A novel glycoglycerolipid from Holotrichia diomphalia Bates: Structure characteristics and protective effect against DNA damage.

A lipidated polysaccharide, HDPS-2II, was isolated from the dried larva of Holotrichia diomphalia, which is used in traditional Chinese medicine. The molecular weight of HDPS-2II was 5.9 kDa, which contained a polysaccharide backbone of →4)-ß-Manp-(1 â†’ 4,6)-ß-Manp-(1 â†’ [6)-α-Glcp-(1]n â†’ 6)-α-Glcp→ with the side chain α-Glcp-(6 â†’ 1)-α-Glcp-(6 â†’ linked to the C-4 of ß-1,4,6-Manp and four types of lipid chains including 4-(4-methyl-2-(methylamino)pentanamido)pentanoic acid, 5-(3-(tert-butyl)phenoxy)hexan-2-ol, N-(3-methyl-5-oxopentan-2-yl)palmitamide, and N-(5-amino-3-methyl-5-oxopentan-2-yl)stearamide. The lipid chains were linked to C-1 of terminal α-1,6-Glcp in carbohydrate chain through diacyl-glycerol. HDPS-2II exhibited DNA protective effects and antioxidative activity on H2O2- or adriamycin (ADM)-induced Chinese hamster lung cells. Furthermore, HDPS-2II significantly ameliorated chromosome aberrations and the accumulation of reactive oxygen species (ROS), reduced γ-H2AX signaling and the expressions of NADPH oxidase (NOX)2, NOX4, P22phox, and P47phox in ADM-induced cardiomyocytes. Mechanistically, HDPS-2II suppressed ADM-induced up-regulation of NOX2 and NOX4 in cardiomyocytes, but not in NOX2 or NOX4 knocked-down cardiomyocytes, indicating that HDPS-2II could relieve intracellular DNA damage by regulating NOX2/NOX4 signaling. These findings demonstrate that HDPS-2II is a new potential DNA protective agent.

Dickkopf-related protein 1 as a biomarker of local immune status and worse prognosis of Oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is an infiltrative malignancy characterized by a significantly elevated recurrence rate. Dickkopf-related protein 1 (DKK1), which plays an oncogene role in many cancers, acts as an inhibitor of the Wingless protein (Wnt) signaling pathway. Currently, there is a lack of consensus regarding the role of DKK1 in OSCC or its clinical significance. OBJECTIVE: To examine the role and effect of DKK1 in OSCC. METHODS: The identification of differentially expressed genes (DEGs) in OSCC was conducted by utilizing databases such as The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A comprehensive analysis of gene expression profile interactions (GEPIA) and Kaplan-Meier curve were conducted to investigate the associations among DEGs, patient survival and prognosis in individuals with OSCC. The biological function of DKK1 in OSCC was investigated by using molecular biology approaches. RESULTS: The expression of DKK1 was found to be upregulated in OSCC tissues at various stages. High levels of DKK1 expression exhibited a positive correlation with the overall survival (OS) and progression-free survival (PFS) rates among OSCC patients. DKK1 knockdown suppressed the proliferation and induced apoptotic response in OSCC cells. Moreover, DKK1 exerted a positive regulatory effect on HMGA2 expression, thereby modulating cell growth and apoptosis in OSCC. The expression of DKK1 was found to be positively correlated with the infiltration of immune cells in patients with OSCC. Additionally, higher levels of CD4+ T cells were associated with improved 5-year survival rates. CONCLUSION: DKK1 is a prognostic biomarker for patients with OSCC.

TRPC channels blockade abolishes endotoxemic cardiac dysfunction by hampering intracellular inflammation and Ca2+ leakage.

