scholarly journals A stem-loop RNA RIG-I agonist protects against acute and chronic SARS-CoV-2 infection in mice

2021 ◽  
Vol 219 (1) ◽  
Author(s):  
Tianyang Mao ◽  
Benjamin Israelow ◽  
Carolina Lucas ◽  
Chantal B.F. Vogels ◽  
Maria Luisa Gomez-Calvo ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Severe Disease ◽  
Adaptive Immune System ◽  
Type I ◽  
Dependent Manner ◽  
Protective Capacity ◽  
Viral Control ◽  
Stem Loop ◽  
Immunodeficient Mice ◽  
Immunosuppressed Patients

As SARS-CoV-2 continues to cause morbidity and mortality around the world, there is an urgent need for the development of effective medical countermeasures. Here, we assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in viral control, disease prevention, post-infection therapy, and cross-variant protection in mouse models of SARS-CoV-2 infection. A single dose of SLR14 prevented viral infection in the lower respiratory tract and development of severe disease in a type I interferon (IFN-I)–dependent manner. SLR14 demonstrated remarkable prophylactic protective capacity against lethal SARS-CoV-2 infection and retained considerable efficacy as a therapeutic agent. In immunodeficient mice carrying chronic SARS-CoV-2 infection, SLR14 elicited near-sterilizing innate immunity in the absence of the adaptive immune system. In the context of infection with variants of concern (VOCs), SLR14 conferred broad protection against emerging VOCs. These findings demonstrate the therapeutic potential of SLR14 as a host-directed, broad-spectrum antiviral for early post-exposure treatment and treatment of chronically infected immunosuppressed patients.

scholarly journals A stem-loop RNA RIG-I agonist confers prophylactic and therapeutic protection against acute and chronic SARS-CoV-2 infection in mice

2021 ◽  
Author(s):  
Tianyang Mao ◽  
Benjamin Israelow ◽  
Carolina Lucas ◽  
Chantal B. F. Vogels ◽  
Olga Fedorova ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Severe Disease ◽  
Adaptive Immune System ◽  
Type I ◽  
Dependent Manner ◽  
Protective Capacity ◽  
Viral Control ◽  
Stem Loop ◽  
Immunodeficient Mice ◽  
Immunosuppressed Patients

As SARS-CoV-2 continues to cause morbidity and mortality around the world, there is an urgent need for the development of effective medical countermeasures. Here, we assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in viral control, disease prevention, post-infection therapy, and cross-variant protection in mouse models of SARS-CoV-2 infection. A single dose of SLR14 prevented viral replication in the lower respiratory tract and development of severe disease in a type I interferon (IFN-I) dependent manner. SLR14 demonstrated remarkable protective capacity against lethal SARS-CoV-2 infection when used prophylactically and retained considerable efficacy as a therapeutic agent. In immunodeficient mice carrying chronic SARS-CoV-2 infection, SLR14 elicited near-sterilizing innate immunity by inducing IFN-I responses in the absence of the adaptive immune system. In the context of infection with variants of concern (VOC), SLR14 conferred broad protection and uncovered an IFN-I resistance gradient across emerging VOC. These findings demonstrate the therapeutic potential of SLR14 as a host-directed, broad-spectrum antiviral for early post-exposure treatment and for treatment of chronically infected immunosuppressed patients.

U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7

Blood ◽  
2006 ◽  
Vol 107 (8) ◽  
pp. 3229-3234 ◽  
Author(s):  
Emina Savarese ◽  
Ohk-wha Chae ◽  
Simon Trowitzsch ◽  
Gert Weber ◽  
Berthold Kastner ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lupus Erythematosus ◽  
Immune Complexes ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Dependent Manner ◽  
Stem Loop ◽  
Murine Bone Marrow ◽  
Small Nuclear Ribonucleoprotein ◽  
Nuclear Antigens

