Platelet-leukocyte interactions amplify inflammatory reactions, but the underlying mechanism is still unclear. CLEC5A and CLEC2 are spleen tyrosine kinase (Syk)-coupled C-type lectin receptors, ...abundantly expressed by leukocytes and platelets, respectively. Whereas CLEC5A is a pattern recognition receptor (PRR) to flaviviruses and bacteria, CLEC2 is the receptor for platelet-activating snake venom aggretin. Here we show that dengue virus (DV) activates platelets via CLEC2 to release extracellular vesicles (EVs), including exosomes (EXOs) and microvesicles (MVs). DV-induced EXOs (DV-EXOs) and MVs (DV-MVs) further activate CLEC5A and TLR2 on neutrophils and macrophages, thereby induce neutrophil extracellular trap (NET) formation and proinflammatory cytokine release. Compared to stat1
mice, simultaneous blockade of CLEC5A and TLR2 effectively attenuates DV-induced inflammatory response and increases survival rate from 30 to 90%. The identification of critical roles of CLEC2 and CLEC5A/TLR2 in platelet-leukocyte interactions will support the development of novel strategies to treat acute viral infection in the future.
The protective roles of endosomal toll-like receptors (TLRs) and cytosolic nucleic acid sensors are well elucidated, but the pathogenic host factors during viral infections remain unclear. Spleen ...tyrosine kinase (Syk)-coupled C-type lectins (CLECs) CLEC2 and CLEC5A are highly expressed on platelets and myeloid cells, respectively. CLEC2 has been shown to recognize snake venom aggretin and the endogenous ligand podoplanin and acts as a critical regulator in the development and immunothrombosis. Although CLEC2 has been reported to interact with type I immunodeficiency virus (HIV-1), its role in viral infections is still unclear. CLEC5A binds to fucose and mannose moieties of dengue virus membrane glycans, as well as to N-acetylglucosamine (GlcNAc)/N-acetylmuramic acid (MurNAc) disaccharides that form the backbone of
peptidoglycans. Recently, we demonstrated that both CLEC2 and CLEC5A are critical in microbe-induced "neutrophil extracellular trap" (NET) formation and proinflammatory cytokine production. Moreover, activation of CLEC2 by dengue virus (DV) and H5N1 influenza virus (IAV) induces the release of extracellular vesicles (EVs), which further enhance NETosis and proinflammatory cytokine production via CLEC5A and Toll-like receptor 2 (TLR2). These findings not only illustrate the immunomodulatory effects of EVs during platelet-leukocyte interactions, but also demonstrate the critical roles of CLEC2 and CLEC5A in acute viral infections.
Dysregulated formation of neutrophil extracellular traps (NETs) is observed in acute viral infections. Moreover, NETs contribute to the pathogenesis of acute viral infections, including those caused ...by the dengue virus (DV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Furthermore, excessive NET formation (NETosis) is associated with disease severity in patients suffering from SARS-CoV-2-induced multiple organ injuries. Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) and other members of C-type lectin family (L-SIGN, LSECtin, CLEC10A) have been reported to interact with viral glycans to facilitate virus spreading and exacerbates inflammatory reactions. Moreover, spleen tyrosine kinase (Syk)-coupled C-type lectin member 5A (CLEC5A) has been shown as the pattern recognition receptor for members of flaviviruses, and is responsible for DV-induced cytokine storm and Japanese encephalomyelitis virus (JEV)-induced neuronal inflammation. Moreover, DV activates platelets via CLEC2 to release extracellular vesicles (EVs), including microvesicles (MVs) and exosomes (EXOs). The DV-activated EXOs (DV-EXOs) and MVs (DV-MVs) stimulate CLEC5A and Toll-like receptor 2 (TLR2), respectively, to enhance NET formation and inflammatory reactions. Thus, EVs from virus-activated platelets (PLT-EVs) are potent endogenous danger signals, and blockade of C-type lectins is a promising strategy to attenuate virus-induced NETosis and intravascular coagulopathy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Thromboinflammation is the major cause of morbidity and mortality in COVID‐19 patients, and post‐mortem examination demonstrates the presence of platelet‐rich thrombi and microangiopathy in visceral ...organs. Moreover, persistent microclots were detected in both acute COVID‐19 and long COVID plasma samples. However, the molecular mechanism of SARS‐CoV‐2‐induced thromboinflammation is still unclear. We found that the spleen tyrosine kinase (Syk)‐coupled C‐type lectin member 2 (CLEC2), which was highly expressed in platelets and alveolar macrophages, interacted with the receptor‐binding domain (RBD) of SARS‐CoV‐2 spike protein (SARS‐CoV‐2 RBD) directly. Unlike the thread‐like NETs, SARS‐CoV‐2‐induced aggregated NET formation in the presence of wild‐type (WT), but not CLEC2‐deficient platelets. Furthermore, SARS‐CoV‐2 spike pseudotyped lentivirus was able to induce NET formation via CLEC2, indicating SARS‐CoV‐2 RBD engaged CLEC2 to activate platelets to enhance NET formation. Administration of CLEC2.Fc inhibited SARS‐CoV‐2‐induced NET formation and thromboinflammation in AAV‐ACE2‐infected mice. Thus, CLEC2 is a novel pattern recognition receptor for SARS‐CoV‐2, and CLEC2.Fc and may become a promising therapeutic agent to inhibit SARS‐CoV‐2‐induced thromboinflammation and reduced the risk of post‐acute sequelae of COVID‐19 (PASC) in the future.
