ABSTRACT
Hypoxia can lead to liver fibrosis and severely limits the efficacy of photodynamic therapy (PDT). Herein, carbon nitride (CN)-based hybrid nanoparticles (NPs) VPSGCNs@TSI for light-driven water splitting were utilized to solve this problem. CNs were doped with selenide glucose (Se-glu) to enhance their red/NIR region absorption. Then, vitamin A-poly(ethylene glycol) (VA-PEG) fragments and aggregation-induced emission (AIE) photosensitizers TSI were introduced into Se-glu-doped CN NPs (VPSGCNs) to construct VPSGCNs@TSI NPs. The introduction of VA-PEG fragments enhanced the targeting of the NPs to activated hepatic stellate cells (HSCs) and reduced their toxicity to ordinary liver cells. VPSGCN units could trigger water splitting to generate O2 under 660 nm laser irradiation, improve the hypoxic environment of the fibrosis site, downregulate HIF-1α expression, and activate HSC ferroptosis via the HIF-1α/SLC7A11 pathway. In addition, generated O2 could also increase the reactive oxygen species (ROS) production of TSI units in a hypoxic environment, thereby completely reversing hypoxia-triggered PDT resistance to enhance the PDT effect. The combination of water-splitting materials and photodynamic materials showed a 1 + 1 > 2 effect in increasing oxygen levels in liver fibrosis, promoting ferroptosis of activated HSCs and reversing PDT resistance caused by hypoxia.
Subject(s)
Ferroptosis , Hepatic Stellate Cells , Liver Cirrhosis , Nanoparticles , Photochemotherapy , Nanoparticles/chemistry , Animals , Ferroptosis/drug effects , Liver Cirrhosis/drug therapy , Liver Cirrhosis/pathology , Liver Cirrhosis/metabolism , Mice , Hepatic Stellate Cells/drug effects , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/pathology , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Nitriles/chemistry , Nitriles/pharmacology , Humans , Hypoxia/drug therapy , Hypoxia/metabolism , Reactive Oxygen Species/metabolismABSTRACT
Hypoxia is an important feature, which can upregulate the hypoxia-inducible factor-1α (HIF-1α) expression and promote the activation of hepatic stellate cells (HSCs), leading to liver fibrosis. Currently, effective treatment for liver fibrosis is extremely lacking. Herein, a safe and effective method is established to downregulate the expression of HIF-1α in HSCs via targeted delivery of VA-PEG-modified CNs-based nanosheets-encapsulated (VA-PEG-CN@GQDs) HIF-1α small interfering RNA (HIF-1α-siRNA). Due to the presence of lipase in the liver, the reversible release of siRNA can be promoted to complete the transfection process. Simultaneously, VA-PEG-CN@GQD nanosheets enable trigger the water splitting process to produce O2 under near-infrared (NIR) irradiation, thereby improving the hypoxic environment of the liver fibrosis site and maximizing the downregulation of HIF-1α expression to improve the therapeutic effect, as demonstrated in liver fibrosis mice. Such combination therapy can inhibit the activation of HSCs via HIF-1α-mediated TGF-ß1/Smad pathway, achieving outstanding therapeutic effects in liver fibrosis mice. In conclusion, this study proposes a novel strategy for the treatment of liver fibrosis by regulating the hypoxic environment and the expression of HIF-1α at lesion site.
Subject(s)
Hypoxia-Inducible Factor 1, alpha Subunit , Transforming Growth Factor beta1 , Mice , Animals , Transforming Growth Factor beta1/metabolism , RNA, Small Interfering/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Liver Cirrhosis/therapy , HypoxiaABSTRACT
At the beginning of 2020, the novel coronavirus disease (COVID-19) became an outbreak in China. On January 23, China raised its national public health response to the highest level. As part of the emergency response, a series of public social distancing interventions were implemented to reduce the transmission rate of COVID-19. In this article, we explored the feasibility of using mobile terminal positioning data to study the impact of some nonpharmaceutical public health interventions implemented by China. First, this article introduced a hybrid method for measuring the number of people in public places based on anonymized mobile terminal positioning data. Additionally, the difference-in-difference (DID) model was used to estimate the effect of the interventions on reducing public gatherings in different provinces and during different stages. The data-driven experimental results showed that the interventions that China implemented reduced the number of people in public places by approximately 60% between January 24 and February 28. Among the 31 provinces in the Chinese mainland, some provinces, such as Tianjin and Chongqing, were more affected by the interventions, while other provinces, such as Gansu, were less affected. In terms of the stages, the phase with the greatest intervention effect was from February 3 to 14, during which the number of daily confirmed cases in China showed a turning point. In conclusion, the interventions significantly reduced public gatherings, and the effects of interventions varied with provinces and time.