Chemodynamic therapy combined with endogenous ferroptosis based on "sea urchin-like" copper sulfide hydrogel for enhancing anti-tumor efficacy.

Chemodynamic therapy (CDT) is a promising strategy for cancer treatment, however, its application is restricted by low hydrogen peroxide (H2O2) concentration, insufficient reactive oxygen species (ROS) generation, and high glutathione (GSH) levels. Here, we developed an injectable thermosensitive hydrogel (DSUC-Gel) based on "sea urchin-like" copper sulfide nanoparticles (UCuS) loaded with dihydroartemisinin (DHA) and sulfasalazine (SAS) to overcome these limitations of CDT. DSUC was cleaved to release DHA, SAS and Cu2+ under acidic tumor microenvironment to enhance CDT. DHA with peroxide bridge responded to intracellular Fe2+ to alleviate H2O2 deficiency. SAS prevented GSH synthesis by targeting SLC7A11 and inhibited glutathione peroxidase (GPX4) activity to induce endogenous ferroptosis. ROS produced by Fenton-like reaction of Cu2+ promoted lipid peroxidation (LPO) accumulation to promote ferroptosis. Enhanced CDT and ferroptosis induced immunogenic cell death (ICD), promoted dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) infiltration. As a result, DSUC-Gel significantly inhibited tumor growth both in vitro and in vivo. Our study provides a novel approach for enhancing anti-tumor efficacy by combining CDT, endogenous ferroptosis and ICD.

Circulating immunotherapy strategy based on pyroptosis and STING pathway: Mn-loaded paclitaxel prodrug nanoplatform against tumor progression and metastasis.

Immunotherapy has emerged as a promising strategy against tumors. However, its efficacy is limited by low immunogenicity, poor antigen presentation, and inadequate lymphocyte infiltration. Herein, we develop a nanoplatform (Mn-HSP) loaded with manganese ions (Mn2+) and paclitaxel (PTX) prodrug based on hyaluronic acid. PTX in Mn-HSP induces DNA damage and pyroptosis to release tumor-associated antigens (TAAs), enhancing tumor-specific adaptive immunity. Meanwhile, Mn2+ in Mn-HSP, together with PTX-induced DNA damage, activates the stimulator of interferon gene (STING) pathway to amplify innate immunity. Mn-HSP combines with adaptive and innate immunity, effectively enhancing the presentation of antigen-presenting cells (APCs) and promoting tumor infiltration of cytotoxic T lymphocytes (CTLs). In turn, the granzyme B (GZMB) secreted by CTLs triggers pyroptosis again, thereby establishing a "circulating immunotherapy" against tumors. Our results demonstrate that Mn-HSP efficiently inhibits primary breast tumors, as well as rechallenge tumors and lung metastasis in vivo. Therefore, the circulating immunotherapy that combines pyroptosis mediated adaptive immunity and STING pathway amplified innate immunity provides a novel strategy for enhancing tumor immunotherapy.

TAM-Hijacked Immunoreaction Rescued by Hypoxia-Pathway-Intervened Strategy for Enhanced Metastatic Cancer Immunotherapy.

Immunotherapy is regarded as a prospective strategy against metastatic cancer. However, tumor-associated macrophages (TAMs), which accumulate in hypoxic tumor microenvironment, reduce the effectiveness of immunotherapy by blocking or "hijacking" the initiation of the immune response. Here, a novel tumor-targeted nanoplatform loaded with hypoxia-pathway-intervened docosahexaenoic acid (DHA) and chemotherapeutic drug carfilzomib (CFZ) is developed, which realizes the rescue of TAM-hijacked immune response and effective metastatic cancer immunotherapy. DHA is conjugated to fucoidan (Fuc) via a reduction cleavable selenylsulfide bond (SSe) for micelle preparation, and CFZ is encapsulated in the hydrophobic cores of micelles. The functionalized nanoplatforms (Fuc─SSe─DHA (FSSeD)-CFZs) induce immunogenic cell death, inhibit hypoxia-inducible factor-1α expression, and improve immunosuppression by TAM suppression. FSSeD-CFZs enhance immune response against primary tumor development and metastasis formation. In brief, the novel rescue strategy for TAM-hijacked immunoreaction by inhibiting hypoxia pathway has the potential and clinically translational significance for enhanced metastatic cancer immunotherapy.

Downregulation of Circ_0088196 Contributes to the Development of Trophoblastic Cells through miR-133b Sponging Function to Affect the AHNAK Expression.

