scholarly journals Activation of Innate Immunity by Therapeutic Nucleic Acids

2021 ◽  
Vol 22 (24) ◽  
pp. 13360
Author(s):  
Ali Bishani ◽  
Elena L. Chernolovskaya
Keyword(s):  
Innate Immunity ◽  
Nucleic Acids ◽  
Target Cells ◽  
Unresolved Issue ◽  
Wide Range ◽  
Low Toxicity ◽  
Cytokine Synthesis ◽  
Excessive Secretion ◽  
Anti Inflammatory Cytokine ◽  
Stimulation Of

Nucleic acid-based therapeutics have gained increased attention during recent decades because of their wide range of application prospects. Immunostimulatory nucleic acids represent a promising class of potential drugs for the treatment of tumoral and viral diseases due to their low toxicity and stimulation of the body’s own innate immunity by acting on the natural mechanisms of its activation. The repertoire of nucleic acids that directly interact with the components of the immune system is expanding with the improvement of both analytical methods and methods for the synthesis of nucleic acids and their derivatives. Despite the obvious progress in this area, the problem of delivering therapeutic acids to target cells as well as the unresolved issue of achieving a specific therapeutic effect based on activating the mechanism of interferon and anti-inflammatory cytokine synthesis. Minimizing the undesirable effects of excessive secretion of inflammatory cytokines remains an unsolved task. This review examines recent data on the types of immunostimulatory nucleic acids, the receptors interacting with them, and the mechanisms of immunity activation under the action of these molecules. Finally, data on immunostimulatory nucleic acids in ongoing and completed clinical trials will be summarized.

scholarly journals An optimized live bacterial delivery platform for the production and delivery of therapeutic nucleic acids and proteins

2021 ◽  
Author(s):  
Darcy S.O. Mora ◽  
Madeline Cox ◽  
Forgivemore Magunda ◽  
Ashley B. Williams ◽  
Lyndsey Linke
Keyword(s):  
Epithelial Cells ◽  
Mouse Model ◽  
Nucleic Acids ◽  
Endosomal Escape ◽  
Therapeutic Window ◽  
Target Cells ◽  
Full Potential ◽  
Wide Range ◽  
Delivery Platform

There is an unmet need for delivery platforms that realize the full potential of next-generation therapeutic and vaccine technologies, especially those that require intracellular delivery of nucleic acids. The in vivo usefulness of the current state-of-the-art delivery systems is limited by numerous intrinsic weaknesses, including lack of targeting specificity, inefficient entry and endosomal escape into target cells, undesirable immune activation, off-target effects, a small therapeutic window, limited genetic encoding and cargo capacity, and manufacturing challenges. Here we present our characterization of a delivery platform based on the use of engineered live, tissue-targeting, non-pathogenic bacteria (Escherichia coli strain SVC1) for intracellular cargo delivery. The SVC1 bacteria are engineered to specifically bind to epithelial cells via a surface-expressed targeting ligand, to escape the endosome upon intracellularization, and to have minimal immunogenicity. Here we report findings on key features of this system. First, we demonstrated that bacterial delivery of a short hairpin RNA (shRNA) can target and silence a gene in an in vitro mammalian respiratory cell model. Next, we used an in vivo mouse model to demonstrate that SVC1 bacteria are invasive to epithelial cells of various tissues and organs (eye, nose, mouth, stomach, vagina, skeletal muscle, and lungs) via local administration. We also showed that repeat dosing of SVC1 bacteria to the lungs is minimally immunogenic and that it does not have adverse effects on tissue homeostasis. Finally, to validate the potential of SVC1 bacteria in therapeutic applications, we demonstrated that bacterial delivery of influenza- targeting shRNAs to the respiratory tissues can mitigate viral replication in a mouse model of influenza infection. Our ongoing work is focused on further refining this platform for efficient delivery of nucleic acids, gene editing machinery, and therapeutic proteins, and we expect that this platform technology will enable a wide range of advanced therapeutic approaches.

