Stearoyl-CoA desaturase 1 inhibition induces ER stress-mediated apoptosis in ovarian cancer cells.

Ovarian cancer is a leading cause of death among gynecologic tumors, often detected at advanced stages. Metabolic reprogramming and increased lipid biosynthesis are key factors driving cancer cell growth. Stearoyl-CoA desaturase 1 (SCD1) is a crucial enzyme involved in de novo lipid synthesis, producing mono-unsaturated fatty acids (MUFAs). Here, we aimed to investigate the expression and significance of SCD1 in epithelial ovarian cancer (EOC). Comparative analysis of normal ovarian surface epithelial (NOSE) tissues and cell lines revealed elevated SCD1 expression in EOC tissues and cells. Inhibition of SCD1 significantly reduced the proliferation of EOC cells and patient-derived organoids and induced apoptotic cell death. Interestingly, SCD1 inhibition did not affect the viability of non-cancer cells, indicating selective cytotoxicity against EOC cells. SCD1 inhibition on EOC cells induced endoplasmic reticulum (ER) stress by activating the unfolded protein response (UPR) sensors and resulted in apoptosis. The addition of exogenous oleic acid, a product of SCD1, rescued EOC cells from ER stress-mediated apoptosis induced by SCD1 inhibition, underscoring the importance of lipid desaturation for cancer cell survival. Taken together, our findings suggest that the inhibition of SCD1 is a promising biomarker as well as a novel therapeutic target for ovarian cancer by regulating ER stress and inducing cancer cell apoptosis.

Bridging the Catalytic Turnover Gap Between Single-Atom Iron Nanozymes and Natural Enzymes by Engineering the First and Second Shell Coordination.

Single-atom nanozymes (SAzymes) constitute a promising category of enzyme-mimicking materials with outstanding catalytic performance. The performance of SAzymes improves through modification of the coordination environments around the metal center. However, the catalytic turnover rates of SAzymes, which are key measures of the effectiveness of active site modifications, remain lower than those of natural enzymes, especially in peroxidase-reactions. Here, the first and second shell coordination tuning strategy that yields SAzymes with structures and activities analogous to those of natural enzymes is reported. The optimized SAzyme exhibits a turnover rate of 52.7 s-1 and a catalytic efficiency of 6.97 × 105 M-1 s-1. A computational study reveals that axial S-ligands induce an alternative reaction mechanism, and SO2- functional groups provide hydrogen bonds to reduce the activation energy. In addition, SAzyme shows superior anti-tumor ability in vitro and in vivo. These results demonstrate the validity of coordination engineering strategies and the carcinostatic potential of SAzymes.

Bone-Adhesive Anisotropic Tough Hydrogel Mimicking Tendon Enthesis.

Tendon consists of soft collagen, yet it is mechanically strong and firmly adhered to the bone owing to its hierarchically anisotropic structure and unique tendon-to-bone integration (enthesis), respectively. Despite the recent advances in biomaterials, hydrogels simultaneously providing tendon-like high mechanical properties and strong adhesion to bone-mimicking enthesis is still challenging. Here, a strong, stiff, and adhesive triple-network (TN) anisotropic hydrogel that mimics a bone-adhering tendon is shown. The tough adhesive TN hydrogel is developed by combining imidazole-containing polyaspartamide (providing multiple hydrogen bonds to the bone surface) and energy-dissipative alginate-polyacrylamide double-network. To mimic the anisotropic structure and high mechanical properties of tendons, the bone-adhered TN hydrogel is linearly stretched and subsequently fixed via secondary cross-linking. The resulting hydrogel exhibits high tensile modulus and strength while maintaining a high bone adhesion without chemical modification of the bone surface. Furthermore, a bone-ligament-bone structure with strong bone adhesion reminiscent of the natural ligament is realized.

Immunosuppressive biomaterial-based therapeutic vaccine to treat multiple sclerosis via re-establishing immune tolerance.

