Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
6,601
result(s) for
"Luo, R."
Sort by:
FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation
Cytosolic sensing of pathogens and damage by myeloid and barrier epithelial cells assembles large complexes called inflammasomes, which activate inflammatory caspases to process cytokines (IL-1β) and gasdermin D (GSDMD). Cleaved GSDMD forms membrane pores, leading to cytokine release and inflammatory cell death (pyroptosis). Inhibiting GSDMD is an attractive strategy to curb inflammation. Here we identify disulfiram, a drug for treating alcohol addiction, as an inhibitor of pore formation by GSDMD but not other members of the GSDM family. Disulfiram blocks pyroptosis and cytokine release in cells and lipopolysaccharide-induced septic death in mice. At nanomolar concentration, disulfiram covalently modifies human/mouse Cys191/Cys192 in GSDMD to block pore formation. Disulfiram still allows IL-1β and GSDMD processing, but abrogates pore formation, thereby preventing IL-1β release and pyroptosis. The role of disulfiram in inhibiting GSDMD provides new therapeutic indications for repurposing this safe drug to counteract inflammation, which contributes to many human diseases.
Disulfiram is an FDA-approved drug for treating alcoholism. Wu and colleagues show that disulfiram can be repurposed to efficiently inhibit pyroptosis by specifically blocking gasdermin-mediated pore formation.
Journal Article
EBV-miR-BART7-3p promotes the EMT and metastasis of nasopharyngeal carcinoma cells by suppressing the tumor suppressor PTEN
The epithelial-mesenchymal transition (EMT) is crucial to cancer progression and metastasis. Although multiple cellular miRNAs have been identified to regulate the EMT and metastasis in cancers, the role of viral miRNAs in cancer progression remains largely unknown. Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy typically characterized by its early metastasis. In the present study, we have discovered the involvement of a viral miRNA, EBV-miR-BART7-3p, in the EMT and metastasis of NPC cells. Initially, we observed that EBV-miR-BART7-3p was highly expressed in NPC and positively correlated with lymph node metastasis and clinical stage of NPC. Subsequently, we demonstrated that EBV-miR-BART7-3p enhanced cell migration/invasion
in vitro
, cancer metastasis
in vivo
, and particularly the EMT characterized by loss of epithelial markers and gain of mesenchymal features in NPC cells. Furthermore, mechanistic studies disclosed that EBV-miR-BART7-3p targeted a major human tumor suppressor PTEN, modulating PI3K/Akt/GSK-3β signaling and eventually leading to the high expression and nuclear accumulation of Snail and β-catenin, which favor EMT. Knockdown of PTEN could phenocopy the effect of EBV-miR-BART7-3p, whereas re-expression of PTEN resulted in a phenotypic reversion. Moreover, these findings were supported by an observation of an EBV-positive cell model in which silencing of endogenous EBV-miR-BART7-3p partially attenuated cell migration/invasion and altered EMT protein expression pattern via reverting PI3K/Akt, Snail and β-catenin expression. Thus, this study suggests a novel mechanism by which EBV-miR-BART7-3p modulates the EMT and metastasis of NPC cells, and a clinical implication of EBV-miR-BART7-3p as a potential biomarker or therapeutic target.
Journal Article
Diverse polarization angle swings from a repeating fast radio burst source
Fast radio bursts (FRBs) are millisecond-duration radio transients
1
,
2
of unknown origin. Two possible mechanisms that could generate extremely coherent emission from FRBs invoke neutron star magnetospheres
3
–
5
or relativistic shocks far from the central energy source
6
–
8
. Detailed polarization observations may help us to understand the emission mechanism. However, the available FRB polarization data have been perplexing, because they show a host of polarimetric properties, including either a constant polarization angle during each burst for some repeaters
9
,
10
or variable polarization angles in some other apparently one-off events
11
,
12
. Here we report observations of 15 bursts from FRB 180301 and find various polarization angle swings in seven of them. The diversity of the polarization angle features of these bursts is consistent with a magnetospheric origin of the radio emission, and disfavours the radiation models invoking relativistic shocks.
Polarization observations of the fast radio burst FRB 180301 with the FAST radio telescope show diverse polarization angle swings, consistent with a magnetospheric origin of the emission.
Journal Article
Balancing immune response: SHP1 controls neutrophil activation in inflamed lungs
Following respiratory infection or injury, neutrophil hyperactivation can damage surrounding lung tissue by releasing harmful compounds. In this issue of the JCI, Moussavi-Harami and colleagues identified tyrosine phosphatase SHP1 as a key negative regulator of neutrophil activation in acute respiratory distress syndrome (ARDS). Neutrophil-specific Shp1 disruption leads to hyperinflammation, pulmonary hemorrhage, and increased mortality in both sterile and pathogen-induced acute lung injury (ALI). Large intravascular neutrophil clusters and excessive PAD4-independent neutrophil extracellular traps (NETs) were identified as key features of lung injury. Mechanistically, Shp1 deficiency resulted in uncontrolled SYK kinase activation, driving chaotic neutrophil hyperactivation and inflammation.
