Palmitoyl transferases act as novel drug targets for pancreatic cancer.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is one of the most leading causes of cancer-related death across the world with the limited efficiency and response rate of immunotherapy. Protein S-palmitoylation, a powerful post-translational lipid modification, is well-known to regulate the stability and cellular distribution of cancer-related proteins, which is mediated by a family of 23 palmitoyl transferases, namely zinc finger Asp-His-His-Cys-type (ZDHHC). However, whether palmitoyl transferases can determine tumor progression and the efficacy of immunotherapy in PAAD remains unknown. METHODS: Bioinformatics methods were used to identify differential ZDHHCs expression in PAAD. A systematic pan-cancer analysis was conducted to assess the immunological role of ZDHHC3 using RNA sequencing data from The Cancer Genome Atlas database. In vivo Panc 02 subcutaneous tumor model validated the anti-tumor effect of knockdown of ZDHHC3 or intraperitoneal injection of 2-bromopalmitate (2-BP), a typical broad-spectrum palmitoyl transferases inhibitor. Furthermore, we explored therapeutic strategies with combinations of 2-BP with PD-1/PD-L1-targeted immunotherapy in C57BL/6 mice bearing syngeneic Panc 02 pancreatic tumors. RESULTS: ZDHHC enzymes were associated with distinct prognostic values of pancreatic cancer. We identified that ZDHHC3 expression promotes an immunosuppressive tumor microenvironment in PAAD. 2-BP suppressed pancreatic-tumor cell viability and tumor sphere-forming activities, as well as increased cell apoptosis in vitro, without affecting normal human pancreatic ductal epithelial cells. Furthermore, genetic inactivation of ZDHHC3 or intraperitoneal injection of 2-BP impeded tumor progression in Panc 02 pancreatic tumors with enhanced anti-tumor immunity. 2-BP treatment significantly enhanced the therapeutic efficacy of PD-1/PD-L1 inhibitors in Panc 02 pancreatic tumors. CONCLUSION: This study revealed some ZDHHC enzyme genes for predicting the prognosis of pancreatic cancer, and demonstrated that ZDHHC3 plays a critical oncogenic role in pancreatic cancer progression, highlighting its potential as an immunotherapeutic target of pancreatic cancer. In addition, combination therapy of 2-BP and PD-1/PD-L1 achieved synergic therapy effects in a mouse model of pancreatic cancer.

MMP9-Responsive Graphene Oxide Quantum Dot-Based Nano-in-Micro Drug Delivery System for Combinatorial Therapy of Choroidal Neovascularization.

Age-related macular degeneration (AMD), especially wet AMD with choroidal neovascularization (CNV), commonly causes blindness in older patients and disruption of the choroid followed by second-wave injuries, including chronic inflammation, oxidative stress, and excessive matrix metalloproteinase 9 (MMP9) expression. Increased macrophage infiltrate in parallel with microglial activation and MMP9 overexpression on CNV lesions is shown to contribute to the inflammatory process and then enhance pathological ocular angiogenesis. Graphene oxide quantum dots (GOQDs), as natural antioxidants, exert anti-inflammatory effects and minocycline is a specific macrophage/microglial inhibitor that can suppress both macrophage/microglial activation and MMP9 activity. Herein, an MMP9-responsive GOQD-based minocycline-loaded nano-in-micro drug delivery system (C18PGM) is developed by chemically bonding GOQDs to an octadecyl-modified peptide sequence (C18-GVFHQTVS, C18P) that can be specifically cleaved by MMP9. Using a laser-induced CNV mouse model, the prepared C18PGM shows significant MMP9 inhibitory activity and anti-inflammatory action followed by antiangiogenic effects. Moreover, C18PGM combined with antivascular endothelial growth factor antibody bevacizumab markedly increases the antiangiogenesis effect by interfering with the "inflammation-MMP9-angiogenesis" cascade. The prepared C18PGM shows a good safety profile and no obvious ophthalmic or systemic side effects. The results taken together suggest that C18PGM is an effective and novel strategy for combinatorial therapy of CNV.

Multifunctional porous poly (L-lactic acid) nanofiber membranes with enhanced anti-inflammation, angiogenesis and antibacterial properties for diabetic wound healing.