Gene therapy promises accurate, targeted administration and overcoming drug resistance in diverse cancer cells

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Drug Resistance ◽  
Nucleic Acid ◽  
Nucleic Acids ◽  
Clinical Research ◽  
Cancer Cells ◽  
Cationic Lipids ◽  
Target Cells ◽  
Genetic Components ◽  
Wide Range

Nucleic acid-based therapeutics such as siRNA and miRNA employ the silencing capabilities of the RNAi mechanism to affect the expression of one gene or several genes in target cells. Nucleic acid-based therapies enable accurate, targeted administration and overcoming drug resistance in diverse cancer cells. Several studies have shown that they can be utilized alongside pharmacological therapy to increase the efficacy of existing therapies. In addition, nucleic acid-based therapies have the potential to widen the spectrum of druggable targets for a range of diseases and emerge as a novel therapeutic technique for treating a number of diseases that are today untreatable. Nucleic acids are dependent on their effective distribution to target cells, which need correct complexation and encapsulation in a delivery mechanism. Although nucleic acids exist in a variety of forms and sizes, their physical and chemical commonality allow them to be loaded into a wide range of delivery vehicles. The primary biomaterials used to encapsulate genetic components were cationic lipids and polymers. Furthermore, the experiments focused particularly on effective transfection in target cells.Recent breakthroughs in NP-based RNA therapeutics have spurred a flood of clinical research, facing many challenges. In vivo, pharmacokinetics of different RNA-based medications must be researched to establish the viability and therapeutic potential of nucleic acid-based therapeutics. The U.S. Food and Drug Administration recently authorized many NP-based gene therapy. In 2019, Novartis authorized Zolgensma (onasemnogene abeparvovec-xioi) to treat spinal muscle atrophy. The first clinical research employing siRNA began in 2004 and is considered a milestone in nucleic acid-based drug development. Thirty clinical investigations have subsequently been completed. In 2018, the US FDA cleared Onpattro (Patisiran, Alnylam Pharmaceuticals) for the treatment of polyneuropathy caused by transthyretin amyloidosis.Several new generations of nucleic acid compositions employing polymer nanoparticles or liposomes are presently undergoing clinical testing. If allowed, the debut of nucleic acid-based treatments would represent a watershed event in immunotherapy. Advances in the design and development of biocompatible nanomaterials would allow us to overcome the above-mentioned problems and so show the potential to deliver nucleic acids in the treatment of a number of illnesses.

Carbon Dots for Bacterial Detection and Antibacterial Applications-A Minireview

2020 ◽  
Vol 25 (46) ◽  
pp. 4848-4860 ◽  
Author(s):  
Anisha Anand ◽  
Gopinathan Manavalan ◽  
Ranju Prasad Mandal ◽  
Huan-Tsung Chang ◽  
Yi-Ru Chiou ◽  
...  
Keyword(s):  
Optical Properties ◽  
Carbon Dots ◽  
Antibacterial Effect ◽  
Bacterial Detection ◽  
High Brightness ◽  
Photo Catalysis ◽  
Wide Range ◽  
Prevention And Treatment ◽  
Low Toxicity ◽  
Conventional Antibiotics

: The prevention and treatment of various infections caused by microbes through antibiotics are becoming less effective due to antimicrobial resistance. Researches are focused on antimicrobial nanomaterials to inhibit bacterial growth and destroy the cells, to replace conventional antibiotics. Recently, carbon dots (C-Dots) become attractive candidates for a wide range of applications, including the detection and treatment of pathogens. In addition to low toxicity, ease of synthesis and functionalization, and high biocompatibility, C-Dots show excellent optical properties such as multi-emission, high brightness, and photostability. C-Dots have shown great potential in various fields, such as biosensing, nanomedicine, photo-catalysis, and bioimaging. This review focuses on the origin and synthesis of various C-Dots with special emphasis on bacterial detection, the antibacterial effect of CDots, and their mechanism.

