Pan Li

Recent studies have revealed that vascular cells can produce reactive oxygen species (ROS) through NAD(P)H oxidase, which may be involved in vascular injury. However, the pathological role of vascular NAD(P)H oxidase in diabetes or in the insulin-resistant state remains unknown. In this study, we examined the effect of high glucose level and free fatty acid (FFA) (palmitate) on ROS production in cultured aortic smooth muscle cells (SMCs) and endothelial cells (ECs) using electron spin resonance spectroscopy. Exposure of cultured SMCs or ECs to a high glucose level (400 mg/dl) for 72 h significantly increased the free radical production compared with low glucose level exposure (100 mg/dl). Treatment of the cells for 3 h with phorbol myristic acid (PMA), a protein kinase C (PKC) activator, also increased free radical production. This increase was restored to the control value by diphenylene iodonium, a NAD(P)H oxidase inhibitor, suggesting ROS production through PKC-dependent activation of NAD(P)H oxidase. The increase in free radical production by high glucose level exposure was completely restored by both diphenylene iodonium and GF109203X, a PKC-specific inhibitor. Exposure to palmitate (200 micromol/l) also increased free radical production, which was concomitant with increases in diacylglycerol level and PKC activity. Again, this increase was restored to the control value by both diphenylene iodonium and GF109203X. The present results suggest that both high glucose level and palmitate may stimulate ROS production through PKC-dependent activation of NAD(P)H oxidase in both vascular SMCs and ECs. This finding may be involved in the excessive acceleration of atherosclerosis in patients with diabetes and insulin resistance syndrome.

Vascular development depends on the highly coordinated actions of a variety of angiogenic regulators, most of which apparently act downstream of vascular endothelial growth factor (VEGF). One potential such regulator is delta-like 4 ligand (Dll4), a recently identified partner for the Notch receptors. We generated mice in which the Dll4 gene was replaced with a reporter gene, and found that Dll4 expression is initially restricted to large arteries in the embryo, whereas in adult mice and tumor models, Dll4 is specifically expressed in smaller arteries and microvessels, with a striking break in expression just as capillaries merge into venules. Consistent with these arterial-specific expression patterns, heterozygous deletion of Dll4 resulted in prominent albeit variable defects in arterial development (reminiscent of those in Notch knockouts), including abnormal stenosis and atresia of the aorta, defective arterial branching from the aorta, and even arterial regression, with occasional extension of the defects to the venous circulation; also noted was gross enlargement of the pericardial sac and failure to remodel the yolk sac vasculature. These striking phenotypes resulting from heterozygous deletion of Dll4 indicate that vascular development may be as sensitive to subtle changes in Dll4 dosage as it is to subtle changes in VEGF dosage, because VEGF accounts for the only other example of haploid insufficiency, resulting in obvious vascular abnormalities. In summary, Dll4 appears to be a major trigger of Notch receptor activities previously implicated in arterial and vascular development, and it may represent a new opportunity for pro- and anti-angiogenic therapies.

Abstract Two‐dimensional (2D) MXenes, as a new 2D functional material nanosystem, have been extensively explored for broad applications. However, their specific performance and applications in theranostic nanomedicine have still rarely been explored. This work reports on the drug‐delivery performance and synergistic therapeutic efficiency of Ti 3 C 2 MXenes for highly efficient tumor eradication. These Ti 3 C 2 MXenes not only possess high drug‐loading capability of as high as 211.8%, but also exhibit both pH‐responsive and near infrared laser‐triggered on‐demand drug release. Especially, based on the high photothermal‐conversion capability of Ti 3 C 2 MXenes, they have been further explored for efficient tumor eradication by synergistic photothermal ablation and chemotherapy, which has been systematically demonstrated both in vitro and in vivo. These Ti 3 C 2 MXenes have also been demonstrated as the desirable contrast agents for photoacoustic imaging, showing the potential for diagnostic‐imaging guidance and monitoring during therapy. The high in vivo histocompatibility of Ti 3 C 2 and their easy excretion out of the body have been evaluated and demonstrated, showing the potential high biosafety for further clinical translation. This work paves a new way for broadening biomedical applications of MXenes in nanomedicine where they can exert the high performance and functionality for synergistic therapy, especially on combating cancer.

The conventional inorganic semiconductors are not suitable for in vivo therapeutic nanomedicine because of the lack of an adequate and safe irradiation source to activate them. This work reports on the rational design of titania (TiO2)-based semiconductors for enhanced and synergistic sono-/photoinduced tumor eradication by creating an oxygen-deficient TiO2–x layer onto the surface of TiO2 nanocrystals, which can create a crystalline-disordered core/shell structure (TiO2@TiO2–x) with black color. As found in the lessons from traditional photocatalysis, such an oxygen-deficient TiO2–x layer with abundant oxygen defects facilitates and enhances the separation of electrons (e–) and holes (h+) from the energy-band structure upon external ultrasound irradiation, which can significantly improve the efficacy of sono-triggered sonocatalytic tumor therapy. Such an oxygen-deficient TiO2–x layer can also endow black titania nanoparticles with high photothermal-conversion efficiency (39.8%) at the NIR-II biowindow (1064 nm) for enhanced photothermal hyperthermia. Both in vitro cell level and systematic in vivo tumor-bearing mice xenograft evaluations have demonstrated the high synergistic efficacy of combined and enhanced sonodynamic therapy and photothermal ablation as assisted by oxygen-deficient black titania, which has achieved complete tumor eradication with high therapeutic biosafety and without obvious reoccurrence. This work not only provides the paradigm of high therapeutic efficacy of a combined sono-/photoinduced tumor-treatment protocol but also significantly broadens the nanomedical applications of semiconductor-based nanoplatforms by rational design of their nanostructures and control of their physiochemical properties.

We present a systematic investigation of the microscopic mechanism of interface interaction, charge transfer and separation, as well as their influence on the photocatalytic activity of heterojunctions by a combination of theoretical calculations and experimental techniques for the g-C3N4–ZnWO4 composite. HRTEM results and DFT calculations mutually validate each other to indicate the reasonable existence of g-C3N4 (001)–ZnWO4 (010) and g-C3N4 (001)–ZnWO4 (011) interfaces. The g-C3N4–ZnWO4 heterojunctions show higher photocatalytic activity for degradation of MB than pure g-C3N4 and ZnWO4 under visible-light irradiation. Moreover, the heterojunctions significantly enhance the oxidation of phenol in contrast to pure g-C3N4, the phenol oxidation capacity of which is weak, clearly demonstrating a synergistic effect between g-C3N4 and ZnWO4. Interestingly, based on the theoretical calculations, we find that electrons in the upper valence band can be directly excited from g-C3N4 to the conduction band, that is, the W 5d orbital of ZnWO4, under visible-light irradiation, which should yield well-separated electron–hole pairs, with high photocatalytic performance in g-C3N4–ZnWO4 heterojunctions as shown by our experiment. The microcosmic mechanisms of interface interaction and charge transfer in this system can be helpful for fabricating other effective hetero-structured photocatalysts.