Controlled activation is a critical component in prodrug development. Herein we report a concentration-sensitive platform approach for bioorthogonal prodrug activation by taking advantage of reaction kinetics. Using two “click and release” systems, we demonstrate enrichment and prodrug activation specifically in mitochondria to demonstrate the principle of this approach. In both cases, the payload (doxorubicin or carbon monoxide) was released inside the mitochondrial matrix upon the enrichment-initiated click reaction. Furthermore, mitochondria-targeted delivery yielded substantial augmentation of functional biological and therapeutic effects in vitro and in vivo, as compared to controls that did not result in enrichment. This method is thus a platform for targeted drug delivery amenable to conjugation with a variety of molecules and not limited to cell-surface delivery. Taken together, these two click and release pairs clearly demonstrate the concept of enrichment-triggered drug release and critical feasibility of treating clinically relevant diseases such as acute liver injury and cancer.
Diabetic kidney disease is known as a major cause of chronic kidney disease and end stage renal disease. Polysulfides, a class of chemical agents with a chain of sulfur atoms, are found to confer renal protective effects in acute kidney injury. However, whether a polysulfide donor, sodium tetrasulfide (Na 2 S 4 ), confers protective effects against diabetic nephropathy remains unclear. Our results showed that Na 2 S 4 treatment ameliorated renal dysfunctional and histological damage in diabetic kidneys through inhibiting the overproduction of inflammation cytokine and reactive oxygen species (ROS), as well as attenuating renal fibrosis and renal cell apoptosis. Additionally, the upregulated phosphorylation and acetylation levels of p65 nuclear factor κB (p65 NF-κB) and signal transducer and activator of transcription 3 (STAT3) in diabetic nephropathy were abrogated by Na 2 S 4 in a sirtuin-1 (SIRT1)-dependent manner. In renal tubular epithelial cells, Na 2 S 4 directly sulfhydrated SIRT1 at two conserved CXXC domains (Cys371/374; Cys395/398), then induced dephosphorylation and deacetylation of its targeted proteins including p65 NF-κB and STAT3, thereby reducing high glucose (HG)-caused oxidative stress, cell apoptosis, inflammation response and epithelial-to-mesenchymal transition (EMT) progression. Most importantly, inactivation of SIRT1 by a specific inhibitor EX-527, small interfering RNA (siRNA), a de-sulfhydration reagent dithiothreitol (DTT), or mutation of Cys371/374 and Cys395/398 sites at SIRT1 abolished the protective effects of Na 2 S 4 on diabetic kidney insulting. These results reveal that polysulfides may attenuate diabetic renal lesions via inactivation of p65 NF-κB and STAT3 phosphorylation/acetylation through sulfhydrating SIRT1.
Diabetic kidney disease develops in approximately 40% of diabetic patients and is a major cause of chronic kidney diseases (CKD) and end stage kidney disease (ESKD) worldwide. Hydrogen sulfide (H2S), the third gasotransmitter after nitric oxide (NO) and carbon monoxide (CO), is synthesized in nearly all organs, including the kidney. Though studies on H2S regulation of renal physiology and pathophysiology are still in its infancy, emerging evidence shows that H2S production by renal cells is reduced under disease states and H2S donors ameliorate kidney injury. Specifically, aberrant H2S level is implicated in various renal pathological conditions including diabetic nephropathy. This review presents the roles of H2S in diabetic renal disease and the underlying mechanisms for the protective effects of H2S against diabetic renal damage. H2S may serve as fundamental strategies to treat diabetic kidney disease. These H2S treatment modalities include precursors for H2S synthesis, H2S donors, and natural plant-derived compounds. Despite accumulating evidence from experimental studies suggests the potential role of the H2S signaling pathway in the treatment of diabetic nephropathy, these results need further clinical translation. Expanding understanding of H2S in the kidney may be vital to translate H2S to be a novel therapy for diabetic renal disease.
Carbon monoxide (CO) is an endogenously produced gasotransmitter in mammals, and may have signaling roles in bacteria as well. It has many recognized therapeutic effects. A significant challenge in this field is the development of pharmaceutically acceptable forms of CO delivery with controllable and tunable release rates. Herein, we describe the structure-release rate studies of the first class of organic CO-prodrugs that release CO in aqueous solution at neutral pH.
As considered one of the most important sustainable transportation, the development of urban rail transit has been thriving over the last decade, especially in the densely populated cities. Using an accurate measurement tool to find out the shortage factors in the rail transit service is the vital prerequisite for improving the services, increasing ridership, and implementing the sustainable transport policy. The purpose of the study is to use structural equation model (SEM) to assess the important dimensions of service quality and customer satisfaction on rail transit passengers’ reuse intention. Data are collected from a questionnaire survey and an empirical study is conducted by using SEM to test the hypotheses, as well as the structural relationships among these factors. The results of the empirical study confirmed that service quality can be conceptualized as functional service quality, technical service quality, comfort and cleanness, and service planning and reliability. And it has positive effect on reuse intention by enhancing customer satisfaction, as customer satisfaction has intermediary effect on passengers’ repurchase intention. This study contributes to transport agencies for analyzing the relationship between service quality attributes and passengers’ reuse intention for improving the supplied service, increasing the ridership, and implementing the sustainable transport policy.
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