Enzymes as a Reservoir of Host Defence Peptides

2020 ◽  
Vol 20 (14) ◽  
pp. 1310-1323
Author(s):  
Andrea Bosso ◽  
Antimo Di Maro ◽  
Valeria Cafaro ◽  
Alberto Di Donato ◽  
Eugenio Notomista ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Biological Activity ◽  
Internal Structure ◽  
Catalytic Properties ◽  
Cellular Responses ◽  
Host Defence ◽  
Present Review ◽  
Active Peptides ◽  
Wide Range

Host defence peptides (HDPs) are powerful modulators of cellular responses to various types of insults caused by pathogen agents. To date, a wide range of HDPs, from species of different kingdoms including bacteria, plant and animal with extreme diversity in structure and biological activity, have been described. Apart from a limited number of peptides ribosomally synthesized, a large number of promising and multifunctional HDPs have been identified within protein precursors, with properties not necessarily related to innate immunity, consolidating the fascinating hypothesis that proteins have a second or even multiple biological mission in the form of one or more bio-active peptides. Among these precursors, enzymes constitute certainly an interesting group, because most of them are mainly globular and characterized by a fine specific internal structure closely related to their catalytic properties and also because they are yet little considered as potential HDP releasing proteins. In this regard, the main aim of the present review is to describe a panel of HDPs, identified in all canonical classes of enzymes, and to provide a detailed description on hydrolases and their corresponding HDPs, as there seems to exist a striking link between these structurally sophisticated catalysts and their high content in cationic and amphipathic cryptic peptides.

Kaempferol Improves TRAIL-Mediated Apoptosis in Leukemia MOLT-4 Cells by the Inhibition of Anti-apoptotic Proteins and Promotion of Death Receptors Expression

2019 ◽  
Vol 19 (15) ◽  
pp. 1835-1845
Author(s):  
Ali Hassanzadeh ◽  
Adel Naimi ◽  
Majid F. Hagh ◽  
Raedeh Saraei ◽  
Faroogh Marofi ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Cancer Cells ◽  
Tumor Necrosis ◽  
Lymphoblastic Leukemia ◽  
Annexin V ◽  
Death Receptors ◽  
Target Cells ◽  
Wide Range ◽  
Apoptotic Proteins ◽  
Necrosis Factor

Introduction: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) is a member of the tumor necrosis factor (TNF) superfamily, which stimulates apoptosis in a wide range of cancer cells via binding to death receptors 4 and 5 (DR4/5). Nevertheless, TRAIL has noticeable anti-cancer abilities; some cancer cells acquire resistance to TRAIL, and consequently its potential for inducing apoptosis in target cells is strongly diminished. Acute lymphoblastic leukemia MOLT-4 cell line is one of the most resistant cells to TRAIL that developed resistance to TRAIL via different pathways. We used TRAIL plus kaempferol to eliminate resistance of the MOLT-4 cells to TRAIL. Material and Methods: First, IC50 for kaempferol (95 µM) was determined by using the MTT assay. Second, the viability of the MOLT-4 cells was assayed by FACS after Annexin V/PI staining, following treatment with TRAIL (50 and 100 nM) and kaempferol (95 µM) alone and together. Finally, the expression levels of the candidate genes involved in resistance to TRAIL were assayed by real-time PCR technique. Results: Kaempferol plus TRAIL induced apoptosis robustly in MOLT-4 cells at 12, 24 and 48 hours after treatment. Additionally, we found that kaempferol could inhibit expression of the c-FLIP, X-IAP, cIAP1/2, FGF-8 and VEGF-beta, and conversely augment expression of the DR4/5 in MOLT-4 cells. Conclusion: We suggest that co-treatment of MOLT-4 cells with TRAIL plus kaempferol is a practical and attractive approach to eliminate cancers’ resistance to TRAIL via inhibition of the intracellular anti-apoptotic proteins, upregulation of DR4/5 and also by suppression of the VEGF-beta (VEGFB) and FGF-8 expressions.

