Inflammasomes are newly recognized, vital players in innate immunity. The best characterized is the NLRP3 inflammasome, so-called because the NLRP3 protein in the complex belongs to the family of ...nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as "pyrin domain-containing protein 3". The NLRP3 inflammasome is associated with onset and progression of various diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic fever syndrome, as well as other auto-immune and auto-inflammatory diseases. Several NLRP3 inflammasome inhibitors have been described, some of which show promise in the clinic. The present review will describe the structure and mechanisms of activation of the NLRP3 inflammasome, its association with various auto-immune and auto-inflammatory diseases, and the state of research into NLRP3 inflammasome inhibitors.
Abstract
We study the extended Kitaev chain with both nearest-neighbor and next-nearest-neighbor hopping terms and find the model system exhibiting nontrivial phases, which can be characterized by a ...nonzero Berry phase and winding number when the system is in a pure state. While in a mixed state, we investigate the robustness of the topological Uhlmann phases and show how it responses to the presence of next-nearest-neighbor hopping terms. Furthermore, we analyse the complicated behavior of the Uhlmann phase of the extended Kitaev chain at finite temperature as
k
moves along the Brillouin zone, and we think this may serve as a topological indicator for mixed states in condensed matter systems.
By using first-principles calculations and symmetry analysis, we study the topologically nontrivial features of sextuple nodal-point phonons together with other kinds of topological phonons in ...realistic materials. The sextuple nodal-point phonons in all 230 space groups, enumerated in this paper, are localized at the boundaries of the three-dimensional Brillouin zone (BZ), and protected both by time-reversal symmetry () and little-group symmetries. Moreover, in a realistic material sample of insulator SiO2, we find that the sextuple nodal-point phonons exist at the high-symmetry point H of the first BZ, and generate four-fold surface states. Interestingly, owing to the special crystal symmetries in SiO2, triple nodal-point phonons and Dirac phonons exist at the point Γ and P, respectively, and exhibit exotic quadruple surface states. More than these, the topological phononic nodal links also appear around the point Γ, and exhibit drumhead like surface states in this material. Our theoretical work not only proposes an effective way to search for multi-fold topological phonons including Dirac phonons and sextuple nodal-point phonons, but also presents a realistic material sample to realize the coexistence of multiple nodal-point and nodal-link phonons.
Activation of cannabinoid receptor 2 (CB2R) ameliorates inflammation, but the underlying mechanism remains unclear. In the present study, we examined whether activation of CB2R could suppress the ...nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome. In peritoneal macrophages isolated from C57BL/6 mice, LPS/DSS challenge for 24 h increased the expression of the components of NLRP3 inflammasome NLRP3, Casp-1 p20/Casp-1 p45 ratio, proIL-1β and IL-1β and also enhanced autophagy (LC3-II/LC3-I ratio, Beclin-1 and SQSTM1). Pretreatment of peritoneal macrophages with HU 308, a selective CB2R agonist, attenuated LPS/DSS-induced NLRP3 inflammasome activation, but further enhanced autophagy. In comparison with wild-type (WT) control, peritoneal macrophages from CB2R knockout (KO) mice had more robust NLRP3 inflammasome activation and attenuated autophagy upon LPS/DSS challenge. Knockdown autophagy-related gene 5 (Atg5) with a siRNA in peritoneal macrophages attenuated the inhibitory effects of HU 308 on LPS/DSS-induced NLRP3 inflammasome activation in vitro. In vivo, HU308 treatment attenuated DSS-induced colitis mice associated with reduced colon inflammation and inhibited NLRP3 inflammasome activation in wild-type mice. In CB2R KO mice, DSS-induced inflammation and NLRP3 inflammasome activation were more pronounced than those in WT control. Finally, we demonstrated that AMPK-mTOR-P70S6K signaling pathway was involved in this CB2R-mediated process. We conclude that activation of CB2R ameliorates DSS-induced colitis through enhancing autophagy that may inhibit NLRP3 inflammasome activation in macrophages.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Absence of any surface arc state has been regarded as the fundamental property of singular Weyl points, because they are circumvented from the Nielsen‐Ninomiya no‐go theorem. In this work, through ...systematic investigations on topological properties of isolated Weyl phonons (IWPs) surrounded by closed Weyl nodal walls (WNWs), which are located at the Brillouin zone (BZ) boundaries of bosonic systems, it uncovers that a new kind of phononic surface state, that is, the multi‐fold fan‐shape surface state named by us, is exhibited to connect the projections of IWP and WNWs. Importantly, the number of fan leaves in this surface state is associated with the Chern number of IWP. Moreover, the topological features of charge‐two IWP in K2Mg2O3 (SG No. 96) and charge‐four IWP in Nb3Al2N (SG No. 213) confirm further the above fundamental properties of this kind of surface state. The theoretical work not only provides an effective way to seek for IWPs as well as to determine their Chern number in real materials, but also uncovers a new class of surface states in the topological Weyl complex composed of IWPs and WNWs.
