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International Immunopharmacology Sep 2023Psoriasis, which involves mast cells, is a chronic inflammatory skin disorder whose pathophysiology is still not fully understood. We investigated the role of secretory...
Psoriasis, which involves mast cells, is a chronic inflammatory skin disorder whose pathophysiology is still not fully understood. We investigated the role of secretory leukocyte protease inhibitor (SLPI), a potential inhibitor of mastocyte serine proteases, on mast cell-dependent processes of relevance to the skin barrier defense in psoriasis. Here, we demonstrate that the dermal mast cells of patients with psoriasis express SLPI but not those of healthy donors. Moreover, SLPI transcripts were found to be markedly upregulated in murine mast cells by mediators derived from psoriasis skin explant cultures. Using mast cells from SLPI-deficient mice and their SLPI wild-type controls, we show that SLPI inhibits the activity of serine protease chymase in mastocytes. SLPI was also found to enhance the degranulation of mast cells activated via anti-IgE Abs but not Mrgprb2 ligands. Finally, we demonstrate that the expression and function of Mrgprb2 in mast cells are suppressed by a normal and, to a larger extent, psoriatic skin environment. Together, these findings reveal mechanisms underlying FcεRI- and Mrgprb2-dependent mast cell function that have not been described previously.
Topics: Animals; Mice; Secretory Leukocyte Peptidase Inhibitor; Mast Cells; Proteinase Inhibitory Proteins, Secretory; Psoriasis; Skin
PubMed: 37453153
DOI: 10.1016/j.intimp.2023.110631 -
Viruses Sep 2023Nirmatrelvir, which targets the SARS-CoV-2 main protease (Mpro), is the first-in-line drug for prevention and treatment of severe COVID-19, and additional Mpro... (Review)
Review
Nirmatrelvir, which targets the SARS-CoV-2 main protease (Mpro), is the first-in-line drug for prevention and treatment of severe COVID-19, and additional Mpro inhibitors are in development. However, the risk of resistance development threatens the future efficacy of such direct-acting antivirals. To gain knowledge on viral correlates of resistance to Mpro inhibitors, we selected resistant SARS-CoV-2 under treatment with the nirmatrelvir-related protease inhibitor boceprevir. SARS-CoV-2 selected during five escape experiments in VeroE6 cells showed cross-resistance to nirmatrelvir with up to 7.3-fold increased half-maximal effective concentration compared to original SARS-CoV-2, determined in concentration-response experiments. Sequence analysis revealed that escape viruses harbored Mpro substitutions L50F and A173V. For reverse genetic studies, these substitutions were introduced into a cell-culture-infectious SARS-CoV-2 clone. Infectivity titration and analysis of genetic stability of cell-culture-derived engineered SARS-CoV-2 mutants showed that L50F rescued the fitness cost conferred by A173V. In the concentration-response experiments, A173V was the main driver of resistance to boceprevir and nirmatrelvir. Structural analysis of Mpro suggested that A173V can cause resistance by making boceprevir and nirmatrelvir binding less favorable. This study contributes to a comprehensive overview of the resistance profile of the first-in-line COVID-19 treatment nirmatrelvir and can thus inform population monitoring and contribute to pandemic preparedness.
Topics: Humans; Protease Inhibitors; Antiviral Agents; SARS-CoV-2; COVID-19 Drug Treatment; COVID-19; Hepatitis C, Chronic; Enzyme Inhibitors; Anti-Infective Agents; Lactams
PubMed: 37766376
DOI: 10.3390/v15091970 -
Current Hypertension Reports Jan 2024To provide an overview of the association between angiotensin II receptor blocker (ARB) use and cognitive outcomes. (Review)
Review
PURPOSE OF REVIEW
To provide an overview of the association between angiotensin II receptor blocker (ARB) use and cognitive outcomes.