scholarly journals Toxic or Not Toxic, That Is the Carbon Quantum Dot’s Question: A Comprehensive Evaluation with Zebrafish Embryo, Eleutheroembryo, and Adult Models

Polymers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1598
Author(s):  
Chih-Yu Chung ◽  
Yu-Ju Chen ◽  
Chia-Hui Kang ◽  
Hung-Yun Lin ◽  
Chih-Ching Huang ◽  
...  
Keyword(s):  
Zebrafish Embryo ◽  
Comprehensive Evaluation ◽  
Aquatic Organisms ◽  
Carbon Quantum Dots ◽  
Adult Zebrafish ◽  
Fish Embryo ◽  
Wide Range ◽  
Different Types ◽  
Low Toxicity

Carbon quantum dots (CQDs) are emerging novel nanomaterials with a wide range of applications and high biocompatibility. However, there is a lack of in-depth research on whether CQDs can cause acute or long-term adverse reactions in aquatic organisms. In this study, two different types of CQDs prepared by ammonia citrate and spermidine, namely CQDAC and CQDSpd, were used to evaluate their biocompatibilities. In the fish embryo acute toxicity test (FET), the LD50 of CQDAC and CQDSpd was about 500 and 100 ppm. During the stage of eleutheroembryo, the LD50 decreased to 340 and 55 ppm, respectively. However, both CQDs were quickly eliminated from embryo and eleutheroembryo, indicating a lack of bioaccumulation. Long-term accumulation of CQDs was also performed in this study, and adult zebrafish showed no adverse effects in 12 weeks. In addition, there was no difference in the hatchability and deformity rates of offspring produced by adult zebrafish, regardless of whether they were fed CQDs or not. The results showed that both CQDAC and CQDSpd have low toxicity and bioaccumulation to zebrafish. Moreover, the toxicity assay developed in this study provides a comprehensive platform to assess the impacts of CQDs on aquatic organisms in the future.

scholarly journals Amphipathic Peptide Antibiotics with Potent Activity against Multidrug-Resistant Pathogens

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 438
Author(s):  
Jingru Shi ◽  
Chen Chen ◽  
Dejuan Wang ◽  
Ziwen Tong ◽  
Zhiqiang Wang ◽  
...  
Keyword(s):  
Membrane Damage ◽  
Multidrug Resistant ◽  
Peptide Antibiotics ◽  
Biofilm Inhibition ◽  
Amphipathic Peptide ◽  
Host Defense Peptides ◽  
Gram Negative ◽  
Wide Range ◽  
New Antibiotics ◽  
Low Toxicity

The emergence and prevalence of multidrug-resistant (MDR) bacteria have posed a serious threat to public health. Of particular concern are methicillin-resistant Staphylococcus aureus (MRSA) and blaNDM, mcr-1 and tet(X)-positive Gram-negative pathogens. The fact that few new antibiotics have been approved in recent years exacerbates this global crisis, thus, new alternatives are urgently needed. Antimicrobial peptides (AMPs) originated from host defense peptides with a wide range of sources and multiple functions, are less prone to achieve resistance. All these characteristics laid the foundation for AMPs to become potential antibiotic candidates. In this study, we revealed that peptide WW307 displayed potent antibacterial and bactericidal activity against MDR bacteria, including MRSA and Gram-negative bacteria carrying blaNDM-5, mcr-1 or tet(X4). In addition, WW307 exhibited great biofilm inhibition and eradication activity. Safety and stability experiments showed that WW307 had a strong resistance against various physiological conditions and displayed relatively low toxicity. Mechanistic experiments showed that WW307 resulted in membrane damage by selectively targeting bacterial membrane-specific components, including lipopolysaccharide (LPS), phosphatidylglycerol (PG), and cardiolipin (CL). Moreover, WW307 dissipated membrane potential and triggered the production of reactive oxygen species (ROS). Collectively, these results demonstrated that WW307 represents a promising candidate for combating MDR pathogens.