We uncover that a new kind of phononic surface state, that is, the multi‐fold fan‐shape surface state named by us, is exhibited to connect the projections of isolated Weyl point (IWP) and the surrounded Weyl nodal walls. Importantly, the number of fan leaves in this surface state is associated with the Chern number of IWP.
Site- and stereoselective C-H functionalization is highly challenging in the synthetic chemistry community. Although the chemistry of vinyl cations has been vigorously studied in C(sp
)-H ...functionalization reactions, the catalytic enantioselective C(sp
)-H functionalization based on vinyl cations, especially for an unactivated C(sp
)-H bond, has scarcely explored. Here, we report an asymmetric copper-catalyzed tandem diyne cyclization/unactivated C(sp
)-H insertion reaction via a kinetic resolution, affording both chiral polycyclic pyrroles and diynes with generally excellent enantioselectivities and excellent selectivity factors (up to 750). Importantly, this reaction demonstrates a metal-catalyzed enantioselective unactivated C(sp
)-H functionalization via vinyl cation and constitutes a kinetic resolution reaction based on diyne cyclization. Theoretical calculations further support the mechanism of vinyl cation-involved C(sp
)-H insertion reaction and elucidate the origin of enantioselectivity.
Summary
Aims
Activation of cannabinoid receptor 2 (CB2R) has been reported to ameliorate the pathogenesis of experimental autoimmune encephalomyelitis (EAE). In this study, we examined whether ...autophagy is involved in the beneficial effect of CB2R on EAE and explored the mechanism with a focus on inflammasome activation.
Methods
EAE severity was analyzed with clinical score and histological score stained by hematoxylin and eosin or luxol fast blue in spinal cord. Immunoblot analysis was conducted to detect proteins of NOD‐like receptor family, pyrin domain containing 3 (NLRP3) inflammasome‐related caspase‐1 (Casp‐1) and the maturation of interleukin (IL)‐1β as well as autophagy‐related light chain 3 (LC3), and Beciln 1 both in vivo and in vitro. Reverse transcription and real‐time PCR were used to detect mRNA of NLRP3, IL‐1β and Casp‐1. Autophagy‐related gene 5 (ATG5)‐specific siRNA was transiently transfected in BV2 microglia, and immunofluorescence staining was carried out to detect the expression of NLRP3, caspase recruitment domain (ASC), and pro‐caspase‐1.
Results
The current data indicated that deleting CB2R decreased the expression of LC3‐II/LC3‐I ratio, Beclin 1 and increased caspase‐1 activation and IL‐1β production in the spinal cord of EAE mice, whereas activation of CB2R with a specific agonist HU‐308 induced inverse effects. Further study indicated that HU‐308 could promote autophagy and inhibit expression and activation of NLRP3 inflammasome in BV2 microglia. Blocking autophagy by ATG5‐specific siRNA dismissed the effort of CB2R in mediating NLRP3 inflammasome in vitro.
