Background and AimsThe role of platelet autophagy in cirrhotic thrombocytopenia (CTP) remains unclear. This study aimed to investigate the impact of platelet autophagy in CTP and elucidate the regulatory mechanism of hydrogen sulfide (H₂S) on platelet autophagy.MethodsPlatelets from 56 cirrhotic patients and 56 healthy individuals were isolated for in vitro analyses. Autophagy markers (ATG7, BECN1, LC3, and SQSTM1) were quantified using enzyme-linked immunosorbent assay, while autophagosomes were visualized through electron microscopy. Western blotting was used to assess the autophagy-related proteins and the PDGFR/PI3K/Akt/mTOR pathway following treatment with NaHS (an H₂S donor), hydroxocobalamin (an H₂S scavenger), or AG 1295 (a selective PDGFR-α inhibitor). A carbon tetrachloride-induced cirrhotic BALB/c mouse model was established. Cirrhotic mice with thrombocytopenia were randomly treated with normal saline, NaHS, or hydroxocobalamin for 15 days. Changes in platelet count and aggregation rate were observed every three days.ResultsCirrhotic patients with thrombocytopenia exhibited significantly decreased platelet autophagy markers and endogenous H₂S levels, alongside increased platelet aggregation, compared to healthy controls. In vitro, NaHS treatment of platelets from severe CTP patients elevated LC3-II levels, reduced SQSTM1 levels, and decreased platelet aggregation in a dose-dependent manner. H₂S treatment inhibited PDGFR, PI3K, Akt, and mTOR phosphorylation. In vivo, NaHS significantly increased LC3-II and decreased SQSTM1 expressions in platelets of cirrhotic mice, reducing platelet aggregation without affecting the platelet count.ConclusionsDiminished platelet autophagy potentially contributes to thrombocytopenia in cirrhotic patients. H₂S modulates platelet autophagy and functions possibly via the PDGFR-α/PI3K/Akt/mTOR signaling pathway.

01 Jan 2024·Journal of Cancer

Lysyl Oxidase Promotes the Formation of Vasculogenic Mimicry in Gastric Cancer through PDGF-PDGFR Pathway

Article

Author: Han, Mei ; Deng, Hong ; Xu, Chuanhao ; Liu, Rongqing ; Lin, Yuan ; Sun, Bojian ; Liu, Yifan ; Yu, Nan ; Wang, Xinyi ; Wang, Kaibo

Objective: Vasculogenic mimicry (VM) generates an important supplementary form of blood supply in cancer, which many factors regulate. However, the effect of lysyl oxidase (LOX) on VM formation is unclear. In this study, gastric cancer tissues and cells were used to investigate the role of LOX in the formation of VM. Materials and Methods: The samples were collected from 49 patients with a final diagnosis of gastric cancer. According to metastasis (including lymph node metastases and distant metastases), gastric cancer samples were divided into metastasis and non-metastasis groups. Based on the degree of invasion, gastric cancer specimens were divided into T1 + T2 and T3 + T4 groups. The relative expression of LOX was detected using Western blot. The formation of VM was measured by double staining with CD34 and Periodic acid-Schiff (PAS) in gastric cancer tissue slices, and the correlation between LOX and VM was analyzed with Pearson's correlation analysis. Gastric cancer cell line BGC-803 was treated with LOX, β-aminopropionitrile (BAPN, an inhibitor of LOX), and AG1295 or AG1296 (inhibitors of the platelet-derived growth factor receptor). The formation of VM was then measured using PAS staining. The expression of platelet-derived growth factor receptor (PDGFR)α and PDGFRβ in gastric cancer cells was detected by Western blot. Results: In gastric cancer samples, the level of LOX was higher in the metastasis group than in the non-metastasis group (P < 0.05) and in the T3 + T4 group than in the T1 + T2 group (P < 0.05). VM formation was greater in the T3+T4 group than in the T1+T2 group (P < 0.05) and in the metastasis group than in the non-metastasis group (P < 0.05). The expression level of LOX was positively correlated with VM formation (P < 0.01). In gastric cancer cells, LOX concentration was positively correlated with the degree of VM, and BAPN concentration was negatively correlated with the degree of VM (P <0.05). PDGFR levels in the T3+T4 and metastasis groups were relatively higher (P <0.01) and positively correlated with LOX levels in gastric cancer specimens (P < 0.01). The relative expression of PDGFRα and PDGFRβ in gastric cancer cells was up-regulated with increasing LOX and downregulated with increasing BAPN (P < 0.05). With inhibition of PDGFRα and PDGFRβ using AG1295 or AG1296, VM formation in gastric cancer cells decreased (P <0.05), but the number of VM structures increased while LOX was added (P < 0.05). Conclusion: LOX partially promotes the formation of VM in gastric cancer through the PDGF-PDGFR signaling pathway.

08 Nov 2022·ChemSusChem

Successive Cleavage and Reconstruction of Lignin β‐O‐4 Models and Polymer to Access Quinoxalines

Article

Author: Qiang, Qian ; Xiao, Jianliang ; Wang, Chao ; Li, Changzhi ; Wang, Hua ; Luo, Qi ; Liu, Yuxuan ; Ding, Yangming ; Zhang, Tao

AbstractThe construction of N‐heterocyclic compounds from lignin remains a great challenge due to the complex lignin structure and the involvement of multiple steps, including the cleavage of lignin C−O linkages and the formation of heterocyclic aromatic rings. Herein, the first example of KOH mediated sustainable synthesis of quinoxaline derivatives from lignin β‐O‐4 model compounds in a one‐pot fashion under transition‐metal‐free conditions has been achieved. Mechanistic studies suggested that this transformation includes highly coupled cascade steps of cleavage of C−O bonds, dehydrative condensation, sp3C−H bond oxidative activation, and intramolecular dehydrative coupling reaction. With this protocol, a wide range of functionalized quinoxalines, including an important drug compound AG1295, were synthesized from lignin β‐O‐4 model compounds and β‐O‐4 polymer, showcasing the application potential of lignin in pharmaceutical synthesis.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	DE	Friedrich Schiller University of Jena	-

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