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Abstract Background Vascular calcification (VC) is a complication in diabetes mellitus (DM) patients. Osteogenic phenotype switching of vascular smooth muscle cells (VSMCs) plays a critical role in diabetes-related VC. Mitophagy can inhibit phenotype switching in VSMCs. This study aimed to investigate the role of the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin 4 (EX4) in mitophagy-induced phenotype switching. Materials and methods The status of VC in T2DM mice was monitored using Von Kossa and Alizarin Red S (ARS) staining in mouse aortic tissue. Human aortic smooth muscle cells were cultured in high glucose (HG) and β-glycerophosphate (β-GP) conditioned medium. Accumulation of LC3B and p62 was detected in the mitochondrial fraction. The effect of EX4 in vitro and in vivo was investigated by knocking down AMPKα1. Results In diabetic VC mice, EX4 decreased the percentage of von Kossa/ARS positive area. EX4 inhibited osteogenic differentiation of HG/β-GP-induced VSMCs. In HG/β-GP-induced VSMCs, the number of mitophagosomes was increased, whereas the addition of EX4 restored mitochondrial function, increased the number of mitophagosome-lysosome fusions, and reduced p62 in mitochondrial frictions. EX4 increased the phosphorylation of AMPKα (Thr172) and ULK1 (Ser555) in HG/β-GP-induced VSMCs. After knockdown of AMPKα1, ULK1 could not be activated by EX4. The accumulation of LC3B and p62 could not be reduced after AMPKα1 knockdown. Knockdown of AMPKα1 negated the therapeutic effects of EX4 on VC of diabetic mice. Conclusion EX4 could promote mitophagy by activating the AMPK signaling pathway, attenuate insufficient mitophagy, and thus inhibit the osteogenic phenotype switching of VSMCs.

Abstract Background The pathogenesis of memory impairment, a common complication of chronic neuropathic pain (CNP), has not been fully elucidated. Schwann cell (SC)-derived extracellular vesicles (EVs) contribute to remote organ injury. Here, we showed that SC-EVs may mediate pathological communication between SCs and hippocampal neurons in the context of CNP. Methods We used an adeno-associated virus harboring the SC-specific promoter Mpz and expressing the CD63-GFP gene to track SC-EVs transport. microRNA (miRNA) expression profiles of EVs and gain-of-function and loss-of-function regulatory experiments revealed that miR-142-5p was the main cargo of SC-EVs. Next, luciferase reporter gene and phenotyping experiments confirmed the direct targets of miR-142-5p. Results The contents and granule sizes of plasma EVs were significantly greater in rats with chronic sciatic nerve constriction injury (CCI)than in sham rats. Administration of the EV biogenesis inhibitor GW4869 ameliorated memory impairment in CCI rats and reversed CCI-associated dendritic spine damage. Notably, during CCI stress, SC-EVs could be transferred into the brain through the circulation and accumulate in the hippocampal CA1-CA3 regions. miR-142-5p was the main cargo wrapped in SC-EVs and mediated the development of CCI-associated memory impairment. Furthermore, α-actinin-4 (ACTN4), ELAV-like protein 4 (ELAVL4) and ubiquitin-specific peptidase 9 X-linked (USP9X) were demonstrated to be important downstream target genes for miR-142-5p-mediated regulation of dendritic spine damage in hippocampal neurons from CCI rats. Conclusion Together, these findings suggest that SCs-EVs and/or their cargo miR-142-5p may be potential therapeutic targets for memory impairment associated with CNP.

