Angong Niuhuang Wan inhibit ferroptosis on ischemic and hemorrhagic stroke by activating PPARγ/AKT/GPX4 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Angong Niuhuang Wan (AGNHW) is a prescription from traditional Chinese medicine (TCM) that has been used for centuries to treat ischemic stroke (IS) and hemorrhagic stroke (HS). According to a recent study, targeting ferroptosis might be effective in the management of IS and HS. However, the ferroptosis-related effects and mechanisms of AGNHW have not yet been reported. AIM OF THE STUDY: This research examines the anti-ferroptosis mechanisms of AGNHW in the treatment of IS and HS. MATERIALS AND METHODS: A system pharmacological approach including in vivo experiment, UHPLC-Q-Orbitrap HRMS, network pharmacology, molecular docking, microscale thermophoresis, and in vitro experiment was utilized to study the anti-ferroptosis mechanisms of AGNHW against IS and HS. RESULTS: In vivo experiments indicated that AGNHW enhanced nerve function, decreased cerebral infarct volume, ameliorated histological brain injuries, improved the structural integrity of the blood-brain barrier, ameliorated the mitochondrial dysfunction and morphology disruption, and inhibits ROS, LPO and Fe2+ accumulations in IS and HS rats. Using UHPLC-Q-Orbitrap HRMS, the key ingredients of AGNHW-containing serum were identified as bilirubin, berberine, baicalin, and wogonoside. According to the network pharmacology analyses, AGNHW could inhibit ferroptosis by modulating the PPAR and PI3K/AKT signaling pathways. The core targets are PPARγ, AKT, and GPX4. Molecular docking and microscale thermophoresis experiments further revealed that the key ingredients have strong interactions with ferroptosis-regulating core proteins. Moreover, in vitro experiment results showed that AGNHW alleviated ferroptosis injury induced by erastin in PC12 cells, increased cell viability, reduced the LPO and Fe2+ levels, and up-regulated mRNA expressions of PPARγ, AKT, and GPX4. AGNHW also up-regulated protein expressions of PPARγ, p-AKT/AKT, and GPX4 in IS and HS rats. CONCLUSIONS: AGNHW attenuated ferroptosis in treating IS and HS by targeting the PPARγ/AKT/GPX4 pathway. This work reveals AGNHW's anti-ferroptosis mechanism against IS and HS, but it also develops an integrated approach to demonstrate the common characteristics of drugs in treating different diseases.

Exploration into Plasma Hsa_circ_0052184 as a New Biomarker of Colorectal Cancer Prognosis.

Background: Circular RNAs (circRNAs) are strong modulators of tumor pathology. Herein, our goal was to examine the plasma hsa_circ_0052184 content among colorectal cancer (CRC) patients, and assess its association with patient clinicopathological profile and diagnostic values. Methods: Overall, we collected 228 presurgical CRC and 146 normal plasma samples from The First People's Hospital of Wenling. Circulating hsa_circ_0052184 levels were assessed via qRT-PCR, and the diagnostic prediction was conducted with the receiver operating characteristic (ROC) curve. Results: Relative to healthy controls, CRC patients exhibited markedly enhanced circulating hsa_circ_0052184 levels, which were closely correlated with advanced stage of disease and worse outcome. Based on our uni- (UA) and multivariate assessments (MA), elevated hsa_circ_0052184 levels were a stand-alone predictor of poor prognosis. The ROC curve depicted an area under the curve (AUC) for CRC diagnosis to be 0.9072. Conclusion: Circulating hsa_circ_0052184 is a potential bioindicator of CRC outcome.

Achaete-scute complex-like 2 regulated inflammatory mechanism through Toll-like receptor 4 activating in stomach adenocarcinoma.

