Baculovirus-mediated endostatin and angiostatin activation of autophagy through the AMPK/AKT/mTOR pathway inhibits angiogenesis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly vascularized carcinoma, and targeting its neovascularization represents an effective therapeutic approach. Our previous study demonstrated that the baculovirus-mediated endostatin and angiostatin fusion protein (BDS-hEA) effectively inhibits the angiogenesis of vascular endothelial cells and the growth of HCC tumors. However, the mechanism underlying its anti-angiogenic effect remains unclear. Increasing evidence suggests that autophagy has a significant impact on the function of vascular endothelial cells and response to cancer therapy. Hence, the objective of this research was to investigate the correlation between BDS-hEA-induced angiogenesis inhibition and autophagy, along with potential regulatory mechanisms. Our results demonstrated that BDS-hEA induced autophagy in EA.hy926 cells, as evidenced by the increasing number of autophagosomes and reactive oxygen species, accompanied by an upregulation of Beclin-1, LC3-II/LC3-I, and p62 protein expression. Suppression of autophagy using 3-methyladenine attenuated the functions of BDS-hEA-induced EA.hy926 cells, including the viability, proliferation, invasion, migration, and angiogenesis. Moreover, BDS-hEA induced autophagy by downregulating the expression of CD31, VEGF, and VEGFR2, as well as phosphorylated protein kinase B (p-AKT) and phosphorylated mammalian target of rapamycin (p-mTOR), while concurrently upregulating phosphorylated AMP-activated protein kinase (p-AMPK). The in vivo results further indicated that inhibition of autophagy by chloroquine significantly impeded the ability of BDS-hEA to suppress HCC tumor growth in mice. Mechanistically, BDS-hEA prominently facilitated autophagic apoptosis in tumor tissues and decreased the levels of ki67, CD31, VEGF, MMP-9, p-AKT, and p-mTOR while simultaneously enhancing the p-AMPK expression. In conclusion, our findings suggest that BDS-hEA induces autophagy as a cytotoxic response by modulating the AMPK/AKT/mTOR signaling pathway, thereby exerting anti-angiogenic effects against HCC.

Exploring the association between inflammatory biomarkers and gastric cancer development: A two-sample mendelian randomization analysis.

This study aimed to elucidate the potential causative links between inflammatory biomarkers and gastric cancer risk via a two-sample Mendelian randomization approach. Leveraging genome-wide association study (GWAS) data, we conducted a two-sample Mendelian randomization analysis. Instrumental variable selection for inflammatory markers - namely, tissue factor, monocyte chemotactic protein-1, E-selectin, interleukin 6 receptor, and fatty acid-binding protein 4 - was informed by SNP data from the IEU database. Strongly associated SNPs served as instrumental variables. We applied a suite of statistical methods, including Inverse Variance Weighted (IVW), Weighted Median Estimator (WME), MR-Egger, and mode-based estimates, to compute the odds ratios (ORs) that articulate the impact of these markers on gastric cancer susceptibility. The IVW method revealed that the interleukin 6 receptor was inversely correlated with gastric cancer progression (OR = 0.86, 95% CI = 0.74-0.99, P = .03), whereas fatty acid-binding protein 4 was found to elevate the risk (OR = 1.21, 95% CI = 1.05-1.39, P = .03). Instrumental variables comprised 5, 4, 7, 2, and 3 SNPs respectively. Convergent findings from WME, MR-Egger, and mode-based analyses corroborated these associations. Sensitivity checks, including heterogeneity, horizontal pleiotropy assessments, and leave-one-out diagnostics, affirmed the robustness and reliability of our instruments across diverse gastric malignancy tissues without substantial bias. Our research suggests that the interleukin 6 receptor potentially mitigates, while fatty acid-binding protein 4 may contribute to the pathogenesis of gastric cancer (GC). Unraveling the intricate biological interplay between inflammation and oncogenesis offers valuable insights for preemptive strategies and therapeutic interventions in gastric malignancy management.

Orelabrutinib versus ibrutinib for patients with refractory/relapsed primary central nervous system lymphoma: An efficacy and safety analysis.