RECENT FINDINGS
ARBs have previously shown greater neuroprotection compared to other anti-hypertensive classes. The benefits are primarily attributed to the ARB's effect on modulating the renin-angiotensin system via inhibiting the Ang II/AT1R pathway and activating the Ang II/AT2R, Ang IV/AT4R, and Ang-(1-7)/MasR pathways. These interactions are associated with pleiotropic neurocognitive benefits, including reduced β-amyloid accumulation and abnormal hyperphosphorylation of tau, ameliorated brain hypo-fusion, reduced neuroinflammation and synaptic dysfunction, better neurotoxin clearing, and blood-brain barrier function restoration. While ACEis also inhibit AT1R, they simultaneously lower Ang II and block the Ang II/AT2R and Ang IV/AT4R pathways that counterbalance the potential benefits. ARBs may be considered an adjunctive approach for neuroprotection. This preliminary evidence, coupled with their underlying mechanistic pathways, emphasizes the need for future long-term randomized trials to yield more definitive results.
Topics: Humans; Angiotensin Receptor Antagonists; Hypertension; Angiotensin-Converting Enzyme Inhibitors; Renin-Angiotensin System; Cognition
PubMed: 37733162
DOI: 10.1007/s11906-023-01266-0 -
EMBO Molecular Medicine Sep 2023SARS-CoV-2 acute respiratory distress syndrome (ARDS) induces uncontrolled lung inflammation and coagulopathy with high mortality. Anti-viral drugs and monoclonal...
SARS-CoV-2 acute respiratory distress syndrome (ARDS) induces uncontrolled lung inflammation and coagulopathy with high mortality. Anti-viral drugs and monoclonal antibodies reduce early COVID-19 severity, but treatments for late-stage immuno-thrombotic syndromes and long COVID are limited. Serine protease inhibitors (SERPINS) regulate activated proteases. The myxoma virus-derived Serp-1 protein is a secreted immunomodulatory serpin that targets activated thrombotic, thrombolytic, and complement proteases as a self-defense strategy to combat clearance. Serp-1 is effective in multiple animal models of inflammatory lung disease and vasculitis. Here, we describe systemic treatment with purified PEGylated Serp-1 as a therapy for immuno-coagulopathic complications during ARDS. Treatment with PEGSerp-1 in two mouse-adapted SARS-CoV-2 models in C57Bl/6 and BALB/c mice reduced lung and heart inflammation, with improved outcomes. PEGSerp-1 significantly reduced M1 macrophages in the lung and heart by modifying urokinase-type plasminogen activator receptor (uPAR), thrombotic proteases, and complement membrane attack complex (MAC). Sequential changes in gene expression for uPAR and serpins (complement and plasminogen inhibitors) were observed. PEGSerp-1 is a highly effective immune-modulator with therapeutic potential for severe viral ARDS, immuno-coagulopathic responses, and Long COVID.
Topics: Mice; Animals; Humans; Serpins; SARS-CoV-2; Post-Acute COVID-19 Syndrome; COVID-19; Anti-Inflammatory Agents; Disease Models, Animal; Peptide Hydrolases; Respiratory Distress Syndrome
PubMed: 37534622
DOI: 10.15252/emmm.202317376 -
Molecules (Basel, Switzerland) Aug 2023This article sheds light on the various scaffolds that can be used in the designing and development of novel synthetic compounds to create DPP-4 inhibitors for the... (Review)
Review
This article sheds light on the various scaffolds that can be used in the designing and development of novel synthetic compounds to create DPP-4 inhibitors for the treatment of type 2 diabetes mellitus (T2DM). This review highlights a variety of scaffolds with high DPP-4 inhibition activity, such as pyrazolopyrimidine, tetrahydro pyridopyrimidine, uracil-based benzoic acid and esters, triazole-based, fluorophenyl-based, glycinamide, glycolamide, β-carbonyl 1,2,4-triazole, and quinazoline motifs. The article further explains that the potential of the compounds can be increased by substituting atoms such as fluorine, chlorine, and bromine. Docking of existing drugs like sitagliptin, saxagliptin, and vildagliptin was done using Maestro 12.5, and the interaction with specific residues was studied to gain a better understanding of the active sites of DPP-4. The structural activities of the various scaffolds against DPP-4 were further illustrated by their inhibitory concentration (IC) values. Additionally, various synthesis schemes were developed to make several commercially available DPP4 inhibitors such as vildagliptin, sitagliptin and omarigliptin. In conclusion, the use of halogenated scaffolds for the development of DPP-4 inhibitors is likely to be an area of increasing interest in the future.
