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Aberrant activation of the nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome drives the development of many complex inflammatory diseases, such as obesity, Alzheimer's disease, and atherosclerosis. However, no medications specifically targeting the NLRP3 inflammasome have become clinically available. Therefore, we aim to identify new inhibitors of the NLRP3 inflammasome in this study. Methods: Vesicle-like nanoparticles (VLNs) were extracted from garlic chives and other Allium vegetables and their effects on the NLRP3 inflammasome were evaluated in primary macrophages. After garlic chive-derived VLNs (GC-VLNs) were found to exhibit potent anti-NLRP3 inflammasome activity in cell culture, such function was further assessed in a murine acute liver injury disease model, as well as in diet-induced obesity. Finally, GC-VLNs were subjected to omics analysis to identify the active components with anti-NLRP3 inflammasome function. Results: GC-VLNs are membrane-enclosed nanoparticles containing lipids, proteins, and RNAs. They dose-dependently inhibit pathways downstream of NLRP3 inflammasome activation, including caspase-1 autocleavage, cytokine release, and pyroptotic cell death in primary macrophages. The inhibitory effects of GC-VLNs on the NLRP3 inflammasome are specific, considering their marginal impact on activation of other inflammasomes. Local administration of GC-VLNs in mice alleviates NLRP3 inflammasome-mediated inflammation in chemical-induced acute liver injury. When administered orally or intravenously, GC-VLNs accumulate in specific tissues and suppress activation of the NLRP3 inflammasome and chronic inflammation in diet-induced obese mice. The phospholipid 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) in GC-VLNs has been identified to inhibit NLRP3 inflammasome activation. Conclusions: Identification of GC-VLNs and their active component DLPC as potent inflammasome inhibitors provides new therapeutic candidates in the treatment of NLRP3 inflammasome-driven diseases.

Pregnancy-associated breast cancer (PABC) is a rare disease, which is frequently diagnosed at an advanced stage due to limitations in current diagnostic methods. In this study, fluorescence lifetime imaging microscopy (FLIM) was used to study the metabolic changes by measuring maternal blood and umbilical cord blood via the autofluorescence of coenzymes, reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H), and flavin adenine dinucleotide (FAD). The NAD(P)H data showed that a PABC case had significant differences compared with normal cases, which may indicate increased glycolysis. The FAD data showed that both maternal and cord blood of PABC had shorter mean lifetimes and higher bound-FAD ratios. The significant differences suggested that FLIM testing of blood samples may be a potential method to assist in PABC non-radiative screening.

Honey has been used as a nutrient, an ointment, and a medicine worldwide for many centuries. Modern research has demonstrated that honey has many medicinal properties, reflected in its anti‐microbial, anti‐oxidant, and anti‐inflammatory bioactivities. Honey is composed of sugars, water and a myriad of minor components, including minerals, vitamins, proteins and polyphenols. Here, we report a new bioactive component‒vesicle‐like nanoparticles‒in honey (H‐VLNs). These H‐VLNs are membrane‐bound nano‐scale particles that contain lipids, proteins and small‐sized RNAs. The presence of plant‐originated plasma transmembrane proteins and plasma membrane‐associated proteins suggests the potential vesicle‐like nature of these particles. H‐VLNs impede the formation and activation of the nucleotide‐binding domain and leucine‐rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome, which is a crucial inflammatory signalling platform in the innate immune system. Intraperitoneal administration of H‐VLNs in mice alleviates inflammation and liver damage in the experimentally induced acute liver injury. miR‐4057 in H‐VLNs was identified in inhibiting NLRP3 inflammasome activation. Together, our studies have identified anti‐inflammatory VLNs as a new bioactive agent in honey.

Coxsackievirus A16 (CA16) is one of predominant Enterovirus that possesses high pathogenicity. Lipid rafts, as cholesterol - and sphingolipid - enriched membrane nanodomains, are involved into many aspects of the virus life cycle. Our previous study found that lipid rafts integrity was essential for CA16 replication, but how lipid rafts regulate CA16 replication through activating downstream signaling remains largely unknown. Thus, in this study, we revealed that lipid rafts were required for activation of PI3K/Akt signaling at early stage of CA16 infection. Treatment with wortmannin significantly reduced the expression of virus protein, indicating PI3K/Akt signaling was beneficial for early stage of virus infection. In addition, lipid rafts integrity was also indispensable for PI3K/Akt activation during the late stage of CA16 infection, which played critical functions in mediating sterol regulatory element-binding proteins 1 (SREBP1) maturation. Whereas, over-expression of SREBP1 exhibited inhibition on virus replication, suggesting that PI3K/Akt signaling and SREBP1 might positively and negatively influence virus replication in two different stages of infection, respectively. Taken together, our study demonstrates an important role of the lipid raft-associated PI3K/Akt/SREBP1 signaling in modulating CA16 replication, which will deepen our understanding mechanism of CA16 infection.

