Astragalus polysaccharides (APS), which is widely used as a remedy to promote immunity of breast cancer patients, can enhance immune responses and exert anti-tumor effects. In this study, we investigated the effects and mechanisms of APS on macrophage RAW 264.7 and EAC tumor-bearing mice. Griess reaction and ELISA assays revealed that the concentrations of nitric oxide, TNF-α, IL-1β and IL-6 were increased by APS. However, this effect was diminished in the presence of TAK-242 (TLR4 inhibitor) or ST-2825(MyD88 inhibitor). In C57BL/10J (TLR4+/+wild-type) and C57BL/6J (MyD88+/+wild-type) tumor-bearing mice, the tumor apoptosis rate, immune organ indexes and the levels of TNF-α, IL-1β and IL-6 in blood increased and the tumor weight decreased by oral administration of APS for 25 days. APS had no obvious effects on IL-12p70. However, these effects were not significant in C57BL/10ScNJ (TLR4-deficient) and C57BL/B6.129P2(SJL)-Myd88m1.1Defr/J (MyD88-deficient) tumor-bearing mice. qRT-PCR and Western blot indicated that APS stimulated the key nodes in the TLR4-MyD88 dependent signaling pathway, including TLR4, MyD88, TRAF-6, NF-κB and AP-1, both in vitro and in vivo. However, TRAM was an exception. Moreover, TRAF-6 and NF-κB were not triggered by APS in gene-deficient tumor-bearing mice. Therefore, APS may modulate immunity of host organism through activation of TLR4-mediated MyD88-dependent signaling pathway.
Background and Aims
Nonalcoholic fatty liver disease (NAFLD) has been widely recognized as a precursor to metabolic complications. Elevated inflammation levels are predictive of NAFLD‐associated metabolic disorder. Inactive rhomboid‐like protein 2 (iRhom2) is regarded as a key regulator in inflammation. However, the precise mechanisms by which iRhom2‐regulated inflammation promotes NAFLD progression remain to be elucidated.
Approach and Results
Here, we report that insulin resistance, hepatic steatosis, and specific macrophage inflammatory activation are significantly alleviated in iRhom2‐deficient (knockout [KO]) mice, but aggravated in iRhom2 overexpressing mice. We further show that, mechanistically, in response to a high‐fat diet (HFD), iRhom2 KO mice and mice with iRhom2 deficiency in myeloid cells only showed less severe hepatic steatosis and insulin resistance than controls. Inversely, transplantation of bone marrow cells from healthy mice to iRhom2 KO mice expedited the severity of insulin resistance and hepatic dyslipidemia. Of note, in response to HFD, hepatic iRhom2 binds to mitogen‐activated protein kinase kinase kinase 7 (MAP3K7) to facilitate MAP3K7 phosphorylation and nuclear factor kappa B cascade activation, thereby promoting the activation of c‐Jun N‐terminal kinase/insulin receptor substrate 1 signaling, but disturbing AKT/glycogen synthase kinase 3β–associated insulin signaling. The iRhom2/MAP3K7 axis is essential for iRhom2‐regulated liver steatosis.
Conclusions
iRhom2 may represent a therapeutic target for the treatment of HFD‐induced hepatic steatosis and insulin resistance.
Objectives
The study is to evaluate biodistribution, dosimetry, safety, and clinical usefulness of 18F-AlF-NOTA-octreotide (18F-OC) PET/CT in combination with 18F-FDG PET/CT for detection of neuroendocrine neoplasms (NENs).
Methods
The biodistribution, dosimetry, and safety of 18F-OC were evaluated in 3 healthy volunteers. Twenty-two NEN patients underwent PET/CT at 60 minutes after intravenous injection of 3.7 to 4.44 MBq (0.1–0.12 mCi) per kilogram of body weight of 18F-OC. This was followed by 18F-FDG PET/CT within a 2-week period.
Results
18F-OC was well tolerated by all healthy volunteers and NEN patients. The calculated effective dose of 18F-OC was 0.023 ± 0.002 mSv/MBq. In NEN patients, we observed prominent 18F-OC tumor uptake and high tumor-to-background ratios. Tumor uptake of 18F-OC was greater than that of 18F-FDG, and this was particularly evident in G2 NENs (median SUVmax, 45.6 vs 4.3; P < 0.015). Tumor uptake of 18F-OC or 18F-FDG was significantly correlated with tumor differentiation (P < 0.05). Dual tracer PET/CT detected more lesions and also yielded information on the biological status of tumors.
Conclusions
The tracer 18F-OC exhibited favorable safety and dosimetry profiles. 18F-OC provided superior imaging of well-differentiated NENs and significantly higher tumor-to-background ratio compared with 18F-FDG. Combining 18F-FDG with 18F-OC PET/CT has the potential to improve NEN staging and management of patient treatment.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.