Dihydroquercetin as potential immunonutrient in treatment of COVID-19

2021 ◽  
pp. 28-32
Author(s):  
V. V. Tatarinov ◽  
S. V. Orlova ◽  
E. A. Nikitina ◽  
E. V. Prokopenko ◽  
A. N. Vodolazkaya ◽  
...  
Keyword(s):  
Biological Activity ◽  
Recovery Period ◽  
Enzymatic Reactions ◽  
Target Organs ◽  
Wide Range ◽  
Complex Therapy ◽  
Main Target ◽  
Low Toxicity ◽  
Anti Inflammatory

The main aspects of the antiviral, anti-inflammatory, antioxidant and hepatoprotective properties of dihydroquercetin (DHQ), which may affect the course of COVID-19, are considered. Given the low toxicity and a wide range of biological activity, aimed not only at suppressing enzymatic reactions with the participation of coronavirus, but also at eliminating the lesions caused by it in all the main target organs, dihydroquercetin can be recommended for inclusion in the complex therapy of the disease and during the recovery period of COVID-19.

Gustatory neural coding in the monkey cortex: stimulus quality

1991 ◽  
Vol 66 (4) ◽  
pp. 1156-1165 ◽  
Author(s):  
V. L. Smith-Swintosky ◽  
C. R. Plata-Salaman ◽  
T. R. Scott
Keyword(s):  
Cortical Neurons ◽  
Neural Coding ◽  
Monosodium Glutamate ◽  
Stimulus Array ◽  
Cortical Region ◽  
Stimulus Similarity ◽  
Somatosensory Stimulation ◽  
Wide Range ◽  
Response Profiles ◽  
Stimulation Of

1. Extracellular action potentials were recorded from 50 single neurons in the insular-opercular cortex of two alert cynomolgus monkeys during gustatory stimulation of the tongue and palate. 2. Sixteen stimuli, including salts, sugars, acids, alkaloids, monosodium glutamate, and aspartame, were chosen to represent a wide range of taste qualities. Concentrations were selected to elicit a moderate gustatory response, as determined by reference to previous electrophysiological data or to the human psychophysical literature. 3. The cortical region over which taste-evoked activity could be recorded included the frontal operculum and anterior insula, an area of approximately 75 mm3. Taste-responsive cells constituted 50 (2.7%) of the 1,863 neurons tested. Nongustatory cells responded to mouth movement (20.7%), somatosensory stimulation of the tongue (9.6%), stimulus approach or anticipation (1.7%), and tongue extension (0.6%). The sensitivities of 64.6% of these cortical neurons could not be identified by our stimulation techniques. 4. Taste cells had low spontaneous activity levels (3.7 +/- 3.0 spikes/s, mean +/- SD) and showed little inhibition. They were moderately broadly tuned, with a mean entropy coefficient of 0.76 +/- 0.17. Excitatory responses were typically not robust. 5. Hierarchical cluster analysis was used to determine whether neurons could be divided into discrete types, as defined by their response profiles to the entire stimulus array. There was an apparent division of response profiles into four general categories, with primary sensitivities to sodium (n = 18), glucose (n = 15), quinine (n = 12), and acid (n = 5). However, these categories were not statistically independent. Therefore the notion of functionally distinct neuron types was not supported by an analysis of the distribution of response profiles. It was the case, however, that neurons in the sodium category could be distinguished from other neurons by their relative specificity. 6. The similarity among the taste qualities represented by this stimulus array was assessed by calculating correlations between the activity profiles they elicited from these 50 neurons. The results generally confirmed expectations derived from human psychophysical studies. In a multidimensional representation of stimulus similarity, there were groups that contained acids, sodium salts, and chemicals that humans label bitter and sweet. 7. The small proportion of insular-opercular neurons that are taste sensitive and the low discharge rates that taste stimuli are able to evoke from them suggest a wider role for this cortical area than just gustatory coding.(ABSTRACT TRUNCATED AT 400 WORDS)

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