OBJECTIVE: Preeclampsia (PE) is the most common gestational disease related to various biomolecules, including circular RNA. Hsa_circ_0088196 (circ_0088196) was aberrantly upregulated in PE tissues. DESIGN: This study focused on the further exploration of circ_0088196 in PE. METHODS: Circ_0088196, microRNA-133b (miR-133b), and AHNAK Nucleoprotein (AHNAK) levels were examined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). EDU assay was used for proliferation detection. Cell cycle and apoptosis were analyzed using flow cytometry. Wound healing assay and transwell assay were performed to assess migration and invasion. The protein levels were determined via Western blot. Target analysis was conducted through dual-luciferase reporter assay and RNA pull-down assay. RESULTS: Circ_0088196 upregulation was detected in PE patients. The knockdown of circ_0088196 induced the promotion of proliferation, cell cycle, migration, and invasion but not the inhibition of apoptosis in trophoblastic cells. Then, circ_0088196 was found to act as a sponge of miR-133b in HTR-8/SVneo cells. The inhibition of miR-133b abolished the regulation of si-circ_0088196 in trophoblastic cells. In addition, miR-133b targeted AHNAK and circ_0088196 evoked the expression change of AHNAK by sponging miR-133b. The function of circ_0088196 was also achieved by regulating AHNAK in trophoblastic cells. LIMITATIONS: The role of circ_0088196 in PE was not verified by in vivo experiments. CONCLUSION: The current evidence demonstrated that circ_0088196 knockdown facilitated trophoblastic cell development by regulating the levels of miR-133b and AHNAK, suggesting that circ_0088196 promoted the PE progression via the miR-133b/AHNAK axis.

CTRP9 decreases high glucose­induced trophoblast cell damage by reducing endoplasmic reticulum stress.

C1q/TNF­α­related protein 9 (CTRP9) is downregulated in gestational diabetes mellitus (GDM) and may exert a protective effect against GDM, although its mechanism of action is yet to be elucidated. To investigate the specific role of CTRP9 in GDM, the human placental trophoblast cell line HTR8/SVneo was treated with high glucose (HG) to simulate the environment of GDM in vitro. The effects of CTRP9 on the HTR8/SVneo cells and endoplasmic reticulum (ER) stress were analyzed before and after CTRP9 overexpression using reverse transcription­quantitative PCR and western blotting. The results obtained demonstrated that CTRP9 alleviated ER stress in the trophoblast cell line. After treating with the ER­stress inducer tunicamycin, cell viability was investigated by performing Cell Counting Kit­8, TUNEL and western blotting assays, which revealed that CTRP9 increased the activity of HTR8/SVneo cells induced by HG through the alleviation of ER stress. Subsequently, ELISA and western blotting assay results demonstrated that CTRP9 inhibited HG­induced inflammation of the HTR8/SVneo cells by the reduction in ER stress. Finally, the detection of reactive oxygen species, nitric oxide (NO) synthase and NO levels confirmed that CTRP9 inhibited the oxidative stress of HTR8/SVneo cells induced by HG through the reduction of ER stress. Collectively, the results of the present study suggested that CTRP9 may decrease trophoblast cell damage caused by HG through the suppression of ER stress, and therefore, CTRP9 may potentially be a therapeutic target in the treatment of GDM.

A multifunctional nano system based on DNA and CeO2 for intracellular imaging of miRNA and enhancing photodynamic therapy.

An increased content of reactive oxygen species (ROS) is a primary feature of tumor cells. When the new homeostasis established by cancer cells with a high ROS level is destroyed, this leads to oxidative stress and apoptosis. In this study, a composite nanosystem was designed in which the DNA structure with the functions of miRNA detection and drug delivery is connected to CeO2 nanoclusters that exhibit enzyme-like activity to enable them to load drugs together. In addition, based on the concept of sequential catalysis, we used CeO2 to decompose H2O2 into O2 with low cytotoxicity, which provides raw materials for the photodynamic therapy (PDT) of the Cy5 fluorescent group modified on the DNA. Subsequently, this is transformed into highly cytotoxic free radicals (OH), and we used PDT to further stimulate the therapeutic ability of doxorubicin (DOX) to improve its effectiveness in killing cancer cells. This composite nanosystem can perform fluorescence detection for miRNA-21 in vitro, intracellular fluorescence imaging, and PDT treatment, and can enhance the effect of DOX.

Knockdown of protein phosphatase 5 inhibits ovarian cancer growth in vitro.

Ovarian cancer is the most common cause of gynecological cancer-related mortality. Serine/threonine protein phosphatase 5 (PP5, PPP5C) has been recognized to be involved in the regulation of multiple cellular signaling cascades that control diverse cellular processes, including cell growth, differentiation, proliferation, motility and apoptosis. In this study, to evaluate the functional role of PP5 in ovarian cancer cells, lentivirus-mediated RNA interference (RNAi) was applied to silence PPP5C in the human ovarian cancer cell line CAOV-3. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell colony forming ability was measured by colony formation. Cell cycle progression was determined by propidium iodide staining and flow cytometry. The results demonstrated that lentivirus-mediated RNAi specifically suppressed the expression of PPP5C at the mRNA and protein levels in CAOV-3 cells. Further investigations revealed that PP5 knockdown significantly inhibited the proliferation and colony formation of CAOV-3 cells. Moreover, the cell cycle of CAOV-3 cells was arrested at the G0/G1 phase following PP5 knockdown. This study highlights the crucial role of PP5 in promoting ovarian cancer cell proliferation, and provides a foundation for further study into the clinical potential of lentiviral-mediated delivery of PP5 RNAi therapy for the treatment of ovarian cancer.