Prediction of herbal medicines based on immune cell infiltration and immune- and ferroptosis-related gene expression levels to treat valvular atrial fibrillation.

Inflammatory immune response is apparently one of the determinants of progressive exacerbation of valvular atrial fibrillation(VAF). Ferroptosis, an iron-dependent modality of regulated cell death, is involved in the immune regulation of cardiovascular disease. However, the relevant regulatory mechanisms of immune infiltration and ferroptosis in VAF have been less studied. In the current study, a highly efficient system for screening immunity- and ferroptosis-related biomarkers and immunomodulatory ability of herbal ingredients has been developed with the integration of intelligent data acquisition, data mining, network pharmacology, and computer-assisted target fishing. VAF patients showed higher infiltration of neutrophils and resting stage dendritic cells, while VSR patients showed higher infiltration of follicular helper T cells. In addition, six (e.g., PCSK2) and 47 (e.g., TGFBR1) ImmDEGs and one (SLC38A1) and four (TGFBR1, HMGB1, CAV1, and CD44) FerDEGs were highly expressed in patients with valvular sinus rhythm (VSR) and VAF, respectively. We further identified a core subnetwork containing 34 hub genes, which were intersected with ImmDEGs and FerDEGs to obtain the key gene TGFBR1. Based on TGFBR1, 14 herbs (e.g., Fructus zizyphi jujubae, Semen Juglandis, and Polygonum cuspidatum) and six herbal ingredients (curcumin, curcumine, D-glucose, hexose, oleovitamin A, and resveratrol) were predicted. Finally, TGFBR1 was found to dock well with curcumin and resveratrol, and it was further verified that curcumin and resveratrol could significantly reduce myocardial fibrosis. We believe that herbs rich in curcumin and resveratrol such as Rhizoma curcumae longae and Curcuma kwangsiensis, mitigate myocardial fibrosis to improve VAF by modulating the TGFß/Smad signaling pathway. This strategy provides a prospective approach systemically characterizing phenotype-target-herbs relationships based on the tissue-specific biological functions in VAF and brings us new insights into the searching lead compounds from Chinese herbs.

Multifunctional Hybrid Hydrogel System Enhanced the Therapeutic Efficacy of Treatments for Postoperative Glioma.

Glioma is the most lethal brain tumor with a poor prognosis, and a combination of multiple therapeutic strategies is critical for postoperative glioma treatment. Herein, a multifunctional hybrid hydrogel system (designated as CP&CL@RNPPTX-Gel) was developed for local treatment of postoperative glioma. The system was composed of self-illuminating chlorin e6 (Ce6) conjugated with luminol molecule (CL)-loaded glioma-targeting paclitaxel prodrug nanoparticles and copper peroxide nanodots (CP NDs) coembedded into a three-dimensional thermosensitive hydroxypropyl chitin hydrogel frame. After injection of CP&CL@RNPPTX-Gel into the cavity of postoperative glioma, the solution could be cross-linked into the gel as a drug reservoir under body temperature stimulation. Then, the sustained-released CP NDs decomposed into Cu2+ and H2O2 in the acidic microenvironment of the glioma cells to exert chemodynamic therapy (CDT). Meanwhile, Cu2+ could catalyze the self-luminescence of CL to induce photodynamic therapy (PDT) without external excitation light. Moreover, paclitaxel prodrug nanoparticles degraded into paclitaxel to restrain residual glioma cells in response to intracellular reduced glutathione (GSH). The in vitro and in vivo results showed that CP&CL@RNPPTX-Gel had great potential as a multifunctional hybrid hydrogel system with remarkable therapeutic effects for postoperative glioma treatment via a combination of chemotherapy, CDT, and PDT.

Advances of nano drug delivery system for the theranostics of ischemic stroke.

From the global perspective, stroke refers to a highly common cause of disability and death. Ischemic stroke (IS), attributed to blood vessel blockage, preventing the flow of blood to brain, acts as the most common form of stroke. Thus far, thrombolytic therapy is the only clinical treatment for IS with the approval from the FDA. Moreover, the physiology barrier complicates therapeutically and diagnostically related intervention development of IS. Accordingly, developing efficient and powerful curative approaches for IS diagnosis and treatment is urgently required. The advent of nanotechnology has brought dawn and hope to better curative and imaging forms for the management of IS. This work reviews the recent advances and challenges correlated with the nano drug delivery system for IS therapy and diagnosis. The overview of the current knowledge of the important molecular pathological mechanisms in cerebral ischemia and how the drugs cross the blood brain barrier will also be briefly summarized.

Enhanced treatment of cerebral ischemia-Reperfusion injury by intelligent nanocarriers through the regulation of neurovascular units.