Synopsis
CLEC2 interacts with SARS‐CoV‐2 spike RBD and is critical for SARS‐CoV‐2‐induced lung injury. In the presence of platelets, SARS‐CoV‐2 induces robust NET formation and cytokine release, while administration of CLEC2.Fc prevents platelet‐mediated enhancement of NET formation and cytokine storm via blocking interactions between CLEC2 and SARS‐CoV‐2 spike protein.
CLEC2 interacts with SARS‐CoV‐2 Spike RBD of wild type, alpha, beta, gamma, delta, and omicron, but not with SARS‐CoV Spike RBD.
SARS‐CoV‐2 Spike RBD activates platelet via CLEC2 inducing aggregated NET formation.
SARS‐CoV‐2 upregulates the expression of podoplanin in the lungs after infection.
Recombinant CLEC2.Fc inhibits SARS‐CoV‐2‐induced thromboinflammation in the lungs and heart.
Recombinant CLEC2.Fc attenuates SARS‐CoV‐2‐induced NET formation and collagen deposition in the lungs.
CLEC2 interacts with SARS‐CoV‐2 spike RBD and is critical for SARS‐CoV‐2‐induced lung injury. In the presence of platelets, SARS‐CoV‐2 induces robust NET formation and cytokine release, while administration of CLEC2.Fc prevents platelet‐mediated enhancement of NET formation and cytokine storm via blocking interactions between CLEC2 and SARS‐CoV‐2 spike protein.
Probiotics are health beneficial bacterial populations colonizing the human gut and skin. Probiotics are believed to be involved in immune system regulation, gut microbiota stabilization, prevention ...of infectious diseases, and adjustments of host metabolic activities. Probiotics such as
Lactobacillus
and
Bifidobacterium
affect glycemic levels, blood lipids, and protein metabolism. However, the interactions between probiotics and metabolic diseases as well as the underlying mechanisms remain unclear. We used streptozotocin (STZ)-induced diabetic animal models to study the effect of Probioglu
TM
, a multi-strain probiotic supplement including
Lactobaccilus salivarius
subsp.
salicinius
AP-32,
L
.
johnsonii
MH-68,
L
.
reuteri
GL-104, and
Bifidobacterium animalis
subsp.
lactis
CP-9, on the regulation of physiochemical parameters related to type-2 diabetes. Experimental rats were randomly assigned into five groups, control group, streptozotocin (STZ)-treated rats (STZ group), STZ + 1× Probioglu
TM
group, STZ + 5× Probioglu
TM
group, and STZ + 10× Probioglu
TM
group, and physiological data were measured at weeks 0, 2, 4, 6, and 8. Our results indicate that supplementation with Probioglu
TM
significantly improved glucose tolerance, glycemic levels, insulin levels, and insulin resistance (HOMA-IR). Furthermore, we observed reduction in urea and blood lipid levels, including low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol (TC). Probioglu
TM
administration increased the β-cell mass in STZ-induced diabetic animal models, whereas it reduced the levels of proinflammatory cytokines TNF-α, IL-6, and IL-1β. In addition, the enhancement of oxidative stress biomarkers and superoxide dismutase (SOD) activities was associated with a decrease in malondialdehyde (MDA) levels. We conclude that Probioglu
TM
attenuates STZ-induced type-2 diabetes by protecting β-cells, stabilizing glycemic levels, and reducing inflammation. Among all probiotic treating groups, the 10×Probioglu
TM
treatment revealed the best results. However, these experimental results still need to be validated by different animal models of type-2 diabetes and human clinical trials in the future.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
Probiotics participate in regulating oral microbiota and reducing the prevalence of oral diseases; however, clinical research on probiotics is insufficient. Therefore, in this study, we ...performed in vitro screening of potential oral protective probiotic strains and then evaluated the clinical efficacy of the selected strains on maintaining oral health.
Materials and methods
Fifty healthy individuals were recruited and randomly assigned into the placebo group and probiotics group, which included three strains of probiotics, Lactobacillus salivarius subs. salicinius AP‐32, Lactobacillus paracasei ET‐66, and Lactobacillus plantarum LPL28. Each group was blindly administered placebo or probiotics for four weeks.
Results
Next‐generation sequencing results showed that the oral microbiota of Lactobacillus salivarius in the oral cavity were significantly increased in subjects supplemented with mixed probiotic lozenges. The anti‐bacterial activities of viable probiotics were observed within two weeks. Both IgA levels and Lactobacillus and Bifidobacterium abundances in the oral cavity were significantly increased in the experimental groups, along with a reduced formation of plaque. Most participants reported that their oral health conditions and intestinal symptoms had improved.
