ABSTRACT
Bacterial or viral infections, such as Brucella, mumps virus, herpes simplex virus, and Zika virus, destroy immune homeostasis of the testes, leading to spermatogenesis disorder and infertility. Of note, recent research shows that SARS-CoV-2 can infect male gonads and destroy Sertoli and Leydig cells, leading to male reproductive dysfunction. Due to the many side effects associated with antibiotic therapy, finding alternative treatments for inflammatory injury remains critical. Here, we found that Dmrt1 plays an important role in regulating testicular immune homeostasis. Knockdown of Dmrt1 in male mice inhibited spermatogenesis with a broad inflammatory response in seminiferous tubules and led to the loss of spermatogenic epithelial cells. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) revealed that Dmrt1 positively regulated the expression of Spry1, an inhibitory protein of the receptor tyrosine kinase (RTK) signaling pathway. Furthermore, immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP) analysis indicated that SPRY1 binds to nuclear factor kappa B1 (NF-κB1) to prevent nuclear translocation of p65, inhibit activation of NF-κB signaling, prevent excessive inflammatory reaction in the testis, and protect the integrity of the blood-testis barrier. In view of this newly identified Dmrt1- Spry1-NF-κB axis mechanism in the regulation of testicular immune homeostasis, our study opens new avenues for the prevention and treatment of male reproductive diseases in humans and livestock.
Subject(s)
COVID-19 , Rodent Diseases , Zika Virus Infection , Zika Virus , Humans , Male , Mice , Animals , Testis , NF-kappa B/metabolism , COVID-19/veterinary , SARS-CoV-2/metabolism , Homeostasis , Fertility , Zika Virus/metabolism , Zika Virus Infection/metabolism , Zika Virus Infection/veterinary , Membrane Proteins/metabolism , Phosphoproteins/metabolism , Phosphoproteins/pharmacology , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/pharmacology , Rodent Diseases/metabolismABSTRACT
COVID-19 has been diffusely pandemic around the world, characterized by massive morbidity and mortality. One of the remarkable threats associated with mortality may be the uncontrolled inflammatory processes, which were induced by SARS-CoV-2 in infected patients. As there are no specific drugs, exploiting safe and effective treatment strategies is an instant requirement to dwindle viral damage and relieve extreme inflammation simultaneously. Here, highly biocompatible glycyrrhizic acid (GA) nanoparticles (GANPs) were synthesized based on GA. In vitro investigations revealed that GANPs inhibit the proliferation of the murine coronavirus MHV-A59 and reduce proinflammatory cytokine production caused by MHV-A59 or the N protein of SARS-CoV-2. In an MHV-A59-induced surrogate mouse model of COVID-19, GANPs specifically target areas with severe inflammation, such as the lungs, which appeared to improve the accumulation of GANPs and enhance the effectiveness of the treatment. Further, GANPs also exert antiviral and anti-inflammatory effects, relieving organ damage and conferring a significant survival advantage to infected mice. Such a novel therapeutic agent can be readily manufactured into feasible treatment for COVID-19.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , Glycyrrhizic Acid/therapeutic use , Inflammation/drug therapy , Nanoparticles/therapeutic use , Virus Diseases/drug therapy , Animals , Anti-Inflammatory Agents/chemistry , Antioxidants/chemistry , Antioxidants/therapeutic use , Antiviral Agents/chemistry , Coronavirus Nucleocapsid Proteins/pharmacology , Cytokines/metabolism , Female , Glycyrrhizic Acid/chemistry , Humans , Liver/pathology , Lung/pathology , Mice , Mice, Inbred BALB C , Murine hepatitis virus/drug effects , Nanoparticles/chemistry , Phosphoproteins/pharmacology , RAW 264.7 Cells , SARS-CoV-2/chemistry , THP-1 Cells , Viral Load/drug effects , Virus Diseases/pathology , Virus Replication/drug effects , COVID-19 Drug TreatmentABSTRACT
Bacterial permeability family member A1 (BPIFA1) is one of the most abundant proteins present in normal airway surface liquid (ASL). It is known to be diminished in asthmatic patients' sputum, which causes airway hyperresponsiveness (AHR). What is currently unclear is how environmental factors, such as allergens' impact on BPIFA1's abundance and functions in the context of allergic asthma. House dust mite (HDM) is a predominant domestic source of aeroallergens. The group of proteases found in HDM is thought to cleave multiple cellular protective mechanisms, and therefore foster the development of allergic asthma. Here, we show that BPIFA1 is cleaved by HDM proteases in a time-, dose-, and temperature-dependent manner. We have also shown the main component in HDM that is responsible for BPIFA1's degradation is Der p1. Fragmented BPIFA1 failed to bind E. coli lipopolysaccharide (LPS), and hence elevated TNFα and IL-6 secretion in human whole blood. BPIFA1 degradation is also observed in vivo in bronchoalveolar fluid (BALF) of mice which are intranasally instilled with HDM. These data suggest that proteases associated with environmental allergens such as HDM cleave BPIFA1 and therefore impair its immune modulator function.