Journal Article
Single-cell transcriptome profiling reveals neutrophil heterogeneity in homeostasis and infection
The full neutrophil heterogeneity and differentiation landscape remains incompletely characterized. Here, we profiled >25,000 differentiating and mature mouse neutrophils using single-cell RNA sequencing to provide a comprehensive transcriptional landscape of neutrophil maturation, function and fate decision in their steady state and during bacterial infection. Eight neutrophil populations were defined by distinct molecular signatures. The three mature peripheral blood neutrophil subsets arise from distinct maturing bone marrow neutrophil subsets. Driven by both known and uncharacterized transcription factors, neutrophils gradually acquire microbicidal capability as they traverse the transcriptional landscape, representing an evolved mechanism for fine-tuned regulation of an effective but balanced neutrophil response. Bacterial infection reprograms the genetic architecture of neutrophil populations, alters dynamic transitions between subpopulations and primes neutrophils for augmented functionality without affecting overall heterogeneity. In summary, these data establish a reference model and general framework for studying neutrophil-related disease mechanisms, biomarkers and therapeutic targets at single-cell resolution.
Luo and colleagues use single-cell RNA sequencing to provide a comprehensive transcriptional landscape of neutrophil maturation, function and fate decision in their steady state and during bacterial infection.
Journal Article
Gasdermin E dictates inflammatory responses by controlling the mode of neutrophil death
Both lytic and apoptotic cell death remove senescent and damaged cells in living organisms. However, they elicit contrasting pro- and anti-inflammatory responses, respectively. The precise cellular mechanism that governs the choice between these two modes of death remains incompletely understood. Here we identify Gasdermin E (GSDME) as a master switch for neutrophil lytic pyroptotic death. The tightly regulated GSDME cleavage and activation in aging neutrophils are mediated by proteinase-3 and caspase-3, leading to pyroptosis. GSDME deficiency does not alter neutrophil overall survival rate; instead, it specifically precludes pyroptosis and skews neutrophil death towards apoptosis, thereby attenuating inflammatory responses due to augmented efferocytosis of apoptotic neutrophils by macrophages. In a clinically relevant acid-aspiration-induced lung injury model, neutrophil-specific deletion of GSDME reduces pulmonary inflammation, facilitates inflammation resolution, and alleviates lung injury. Thus, by controlling the mode of neutrophil death, GSDME dictates host inflammatory outcomes, providing a potential therapeutic target for infectious and inflammatory diseases.
Apoptotic and lytic cell death pathways are both utilised in the removal of damaged cells; however, the downstream inflammatory outcomes widely vary according to the chosen pathway. Here authors show that in mice with genetic deletion of Gasdermin E specifically in neutrophils, these cells undergo apoptosis rather than pyroptotic cell death upon senescence, with consequential attenuation of reactive inflammatory responses.
Journal Article
Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages
Candida albicans
is the most common cause of fungal sepsis. Inhibition of inflammasome activity confers resistance to polymicrobial and LPS-induced sepsis; however, inflammasome signaling appears to protect against
C. albicans
infection, so inflammasome inhibitors are not clinically useful for candidiasis. Here we show disruption of GSDMD, a known inflammasome target and key pyroptotic cell death mediator, paradoxically alleviates candidiasis, improving outcomes and survival of
Candida
-infected mice. Mechanistically,
C. albicans
hijacked the canonical inflammasome-GSDMD axis-mediated pyroptosis to promote their escape from macrophages, deploying hyphae and candidalysin, a pore-forming toxin expressed by hyphae. GSDMD inhibition alleviated candidiasis by preventing
C. albicans
escape from macrophages while maintaining inflammasome-dependent but GSDMD-independent IL-1β production for anti-fungal host defenses. This study demonstrates key functions for GSDMD in
Candida
’s escape from host immunity in vitro and in vivo and suggests that GSDMD may be a potential therapeutic target in
C. albicans
-induced sepsis.
Inflammasome signalling has been shown to protect
Candida albicans
during infection and as such limits inflammasome inhibitors in this context. Here the authors implicate Gasdermin D in
C.ablicans
immune evasion and suggests its targeting therapeutically.
Journal Article
A repeating fast radio burst associated with a persistent radio source
The dispersive sweep of fast radio bursts (FRBs) has been used to probe the ionized baryon content of the intergalactic medium
1
, which is assumed to dominate the total extragalactic dispersion. Although the host-galaxy contributions to the dispersion measure appear to be small for most FRBs
2
, in at least one case there is evidence for an extreme magneto-ionic local environment
3
,
4
and a compact persistent radio source
5
. Here we report the detection and localization of the repeating FRB 20190520B, which is co-located with a compact, persistent radio source and associated with a dwarf host galaxy of high specific-star-formation rate at a redshift of 0.241 ± 0.001. The estimated host-galaxy dispersion measure of approximately
903
−
111
+
72
parsecs per cubic centimetre, which is nearly an order of magnitude higher than the average of FRB host galaxies
2
,
6
, far exceeds the dispersion-measure contribution of the intergalactic medium. Caution is thus warranted in inferring redshifts for FRBs without accurate host-galaxy identifications.
A repeating fast radio burst co-located with a persistent radio source and associated with a dwarf host galaxy of a high star-formation rate has been detected.
Journal Article
Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus
Aberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer's disease-like (AD-like) neuropathology in the human brain. However, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear. Here, we show that 3,4-dihydroxyphenylglycolaldehyde, which is produced exclusively in noradrenergic neurons by monoamine oxidase A metabolism of norepinephrine, activated asparagine endopeptidase that cleaved Tau at residue N368 into aggregation- and propagation-prone forms, thus leading to LC degeneration and the spread of Tau pathology. Activation of asparagine endopeptidase-cleaved Tau aggregation in vitro and in intact cells was triggered by 3,4-dihydroxyphenylglycolaldehyde, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal that norepinephrine metabolism and Tau cleavage represent the specific molecular mechanism underlying the selective vulnerability of LC neurons in AD.
Journal Article