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Background: Macrophages play a pivotal role in the development and recovery of acute lung injury (ALI), wherein their phenotypic differentiation and metabolic programming are orchestrated by mitochondria. Specifically, the mitochondrial calcium uniporter (MCU) regulates mitochondrial Ca 2+ ( m Ca 2+ ) uptake and may bridge the metabolic reprogramming and functional regulation of immune cells. However, the precise mechanism on macrophages remains elusive. Shikonin, a natural naphthoquinone, has demonstrated efficacy in mitigating ALI and suppressing glycolysis in macrophages, yet which mechanism remains to be fully elucidated., Purpose: This study explored whether Shikonin ameliorated ALI via modulating MCU-mediated m Ca 2+ and macrophage polarization., Methods: This study firstly examined the protective effects of Shikonin on LPS-induced ALI mice, and investigated whether it is depends on macrophage by depleting macrophage using clodronate liposomes. The regulatory effect of Shikonin on macrophage polarization and mitochondrial MCU/Ca 2+ signal was testified on RAW264.7 cells, and further validated by knocking-down MCU expression or by using RU360, an MCU inhibitor. Additionally, the crucial role of MCU in the therapeutic effect of Shikonin, along with its regulation on macrophage polarization was validated in mice with LPS-induced ALI under the intervention of RU360., Results: Shikonin alleviated LPS-induced mice ALI, down-regulated inflammatory cytokines and inhibited the pro-inflammatory polarization of macrophages. Intravenous injection of clodronate liposomes on mice abolished the protective effects of Shikonin on ALI. On RAW264.7 cells, LPS&IFN decreased the protein expression of MCU, while induced pro-inflammatory polarization and glycolytic metabolism. In contrast, Shikonin increased MCU expression, activated MCU-mediated m Ca 2+ signal, promoted the polarization of macrophages to anti-inflammatory M2 phenotype, and driven a metabolic shift from glycolysis to oxidative phosphorylation. Either knocking-down MCU expression or pharmacological inhibiting MCU by using RU360 mitigated the effects of Shikonin on Raw 264.7 cells. Furthermore, RU360 counteracted the ameliorative effect of Shikonin on ALI mice., Conclusion: The current data showed that Shikonin alleviated LPS-induced mice ALI by activating mitochondrial MCU/ m Ca 2+ signal and regulating macrophage metabolism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Ethnopharmacological Relevance: Yi Qi Chu Tan Formula (YQCTF), a prescription consisting of eight traditional Chinese medicine for treating lung cancer, has been clinically proven to be effective in improving the life quality and prolonging the survival time of non-small cell lung cancer (NSCLC) patients., Aim of the Study: This study aimed to evaluate the therapeutic efficacy of YQCTF on NSCLC mice model and further explore its therapeutic targets by using network pharmacology, proteomics and pharmacodynamic methodologies., Materials and Methods: The network pharmacology analysis was firstly conducted to screen out the potential active ingredients and therapeutic targets of YQCTF against NSCLC. Three kinds of extracts, i.e. the water extract (WE), water extraction-alcohol precipitation (WEAP) and alcohol extract (AE) of YQCTF were prepared, which chemical compositions were subsequently analyzed by using ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UPLC-MS/MS), and which anti-neoplastic efficacy was examined on NSCLC mice model. Mice tumor tissues were collected for proteomics analysis, and the immunomodulatory effects of YQCTF extracts on the tumor microenvironment (TME) were further validated by using flow cytometry, immunofluorescence, ELISA and Western blot., Results: Network pharmacology identified 60 conjunct genes and ample cancer-related signaling pathways as potential therapeutic targets of YQCTF. Protein-protein interaction (PPI), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that YQCTF might negatively regulate cancer-related inflammation. UPLC-MS/MS analysis showed that the main components of YQCTF include at least ginsenosides, solasodine, solamargine, solasonine, peimisine, peiminine, peimine and sipeimine-3β-D-glucosihde. All kinds of YQCTF extracts significantly inhibited the growth of lung cancer allograft and regulated the ratio of immune cells in tumor tissues, i.e. upregulated the fractions of T cells, promoted the maturation of dendritic cells (DCs), increased the M1/M2 ratio of tumor-related macrophages, but reduced the number of Tregs and immunosuppressive neutrophils. Proteomics identified neutrophils to be the most prominently enriched target linked to NETs formation in mice tumor