Abstract Plasmacytoid dendritic cells (PDCs), which produce IFN-α in response to autoimmune complexes containing nuclear antigens, are thought to be critically involved in the pathogenesis of systemic lupus erythematosus (SLE). One of the immunostimulatory components of SLE immune complexes (SLE-ICs) is self DNA, which is recognized through Tlr9 in PDCs and B cells. Small nuclear ribonucleoproteins (snRNPs) are another major component of SLE-ICs in 30% to 40% of patients. In this study, we show that murine PDCs are activated by purified U1snRNP/anti-Sm ICs to produce IFN-α and proinflammatory cytokines and to up-regulate costimulatory molecules. The induction of IFN-α and IL-6 by U1snRNPs in murine bone marrow–derived PDCs required the presence of intact U1RNA and was largely dependent on Tlr7 but independent of Tlr3. Intracellularly delivered isolated U1snRNA and oligoribonucleotides derived from the stem loop regions and the Sm-binding site of U1snRNA efficiently induced IFN-α and IL-6 in Flt3L-cultured DCs in a Tlr7-dependent manner. The U1snRNA component of U1snRNP immune complexes, found in patients with SLE, acts as an endogenous “self” ligand for Tlr7 and triggers IFN-α and IL-6 production in PDCs.

scholarly journals Use of Fibroquel® (Polymerized type I collagen) in patients with hypoxemic inflammatory pneumonia secondary to COVID-19 in Veracruz, Mexico

2021 ◽  
Vol 13 (1) ◽  
pp. 69-73
Author(s):  
Luis Del Carpio-Orantes ◽  
Sergio García-Méndez ◽  
Jesús Salvador Sánchez-Díaz ◽  
Andrés Aguilar-Silva ◽  
Edna Rosario Contreras-Sánchez ◽  
...  
Keyword(s):  
Pulse Oximetry ◽  
Type I Collagen ◽  
Therapeutic Potential ◽  
Severe Disease ◽  
Specific Treatment ◽  
Ambient Air ◽  
Type I ◽  
Number Of Patients ◽  
Baseline Evaluation ◽  
D Dimer

Since the beginning of the pandemic, there is currently no specific treatment, however some drugs, after systematic reviews and meta-analysis have been positioned as potential treatments (dexamethasone, tocilizumab, baricitinib), however, other drugs with therapeutic potential are being investigated, such as Polymerized type I collagen (Fibroquel). Material and methods: Adult patients are admitted to the study from December 2020 to January 2021, with prior informed consent, carriers of viral pneumonia confirmed by axial tomography, secondary to infection by Sars Cov2 virus identified by RT-PCR or antigen test, who also present severity data (dyspnea, desaturation -saturation at room air of 92% or less-, persistent fever), as well as inflammation markers (D-dimer 1000ng/ml±100; ferritin> 300mg) and that allow treatment with Polymerized type I collagen (Fibroquel®) at home or in a hospital area. Results: We include data from 35 patients, 19 (54.3%) women and 16 (45.7%) men, with a median age of 51.0 (38.0-76.0) years. The number of patients with a history of previous comorbidities was 34 (97.1%) and 20 (57.1%) had multiple comorbidities (3 or more synchronous comorbidities). The most frequent comorbidities among these patients were obesity in 94.3%, DM2 62.9%, Arterial hypertension 60.0%, COPD 14.3%, heart disease 8.6%, nephropathy 5.7%, in addition to SLE and trisomy 21, both in 2.9% of patients. In the baseline evaluation laboratory, we found that 33 (94.3%) patients had lymphocytopenia and 3 (8.6%) had thrombocytopenia. Median D-Dimer and Ferritin serum levels were 1,200.0 (990.0- 1,800.0) ng/mL and 394.5 (320.0-492.5) ug/L, respectively. The neutrophil-lymphocyte index was calculated, which on average was 10.8 (8.0 - 14.7) and an ABC-GOALSclx index of 14.0 (11.0 - 16.0) was calculated, which translate severe disease and an indication of stay in an intensive care unit. Relation to the pulse oximetry at ambient air in the baseline evaluation, we found that the median O2 saturation was 88.0% (86.0% - 89.0%). The median number of days of evolution from the onset of symptoms to the moment in which treatment with Fibroquel was started was 8.0 (7.0-9.0) days. The pulse oximetry quantified 7 days after the start of treatment had a median of 94.0% (93.0-95.0%); Regarding the measurement of prognostic biomarkers, the median d-dimer and ferritin in serum measured at 7 days of follow-up were 656.0 (497.0 - 697.5) ng/mL and 394.5 (320.0-492.5) ug/L, respectively. Conclusion: Polymerized type I collagen (Fibroquel) is an effective drug in patients with inflammatory and hypoxemic pneumonia secondary to Sars COV 2 infection, favoring clinical improvement and favoring extubation, oxygenation, and inflammation indices, as well as a biosafety profile that ensures its use without restrictions in these patients.