With increased diabetes incidence, diabetic wound healing is one of the most common diabetes complications and is characterized by easy infection, chronic inflammation, and reduced vascularization. To address these issues, biomaterials with multifunctional antibacterial, immunomodulatory, and angiogenic properties must be developed to improve overall diabetic wound healing for patients. In our study, we prepared porous poly (L-lactic acid) (PLA) nanofiber membranes using electrospinning and solvent evaporation methods. Then, sulfated chitosan (SCS) combined with polydopamine-gentamicin (PDA-GS) was stepwise modified onto porous PLA nanofiber membrane surfaces. Controlled GS release was facilitated via dopamine self-polymerization to prevent early stage infection. PDA was also applied to PLA nanofiber membranes to suppress inflammation. In vitro cell tests results showed that PLA/SCS/PDA-GS nanofiber membranes immuomodulated macrophage toward the M2 phenotype and increased endogenous vascular endothelial growth factor secretion to induce vascularization. Moreover, SCS-contained PLA nanofiber membranes also showed good potential in enhancing macrophage trans-differentiation to fibroblasts, thereby improving wound healing processes. Furthermore, our in vitro antibacterial studies against Staphylococcus aureus indicated the effective antibacterial properties of the PLA/SCS/PDA-GS nanofiber membranes. In summary, our novel porous PLA/SCS/PDA-GS nanofiber membranes possessing enhanced antibacterial, anti-inflammatory, and angiogenic properties demonstrate promising potential in diabetic wound healing processes.

Immunomodulation of MiRNA-223-based nanoplatform for targeted therapy in retinopathy of prematurity.

Retinopathy of prematurity (ROP) is characterized by pathological angiogenesis and associated inflammation in the retina and is the leading cause of childhood blindness. MiRNA-223 (miR-223) drives microglial polarization toward the anti-inflammatory phenotype and offers a therapeutic approach to suppress inflammation and consequently pathological neovascularization. However, miRNA-based therapy is hindered by the low stability and non-specific cell-targeting ability of delivery systems. In the present study, we developed folic acid-chitosan (FA-CS)-modified mesoporous silica nanoparticles (PMSN) loaded with miR-223 to regulate retinal microglial polarization. The FA-CS/PMSN/miR-223 nanoparticles exhibited high stability and loading efficiency, achieved targeted delivery, and successfully escaped from lysosomes. In cultured microglial cells, treatment with FA-CS/PMSN/miR-223 nanoparticles upregulated the anti-inflammatory gene YM1/2 and IL-4RA, and downregulated the proinflammatory genes iNOS, IL-1ß, and IL-6. Notably, in a mouse oxygen-induced retinopathy model of ROP, intravitreally injected FA-CS/PMSN/miR-223 nanoparticles (1 µg) decreased the retinal neovascular area by 52.6%. This protective effect was associated with the reduced and increased levels of pro-inflammatory (M1) and anti-inflammatory (M2) cytokines, respectively. Collectively, these findings demonstrate that FA-CS/PMSN/miR-223 nanoparticles provide an effective therapeutic strategy for the treatment of ROP by modulating the miR-223-mediated microglial polarization to the M2 phenotype.

Long-term induction of endogenous BMPs growth factor from antibacterial dual network hydrogels for fast large bone defect repair.

Osteoinductive, osteoconductive, and antibacterial properties of bone repair materials play important roles in regulating the successful bone regeneration. In the present work, we developed pH-sensitive gelatin methacryloyl (GelMA)-oxidized sodium alginate (OSA) hydrogels for dual-release of gentamicin sulfate (GS) and phenamil (Phe) to enhance the antibacterial activity and to promote large bone defect repair. Controlled release of GS was achieved through physical blending with GelMA-OSA solution before photo-polymeriaztion, while Phe was encapsulated into mesoporous silicate nanoparticles (MSN) within the hydrogels. In vitro antibacterial studies against Staphylococcus aureus and Escherichia coli indicated the broad-spectrum antibacterial property. Moreover, in vitro cell tests verified the synergistically enhanced osteogenic differentiation ability. Furthermore, in vivo studies revealed that the hydrogels significantly increased new bone formation in a critical-sized mouse cranial bone defect model. In summary, the novel dual-network hydrogels with both antibacterial and osteoinductive properties showed promising potential applications in bone tissue engineering.