tissue, which is verified by the downregulation of neutrophil recruiting factors involving IL-6, HIF-1α and IL-8, as well as the decreases of NETs-related biomarkers including H3cit, MPO, CD18, MMP9 and ICAM-1 in immunofluorescence, ELISA and Western blot analysis., Conclusion: YQCTF inhibited the progress of mice NSCLC allograft, suppressed the pro-tumorigenic tumor-associated neutrophils and improved the tumor immune microenvironment (TIME)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Aim: To investigate the effect of zinc protoporphyrin IX on the response of hepatoma cells to cisplatin and the possible mechanism involved., Methods: Cytotoxicity was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis was determined by a flow cytometric assay. Western blotting was used to measure protein expression. Heme oxygenase (HO)-1 activity was measured by determining the level of bilirubin generated in isolated microsomes. Reactive oxygen species (ROS) production was monitored by flow cytometry. Caspase-3 activity was measured with a colorimetric assay kit. Mice were inoculated with 1 × 10(7) tumor cells subcutaneously into the right flanks. All mice were sacrificed 6 wk after the first treatment and tumors were weighed and measured., Results: Overexpression of HO-1 in HepG2 cell line was associated with increased chemoresistance to cis-diaminedichloroplatinum (cisplatin; CDDP) compared to other cell lines in vitro. Inhibition of HO-1 expression or activity by zinc protoporphyrin IX (ZnPP IX) markedly augmented CDDP-mediated cytotoxicity towards all liver cancer cell lines in vitro and in vivo. In contrast, induction of HO-1 with hemin increased resistance of tumor cells to CDDP-mediated cytotoxicity in vitro and in vivo. Furthermore, cells treated with ZnPP IX plus CDDP exhibited marked production of intracellular ROS and caspase-3 activity, which paralleled the incidence of cell apoptosis, whereas hemin decreased cellular ROS and caspase-3 activity induced by CDDP., Conclusion: ZnPP IX increases cellular sensitivity and susceptibility of liver cancer cell lines to CDDP and this may represent a mechanism of increasing ROS.

The objective of this study is to present a relatively simple method to reconstruct cerebral aneurysms as 3D numerical grids. The method accurately duplicates the geometry to provide computer simulations of the blood flow. Initial images were obtained by using CT angiography and 3D digital subtraction angiography in DICOM format. The image was processed by using MIMICS software, and the 3D fluid model (blood flow) and 3D solid model (wall) were generated. The subsequent output was exported to the ANSYS workbench software to generate the volumetric mesh for further hemodynamic study. The fluid model was defined and simulated in CFX software while the solid model was calculated in ANSYS software. The force data calculated firstly in the CFX software were transferred to the ANSYS software, and after receiving the force data, total mesh displacement data were calculated in the ANSYS software. Then, the mesh displacement data were transferred back to the CFX software. The data exchange was processed in workbench software. The results of simulation could be visualized in CFX-post. Two examples of grid reconstruction and blood flow simulation for patients with internal carotid artery aneurysms were presented. The wall shear stress, wall total pressure, and von Mises stress could be visualized. This method seems to be relatively simple and suitable for direct use by neurosurgeons or neuroradiologists, and maybe a practical tool for planning treatment and follow-up of patients after neurosurgical or endovascular interventions with 3D angiography.

Primary hepatic leiomyosarcoma (PHL), a malignant mesenchymal tumor of myogenic origin, is exceedingly rare. Patients may be afflicted with a wide spectrum of nonspecific symptoms, and most of the laboratory data are unhelpful to diagnosis. Here, we report a 44-year-old woman with anorexia and right upper quadrant pain who was diagnosed as having malignant hepatic tumor within the Milan criteria and treated by orthotopic liver transplantation (OLT), the pathologic diagnosis of PHL was made by postoperative immunohistochemical study. She underwent six courses of intravenous chemotherapy and enjoyed a 14-month tumor recurrence-free survival until the lymph node metastasis was detected, then we switched the tacrolimus to sirolimus and the patient survived for 20 months additionally. Unfortunately, she finally died of extensively lymphatic metastasis and cachexia. The diagnostic and therapeutic features of PHL are also discussed by reviewing the literatures. To our knowledge, this is the second report of administering OLT to PHL patients.