Topics: Humans; Dipeptidyl-Peptidase IV Inhibitors; Hypoglycemic Agents; Vildagliptin; Diabetes Mellitus, Type 2; Sitagliptin Phosphate; Structure-Activity Relationship
PubMed: 37570832
DOI: 10.3390/molecules28155860 -
Frontiers in Physiology 2023The predatory natural enemy plays a crucial role in agricultural ecosystems due to its effective pest control measures and defensive venom. Predator venom contains...
The predatory natural enemy plays a crucial role in agricultural ecosystems due to its effective pest control measures and defensive venom. Predator venom contains serine protease inhibitors (SPIs), which are the primary regulators of serine protease activity and play key roles in digestion, development, innate immunity, and other physiological regulatory processes. However, the regulation mechanism of SPIs in the salivary glands of predatory natural enemies is still unknown. In this study, we sequenced the transcriptome of salivary gland and identified 38 SPIs genes named . Through gene structure, multiple sequence alignment and phylogenetic tree analysis, real-time quantitative PCR (RT-PCR) expression profiles of different developmental stages and different tissues were analyzed. RNAi technology was used to explore the gene function of . The results showed that these 38 EfSPIs genes contained 8 SPI domains, which were serpin, TIL, Kunitz, Kazal, Antistasin, Pacifastin, WAP and A2M. The expression profile results showed that the expression of different types of EfSPIs genes was different at different developmental stages and different tissues. Most of the EfSPIs genes were highly expressed in the egg stage. The , and genes of the Pacifastin subfamily and the gene of the A2M subfamily were highly expressed in the nymphal and adult stages, which was consistent with the RT-qPCR verification results. These five genes are positively correlated with each other and have a synergistic effect on , and they were highly expressed in salivary glands. After interfering with the expression of the gene, the survival rate and predatory amount of male and female adults were significantly decreased. Taken together, we speculated some EfSPIs may inhibit trypsin, chymotrypsin, and elastase, and some EfSPIs may be involved in autoimmune responses. was essential for the predation and digestion of , and the functions of other EfSPIs were discussed. Our findings provide valuable insights into the diversity of EfSPIs in and the potential functions of regulating their predation, digestion and innate immunity, which may be of great significance for developing new pest control strategies.
PubMed: 37795265
DOI: 10.3389/fphys.2023.1248354 -
The Journal of Biological Chemistry Aug 2023Human neutrophil elastase (HNE) plays a pivotal role in innate immunity, inflammation, and tissue remodeling. Aberrant proteolytic activity of HNE contributes to organ...
Human neutrophil elastase (HNE) plays a pivotal role in innate immunity, inflammation, and tissue remodeling. Aberrant proteolytic activity of HNE contributes to organ destruction in various chronic inflammatory diseases including emphysema, asthma, and cystic fibrosis. Therefore, elastase inhibitors could alleviate the progression of these disorders. Here, we used the systematic evolution of ligands by exponential enrichment to develop ssDNA aptamers that specifically target HNE. We determined the specificity of the designed inhibitors and their inhibitory efficacy against HNE using biochemical and in vitro methods, including an assay of neutrophil activity. Our aptamers inhibit the elastinolytic activity of HNE with nanomolar potency and are highly specific for HNE and do not target other tested human proteases. As such, this study provides lead compounds suitable for the evaluation of their tissue-protective potential in animal models.