Porcine epidemic diarrhea virus (PEDV) is an enveloped, single-stranded positive-sense RNA virus that belongs to a porcine entero-pathogenic alphacoronavirus, causing lethal watery diarrhea in piglets. Despite existing study reports the sole accessory protein ORF3 identified as NF-κB antagonist, the contribution of PEDV ORF3 to production of the pro-inflammatory cytokines mediated by NF-κB signaling remains largely unknown. Thus in this present study, we showed that PEDV ORF3 protein significantly inhibited the productions of pro-inflammatory cytokines interleukin-6 (IL-6) and IL-8. The phosphorylation of IκBα was inhibited by ORF3 protein, but no degradation of IκBα was induced in ORF3-expressing cells. Furthermore, PEDV ORF3 inhibited NF-κB activation through preventing nuclear factor p65 phosphorylation and down-regulating p65 expression level, as well as interfering nuclear translocation of p65, eventually resulting into the inhibition of IL-6 and IL-8 production. Our study definitely links PEDV ORF3 to inhibition of pro-inflammatory cytokines production, which will provide new insight into the molecular mechanisms of NF-κB activity inhibited by PEDV proteins to facilitate virus evasion of host innate immune.

Fulminant hepatic failure (FHF) is a rare, life-threatening liver disease with a poor prognosis. Administration of D-galactosamine (GalN) and lipopolysaccharide (LPS) triggers acute liver injury in mice, simulating many clinical features of FHF in humans, therefore, this disease model is often used to investigate potential therapeutic interventions to treat FHF. Recently, suppression of the nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome, was shown to alleviate the severity of GalN/LPS-induced liver damage in mice. Therefore, the goal of this study was to find dietary exosome-like nanoparticles (ELNs) with therapeutic potential in curbing FHF by suppressing the NLRP3 inflammasome. Seven commonly consumed mushrooms were used to extract ELNs. These mushrooms were found to contain ELNs composed of RNAs, proteins, and lipids. Among these mushroom-derived ELNs, only shiitake mushroom-derived ELNs (S-ELNs) substantially inhibited NLRP3 inflammasome activation by preventing inflammasome formation in primary macrophages. S-ELNs also suppressed the secretion of interleukin (IL)-6, as well as both protein and mRNA levels of the Il1b gene. Remarkably, pre-treatment with S-ELNs protected mice from GalN/LPS-induced acute liver injury. Therefore, S-ELNs, identified as potent new inhibitors of the NLRP3 inflammasome, represent a promising class of agents with the potential to combat FHF.

Objective To determine the involvement of Toll-like receptor (TLR) 2, TLR9, and TLR2+9 in renal ischemia/reperfusion (I/R) injury. Methods Mice with gene knock-out of TLR2, TLR9, and TLR2+9 underwent renal I/R injury. Tubular damage, expression of proinflammatory cytokines and chemokines, and kidney dysfunction were evaluated on different days after reperfusion. Results Mice deficient in TLR2, but not TLR9, were protected from renal I/R injury with less tubular damage, decreased cytokine production, and lower serum creatinine and urea levels than wild-type mice. TLR2+9 double-deficiency did not have an additional effect on tissue injury compared with TLR2 deficiency alone. Conclusion These results suggest that activation of TLR2 signaling contributes to the pathogenesis of renal I/R injury, whereas TLR9 may be redundant for the development of this injury.

In this work, we propose a signal selection procedure for determination of hemoglobin (Hb) concentration in whole blood using near infrared (NIR) transmission spectral signals. A dataset of 190 whole blood NIR transmission spectra with reference Hb concentrations was used to evaluate the method. Spectral signals were selected based on the squared correlation coefficient ( R 2 ) between the signal and the Hb concentration. An improved uninformative variable elimination (UVE) procedure was performed to remove redundant signals from the primary selected signal set. A partial least squares (PLS) regression model was built with the final selected signals and the corresponding Hb concentrations. The results indicate that the proposed method is effective at increasing the predictive power of the NIR–PLS spectral model for determining Hb concentration in whole blood samples.