Reperfusion injury is one of the major causes of disability and death caused by ischemic stroke, and drug development focuses mainly on single neuron protection. However, different kinds of cells in the neurovascular units (NVUs), including neurons, microglia and vascular endothelial cells, are pathologically changed after cerebral ischemia-reperfusion injury, resulting in an urgent need to develop a drug delivery system to comprehensively protect the kinds of cells involved in the NVU. Herein, we have constructed a c(RGDyK) peptide modified, NF-κB inhibitor caffeic acid phenethyl ester (CAPE)-loaded and reactive nitrogen species (RNS) stimuli-responsive liposomal nanocarrier (R-Lipo-CAPE) to target ischemic lesions and then remodel the NVU to reduce the progression of cerebral ischemia-reperfusion injury. The R-Lipo-CAPE liposomes were approximately 170 nm with a zeta potential of -30.8 ± 0.2 mV. The in vitro CAPE release behavior from R-Lipo-CAPE showed an RNS-dependent pattern. For in vivo studies, transient middle cerebral artery occlusion/reperfusion (MCAO) model mice treated with R-Lipo-CAPE had the least neurological impairment and decreased brain tissue damage, with an infarct area of 13%, compared with those treated with saline of 53% or free CAPE of 38%. Furthermore, microglia in the ischemic brain were polarized to the tissue-repairing M2 phenotype after R-Lipo-CAPE treatment. In addition, R-Lipo-CAPE-treated mice displayed a prominent down-regulated expression of MMP-9 and restored expression of the tight junction protein claudin-5. This proof-of-concept indicates that R-Lipo-CAPE is a promising nanomedicine for the treatment of cerebral ischemia-reperfusion injury through the regulation of neurovascular units. STATEMENT OF SIGNIFICANCE: Based on the complex mechanism and difficulty in treatment of cerebral ischemia-reperfusion injury, the overall regulation of neurovascular unit has become an extremely important target. However, little nanomedicine has been directed to remodel the neurovascular units in targeted cerebral ischemia-reperfusion injury therapy. Here, c(RGDyK) peptide modified reactive nitrogen species (RNS) stimuli-responsive liposomal nanocarrier loaded with a NF-κB inhibitor (CAPE), was designed to simultaneously regulate various cells in the microenvironment of cerebral ischemia-reperfusion injury to remodel the neurovascular units. Our in vitro and in vivo data showed that the intelligent nanocarrier exerted the ability of pathological signal stimuli-responsive drug release, cerebral ischemia-reperfusion injury site targeting and neurovascular units remodeling through reducing neuron apoptosis, regulating microglia polarization and repairing vascular endothelial cell. Overall, the intelligent liposomal drug delivery system was a promising and safe nanomedicine in the perspective of cerebral ischemia-reperfusion injury treatment.

In situ targeting nanoparticles-hydrogel hybrid system for combined chemo-immunotherapy of glioma.

It is well known that glioma is currently the most malignant brain tumor. Because of the existence of blood-brain barrier (BBB) and tumor cell heterogeneity, systemic chemotherapy exerts unsatisfied therapeutic effect for the treatment of glioma after surgical resection and may even damage the body's immune system. Here, we developed an in situ sustained-release hydrogel delivery system for combined chemo-immunotherapy of glioma by combined chemotherapy drug and immunoadjuvant through the resection cavity local delivery. Briefly, glioma homing peptide modified paclitaxel targeting nanoparticles (PNPPTX) and mannitolated immunoadjuvant CpG targeting nanoparticles (MNPCpG) were embedded into PLGA1750-PEG1500-PLGA1750 thermosensitive hydrogel framework (PNPPTX&MNPCpG@Gel). The in vitro and in vivo results showed that the targeting nanoparticles-hydrogel hybrid system could cross-link into a gel drug reservoir when injected into the resection cavity of glioma. And then, the sustained-release PNPPTX could target the residual infiltration glioma cells and produce tumor antigens. Meanwhile, MNPCpG targeted and activated the antigen-presenting cells, which enhanced the tumor antigen presentation ability and activated CD8+T and NK cells to reverse immunosuppression of glioma microenvironment. This study indicated that the PNPPTX&MNPCpG@Gel system could enhance the therapeutic effect of glioma by chemo-immunotherapy.

Tumor-Associated Neutrophil Extracellular Traps Regulating Nanocarrier-Enhanced Inhibition of Malignant Tumor Growth and Distant Metastasis.

Tumor-associated neutrophil extracellular traps (NETs) play a critical role in promoting tumor growth and assisting tumor metastasis. Herein, a smart nanocarrier (designated as mP-NPs-DNase/PTX) based on regulating tumor-associated NETs has been developed, which consists of a paclitaxel (PTX) prodrug nanoparticle core and a poly-l-lysine (PLL) conjugated with the matrix metalloproteinase 9 (MMP-9)-cleavable Tat-peptide-coupled deoxyribonuclease I (DNase I) shell. After accumulating at the site of the tumor tissue, the nanocarrier can release DNase I in response to MMP-9 to degrade the structure of NETs. Then, the remaining moiety can uptake the tumor cells via the mediation of exposed cell penetrating peptide, and the PTX prodrug nanoparticles will lyse in response to the high intracellular concentration of reduced glutathione to release PTX to exert a cytotoxic effect of tumor cells. Through in vitro and in vivo evaluations, it has been proven that mP-NPs-DNase/PTX could serve as potential NET-regulated nanocarrier for enhanced inhibition of malignant tumor growth and distant metastasis.