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1.
Virol J ; 18(1): 66, 2021 03 29.
Article in English | MEDLINE | ID: mdl-33781287

ABSTRACT

Beginning in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a novel pathogen that causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 has infected more than 111 million people worldwide and caused over 2.47 million deaths. Individuals infected with SARS-CoV-2 show symptoms of fever, cough, dyspnea, and fatigue with severe cases that can develop into pneumonia, myocarditis, acute respiratory distress syndrome, hypercoagulability, and even multi-organ failure. Current clinical management consists largely of supportive care as commonly administered treatments, including convalescent plasma, remdesivir, and high-dose glucocorticoids. These have demonstrated modest benefits in a small subset of hospitalized patients, with only dexamethasone showing demonstrable efficacy in reducing mortality and length of hospitalization. At this time, no SARS-CoV-2-specific antiviral drugs are available, although several vaccines have been approved for use in recent months. In this review, we will evaluate the efficacy of preclinical and clinical drugs that precisely target three different, essential steps of the SARS-CoV-2 replication cycle: the spike protein during entry, main protease (MPro) during proteolytic activation, and RNA-dependent RNA polymerase (RdRp) during transcription. We will assess the advantages and limitations of drugs that precisely target evolutionarily well-conserved domains, which are less likely to mutate, and therefore less likely to escape the effects of these drugs. We propose that a multi-drug cocktail targeting precise proteins, critical to the viral replication cycle, such as spike protein, MPro, and RdRp, will be the most effective strategy of inhibiting SARS-CoV-2 replication and limiting its spread in the general population.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19 Drug Treatment , SARS-CoV-2/drug effects , Animals , Antiviral Agents/pharmacology , COVID-19/prevention & control , COVID-19/therapy , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Coronavirus 3C Proteases/metabolism , Humans , Immunization, Passive , RNA-Dependent RNA Polymerase/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects , Virus Replication/drug effects , COVID-19 Serotherapy
2.
Sci Rep ; 11(1): 6562, 2021 03 22.
Article in English | MEDLINE | ID: mdl-33753784

ABSTRACT

Dysregulation of glucagon secretion in type 1 diabetes (T1D) involves hypersecretion during postprandial states, but insufficient secretion during hypoglycemia. The sympathetic nervous system regulates glucagon secretion. To investigate islet sympathetic innervation in T1D, sympathetic tyrosine hydroxylase (TH) axons were analyzed in control non-diabetic organ donors, non-diabetic islet autoantibody-positive individuals (AAb), and age-matched persons with T1D. Islet TH axon numbers and density were significantly decreased in AAb compared to T1D with no significant differences observed in exocrine TH axon volume or lengths between groups. TH axons were in close approximation to islet α-cells in T1D individuals with long-standing diabetes. Islet RNA-sequencing and qRT-PCR analyses identified significant alterations in noradrenalin degradation, α-adrenergic signaling, cardiac ß-adrenergic signaling, catecholamine biosynthesis, and additional neuropathology pathways. The close approximation of TH axons at islet α-cells supports a model for sympathetic efferent neurons directly regulating glucagon secretion. Sympathetic islet innervation and intrinsic adrenergic signaling pathways could be novel targets for improving glucagon secretion in T1D.


Subject(s)
Diabetes Mellitus, Type 1/etiology , Disease Susceptibility , Islets of Langerhans/innervation , Sympathetic Nervous System/physiopathology , Axons/metabolism , Biomarkers , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/pathology , Fluorescent Antibody Technique , Gene Expression Regulation , Glucagon-Secreting Cells/metabolism , Humans , Islets of Langerhans/metabolism , Pancreas, Exocrine/innervation , Pancreas, Exocrine/metabolism , Somatostatin-Secreting Cells/metabolism , Tyrosine 3-Monooxygenase/metabolism
3.
J Histochem Cytochem ; 67(1): 41-52, 2019 01.
Article in English | MEDLINE | ID: mdl-29771178

ABSTRACT

Islet microvasculature provides key architectural and functional roles, yet the morphological features of islets from patients with type 1 diabetes are poorly defined. We examined islet and exocrine microvasculature networks by multiplex immunofluorescence imaging of pancreases from organ donors with and without type 1 diabetes (n=17 and n=16, respectively) and determined vessel diameter, density, and area. We also analyzed these variables in insulin-positive and insulin-negative islets of 7 type 1 diabetes donors. Control islet vessel diameter was significantly larger (7.6 ± 1.1 µm) compared with vessels in diabetic islets (6.2 ± 0.8 µm; p<0.001). Control islet vessel density (number/islet) was significantly lower (5.3 ± 0.6) versus diabetic islets (9.3 ± 0.2; p<0.001). Exocrine vessel variables were not significantly different between groups. Islets with residual beta-cells were comparable to control islets for both vessel diameter and density and were significantly different from insulin-negative islets within diabetic donors (p<0.05). Islet smooth muscle actin area had a significant positive correlation with age in both groups (p<0.05), which could negatively impact islet transplantation efficiency from older donors. These data underscore the critical relationship of islet beta-cells and islet vessel morphology in type 1 diabetes. These studies provide new knowledge of the islet microvasculature in diabetes and aging.


Subject(s)
Diabetes Mellitus, Type 1/pathology , Insulin-Secreting Cells/pathology , Microvessels/pathology , Actins/analysis , Adolescent , Adult , Child , Female , Fluorescent Antibody Technique/methods , Humans , Insulin/analysis , Insulin-Secreting Cells/ultrastructure , Islets of Langerhans/blood supply , Islets of Langerhans/pathology , Islets of Langerhans/ultrastructure , Male , Microscopy, Confocal/methods , Microvessels/ultrastructure , Tissue Donors , Young Adult
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