Upconversion Nanoplatform Enables Multimodal Imaging and Combinatorial Immunotherapy for Synergistic Tumor Treatment and Monitoring.

Designing a novel nanoplatform that integrates multimodal imaging and synergistic therapy for precision tumor nanomedicines is challenging. Herein, we prepared rare-earth ion-doped upconversion hydroxyapatite (FYH) nanoparticles as nanocarriers coated and loaded respectively with polydopamine (PDA) and doxorubicin (DOX), i.e., FYH-PDA-DOX, for tumor theranostics. The developed FYH-PDA-DOX complexes exhibited desirable photothermal conversion, pH/near-infrared-irradiation-responsive DOX release, and multimodal upconversion luminescence/computed tomography/magnetic resonance imaging performance and helped monitor the metabolic distribution process of the complexes and provided feedback to the therapeutic effect. Upon 808 nm laser irradiation, the fast release of DOX facilitated the photothermal-chemotherapy effect, immunogenic cell death, and antitumor immune response. On combining with the anti-programmed cell death 1 ligand 1 antibody, an enhanced tri-mode photothermal-chemo-immunotherapy synergistic treatment against tumors can be realized. Thus, this treatment elicited potent antitumor immunity, producing appreciable T-cell cytotoxicity against tumors, amplifying tumor suppression, and extending the survival of mice. Therefore, the FYH-PDA-DOX complexes are promising as a smart nanoplatform for imaging-guided synergistic cancer treatment.

NIR-II Hydrogen-Bonded Organic Frameworks (HOFs) Used for Target-Specific Amyloid-ß Photooxygenation in an Alzheimer's Disease Model.

Phototherapy has emerged as a powerful approach for interrupting ß-amyloid (Aß) self-assembly. However, deeper tissue penetration and safer photosensitizers are urgent to be exploited for avoiding damaging nearby normal tissues and improving therapeutic effectiveness. A hydrogen-bonded organic framework (HOF)-based NIR-II photooxygenation catalyst is presented here to settle the abovementioned challenges. By encapsulating the pyridinium hemicyanine dye DSM with a large two-photon absorption (TPA) cross-section in NIR-II window into the porphyrin-based HOF, the resultant DSM@n-HOF-6 exhibits significant two-photon NIR-II-excited Fluorescence Resonance Energy Transfer (FRET) to generate singlet oxygen (1 O2 ) for Aß oxidation. Further, the target peptides of KLVFFAED (KD8) are covalently grafted on DSM@n-HOF-6 to enhance the blood-brain barrier (BBB) permeability and Aß selectivity. The HOF-based photooxygenation catalyst shows an outstanding inhibitory effect of Aß aggregation upon the NIR-II irradiation. Further in vivo studies demonstrate the obvious decrease of craniocerebral Aß plaques and recovery of memory deficits in triple-transgenic AD (3×Tg-AD) model mice.

A Biocompatible Second Near-Infrared Nanozyme for Spatiotemporal and Non-Invasive Attenuation of Amyloid Deposition through Scalp and Skull.

Phototherapy, such as photodynamic therapy and photothermal therapy, holds great potential for modulation of Alzheimer's ß-amyloid (Aß) self-assembly. Unfortunately, current works for phototherapy of Alzheimer's disease (AD) are just employing either visible or first near-infrared (NIR-I) light with limited tissue penetration, which can not avoid damaging nearby normal tissues of AD patients through the dense skull and scalp. To overcome the shortcomings of AD phototherapy, herein we report an amyloid targeting, N-doped three-dimensional mesoporous carbon nanosphere (KD8@N-MCNs) as a second near-infrared (NIR-II) PTT agent. This makes it possible for photothermal dissociation of Aß aggregates through the scalp and skull in a NIR-II window without hurting nearby normal tissues. Besides, KD8@N-MCNs have both superoxide dismutase and catalase activities, which can scavenge intracellular superfluous reactive oxygen species and alleviate neuroinflammation in vivo. Furthermore, KD8@N-MCNs efficiently cross the blood-brain barrier owing to the covalently grafted target peptides of KLVFFAED on the nanosphere surface. In vivo studies demonstrate that KD8@N-MCNs decrease Aß deposits, ameliorate memory deficits, and alleviate neuroinflammation in the 3xTg-AD mouse model. Our work provides a biocompatible and non-invasive way to attenuate AD-associated pathology.