Natural Products: Experimental Efficient Agents for Inflammatory Bowel Disease Therapy

2020 ◽  
Vol 25 (46) ◽  
pp. 4893-4913 ◽  
Author(s):  
Fan Cao ◽  
Jie Liu ◽  
Bing-Xian Sha ◽  
Hai-Feng Pan
Keyword(s):  
Inflammatory Bowel Disease ◽  
Natural Products ◽  
Immune System ◽  
Bowel Disease ◽  
Therapeutic Potential ◽  
Adaptive Immune System ◽  
Receptor Protein ◽  
Intestinal Epithelia ◽  
Inflammatory Bowel ◽  
The Individual

: Inflammatory bowel disease (IBD) is a chronic, elusive disorder resulting in relapsing inflammation of intestine with incompletely elucidated etiology, whose two representative forms are ulcerative colitis (UC) and Crohn’s disease (CD). Accumulating researches have revealed that the individual genetic susceptibility, environmental risk elements, intestinal microbial flora, as well as innate and adaptive immune system are implicated in the pathogenesis and development of IBD. Despite remarkable progression of IBD therapy has been achieved by chemical drugs and biological therapies such as aminosalicylates, corticosteroids, antibiotics, anti-tumor necrosis factor (TNF)-α, anti-integrin agents, etc., healing outcome still cannot be obtained, along with inevitable side effects. Consequently, a variety of researches have focused on exploring new therapies, and found that natural products (NPs) isolated from herbs or plants may serve as promising therapeutic agents for IBD through antiinflammatory, anti-oxidant, anti-fibrotic and anti-apoptotic effects, which implicates the modulation on nucleotide- binding domain (NOD) like receptor protein (NLRP) 3 inflammasome, gut microbiota, intestinal microvascular endothelial cells, intestinal epithelia, immune system, etc. In the present review, we will summarize the research development of IBD pathogenesis and current mainstream therapy, as well as the therapeutic potential and intrinsic mechanisms of NPs in IBD.

Isoform-Selective PI3K Inhibitors for Various Diseases

2020 ◽  
Vol 20 (12) ◽  
pp. 1074-1092 ◽  
Author(s):  
Rammohan R.Y. Bheemanaboina
Keyword(s):  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Type I ◽  
Selective Inhibitors ◽  
Pi3k Inhibitors ◽  
Wide Range ◽  
Lipid Kinases ◽  
Isoform Selectivity

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.

scholarly journals Bioengineered model of the human motor unit with physiologically functional neuromuscular junctions

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rowan P. Rimington ◽  
Jacob W. Fleming ◽  
Andrew J. Capel ◽  
Patrick C. Wheeler ◽  
Mark P. Lewis
Keyword(s):  
Neuromuscular Junction ◽  
Motor Neuron ◽  
Motor Unit ◽  
Motor Nerve ◽  
Motor Units ◽  
Extracellular Matrices ◽  
Synaptic Membrane ◽  
Type I ◽  
Dependent Manner ◽  
Human Motor