Current therapies for autoimmune diseases, such as multiple sclerosis (MS), induce broad suppression of the immune system, potentially promoting opportunistic infections. Here, we report an immunosuppressive biomaterial-based therapeutic vaccine carrying self-antigen and tolerance-inducing inorganic nanoparticles to treat experimental autoimmune encephalomyelitis (EAE), a mouse model mimicking human MS. Immunization with self-antigen-loaded mesoporous nanoparticles generates Foxp3+ regulatory T-cells in spleen and systemic immune tolerance in EAE mice, reducing central nervous system-infiltrating antigen-presenting cells (APCs) and autoreactive CD4+ T-cells. Introducing reactive oxygen species (ROS)-scavenging cerium oxide nanoparticles (CeNP) to self-antigen-loaded nanovaccine additionally suppresses activation of APCs and enhances antigen-specific immune tolerance, inducing recovery in mice from complete paralysis at the late, chronic stage of EAE, which shows similarity to chronic human MS. This study clearly shows that the ROS-scavenging capability of catalytic inorganic nanoparticles could be utilized to enhance tolerogenic features in APCs, leading to antigen-specific immune tolerance, which could be exploited in treating MS.

ROS-Induced SIRT2 Upregulation Contributes to Cisplatin Sensitivity in Ovarian Cancer.

Cisplatin resistance remains a significant obstacle for improving the clinical outcome of ovarian cancer patients. Recent studies have demonstrated that cisplatin is an important inducer of intracellullar reactive oxygen species (ROS), triggering cancer cell death. Sirtuin 2 (SIRT2), a member of class III NAD+ dependent histone deacetylases (HDACs), has been reported to be involved in regulating cancer hallmarks including drug response. In this study, we aimed to identify the role of SIRT2 in oxidative stress and cisplatin response in cancer. Two ovarian cancer cell lines featuring different sensitivities to cisplatin were used in this study. We found different expression patterns of SIRT2 in cisplatin-sensitive (A2780/S) and cisplatin-resistant (A2780/CP) cancer cells with cisplatin treatment, where SIRT2 expression was augmented only in A2780/S cells. Furthermore, cisplatin-induced ROS generation was responsible for the upregulation of SIRT2 in A2780/S cells, whereas overexpression of SIRT2 significantly enhanced the sensitivity of cisplatin-resistant counterpart cells to cisplatin. Our study proposes that targeting SIRT2 may provide new strategies to potentiate platinum-based chemotherapy in ovarian cancer patients.

Dexamethasone Interferes with Autophagy and Affects Cell Survival in Irradiated Malignant Glioma Cells.

OBJECTIVE: Radiation is known to induce autophagy in malignant glioma cells whether it is cytocidal or cytoprotective. Dexamethasone is frequently used to reduce tumor-associated brain edema, especially during radiation therapy. The purpose of the study was to determine whether and how dexamethasone affects autophagy in irradiated malignant glioma cells and to identify possible intervening molecular pathways. METHODS: We prepared p53 mutant U373 and LN229 glioma cell lines, which varied by phosphatase and tensin homolog (PTEN) mutational status and were used to make U373 stable transfected cells expressing GFP-LC3 protein. After performing cell survival assay after irradiation, the IC50 radiation dose was determined. Dexamethasone dose (10 µM) was determined from the literature and added to the glioma cells 24 hours before the irradiation. The effect of adding dexamethasone was evaluated by cell survival assay or clonogenic assay and cell cycle analysis. Measurement of autophagy was visualized by western blot of LC3-I/LC3-II and quantified by the GFP-LC3 punctuated pattern under fluorescence microscopy and acridine orange staining for acidic vesicle organelles by flow cytometry. RESULTS: Dexamethasone increased cell survival in both U373 and LN229 cells after irradiation. It interfered with autophagy after irradiation differently depending on the PTEN mutational status : the autophagy decreased in U373 (PTEN-mutated) cells but increased in LN229 (PTEN wild-type) cells. Inhibition of protein kinase B (AKT) phosphorylation after irradiation by LY294002 reversed the dexamethasone-induced decrease of autophagy and cell death in U373 cells but provoked no effect on both autophagy and cell survival in LN229 cells. After ATG5 knockdown, radiation-induced autophagy decreased and the effect of dexamethasone also diminished in both cell lines. The diminished autophagy resulted in a partial reversal of dexamethasone protection from cell death after irradiation in U373 cells; however, no significant change was observed in surviving fraction LN229 cells. CONCLUSION: Dexamethasone increased cell survival in p53 mutated malignant glioma cells and increased autophagy in PTEN-mutant malignant glioma cell but not in PTEN-wildtype cell. The difference of autophagy response could be mediated though the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin signaling pathway.

