RESUMO
A strategy for designing cancer therapeutic nanovaccines based on immunogenic cell death (ICD)-inducing therapeutic modalities is particularly attractive for optimal therapeutic efficacy. In this work, a highly effective cancer therapeutic nanovaccine (denoted as MPL@ICC) based on immunogenic photodynamic therapy (PDT) was rationally designed and fabricated. MPL@ICC was composed of a nanovehicle of MnO2 modified with a host-guest complex using amino pillar[6]arene and lactose-pyridine, a prodrug of isoniazid (INH), and chlorine e6 (Ce6). The nanovaccine exhibited excellent biosafety, good targeting ability to hepatoma cells and enrichment at tumor sites. Most importantly, it could modulate the tumor microenvironment (TME) to facilitate the existence of Mn(iii) and Mn(iii)-mediated carbon-centered radical generation with INH released from the prodrug in situ to further strengthen ICD. This is the first report on Mn(iii)-mediated generation of carbon-centered radicals for successful anti-tumor immunotherapy using ICD, which provides a novel strategy for designing highly efficient cancer therapeutic nanovaccines.
RESUMO
Hepatitis B virus (HBV) infection is a serious global health problem that threatens the health of human. Tannic acid (TA), a natural polyphenol in foods, fruits, and plants, exhibits a variety of bioactive functions. In our research, we decide to explore the pharmacological mechanism of TA against HBV replication. Our results showed that TA effectively reduced the content of HBV DNA and viral antigens (HBsAg and HBeAg) in HepG2.2.15 cells. Meanwhile, TA significantly decreased the mRNA expression of HBV RNA, which include total HBV RNA, HBV pregenomic RNA, and HBV precore mRNA. Besides, TA evidently downregulated the activity of HBV promoters in HepG2.2.15 cells. Furthermore, we found that TA upregulated the expression of IL-8, TNF-α, IFN-α, and IFN-α-mediated antiviral effectors in HepG2.2.15 cells. On the contrary, TA downregulated the expression of IL-10 and hepatic nuclear factor 4 (HNF4α). In addition, TA activated the NF-κB and MAPK pathways that contributed to the inhibition of HBV replication. Finally, TA treatment led to the occurrence of autophagy, which accelerated the elimination of HBV components in HepG2.2.15 cells. Taken together, our results elucidated the suppressive effect of TA on HBV replication and provided inspiration for its clinical application in HBV treatment.
Assuntos
Vírus da Hepatite B , Hepatite B , Humanos , Vírus da Hepatite B/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Replicação Viral , Hepatite B/tratamento farmacológico , Hepatite B/genética , Células Hep G2 , Taninos/farmacologia , Taninos/metabolismo , RNA/metabolismo , RNA Mensageiro/metabolismo , Autofagia , DNA Viral/genética , DNA Viral/metabolismoRESUMO
In this study, two homogeneous polysaccharides (APS-A1 and APS-B1) were isolated from Astragalus membranaceus by DEAE-52 cellulose and Sephadex G-100 column chromatography. Their chemical structures were characterized by molecular weight distribution, monosaccharide composition, infrared spectrum, methylation analysis, and NMR. The results revealed that APS-A1 (2.62 × 106 Da) was a 1,4-α-D-Glcp backbone with a 1,4,6-α-D-Glcp branch every ten residues. APS-B1 (4.95 × 106 Da) was a heteropolysaccharide composed of glucose, galactose, and arabinose (75.24:17.27:19.35). Its backbone consisted of 1,4-α-D-Glcp, 1,4,6-α-D-Glcp, 1,5-α-L-Araf and the sidechains composed of 1,6-α-D-Galp and T-α/ß-Glcp. Bioactivity assays showed that APS-A1 and APS-B1 had potential anti-inflammatory activity. They could inhibit the production of inflammatory factors (TNF-α, IL-6, and MCP-1) in LPS-stimulated RAW264.7 macrophages via NF-κB and MAPK (ERK, JNK) pathways. These results suggested that the two polysaccharides could be potential anti-inflammatory supplements.
Assuntos
Astragalus propinquus , Polissacarídeos , Astragalus propinquus/química , Polissacarídeos/química , Monossacarídeos/química , Macrófagos , Anti-Inflamatórios/químicaRESUMO
BACKGROUND: Hepatitis B virus (HBV) infection is a severe global health problem, and there has been no effective method to eliminate HBV. This study was designed to explore the pharmacological mechanism of Dihydromyricetin (DHM) treatment on HBV replication in vitro. METHODS AND RESULTS: DHM is a flavonoid compound from Ampelopsis grossedentata. Using HepG2.2.15 cells, which can stably express HBV in vitro, we demonstrated that DHM treatment dramatically reduced HBV replication and secretions of HBsAg and HBeAg. Meanwhile, DHM inhibited mRNA expression of HBV RNAs in HepG2.2.15 cells, including Total HBV RNA, HBV pregenomic RNA (pgRNA), and HBV precore mRNA (pcRNA). Also, DHM elevated the mRNA expressions of inflammatory cytokines and antiviral effectors. In contrast, DHM decreased the mRNA level of HNF4α, which positively correlated with HBV replication. Further studies show that the activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathway played a critical role in DHM-initiated inhibition of HBV replication in HepG2.2.15 cells. Besides, activated autophagy was another contributor that may accelerate the clearance of HBV components. CONCLUSION: In summary, DHM could suppress HBV replication by activating NF-κB, MAPKs, and autophagy in HepG2.2.15 cells. Our studies shed light on the future application of DHM for the clinical treatment of HBV infection.
Assuntos
Vírus da Hepatite B , Hepatite B , Humanos , Vírus da Hepatite B/genética , NF-kappa B/metabolismo , Hepatite B/genética , Células Hep G2 , RNA Mensageiro/metabolismo , Replicação Viral , AutofagiaRESUMO
BACKGROUND: Due to the complex pathogenesis, the molecular mechanism of nonalcoholic steatohepatitis (NASH) remains unclear. In this study, we aimed to reveal the comprehensive metabolic and signaling pathways in the occurrence of NASH. METHODS: C57BL/6 mice were treated with high-fat diet for 4 months to mimic the NASH phenotype. After the treatment, the physiochemical parameters were evaluated, and the liver tissues were prepared for untargeted metabolomic analysis with ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Then, three relevant Gene Expression Omnibus (GEO) datasets were selected for integrative analysis of differentiated messenger RNA and metabolites. RESULTS: The levels of phosphatidylethanolamine (PE) (16:1(9Z)/20:4(5Z,8Z,11Z,14Z)), oleic acid, and sphingomyelin (SM) (d18:0/12:0) were significantly increased, and the content of adenosine was severely reduced in NASH mice. The integrated interpretation of transcriptomic and metabolomic data indicated that the glycerophospholipid metabolism and necroptosis signaling were evidently affected in the development of NASH. The high level of SM (d18:0/12:0) may be related to the expression of acid sphingomyelinase (ASMase), and the elevated arachidonic acid was coordinated with the upregulation of cytosol phospholipase A2 (cPLA2) in the necroptosis pathway. CONCLUSIONS: In summary, the inflammatory response, necroptosis, and glycerophospholipid may serve as potential targets for mechanistic exploration and clinical practice in the treatment of NASH.