AbstractInvestigations of the human neuromuscular junction (NMJ) have predominately utilised experimental animals, model organisms, or monolayer cell cultures that fail to represent the physiological complexity of the synapse. Consequently, there remains a paucity of data regarding the development of the human NMJ and a lack of systems that enable investigation of the motor unit. This work addresses this need, providing the methodologies to bioengineer 3D models of the human motor unit. Spheroid culture of iPSC derived motor neuron progenitors augmented the transcription of OLIG2, ISLET1 and SMI32 motor neuron mRNAs ~ 400, ~ 150 and ~ 200-fold respectively compared to monolayer equivalents. Axon projections of adhered spheroids exceeded 1000 μm in monolayer, with transcription of SMI32 and VACHT mRNAs further enhanced by addition to 3D extracellular matrices in a type I collagen concentration dependent manner. Bioengineered skeletal muscles produced functional tetanic and twitch profiles, demonstrated increased acetylcholine receptor (AChR) clustering and transcription of MUSK and LRP4 mRNAs, indicating enhanced organisation of the post-synaptic membrane. The number of motor neuron spheroids, or motor pool, required to functionally innervate 3D muscle tissues was then determined, generating functional human NMJs that evidence pre- and post-synaptic membrane and motor nerve axon co-localisation. Spontaneous firing was significantly elevated in 3D motor units, confirmed to be driven by the motor nerve via antagonistic inhibition of the AChR. Functional analysis outlined decreased time to peak twitch and half relaxation times, indicating enhanced physiology of excitation contraction coupling in innervated motor units. Our findings provide the methods to maximise the maturity of both iPSC motor neurons and primary human skeletal muscle, utilising cell type specific extracellular matrices and developmental timelines to bioengineer the human motor unit for the study of neuromuscular junction physiology.

scholarly journals Effective use of monoclonal antibodies for treatment of persistent COVID-19 infection in a patient on rituximab

2021 ◽  
Vol 14 (8) ◽  
pp. e243469
Author(s):  
Carlos X Rabascall ◽  
Becky X Lou ◽  
Brianne Navetta-Modrov ◽  
Stella S Hahn
Keyword(s):  
Monoclonal Antibodies ◽  
Symptom Onset ◽  
Severe Disease ◽  
Therapeutic Window ◽  
Immunosuppressed Patient ◽  
Unique Case ◽  
Risk Of Progression ◽  
Immunosuppressed Patients ◽  
Effective Use ◽  
Potential Use

As we are over a year into the COVID-19 pandemic, we have made many forward strides in therapeutics. These treatments, such as monoclonal antibodies, have help mitigate the detrimental and often fatal consequences of COVID-19. The current indication for the use of monoclonal antibodies is mild to moderate COVID-19 infection within 10 days of symptom onset in those who are at high risk of progression to severe disease. However, their role in patients with prolonged symptoms is not clear. We present a unique case of monoclonal antibodies use after 54 days of symptom onset in an immunosuppressed patient with persistent COVID-19 infection despite standard treatment. This case illustrates the potential use of monoclonal antibodies outside of the current recommended therapeutic window in immunosuppressed patients, who may have difficulty with viral clearance.

scholarly journals Establishment of a New Device for Electrical Stimulation of Non-Degenerative Cartilage Cells In Vitro

2021 ◽  
Vol 22 (1) ◽  
pp. 394
Author(s):  
Simone Krueger ◽  
Alexander Riess ◽  
Anika Jonitz-Heincke ◽  
Alina Weizel ◽  
Anika Seyfarth ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Electric Fields ◽  
Cartilage Tissue ◽  
Type I ◽  
Dependent Manner ◽  
New Device ◽  
Alternating Electric Fields ◽  
Cartilage Cells ◽  
Stimulation Of

In cell-based therapies for cartilage lesions, the main problem is still the formation of fibrous cartilage, caused by underlying de-differentiation processes ex vivo. Biophysical stimulation is a promising approach to optimize cell-based procedures and to adapt them more closely to physiological conditions. The occurrence of mechano-electrical transduction phenomena within cartilage tissue is physiological and based on streaming and diffusion potentials. The application of exogenous electric fields can be used to mimic endogenous fields and, thus, support the differentiation of chondrocytes in vitro. For this purpose, we have developed a new device for electrical stimulation of chondrocytes, which operates on the basis of capacitive coupling of alternating electric fields. The reusable and sterilizable stimulation device allows the simultaneous use of 12 cavities with independently applicable fields using only one main supply. The first parameter settings for the stimulation of human non-degenerative chondrocytes, seeded on collagen type I elastin-based scaffolds, were derived from numerical electric field simulations. Our first results suggest that applied alternating electric fields induce chondrogenic re-differentiation at the gene and especially at the protein level of human de-differentiated chondrocytes in a frequency-dependent manner. In future studies, further parameter optimizations will be performed to improve the differentiation capacity of human cartilage cells.