Topics: Humans; Cystic Fibrosis; Emphysema; Leukocyte Elastase; Neutrophils; Serine Proteinase Inhibitors; Aptamers, Nucleotide; Sensitivity and Specificity; Enzyme Activation; Proteolysis; Cells, Cultured
PubMed: 37286041
DOI: 10.1016/j.jbc.2023.104889 -
PLoS Pathogens Nov 2023Zika virus (ZIKV) serine protease, indispensable for viral polyprotein processing and replication, is composed of the membrane-anchored NS2B polypeptide and the...
Zika virus (ZIKV) serine protease, indispensable for viral polyprotein processing and replication, is composed of the membrane-anchored NS2B polypeptide and the N-terminal domain of the NS3 polypeptide (NS3pro). The C-terminal domain of the NS3 polypeptide (NS3hel) is necessary for helicase activity and contains an ATP-binding site. We discovered that ZIKV NS2B-NS3pro binds single-stranded RNA with a Kd of ~0.3 μM, suggesting a novel function. We tested various structural modifications of NS2B-NS3pro and observed that constructs stabilized in the recently discovered "super-open" conformation do not bind RNA. Likewise, stabilizing NS2B-NS3pro in the "closed" (proteolytically active) conformation using substrate inhibitors abolished RNA binding. We posit that RNA binding occurs when ZIKV NS2B-NS3pro adopts the "open" conformation, which we modeled using highly homologous dengue NS2B-NS3pro crystallized in the open conformation. We identified two positively charged fork-like structures present only in the open conformation of NS3pro. These forks are conserved across Flaviviridae family and could be aligned with the positively charged grove on NS3hel, providing a contiguous binding surface for the negative RNA strand exiting helicase. We propose a "reverse inchworm" model for a tightly intertwined NS2B-NS3 helicase-protease machinery, which suggests that NS2B-NS3pro cycles between open and super-open conformations to bind and release RNA enabling long-range NS3hel processivity. The transition to the closed conformation, likely induced by the substrate, enables the classical protease activity of NS2B-NS3pro.
Topics: Humans; Zika Virus; Zika Virus Infection; Viral Nonstructural Proteins; Serine Endopeptidases; Peptides; RNA; Protease Inhibitors
PubMed: 38011215
DOI: 10.1371/journal.ppat.1011795 -
Antiviral Research Jul 2023Although the clinical manifestation of COVID-19 is mainly respiratory symptoms, approximately 20% of patients suffer from cardiac complications. COVID-19 patients with...
Although the clinical manifestation of COVID-19 is mainly respiratory symptoms, approximately 20% of patients suffer from cardiac complications. COVID-19 patients with cardiovascular disease have higher severity of myocardial injury and poor outcomes. The underlying mechanism of myocardial injury caused by SARS-CoV-2 infection remains unclear. Using a non-transgenic mouse model infected with Beta variant (B.1.351), we found that the viral RNA could be detected in lungs and hearts of infected mice. Pathological analysis showed thinner ventricular wall, disorganized and ruptured myocardial fiber, mild inflammatory infiltration, and mild epicardia or interstitial fibrosis in hearts of infected mice. We also found that SARS-CoV-2 could infect cardiomyocytes and produce infectious progeny viruses in human pluripotent stem cell-derived cardiomyocyte-like cells (hPSC-CMs). SARS-CoV-2 infection caused apoptosis, reduction of mitochondrial integrity and quantity, and cessation of beating in hPSC-CMs. In order to dissect the mechanism of myocardial injury caused by SARS-CoV-2 infection, we employed transcriptome sequencing of hPSC-CMs at different time points after viral infection. Transcriptome analysis showed robust induction of inflammatory cytokines and chemokines, up-regulation of MHC class I molecules, activation of apoptosis signaling and cell cycle arresting. These may cause aggravate inflammation, immune cell infiltration, and cell death. Furthermore, we found that Captopril (hypotensive drugs targeting ACE) treatment could alleviate SARS-CoV-2 induced inflammatory response and apoptosis in cardiomyocytes via inactivating TNF signaling pathways, suggesting Captopril may be beneficial for reducing COVID-19 associated cardiomyopathy. These findings preliminarily explain the molecular mechanism of pathological cardiac injury caused by SARS-CoV-2 infection, providing new perspectives for the discovery of antiviral therapeutics.