BACKGROUND: To investigate the role of achaete-scute complex-like 2 (ASCL2) in stomach adenocarcinoma (STAD), we analyze whether ASCL2 suppression could retard cancer development and further observe the relevance between ASCL2 and inflammation via Toll-like receptor 4 (TLR4) activation in STAD, both in vitro and in vivo. METHODS: Proliferation, development, inflammation, and apoptosis in STAD are observed using sh-ASCL2 lentivirus via TLR4 activation in vitro and in vivo. The relationship between ASCL2 and inflammation is analyzed. Western blotting of ASCL2 with the target protein of immune-associated cells is performed. The prognosis of STAD and associated ASCL2 mutation are analyzed. RESULTS: The ASCL2 level in STAD tumor tissues is increased, compared to normal tissues, and brings a worse prognosis. The ASCL2 shows a negative correlation with inflammation, and TLR4 reveals a positive correlation with gastric cancer. ASCL2 expression is high in MGC803 cells. Sh-ASCL2 could reduce STAD development by decreasing proliferation, tumor volume, and biomarker levels and increasing apoptosis in vitro and in vivo. The inflammatory role of ASCL2 is regulated through TLR4 activation. ASCL2 levels may be related to CNTNAP3, CLIP1, C9orf84, ARIH2, and IL1R2 mutations; positively correlated with M2 macrophage and T follicular helper cell levels; negatively correlated with neutrophil, dendritic cell, monocyte, CD8 T cell, and M1 macrophage levels; and involved in STAD prognosis. CONCLUSIONS: The ASCL2 may adjust inflammation in STAD through TLR4 activation and may be associated with related immune cells. ASCL2 is possibly an upstream target factor of the TLR4 signaling pathway.

Association between rs738409 polymorphism in patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene and hepatocellular carcinoma susceptibility: Evidence from case-control studies.

OBJECTIVES: Numerous studies have investigated the association between patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 C > G polymorphism and the risk of hepatocellular carcinoma (HCC). However, the results are conflicting and inconclusive among different populations. Thus, a meta-analysis was performed to resolve this inconsistency. METHODS: Potentially related studies were investigated in PubMed, Cochrane Library, EMBASE, and Chinese Biomedical Database (CBM) up to June 12, 2018. The odds ratio (OR) with a 95% confidence interval (CI) was used to explore the strength of the associations. Subgroup analysis was performed according to ethnicity and etiology of cases. Publication bias detection was conducted using Egger's test. RESULTS: Fourteen case-control studies were included in this meta-analysis, reporting a total of 3527 HCC patients and 7184 controls. Overall results revealed that PNPLA3 rs738409 C > G polymorphism was associated with an increased risk of HCC in the populations studied with various types of etiology under allelic model (OR = 1.59, 95%CI: 1.20-2.10, P = 0.001), dominant model (OR = 1.55, 95%CI: 1.13-2.13, P = 0.007), homozygous model (OR = 2.76, 95%CI: 1.52-5.01, P = 0.001), heterozygous model (OR = 1.31, 95%CI: 1.01-1.69, P = 0.039), and recessive model (OR = 2.42, 95%CI: 1.51-3.87, P < 0.001). A significant increased risk was observed in patients with HCC related to alcoholic cirrhosis under all genetic models (C vs. G: OR = 3.35, 95%CI: 2.14-5.24, P < 0.001; CC vs.GG: OR = 11.02, 95%CI: 4.35-27.88, P < 0.001; CC vs. GC: OR = 2.75, 95%CI: 1.72-4.39, P < 0.001; GG vs. CC + CG: OR = 5.82, 95%CI: 2.93-11.57, P < 0.001; CG + GG vs. CC: OR = 4.08, 95%CI: 2.33-7.13, P < 0.001), with respect to specific etiology of HCC. A significant increased risk was also revealed in patients with HCC due to virus related cirrhosis under allelic model (OR = 1.19, 95%CI: 1.07-1.32, P = 0.001), dominant model (OR = 1.17, 95%CI: 1.02-1.35, P = 0.03), homozygous model (OR = 1.47, 95%CI: 1.17-1.85, P = 0.001), and recessive model (OR = 1.43, 95%CI: 1.15-1.76, P = 0.001). Subgroup analysis on ethnicity revealed that the polymorphism was associated with increased risk of HCC in Caucasians under allelic model (OR = 1.65, 95%CI: 1.12-2.45, P = 0.012), dominant model (OR = 1.63, 95%CI: 1.04-4.25, P = 0.035), homozygous model (OR = 2.88, 95%CI: 1.27-6.55, P = 0.012), and recessive model (OR = 2.48, 95%CI: 1.32-4.65, P = 0.005). CONCLUSIONS: Our study suggests a significant increased association between PNPLA3 rs738409 C > G polymorphism and HCC risk in the entire populations studied, especially in Caucasians. Therefore, PNPLA3 rs738409 C > G polymorphism may be a risk factor for virus and alcoholic-related HCC.