scholarly journals Repurposing cabozantinib with therapeutic potential in KIT-driven t(8;21) acute myeloid leukaemias

2021 ◽  
Author(s):  
Kuan-Wei Su ◽  
Da-Liang Ou ◽  
Yu-Hsuan Fu ◽  
Hwei-Fang Tien ◽  
Hsin-An Hou ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Ribosome Biogenesis ◽  
Kinase Inhibitor ◽  
Therapeutic Potential ◽  
Xenograft Model ◽  
Sequencing Analysis ◽  
Dependent Manner ◽  
Leukocyte Activation ◽  
Mouse Xenograft Model ◽  
Acute Myeloid

AbstractCabozantinib is an orally available, multi-target tyrosine kinase inhibitor approved for the treatment of several solid tumours and known to inhibit KIT tyrosine kinase. In acute myeloid leukaemia (AML), aberrant KIT tyrosine kinase often coexists with t(8;21) to drive leukaemogenesis. Here we evaluated the potential therapeutic effect of cabozantinib on a selected AML subtype characterised by t(8;21) coupled with KIT mutation. Cabozantinib exerted substantial cytotoxicity in Kasumi-1 cells with an IC50 of 88.06 ± 4.32 nM, which was well within clinically achievable plasma levels. The suppression of KIT phosphorylation and its downstream signals, including AKT/mTOR, STAT3, and ERK1/2, was elicited by cabozantinib treatment and associated with subsequent alterations of cell cycle- and apoptosis-related molecules. Cabozantinib also disrupted the synthesis of an AML1-ETO fusion protein in a dose- and time-dependent manner. In a mouse xenograft model, cabozantinib suppressed tumourigenesis at 10 mg/kg and significantly prolonged survival of the mice. Further RNA-sequencing analysis revealed that mTOR-mediated signalling pathways were substantially inactivated by cabozantinib treatment, causing the downregulation of ribosome biogenesis and glycolysis, along with myeloid leukocyte activation. We suggest that cabozantinib may be effective in the treatment of AML with t(8;21) and KIT mutation. Relevant clinical trials are warranted.

scholarly journals Slow viral propagation during initial phase of infection leads to viral persistence in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Haifeng C. Xu ◽  
Ruifeng Wang ◽  
Prashant V. Shinde ◽  
Lara Walotka ◽  
Anfei Huang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Evasion ◽  
Protein Transport ◽  
Adaptive Immune System ◽  
Viral Persistence ◽  
Lymphocytic Choriomeningitis ◽  
Type I ◽  
Viral Propagation

AbstractImmune evasion of pathogens can modify the course of infection and impact viral persistence and pathology. Here, using different strains of the lymphocytic choriomeningitis virus (LCMV) model system, we show that slower propagation results in limited type I interferon (IFN-I) production and viral persistence. Specifically, cells infected with LCMV-Docile exhibited reduced viral replication when compared to LCMV-WE and as a consequence, infection with LCMV-Docile resulted in reduced activation of bone marrow derived dendritic cells (BMDCs) and IFN-I production in vitro in comparison with LCMV-WE. In vivo, we observed a reduction of IFN-I, T cell exhaustion and viral persistence following infection of LCMV-Docile but not LCMV-WE. Mechanistically, block of intracellular protein transport uncovered reduced propagation of LCMV-Docile when compared to LCMV-WE. This reduced propagation was critical in blunting the activation of the innate and adaptive immune system. When mice were simultaneously infected with LCMV-Docile and LCMV-WE, immune function was restored and IFN-I production, T cell effector functions as well as viral loads were similar to that of mice infected with LCMV-WE alone. Taken together, this study suggests that reduced viral propagation can result in immune evasion and viral persistence.

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