Abstract Ovarian cancer is high recurrence and mortality malignant tumor. The most common ovarian cancer was High‐Grade Serous Ovarian Cancer. However, High‐Grade Serous Ovarian Cancer organoid is rare, which organoid with patient immune microenvironment and blood vessels even absence. Here, we report a novel High‐Grade Serous Ovarian Cancer organoid system derived from patient ovarian cancer samples. These organoids recapitulate High‐Grade Serous Ovarian Cancer organoids' histological and molecular heterogeneity while preserving the critical immune microenvironment and blood vessels, as evidenced by the presence of CD34+ endothelial cells. Whole exome sequencing identifies key mutations (CSMD3, TP53, GABRA6). Organoids show promise in testing cisplatin sensitivity for patients resistant to carboplatin and paclitaxel, with notable responses in cancer proteoglycans and p53 (TP53) signaling, like ACTG/ACTB1/AKT2 genes and BBC3/MDM2/PERP. Integration of immune microenvironment and blood vessels enhances potential for novel therapies like immunotherapies and angiogenesis inhibitors. Our work may provide a new detection system and theoretical basis for ovarian cancer research and individual therapy.

ObjectiveTubo-ovarian carcinosarcomas are rare, extremely aggressive malignant tumors that contain both carcinomatous and sarcomatous components. Due to the disease’s rarity, developing an effective treatment strategy for ovarian carcinosarcomas has been challenging. A study was conducted to investigate the clinicopathologic and molecular features of this rare disease.MethodsWe enrolled all patients diagnosed with tubo-ovarian carcinosarcomas from January 2007 to December 2022. The clinical and pathological data were gathered from medical records. Kaplan–Meier curves were plotted to calculate OS and PFS. The Log-rank test and Cox regression model were utilized to explore the relationship between clinicopathological parameters and survival. Patients with cancer tissues available had sequencing with a 242-gene panel done to investigate the mutational landscape and signature of the disease.ResultsIn total, 65% of the patients were diagnosed with advanced-stage cancer. The median PFS and OS of this cohort were 27 and 40 months, respectively, and there was no significant difference in survival between the homologous and heterologous components of sarcoma. Unexpectedly, staging did not have effects on prognosis. All patients had surgical attempts, and suboptimal debulking status was correlated with poorer PFS and OS. MSI was identified in 0% with low Tumor mutation burden (TMB) indicating a poor response to immunotherapy. Low HER2 expression is controversial, according to previous reports, and gives us limited choices with this rare and aggressive disease. We surprisingly found the homologous recombination deficiency (HRD)-positive status was identified in 64% of OCS, which is significantly higher than UCS and other types of epithelial ovarian cancer. The fact that all patients in our cohort who received olaparib as maintenance therapy had survived over 30 months and two had no evidence of recurrence at the latest follow-up might further validate the role of poly (ADP-ribose) polymerase inhibitors (PARPi) in the management of OCS.ConclusionOCS patients seemed to respond to carboplatin/paclitaxel with optimal PFS and OS. Cytoreduction with no residuals proved to be the sole independent prognostic factor. WES should be done to assess the prognosis and assist with the targeted therapy, especially the HRD test, which might help select potential patients who benefit from PARPi.

To investigate the ecological impacts of macroalgae in the framework of shifting global CO2 concentrations, we conducted a study utilizing Ulva fasciata and Sargassum horneri specimens sourced from the Ma’an Archipelago in Zhejiang Province on how ocean acidification (OA) and temperature changes interact to affect the photosynthetic physiological responses of macroalgae. The results of the study showed that OA reduced the tolerance of U. fasciata to bright light at 20 °C, resulting in more pronounced photoinhibition, while 15 °C caused significant inhibition of U. fasciata, reducing its growth and photosynthetic activity, but OA alleviated the inhibition and promoted the growth of the alga to a certain extent. The tolerance of S. horneri to bright light was also reduced at 20 °C; the inhibition was relieved at 15 °C, and the OA further improved the algal growth. The Relative Growth Rate (RGR), photosynthetic pigment content, and the release of the dissolved organic carbon (DOC) of U. fasciata were mainly affected by the change in temperature; the growth of the alga and the synthesis of metabolites were more favored by 20 °C. A similar temperature dependence was observed for S. horneri, with faster growth and high metabolism at 15 °C. Our results suggest that OA reduces the tolerance of macroalgae to high light at suitable growth temperatures; however, at unsuitable growth temperatures, OA effectively mitigates this inhibitory effect and promotes algal growth.