Hepatocellular carcinoma (HCC) is one of the most significant causes of cancer-related deaths in the worldwide. Currently, predicting the survival of patients with HCC and developing treatment drugs ...still remain a significant challenge. In this study, we employed prognosis-related genes to develop and externally validate a predictive risk model. Furthermore, the correlation between signaling pathways, immune cell infiltration, immunotherapy response, drug sensitivity, and risk score was investigated using different algorithm platforms in HCC. Our results showed that 11 differentially expressed genes including UBE2C, PTTG1, TOP2A, SPP1, FCN3, SLC22A1, ADH4, CYP2C8, SLC10A1, F9, and FBP1 were identified as being related to prognosis, which were integrated to construct a prediction model. Our model could accurately predict patients' overall survival using both internal and external datasets. Moreover, a strong correlation was revealed between the signaling pathway, immune cell infiltration, immunotherapy response, and risk score. Importantly, a novel potential drug candidate for HCC treatment was discovered based on the risk score and also validated through ex vivo experiments. Our finds offer a novel perspective on prognosis prediction and drug exploration for cancer patients.
ABSTRACT
Obesity, which is often caused by adipocyte metabolism dysfunction, is rapidly becoming a serious global health issue. Studies in the literature have shown that camellia oil (Camellia ...oleifera Abel) exerted potential lipid regulation and other multiple biological activities. Here, we aimed to investigate the effects of camellia oil on obese mice induced by a high-fat diet and to explore gut microbiota alterations after camellia oil intervention. The results showed that oral administration of camellia oil dramatically attenuated the fat deposits, serum levels of the total cholesterol, triacylglycerol, low-density lipoprotein cholesterol, fasting plasma glucose, the atherosclerosis index, the hepatic steatosis and inflammation in high-fat diet-induced obese mice. Meanwhile, the high-density lipoprotein cholesterol level in obese mice was enhanced after the camellia oil treatment. Furthermore, 16S rRNA analysis showed that certain aspects of the gut microbiota, especially the gut microbiota diversity and the relative abundance of Actinobacteria, Coriobacteriaceae, Lactobacillus and Anoxybacillus, were significantly increased by camellia oil treatment while the ratio of Firmicutes to Bacteroidetes was decreased. Taken together, our finding suggested that camellia oil was a potential dietary supplement and functional food for ameliorating fat deposits, hyperglycemia and fatty liver, probably by modifying the gut microbiota composition.
In the current study, we highlight an interesting pharmacological action of camellia oil against HFD-induced obesity in mice, mainly exerting its ability to slow down fat accumulation regulate hyperlipidemia and hamper liver steatosis and inflammation, with the mechanism probably by modifying the gut microbiota composition.
Atherosclerosis is the main cause of cardiovascular diseases, and healthy dietary habits are a feasible strategy to prevent atherosclerosis development. Camellia oil, an edible plant oil, exhibits ...multiple beneficial cardiovascular effects. Our previous study showed that oral administration of camellia oil attenuated hyperglycemia, fat deposits in the liver, and the atherosclerosis index in high-fat diet (HFD)-induced obese mice. Here, an atherosclerosis model of apolipoprotein E (ApoE)−/− mice induced by HFD was used to study the effect of camellia oil on atherosclerosis, and 16S rRNA gene sequencing was used to analyze the changes in gut microbiota composition. The results showed that camellia oil significantly inhibited the formation of atherosclerotic plaques in ApoE−/− mice, which were characterized by significantly reduced levels of serum total cholesterol and enhanced levels of serum high-density lipoprotein cholesterol. The aortic levels of interleukin-6 and tumor necrosis factor were decreased. The results of the 16S rRNA analysis showed that after camellia oil interventions, the intestinal flora of ApoE−/− mice changed significantly, with the diversity of intestinal flora especially increasing, the relative abundances of Bacteroides, Faecalibaculum, Bilophila, and Leuconostoc increasing, and the Firmicutes/Bacteroidetes ratio and Firmicutes abundance decreasing. Collectively, our findings confirmed the promising value of camellia oil in preventing the development of atherosclerosis in ApoE−/− mice. Mechanistically, this preventive effect of camellia oil was probably due to its lipid-lowering activity, anti-inflammatory effects, and alteration of the gut microbiota composition in the mice.