Tetramethylpyrazine ameliorates high glucose-induced endothelial dysfunction by increasing mitochondrial biogenesis.

Tetramethylpyrazine (TMP) is an active compound isolated from a Chinese herbal prescription that is widely used in traditional Chinese medicine for the treatment of inflammatory and cardiovascular diseases. We have previously reported that TMP acts as a potent antioxidant protecting endothelial cells against high glucose-induced damages. However, the molecular mechanism responsible for the antioxidant effect of TMP remains to be elucidated. In this study, we show that TMP increases nitric oxide production in endothelial cells and promotes endothelium-dependent relaxation in rate aortic rings. The antioxidant effect of TMP appears attributable to its ability to activate the mitochondrial biogenesis, as reflected in an up-regulation of complex III and amelioration of mitochondrial membrane potential. Furthermore, TMP is able to reverse high glucose-induced suppression of SIRT1 and the biogenesis-related factors, including PGC-1α, NRF1 and TFAM, suggesting a new molecular mechanism underlying the protective effect of TMP on the endothelium.

Salsalate attenuates free fatty acid-induced microvascular and metabolic insulin resistance in humans.

OBJECTIVE: Insulin recruits muscle microvasculature, thereby increasing endothelial exchange surface area. Free fatty acids (FFAs) cause insulin resistance by activating inhibitor of κB kinase ß. Elevating plasma FFAs impairs insulin's microvascular and metabolic actions in vivo. Whether salsalate, an anti-inflammatory agent, prevents FFA-induced microvascular and/or metabolic insulin resistance in humans is unknown. RESEARCH DESIGN AND METHODS: Eleven healthy, young adults were studied three times in random order. After an overnight fast, on two occasions each subject received a 5-h systemic infusion of Intralipid ± salsalate pretreatment (50 mg/kg/day for 4 days). On the third occasion, saline replaced Intralipid. A 1 mU/kg/min euglycemic insulin clamp was superimposed over the last 2-h of each study. Skeletal and cardiac muscle microvascular blood volume (MBV), microvascular flow velocity (MFV), and microvascular blood flow (MBF) were determined before and after insulin infusion. Whole body glucose disposal rates were calculated from glucose infusion rates. RESULTS: Insulin significantly increased skeletal and cardiac muscle MBV and MBF without affecting MFV. Lipid infusion abolished insulin-mediated microvascular recruitment in both skeletal and cardiac muscle and lowered insulin-stimulated whole body glucose disposal (P<0.001). Salsalate treatment rescued insulin's actions to recruit muscle microvasculature and improved insulin-stimulated whole body glucose disposal in the presence of high plasma FFAs. CONCLUSIONS: High plasma concentrations of FFAs cause both microvascular and metabolic insulin resistance, which can be prevented or attenuated by salsalate treatment. Our data suggest that treatments aimed at inhibition of inflammatory response might help alleviate vascular insulin resistance and improve metabolic control in patients with diabetes.

Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, suppresses hepatic gluconeogenesis through 5'-AMP-activated protein kinase.

Epigallocatechin-3-gallate (EGCG), a main catechin of green tea, has been suggested to inhibit hepatic gluconeogenesis. However, the exact role and related mechanism have not been established. In this study, we examined the role of EGCG in hepatic gluconeogenesis at concentrations that are reachable by ingestion of pure EGCG or green tea, and are not toxic to hepatocytes. Our results show in isolated hepatocytes that EGCG at relatively low concentrations (