Involvement of ER stress and reactive oxygen species generation in anti-cancer effect of CKD-516 for lung cancer.

PURPOSE: CKD-516 (Valecobulin), a vascular-disrupting agent, inhibits microtubule elongation. We evaluated the effect of CKD-516 on lung cancer cells and the underlying molecular mechanisms. METHODS: The effects of S516, an active metabolite of CKD-516, were evaluated in HUVECs and three lung cancer cell lines and by a microtubule polymerization assay. Tubulin cross-linking was used to identify the binding site of S516 on tubulin, and Western blotting was performed to identify the intracellular pathways leading to cell death. Subcutaneous lung cancer xenograft models were used to assess the in vivo effect of CKD-516 on tumor growth. RESULTS: S516 targeted the colchicine binding site on ß-tubulin. In lung cancer cells, S516 increased endoplasmic reticulum (ER) stress and induced reactive oxygen species (ROS) generation by mitochondria and the ER. In addition, CKD-516 monotherapy strongly inhibited the growth of lung cancer xenograft tumors and exerted a synergistic effect with carboplatin. CONCLUSION: The findings suggest that CKD-516 exerts an anticancer effect in company with inducing ER stress and ROS production via microtubule disruption in lung cancer cells. CKD-516 may thus have therapeutic potential for lung cancer.

Injectable dual-scale mesoporous silica cancer vaccine enabling efficient delivery of antigen/adjuvant-loaded nanoparticles to dendritic cells recruited in local macroporous scaffold.

Despite the potential of nanoparticle-based vaccines, their therapeutic efficacy for cancer immunotherapy is limited. To elicit robust antigen-specific adaptive immune responses, antigen-loaded nanoparticles are employed for transport into host dendritic cells (DCs); however, only a minority of the nanoparticles can be engulfed by host DCs. Herein, an injectable dual-scale mesoporous silica vaccine consisting of mesoporous silica microrods (MSRs) coupled with mesoporous silica nanoparticles (MSNs) is introduced. The MSRs form a three-dimensional macroporous scaffold after injection, and the subsequent release of DC-recruiting chemokine loaded in the mesopores of MSRs leads to the recruitment of numerous DCs into the scaffold. Subsequently, MSNs co-loaded with an antigen and Toll-like receptor 9 agonist, which exist in interparticle space of the MSR scaffold, are internalized by the recruited DCs, leading to the generation of antigen-presenting activated DCs. Strikingly, the MSR-MSN dual-scale vaccine generates a significantly larger number of antigen-specific T cells and inhibits melanoma growth to a greater extent compared with a single MSR or MSN vaccine. Moreover, the dual-scale vaccine is synergized with an immune checkpoint inhibitor to inhibit tumor growth in tumor-bearing mice. The findings suggest that the MSR is a novel platform for delivering nanoparticle vaccines for the enhancement of cancer immunotherapy.

Hierarchically Porous Composite Scaffold Composed of SBA-15 Microrods and Reduced Graphene Oxide Functionalized with Cyclodextrin for Water Purification.

Large-scale decontamination of bisphenol A (BPA) from wastewater under field conditions is an urgent need because of the harmful toxic effects of BPA on living organisms. In this study, we report the fabrication of a three-dimensional (3D) hierarchically porous composite scaffold composed of mesoporous SBA-15 silica microrods and reduced graphene oxide (rGO-CD) functionalized with ß-cyclodextrin (CD) and its application for BPA separation from contaminated water. The macroporous structure was achieved by sacrificial salt leaching, and the mesoporous structure was derived from the interparticle pores between compressed SBA-15 particles and intrinsic mesopores in SBA-15. The 3D hierarchical macroporous and mesoporous architecture of the scaffold enhances mass transport without any external forces, and the rGO-CD component provides good capture sites for BPA in solution via inclusion complexation between CD and BPA. The inorganic SBA-15 component of the scaffold also allows long-term operation of filters by increasing the mechanical strength of the scaffold. The hierarchically porous SBA-15/rGO-CD composite scaffold could separate BPA from contaminated water significantly better than the scaffold without rGO-CD in both batch and filter systems. Our study indicates that the functional hierarchically porous composite scaffold can be a potential material in wastewater treatment technology.