Curcumin is an active component derived from Curcuma longa L. which is a traditional Chinese medicine that is widely used for treating metabolic diseases through regulating different molecular pathways. Here, in this study, we aimed to comprehensively investigate the effects of curcumin on glycolipid metabolism in vivo and in vitro and then determine the underlying mechanism. Male C57BL/6 J obese mice and 3T3-L1 adipocytes were used for in vivo and in vitro study, respectively. Our results demonstrated that treatment with curcumin for eight weeks decreased body weight, fat mass and serum lipid profiles. Meanwhile, it lowered fasting blood glucose and increased the insulin sensitivity in high-fat diet-induced obese mice. In addition, curcumin stimulated lipolysis and improved glycolipid metabolism through upregulating the expressions of adipose triglyceride lipase and hormone-sensitive lipase, peroxisome proliferator activated receptor γ/α (PPARγ/α) and CCAAT/enhancer binding proteinα (C/EBPα) in adipose tissue of the mice. In differentiated 3T3-L1 cells, curcumin reduced glycerol release and increased glucose uptake via upregulating PPARγ and C/EBPα. We concluded that curcumin has the potential to improve glycolipid metabolism disorders caused by obesity through regulating PPARγ signalling pathway.
Rabies virus (RABV) is a widespread pathogen that causes fatal disease in humans and animals. It has been suggested that multiple host factors are involved in RABV host entry. Here, we showed that RABV uses integrin β1 (ITGB1) for cellular entry. RABV infection was drastically decreased after ITGB1 short interfering RNA knockdown and moderately increased after ITGB1 overexpression in cells. ITGB1 directly interacts with RABV glycoprotein. Upon infection, ITGB1 is internalized into cells and transported to late endosomes together with RABV. The infectivity of cell-adapted RABV in cells and street RABV in mice was neutralized by ITGB1 ectodomain soluble protein. The role of ITGB1 in RABV infection depends on interaction with fibronectin in cells and mice. We found that Arg-Gly-Asp (RGD) peptide and antibody to ITGB1 significantly blocked RABV infection in cells in vitro and street RABV infection in mice via intramuscular inoculation but not the intracerebral route. ITGB1 also interacts with nicotinic acetylcholine receptor, which is the proposed receptor for peripheral RABV infection. Our findings suggest that ITGB1 is a key cellular factor for RABV peripheral entry and is a potential therapeutic target for postexposure treatment against rabies.
IMPORTANCE Rabies is a severe zoonotic disease caused by rabies virus (RABV). However, the nature of RABV entry remains unclear, which has hindered the development of therapy for rabies. It is suggested that modulations of RABV glycoprotein and multiple host factors are responsible for RABV invasion. Here, we showed that integrin β1 (ITGB1) directly interacts with RABV glycoprotein, and both proteins are internalized together into host cells. Differential expression of ITGB1 in mature muscle and cerebral cortex of mice led to A-4 (ITGB1-specific antibody), and RGD peptide (competitive inhibitor for interaction between ITGB1 and fibronectin) blocked street RABV infection via intramuscular but not intracerebral inoculation in mice, suggesting that ITGB1 plays a role in RABV peripheral entry. Our study revealed this distinct cellular factor in RABV infection, which may be an attractive target for therapeutic intervention.
Initial cell attachment of rotavirus (RV) to specific cell surface glycan receptors, which is the essential first step in RV infection, is mediated by the VP8* domain of the spike protein VP4. Recently, human histo-blood group antigens (HBGAs) have been identified as receptors or attachment factors for human RV strains. RV strains in the P[4] and P[8] genotypes of the P [II] genogroup share common recognition of the Lewis b (Le b) and H type 1 antigens, however, the molecular basis of receptor recognition by the major human P[8] RVs remains unknown due to lack of experimental structural information. Here, we used nuclear magnetic resonance (NMR) spectroscopy-based titration experiments and NMR-derived high ambiguity driven docking (HADDOCK) methods to elucidate the molecular basis for P[8] VP8* recognition of the Le b (LNDFH I) and type 1 HBGAs. We also used X-ray crystallography to determine the molecular details underlying P[6] recognition of H type 1 HBGAs. Unlike P[6]/ P[19] VP8*s that recognize H type 1 HBGAs in a binding surface composed of an α-helix and a β-sheet, referred as the "βα binding site", the P[8] and P[4] VP8*s bind Le b HBGAs in a previously undescribed pocket formed by the edges of two β-sheets, referred to as the "ββ binding site". Importantly, the P[8] and P[4] VP8*s retain binding capability to non-Le b type 1 HBGAs using the βα binding site. The presence of two distinct binding sites for Le b and non-Le b HBGA glycans in the P[8] and P[4] VP8* domains suggests host-pathogen co-evolution under structural and functional adaptation of RV pathogens to host glycan polymorphisms. Assessment and understanding of the precise impact of this co-evolutionary process in determining RV host ranges and cross-species RV transmission should facilitate improved RV vaccine development and prediction of future RV strain emergence and epidemics.
Abstract:Paeonia is the single genus of ca. 33 known species in the family Paeoniaceae, found in Asia, Europe and Western North America. Up to now, more than 180 compounds have been isolated from nine species of the genus Paeonia, including terpenes, phenols, flavonoids, essential oil and tannins. Terpenes, the most abundant naturally occurring compounds, which accounted for about 57% and occurred in almost every species, are responsible for the observed in vivo and in vitro biological activities. This paper aims to give a comprehensive overview of the recent phytochemical and pharmacological knowledge of the terpenes from Paeonia plants, and enlighten further drug discovery research.
Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16) have caused severe epidemics of hand, foot and mouth disease (HFMD) in the Asia Pacific in recent years, particularly in infants and young children. This disease has become a serious public health problem, as no vaccines or antiviral drugs have been approved for EV71 and CA16 infections. In this study, we compared four monovalent vaccines, including formalin-inactivated EV71 virus (iEV71), EV71 virus-like particles (VLPs) (vEV71), formalin-inactivated CVA16 virus (iCVA16) and CVA16 VLPs (vCVA16), along with two bivalent vaccines, including equivalent doses of formalin-inactivated EV71CCVA16 virus (iEV71CiCVA16) and EV71CCVA16 VLPs (vEV71CvCVA16). The IgG titers and neutralization antibodies titers demonstrated that there are no immune interference exists between the two immunogens of EV71 and CVA16. IgG subclass isotyping revealed that IgG1 and IgG2b were induced primarily in all vaccine groups. Furthermore, cross-neutralization antibodies were elicited in mouse sera against other sub-genotypes of EV71 and CVA16. In vivo challenge experiments showed that the immune sera from vaccinated animals could confer passive protection to newborn mice against lethal challenge with 14 LD 50 of EV71 and 50 LD 50 of CVA16. Our results indicated that bivalent vaccination is promising for HFMD vaccine development. With the advantage of having a better safety profile than inactivated virus vaccines, VLPs should be used to combine both EV71 and CVA16 antigens as a candidate vaccine for prevention of HFMD virus transmission.
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