Conclusions
Overall, our clinical study suggests that oral probiotic lozenges may enhance oral immunity, modulate oral microbiota, and improve oral health.
Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct ...disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma.
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•First deep proteogenomic landscape of non-smoking lung adenocarcinoma in East Asia•Identified age, sex-related endogenous, and environmental carcinogen mutagenic processes•Proteome-informed classification distinguished clinical features within early stages•Protein networks identified tumorigenesis hallmarks, biomarkers, and druggable targets
Deep proteogenomic landscape of early stage lung adenocarcinoma in a cohort of mostly non-smokers reveals unique drivers and biomarkers, as well as gender-associated mutagenesis.
Abstract Background Insomnia is a highly prevalent health complaint in the modern societies; however, insomnia remains under-diagnosed and under-treated. Although screening tools, including the ...Insomnia Severity Index (ISI), Athens Insomnia Scale (AIS), and Pittsburg Sleep Quality Index (PSQI), are widely used for assessing the risk of insomnia, the diagnostic properties have yet to be summarized in a systematic manner. Objectives To estimate and to compare the diagnostic accuracy of the ISI, AIS, and PSQI for insomnia screening. Data sources We systematically searched EMBASE, PubMed, PsycINFO, CINAHL and Chinese Electronic Periodic Services for data from their inception to May 20, 2015. Data selection Original articles that had assessed the sensitivity and specificity of the ISI, AIS, or PSQI against a reference standard in adult participants (age > 18) were included. Results A total of 19 studies comprising 4693 participants were included. The pooled sensitivity for the ISI, AIS, and PSQI was 88% (95% confidence interval CI = 0.79 to 0.93), 91% (0.87 to 0.93), and 94
% (0.86 to 0.98), respectively. The pooled specificity was 85% (0.68 to 0.94), 87% (0.68 to 0.95), and 76% (0.64 to 0.85); and the pooled DORs was 41.93 (8.77 to 200.33), 67.7 (23.4 to 196.1), and 53 (15.5 to 186.2), respectively. The summary estimates did not differ significantly among the ISI, AIS and PSQI (all P > 0
.05). Conclusions The current evidence indicates that the ISI, AIS, and PSQI yield comparable diagnostic properties for insomnia screening.
This study aims to investigate how gamification and virtual reality (VR)-enhanced web services can be integrated to influence consumer behavior in the context of tourism e-commerce. A gamified ...VR-enhanced tourism web system (VRTWS) was designed and developed for this investigation, while a research framework with 12 hypotheses was proposed and empirically tested by adopting PLS-SEM approach to analyze 208 valid data collected from survey. The results reveal that both Enjoyment and Activation in Gamification significantly and positively affected Media Richness. Additionally, Media Richness significantly and positively affected both Usefulness and Ease of Use in using VR technology with gamification. Also, a user’s Perceived Value is not only positively affected by Usefulness and Ease of Use but also Interactivity and Immersion in a gamified VRTWS. Immersion was found to be positively affected by Presence. Through the positive effect on Satisfaction, user’s Perceived Value had positive effect on the Intention toward adoption. The proposed gamified VRTWS and the study results with implications are expected to be referenced by the researchers and practitioners for managing incorporation of gamification into designing, developing, and managing their VR-enhanced service in tourism e-commerce.
Abstract
Background
Coronavirus-induced disease 19 (COVID-19) infects more than three hundred and sixty million patients worldwide, and people with severe symptoms frequently die of acute respiratory ...distress syndrome (ARDS). Recent studies indicated that excessive neutrophil extracellular traps (NETs) contributed to immunothrombosis, thereby leading to extensive intravascular coagulopathy and multiple organ dysfunction. Thus, understanding the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced NET formation would be helpful to reduce thrombosis and prevent ARDS in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Methods
We incubated SARS-CoV-2 with neutrophils in the presence or absence of platelets to observe NET formation. We further isolated extracellular vesicles from COVID-19 patients' sera (COVID-19-EVs) to examine their ability to induce NET formation.
Results
We demonstrated that antagonistic mAbs against anti-CLEC5A mAb and anti-TLR2 mAb can inhibit COVID-19-EVs-induced NET formation, and generated
clec5a
−/−
/tlr2
−/−
mice to confirm the critical roles of CLEC5A and TLR2 in SARS-CoV-2-induced lung inflammation in vivo. We found that virus-free extracellular COVID-19 EVs induced robust NET formation via Syk-coupled C-type lectin member 5A (CLEC5A) and TLR2. Blockade of CLEC5A inhibited COVID-19 EVs-induced NETosis, and simultaneous blockade of CLEC5A and TLR2 further suppressed SARS-CoV-2-induced NETosis in vitro. Moreover, thromboinflammation was attenuated dramatically in
clec5a
−/−
/tlr2
−/−
mice.
Conclusions
This study demonstrates that SARS-CoV-2-activated platelets produce EVs to enhance thromboinflammation via CLEC5A and TLR2, and highlight the importance of CLEC5A and TLR2 as therapeutic targets to reduce the risk of ARDS in COVID-19 patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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