Oxaliplatin (OXL) is a third-generation chemotherapeutic agent commonly used to treat metastatic digestive tumors, but one of the main limiting complications of OXL is painful peripheral neuropathy. ...The present study was to examine the inhibitory effects of blocking microRNA-155 (miR-155) in the dorsal horn of the spinal cord on neuropathic pain induced by OXL in rats and the underlying mechanisms. Behavioral test was performed to examine mechanical pain and cold sensitivity in rats. Real-time RT-PCR and ELISA were employed to determine miR-155 and products of oxidative stress 8-isoprostaglandin F2α (8-iso PGF2α) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the dorsal horn. Western blot analysis was used to examine expression of Nrf2-antioxidant response element (Nrf2-ARE), NADPH oxidases (NOXs), and transient receptor potential ankyrin 1 (TRPA1). In results, intrathecal administration of miR-155 inhibitor attenuated mechanical allodynia and cold hyperalgesia in rats with OXL therapy and this was accompanied with restoring of impaired Nrf2-ARE in the dorsal horn. A blockade of miR-155 also attenuated expression of NOX subtype 4 (NOX4) and thereby decreased the levels of 8-iso PGF2α/8-OHdG in the dorsal horn of OXL rats. In addition, inhibiting NOX4 decreased products of oxidative stress in the dorsal horn and attenuated upregulation of TRPA1 induced by OXL. In conclusion, data show the critical role of miR-155 in regulating OXL-induced neuropathic pain likely via oxidative stress–TRPA1 signal pathway, indicating that inhibition of miR-155 has potential benefits in preventing neuropathic pain development during intervention of OXL.
Programmed death ligand-1 (PD-L1) is an important immune checkpoint for cancer immunotherapy in clinic. In this study, we reported that platycodin D, a natural product isolated from an edible and ...medicinal plant Platycodon grandiflorus (Jacq.) A. DC., down-regulated the protein level of PD-L1 in lung cancer cells. Flow cytometry and immunofluorescence assay showed a weaker surface PD-L1 signal in NCI–H1975 cells after the incubation with platycodin D (10 μM) for 15 min compared to the control group. Jurkat T cells showed enhancive interleukin-2 secretion when co-cultured with platycodin D-treated NCI–H1975 cells, suggesting that platycodin D-induced PD-L1 reduction increases the activation of Jurkat T cells. An augmentation of PD-L1 protein was detected in the cell culture medium from platycodin D treatment group. Chlorpromazine (60 μM) almost abolished the platycodin D-mediated PD-L1 extracellular release and restored the membrane PD-L1. Finally, hemolysis assay exhibited that platycodin D-triggered PD-L1 extracellular release was independent of the hemolytic mechanism. Taken together, our study demonstrates that platycodin D reduces the protein level of PD-L1 in lung cancer cells via triggering its release into the cell culture medium, which sheds new light for the application of natural products in cancer immunotherapy.
•Platycodin D-triggered extracellular release of PD-L1 in lung cancer cells.•Jurkat T cells co-cultured with platycodin D-treated NCI–H1975 cells shows enhanced interleukin-2 secretion.•Chlorpromazine abolishes platycodin D-triggered extracellular release of PD-L1.
Doxorubicin (Dox) is a chemotherapeutic agent widely used for the treatment of numerous cancers. However, the clinical use of Dox is limited by its unwanted cardiotoxicity. Mitochondrial dysfunction ...has been associated with Dox-induced cardiotoxicity. To mitigate Dox-related cardiotoxicity, considerable successful examples of a variety of small molecules that target mitochondria to modulate Dox-induced cardiotoxicity have appeared in recent years. Here, we review the related literatures and discuss the evidence showing that mitochondria-targeting small molecules are promising cardioprotective agents against Dox-induced cardiac events.
Ginkgolides are the major active component of
for inhibition of platelet activating factor receptor. An azide-alkyne Huisgen cycloaddition reaction was used to introduce a triazole nucleus into the ...target ginkgolide molecules. A series of ginkgolide-1,2,3-triazole conjugates with varied functional groups including benzyl, phenyl and heterocycle moieties was thus synthesized. Many of the designed derivatives showed potent antiplatelet aggregation activities with IC
values of 5~21 nM.