Conclusion
Collectively, our results demonstrated for the first time that CB2R plays a protective role in EAE through promoting autophagy and inhibiting NLRP3 inflammasome activation.
Intestinal mucosal barrier, mainly composed of the intestinal mucus layer and the epithelium, plays a critical role in nutrient absorption as well as protection from pathogenic microorganisms. It is ...widely acknowledged that the damage of intestinal mucosal barrier or the disturbance of microorganism balance in the intestinal tract contributes greatly to the pathogenesis and progression of inflammatory bowel disease (IBD), which mainly includes Crohn's disease and ulcerative colitis. Autophagy is an evolutionarily conserved catabolic process that involves degradation of protein aggregates and damaged organelles for recycling. The roles of autophagy in the pathogenesis and progression of IBD have been increasingly studied. This present review mainly describes the roles of autophagy of Paneth cells, macrophages, and goblet cells in IBD, and finally, several potential therapeutic strategies for IBD taking advantage of autophagy.
Proteasome 26S subunit, non-ATPase 7 (PSMD7) is a deubiquitinating enzyme that is involved in the stability of ubiquitinated proteins and participates in the development of multiple types of cancer. ...The roles of PSMD7 and its potential mechanisms in bladder cancer (BC) remain elusive.
In this study, we identified that PSMD7 was overexpressed in BC tissues based on gene expression omnibus (GEO) database and TNMplot web. To investigate the functional role of PSMD7, two BC cell lines, T24 and 5637, were selected. The cells were transfected with vectors containing short hairpin RNAs against PSMD7 or plasmids containing full-length PSMD7 to knockdown or overexpress PSMD7.
Our results revealed that silencing PSMD7 inhibited cell proliferation, cycle progression, migration, invasion, and promoted cell apoptosis, whereas PSMD7 overexpression led to the opposite effects in the BC cells. Mechanically, PSMD7 influenced the protein expression but not the mRNA expression of the Ras-related protein Rab-1 A (RAB1A). PSMD7 combined with RAB1A and negatively regulated its ubiquitination, indicating that PSMD7 enhanced the stability of RAB1A through post-transcriptional modification. Moreover, the rescue experiment demonstrated that RAB1A was an important downstream effector molecule of PSMD7. Besides, the negative regulation of silencing PSMD7 on tumor growth was confirmed in mice.
Our study substantiated a novel mechanism by which PSMD7 stabilized RAB1A to accelerate the progression of BC.
•PSMD7 promoted BC cell malignant behaviors.•Silencing PSMD7 contributed to the inhibition of bladder cancer tumor growth in mice.•PSMD7 accelerated BC progression by deubiquitinating and stabilizing RAB1A protein.
Elsholtzia and its allied genera such as Collinsonia and Perilla (tribe Elsholtzieae, Lamiaceae) are an ecologically and economically important plant group consisting of ~71 species, with most ...species distributed in East and Southeast Asia, and several species in North America. Their phylogeny and historical biogeography resulting in a distant intercontinental disjunction are poorly understood. Here we use two nuclear (ETS, ITS) and five chloroplast (rbcL, matK, trnL-F, ycf1, ycf1-rps15) fragments to reconstruct the phylogeny, biogeographic history, and patterns of diversification of Elsholtzieae. The tribe Elsholtzieae is monophyletic and divided into five clades. The woody Elsholtzia species are nested within herbaceous ones and are inferred to have evolved from herbaceous ancestors. Molecular dating shows that the five major clades were established during the Eocene period, but most of the modern diversity did not originate until the Miocene. The divergence between the New World Collinsonia and the Old World Mosla-Keiskea-Perilla clade was dated to the mid-Miocene. Ancestral area reconstructions suggest that the tribe originated in East Asia, and then dispersed to Southeast Asia and North America. Overall, our findings highlight the important roles of the uplifts of the Qinghai-Tibetan Plateau (QTP) and climate changes from Middle Miocene onwards in promoting species diversification of Elsholtzieae.
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