Ibrutinib is reported effective in the management of refractory/relapsed primary central nervous system lymphoma but it has adverse effects. Orelabrutinib has received its first approval for the treatment of refractory/relapsed lymphoma either alone or with chemotherapy in China. The objectives of the retrospective study were to evaluate the efficacy and safety of treatment a combination of orelabrutinib (150 mg/day) and rituximab (250 mg/m 2 per week), versus orelabrutinib alone (100 mg twice a day) and ibrutinib alone (560 mg/day) among patients with refractory/relapsed primary central nervous system lymphoma. Patients received 150 mg/day orelabrutinib with 250 mg/m 2 rituximab/week (RO cohort, n = 105) or 100 mg twice in a day orelabrutinib (OB cohort, n = 107) or 560 mg/day ibrutinib (IB cohort, n = 117) until intolerable toxicity. Patients of the OB cohort continue treatment(s) for longer time than those patients of the RO and the IB cohorts ( P < .05 for both). Overall response rate (complete response + partial response) and disease control rates (complete response + partial response + no signs of progressive response) were higher for patients of the RO cohort than those of the IB cohort ( P < .0001 for both). The disease control rate was higher for patients of the OB cohort than those of the IB cohort ( P = .0062). The overall response rate was higher for patients of the RO cohort than those of the OB cohort ( P = .0188). Progression-free survival (from the initiation of disease treatment(s) to disease progression) of patients of the RO and OB cohorts were higher than those of the IB cohort ( P < .0001 for both). Overall survival (from the initiation of disease treatment(s) to death) of the patients of the IB cohort was fewer than those of the RO ( P = .0444) and the OB ( P = .0163) cohorts. Ibrutinib cause bleeding events, and orelabrutinib caused leukopenia, purpura diarrhea, fatigue, and drowsiness. Rituximab and ibrutinib cause fungal infections, atrial fibrillation, bacterial and viral infection(s), hypertension, and tumor lysis syndrome. A total of 150 mg/day oral orelabrutinib plus 250 mg/m 2 intravenous rituximab/week is efficacious and safe for patients with refractory/relapsed primary central nervous system lymphoma (Level of Evidence: IV; Technical Efficacy Stage: 5).

Over-expression of miR-193a-3p regulates the apoptosis of colorectal cancer cells by targeting PAK3.

Although dysregulated expression of microRNAs (miRNA) has been investigated in colorectal cancer (CRC), MiR-193a-3p, as a tumor inhibitor, is less studied. To investigate the function and mechanism of miR-193a-3p in CRC, the potential function of miR-193a-3p in regulating PAK3 in CRC with a series of experimental assays including western blotting, qRT-PCR, bioinformatics analysis, a luciferase reporter assay, flow cytometry, Transwell assay, CCK8 assay and immunofluorescence were performed in this study. The results showed that miR-193a-3p was down-regulated in CRC tissues and cell lines, which was also correlated with tumor progression. PAK3 was predicted as a target gene of miR-193a-3p in CRC cells by TargetScan database, which was confirmed by luciferase assays. Moreover, overexpression of miR-193a-3p suppressed the viability, cell cycle progression, migration, and invasion, and induced apoptosis of CRC cells in vitro by regulating the PAK3 signaling pathway. Therefore, miR-193a-3p may serve as a tumor suppressor and potential target for CRC treatment.

Astragalin Exerted Antidepressant-like Action through SIRT1 Signaling Modulated NLRP3 Inflammasome Deactivation.

Inflammation plays a key role in the pathogenesis of depression and antidepressant therapies. Astragalin (AST) is a bioactive flavonoid that possesses an anti-inflammatory property. However, the antidepressant action of astragalin has not been addressed. In this study, we explored the antidepressant effects of astragalin and its underlying mechanism. Our results showed that AST significantly improved the behavioral defects in chronic unpredictable mild stress (CUMS) model, promoted SIRT1 expression, and decreased the protein levels of NF-κB p65, NLRP3, cleaved capase-1, cleaved IL-1ß and cleaved gasdermin D in the hippocampus. Immunohistochemistry revealed AST mitigated CUMS-induced microglia overactivation. In vitro, AST profoundly increased the cell viability in lipopolysaccharides (LPS) and adenosine triphosphate (ATP) treated BV2 cells, with upregulated SIRT1 expression and downregulated protein levels of nuclear NF-κB p65, NLRP3, cleaved capase-1, and cleaved gasdermin D. Declined cleavage of gasdermin D was observed after AST administration in immunocytochemistry. Nevertheless, the in vivo and in vitro effects of AST were compromised by SIRT1 inhibitor EX-527. These results indicated that AST possessed an antidepressant property, which was dependent on SIRT1 signaling modulated NLRP3 inflammasome deactivation.

[Network pharmacology of flavonoids in Sophora alopecuroides].

The aim of this paper was to investigate the potential pharmacological effect of flavonoids in Sophora alopecuroides by network pharmacology. This study predicted the potential targets of 11 flavonoids of S. alopecuroides with help of reversed pharmacophore matching target recognition service platform (PharmMapper). The pathway information was acquired from DAVID and KEGG databases. Cytoscape software was used to construct the "ingredient-target-pathway" network of flavonoids active components of S. alopecuroides. The flavonoids active components of S. alopecuroides play anti-inflammatory, blood sugar regulating and other pharmacological effects by regulating 62 targets (such as INSR，KDR，MET) and intervening 44 pathways, such as B cell receptor signaling pathway, insulin signaling pathway, neurotrophin signaling pathway, and T cell receptor signaling pathway. In this study, the mechanism of "muti components-multitargets-multiple pathway" of flavonoids was studied. It reflects the multi-components, multi-targets and multiple pathway features of traditional Chinese medicine. Meanwhile, it provides a scientific basis for the elucidation the mechanism of S. alopecuroides as a medicine, and the development and utilization resources of S. alopecuroides.