Intracellular Ca2+ dysregulation is a key marker in septic cardiac dysfunction; however, regulation of the classic Ca2+ regulatory modules cannot successfully abolish this symptom. Here we show that the knockout of transient receptor potential canonical (TRPC) channel isoforms TRPC1 and TRPC6 can ameliorate LPS-challenged heart failure and prolong survival in mice. The LPS-triggered Ca2+ release from the endoplasmic reticulum both in cardiomyocytes and macrophages is significantly inhibited by Trpc1 or Trpc6 knockout. Meanwhile, TRPC's molecular partner - calmodulin - is uncoupled during Trpc1 or Trpc6 deficiency and binds to TLR4's Pococurante site and atypical isoleucine-glutamine-like motif to block the inflammation cascade. Blocking the C-terminal CaM/IP3R binding domain in TRPC with chemical inhibitor could obstruct the Ca2+ leak and TLR4-mediated inflammation burst, demonstrating a cardioprotective effect in endotoxemia and polymicrobial sepsis. Our findings provide insight into the pathogenesis of endotoxemic cardiac dysfunction and suggest a novel approach for its treatment.

Oncogenic KPNA2 Serves as a Biomarker and Immune Infiltration in Patients With HPV Positive Tongue Squamous Cell Carcinoma.

Human tongue squamous cell carcinoma (TSCC), the most prevalent type of oral cancer, is associated with human papillomavirus (HPV) infection. Our previous work showed Karyopherin α2 (KPNA2), as an oncogene of TSCC, by relegating the p53/autophagy signaling pathway. Nevertheless, the significance of KPNA2 in TSCC pathogenesis has not been established. KPNA2 levels were evaluated via the TCGA database, and its effects on survival outcomes were assessed by LASSO, Kaplan-Meier, and COX regression analyses. CIBERSORT and ESTIMATE investigated the relationships between KPNA2 and immune infiltration. At the same time, KPNA2 and HPV infection was analyzed by immunohistochemistry. In addition, the association between downstream molecular regulation pathways and KPNA2 levels was determined by GO, GSEA, and WGCNA. In TSCC, KPNA2 levels were associated with clinical prognosis and tumor grade. Moreover, KPNA2 may be involved in cancer cell differentiation and facilitates tumor-related genes and signaling pathways, such as Cell Cycle, Mitotic G1 phase, G1/S transition, DNA Repair, and Transcriptional Regulation TP53 signaling pathways. Nevertheless, regulatory B cells, follicular helper B cells, and immune and stromal scores between low- and high-KPNA2 expression groups were insignificant. These results imply that KPNA2 is highly involved in tumor grade and prognosis of TSCC. KPNA2 levels correct with HPV 16 markedly regulated cell differentiation, several oncogenes, and cancer-related pathways.

Old targets, new strategy: Apigenin-7-O-ß-d-(-6″-p-coumaroyl)-glucopyranoside prevents endothelial ferroptosis and alleviates intestinal ischemia-reperfusion injury through HO-1 and MAO-B inhibition.

With the increasing morbidity and mortality, intestinal ischemia/reperfusion injury (IIRI) has attracted more and more attention, but there is no efficient therapeutics at present. Apigenin-7-O-ß-D-(-6″-p-coumaroyl)-glucopyranoside (APG) is a new flavonoid glycoside isolated from Clematis tangutica that has strong antioxidant abilities in previous studies. However, the pharmacodynamic function and mechanism of APG on IIRI remain unknown. This study aimed to investigate the effects of APG on IIRI both in vivo and in vitro and identify the potential molecular mechanism. We found that APG could significantly improve intestinal edema and increase Chiu's score. MST analysis suggested that APG could specifically bind to heme oxygenase 1 (HO-1) and monoamine oxidase b (MAO-B). Simultaneously, APG could attenuate ROS generation and Fe2+ accumulation, maintain mitochondria function thus inhibit ferroptosis with a dose-dependent manner. Moreover, we used siRNA silencing technology to confirm that knocking down both HO-1 and MAO-B had a positive effect on intestine. In addition, we found the HO-1 and MAO-B inhibitors also could reduce endothelial cell loss and protect vascular endothelial after reperfusion. We demonstrate that APG plays a protective role on decreasing activation of HO-1 and MAO-B, attenuating IIRI-induced ROS generation and Fe2+ accumulation, maintaining mitochondria function thus inhibiting ferroptosis.