Upregulated fibroblast growth factor 19 (FGF19) expression in human hepatocellular carcinoma (HCC) specimens is associated with tumor progression and poor prognosis. Nonalcoholic steatohepatitis ...(NASH) patients are at high risk for malignant transformation into HCC.
A steatohepatitis-HCC model was established in male C57L/J mice treated with N-nitrosodiethylamine (DEN) and high-fat diet (HFD). A mouse HCC cell line (Hepa1-6) and a mouse hepatocyte line (FL83B) were used to elucidate the mechanism by free fatty acids (FFA) treatment. FGF15, the mouse orthologue of FGF19, and it receptor fibroblast growth factor receptor4 (FGFR4) as well as co-receptor β-klotho were studied. FGF19 signaling was also studied in human samples of HCC with steatohepatitis.
HCC incidence and tumor volume were significantly increased in the DEN+HFD group compared to that in the DEN+control diet (CD) group. Increased levels of FGF15/FGFR4/β-klotho, aberrant epithelial-mesenchymal transition (EMT) and Wnt/β-catenin signaling were detected in DEN+HFD mice. Blockage of the FGF15 signal can attenuate cell migration ability and aberrant EMT and Wnt/β-catenin signaling.
Up-regulated FGF15/FGFR4 signaling promoted the development of HCC by activation of EMT and Wnt/β-catenin signaling in the lipid metabolic disorder microenvironment. Further investigation of FGF19/FGFR4 signaling is important for potential early diagnosis and therapeutic targeting in HCC patients.
Ziziphi Spinosae Semen (ZSS) is a plant widely used as medicine and food in Asian countries due to its numerous health benefits. γ-aminobutyric acid (GABA), a non-proteinaceous amino acid, is one of ...the major inhibitory neurotransmitters with a relaxant function. In this study, a system pharmacology approach was employed to assess the effects of a mixture composed of ZSS and GABA (ZSSG) on sleep improvement.
Mice were divided into five groups (n = 10) and received either no treatment, sodium pentobarbital, or sodium barbital with diazepam or ZSSG. The effects of ZSSG on sleep quality were evaluated in mice, and differential metabolites associated with sleep were identified among the control, ZSS, GABA, and ZSSG groups. Additionally, network-based ingredient-insomnia proximity analysis was applied to explore the major ingredients.
ZSSG significantly improved sleep quality by decreasing sleep latency and prolonging sleep duration in sodium pentobarbital-induced sleeping mouse model (P < 0.05). ZSSG significantly enhanced the brain content of GABA in mice. Furthermore, ZSSG also significantly decreased sleep latency-induced by sodium barbital in mice (P < 0.05). Metabolic analysis revealed significant differences in 10 metabolites between ZSSG group and the groups administering ZSS or GABA. Lastly, using the network-based ingredient screening model, we discovered potential four active ingredients and three pairwise ingredient combinations with synergistic effect on insomnia from ZSSG among 85 ingredients identified by UPLC-Q/TOF-MS. Also, we have constructed an online computation platform.
Our data demonstrated that ZSSG improved the sleeping quality of mice and helped to balance metabolic disorders-associated with sleep disorders. Moreover, based on the network-based prediction method, the four potential active ingredients in ZSSG could serve as quality markers-associated with insomnia. The network-based framework may open up a new avenue for the discovery of active ingredients of herbal medicine for treating complex chronic diseases or symptoms, such as insomnia.
This pilot study (NCT03958097; https://www.clinicaltrials.gov/ct2/show/NCT03958097) was aimed to evaluate the efficacy and safety of PD-1 antibody combined autologous NK cells in the treatment of ...patients with stage IIIB/IIIC or IV non-small-cell lung cancer (NSCLC) who failed the first-line platinum-based chemotherapy. All patients received both sintilimab 200mg and 3×10
NK cells every 3 weeks. 20 patients were enrolled, median follow up time was 22.6 months. The median PFS was 11.6 months, ORR was 45%. Median OS was 17.7 months, 6-month OS rate and 12-month OS rate was 95.0% and 80.0%. Unexpected adverse events were not observed. 2 patients reported grade 3 adverse events (hypertriglyceridemia, neutropenia and increased creatine kinase). The autologous NK cells did not add extra adverse events to the ICI treatment. Autologous NK plus sintilimab showed promising antitumor activity and an acceptable safety profile in advanced driven-mutation negative NSCLC who failed on the first line treatment.
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