA need to be addressed to realize practical use. Here, we showed that virus-like particle (VLP) could deliver PspCas13b-crRNA ribonucleoprotein (RNP) in nanomolar range to efficiently suppress dengue virus infection in primary human target cells. Shortening spacer length could significantly enhance RNA-targeting efficiency of PspCas13b in mammalian cells compared to the natural length of 30 nucleotides without compromising multiplex targeting by a crRNA array. Our results demonstrate the potentials of applying PspCas13b RNP to suppress RNA virus infection, with implications in targeting host RNA as well.


Author(s):  
Manuel Albanese ◽  
Yen-Fu Adam Chen ◽  
Corinna Hüls ◽  
Kathrin Gärtner ◽  
Takanobu Tagawa ◽  
...  

ABSTRACTMammalian cells release different types of vesicles, collectively termed extracellular vesicles (EVs). EVs contain cellular microRNAs (miRNAs) with an apparent potential to deliver their miRNA cargo to recipient cells to affect the stability of individual mRNAs and the cells’ transcriptome. The extent to which miRNAs are exported via the EV route and whether they contribute to cell-cell communication are controversial. To address these issues, we analyzed the capacity of EVs to deliver packaged miRNAs into target cells and to exert biological functions. We applied well-defined approaches to produce and characterize purified EVs with or without specific viral miRNAs. We found that only a small fraction of EVs carried miRNAs. EVs readily bound to different target cell types, but there was no EV-cell membrane fusion or delivery of cargo. Importantly, the functionality of cells exposed to miRNA-carrying EVs was not affected. These results suggest EV-borne miRNAs do not act as effectors and question their relevancy in paracrine cell-to-cell communication.AUTHOR SUMMARYThe majority of metazoan cells release vesicles of different types and origins, such as exosomes and microvesicles, now collectively termed extracellular vesicles (EVs). EVs have gained much attention because they contain microRNAs (miRNAs) and thus could regulate their specific mRNA targets in recipient or acceptor cells that take up EVs. Using a novel fusion assay with superior sensitivity and specificity, we revisited this claim but found no convincing evidence for an efficient functional uptake of EVs in many different cell lines and primary human blood cells. Even EVs engineered to fuse and deliver their miRNA cargo to recipient cells had no measurable effect on target mRNAs in very carefully controlled, quantitative experiments. Our negative results clearly indicate that EVs do not act as vehicles for miRNA-based cell-to-cell communication.


2002 ◽  
Vol 2 ◽  
pp. 684-689 ◽  
Author(s):  
Peter M.C. Wong

Host innate immune response represents a vital immediate defense against infections by a diverse group of microorganisms that include bacteria, viruses, and fungi. Many types of cell surface receptors in mammalian cells specifically recognize particular groups of microorganisms and transmit response signals to the nuclei via multiple signal transduction pathways. These signaling pathways must merge at some point and are likely to be redundant, as the host innate immune response to many microorganisms is remarkably similar; it is characterized by the production of proinflammatory cytokines such as TNFα, IL-1, and IL-6 by the principal cell types – macrophages and dendritic cells. Since these cytokines influence greatly the magnitude of the cascade of inflammatory events, the proportion and the actual amount of each among the cytokine group may be a characteristic of each type of infections. Immune modulation by systematically up-regulate or down-modulate these cytokines would conceivably have major therapeutic potential. We have recently shown that two alleles of Ran cDNAs – RanT/n and RanC/d – may possess these characteristics. Thus the applica-tion of Ran to the treatment of septic shock, lethal anthrax shock, or adenovirus-induced toxicities may open up many interesting possibilities in the future.


Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 467 ◽  
Author(s):  
Carl Harrell ◽  
Crissy Fellabaum ◽  
Nemanja Jovicic ◽  
Valentin Djonov ◽  
Nebojsa Arsenijevic ◽  
...  

Mesenchymal stem cell (MSC)-sourced secretome, defined as the set of MSC-derived bioactive factors (soluble proteins, nucleic acids, lipids and extracellular vesicles), showed therapeutic effects similar to those observed after transplantation of MSCs. MSC-derived secretome may bypass many side effects of MSC-based therapy, including unwanted differentiation of engrafted MSCs. In contrast to MSCs which had to be expanded in culture to reach optimal cell number for transplantation, MSC-sourced secretome is immediately available for treatment of acute conditions, including fulminant hepatitis, cerebral ischemia and myocardial infarction. Additionally, MSC-derived secretome could be massively produced from commercially available cell lines avoiding invasive cell collection procedure. In this review article we emphasized molecular and cellular mechanisms that were responsible for beneficial effects of MSC-derived secretomes in the treatment of degenerative and inflammatory diseases of hepatobiliary, respiratory, musculoskeletal, gastrointestinal, cardiovascular and nervous system. Results obtained in a large number of studies suggested that administration of MSC-derived secretomes represents a new, cell-free therapeutic approach for attenuation of inflammatory and degenerative diseases. Therapeutic effects of MSC-sourced secretomes relied on their capacity to deliver genetic material, growth and immunomodulatory factors to the target cells enabling activation of anti-apoptotic and pro-survival pathways that resulted in tissue repair and regeneration.


PLoS Genetics ◽  
2021 ◽  
Vol 17 (12) ◽  
pp. e1009951
Author(s):  
Manuel Albanese ◽  
Yen-Fu Adam Chen ◽  
Corinna Hüls ◽  
Kathrin Gärtner ◽  
Takanobu Tagawa ◽  
...  

Mammalian cells release different types of vesicles, collectively termed extracellular vesicles (EVs). EVs contain cellular microRNAs (miRNAs) with an apparent potential to deliver their miRNA cargo to recipient cells to affect the stability of individual mRNAs and the cells’ transcriptome. The extent to which miRNAs are exported via the EV route and whether they contribute to cell-cell communication are controversial. To address these issues, we defined multiple properties of EVs and analyzed their capacity to deliver packaged miRNAs into target cells to exert biological functions. We applied well-defined approaches to produce and characterize purified EVs with or without specific viral miRNAs. We found that only a small fraction of EVs carried miRNAs. EVs readily bound to different target cell types, but EVs did not fuse detectably with cellular membranes to deliver their cargo. We engineered EVs to be fusogenic and document their capacity to deliver functional messenger RNAs. Engineered fusogenic EVs, however, did not detectably alter the functionality of cells exposed to miRNA-carrying EVs. These results suggest that EV-borne miRNAs do not act as effectors of cell-to-cell communication.


Sign in / Sign up

Export Citation Format

Share Document