Topics: Humans; Mice; Animals; SARS-CoV-2; COVID-19; Captopril; Myocytes, Cardiac; Angiotensin-Converting Enzyme Inhibitors; Inflammation; Apoptosis
PubMed: 37207821
DOI: 10.1016/j.antiviral.2023.105636 -
JAMA Network Open Dec 2023Despite efforts to improve the quality of care for patients with atherosclerotic cardiovascular disease (ASCVD), it is unclear whether the US has made progress in...
IMPORTANCE
Despite efforts to improve the quality of care for patients with atherosclerotic cardiovascular disease (ASCVD), it is unclear whether the US has made progress in reducing racial and ethnic differences in utilization of guideline-recommended therapies for secondary prevention.
OBJECTIVE
To evaluate 21-year trends in racial and ethnic differences in utilization of guideline-recommended pharmacological medications and lifestyle modifications among US adults with ASCVD.
DESIGN, SETTING, AND PARTICIPANTS
This cross-sectional study includes data from the National Health and Nutrition Examination Survey between 1999 and 2020. Eligible participants were adults aged 18 years or older with a history of ASCVD. Data were analyzed between March 2022 and May 2023.
EXPOSURE
Self-reported race and ethnicity.
MAIN OUTCOME AND MEASURES
Rates and racial and ethnic differences in the use of guideline-recommended pharmacological medications and lifestyle modifications.
RESULTS
The study included 5218 adults with a history of ASCVD (mean [SD] age, 65.5 [13.2] years, 2148 women [weighted average, 44.2%]), among whom 1170 (11.6%) were Black, 930 (7.7%) were Hispanic or Latino, and 3118 (80.7%) were White in the weighted sample. Between 1999 and 2020, there was a significant increase in total cholesterol control and statin use in all racial and ethnic subgroups, and in angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) utilization in non-Hispanic White individuals and Hispanic and Latino individuals (Hispanic and Latino individuals: 17.12 percentage points; 95% CI, 0.37-37.88 percentage points; P = .046; non-Hispanic White individuals: 12.14 percentage points; 95% CI, 6.08-18.20 percentage points; P < .001), as well as smoking cessation within the Hispanic and Latino population (-27.13 percentage points; 95% CI, -43.14 to -11.12 percentage points; P = .002). During the same period, the difference in smoking cessation between Hispanic and Latino individuals and White individuals was reduced (-24.85 percentage points; 95% CI, -38.19 to -11.51 percentage points; P < .001), but racial and ethnic differences for other metrics did not change significantly. Notably, substantial gaps persisted between current care and optimal care throughout the 2 decades of data analyzed. In the period of 2017 to 2020, optimal regimens were observed in 47.4% (95% CI, 39.3%-55.4%), 48.7% (95% CI, 36.7%-60.6%), and 53.0% (95% CI, 45.6%-60.4%) of Black, Hispanic and Latino, and White individuals, respectively.
CONCLUSIONS AND RELEVANCE
In this cross-sectional study of US adults with ASCVD, significant disparities persisted between current care and optimal care, surpassing any differences observed among demographic groups. These findings highlight the critical need for sustained efforts to bridge these gaps and achieve better outcomes for all patients, regardless of their racial and ethnic backgrounds.
Topics: Adult; Humans; Female; Aged; Nutrition Surveys; Cross-Sectional Studies; Cardiovascular Diseases; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors
PubMed: 38039001
DOI: 10.1001/jamanetworkopen.2023.45964