Cyclosporine A-loaded apoferritin alleviates myocardial ischemia-reperfusion injury by simultaneously blocking ferroptosis and apoptosis of cardiomyocytes.

Myocardial ischemia-reperfusion injury (MI/RI) seriously restricts the therapeutic effect of reperfusion. It is demonstrated that ferroptosis and apoptosis of cardiomyocytes are widely involved in MI/RI. Therefore, simultaneous inhibition of ferroptosis and apoptosis of cardiomyocytes can be a promising strategy to treat MI/RI. Besides, transferrin receptor 1 (TfR1) is highly expressed in ischemic myocardium, and apoferritin (ApoFn) is a ligand of the transferrin receptor. In this study, CsA@ApoFn was prepared by wrapping cyclosporin A (CsA) with ApoFn and actively accumulated in ischemic cardiomyocytes through TfR1 mediated endoctosis in MI/RI mice. After entering cardiomyocytes, ApoFn in CsA@ApoFn inhibited ferroptosis of ischemic cardiomyocytes by increasing the protein expression of GPX4 and reducing the content of labile iron pool and lipid peroxides. At the same time, CsA in CsA@ApoFn attenuated the apoptosis of ischemic cardiomyocytes through recovering mitochondrial membrane potential and reducing the level of reactive oxygen species, which played a synergistic role with ApoFn in the treatment of MI/RI. In conclusion, CsA@ApoFn restored cardiac function of MI/RI mice by simultaneously blocking ferroptosis and apoptosis of cardiomyocytes. ApoFn itself not only served as a safe carrier to specifically deliver CsA to ischemic cardiomyocytes but also played a therapeutic role on MI/RI. CsA@ApoFn is proved as an effective drug delivery platform for the treatment of MI/RI. STATEMENT OF SIGNIFICANCE: Recent studies have shown that ferroptosis is an important mechanism of myocardial ischemia-reperfusion injury (MI/RI). Therefore, simultaneous inhibition of ferroptosis and apoptosis of cardiomyocytes can be a promising strategy to treat MI/RI. Apoferritin, as a delivery carrier, can actively target to ischemic myocardium through binding with highly expressed transferrin receptor on ischemic cardiomyocytes. At the same time, apoferritin plays a protective role on ischemic cardiomyocytes by inhibiting ferroptosis. This strategy of killing two birds with one stone significantly improves the therapeutic effect on MI/RI while does not need more pharmaceutical excipients, which has the prospect of clinical transformation.

Comparison of flexible fixation and screw fixation for isolated Lisfranc ligament injuries: A protocol for a meta-analysis of comparative studies.

BACKGROUND: The frequency of isolated Lisfranc ligament (ILL) injuries has been increasing recently with the increase in low-energy trauma resulting from sports injuries. For ILL injuries, the optimal method of fixation still remains controversial. The traditional fixation method is achieved by trans-articular screws, but recently, dorsal bridge plates and suture button (SB) fixation have become alternatives. Some biomechanical studies have showed that SB fixation can provide adequate strength compared to trans-articular screws. Therefore, a meta-analysis is imperative to provide evidence on whether flexible fixation is comparable to screw fixation for treatment of ILL injuries. METHODS: We will conduct a comprehensive literature search in PubMed, Cochrane Library, EMBASE and Web of Science databases and for comparative studies. We will apply the risk-of-bias tool of the Cochrane Collaboration for Randomized Controlled Trials to assess the methodological quality. Risk-of-Bias Assessment Tool for Non-randomized Studies was used to evaluate the quality of comparative studies. Statistical analysis will be conducted using RevMan 5.4 software (Cochrane Collaboration, London, England). RESULTS: This systematic review will evaluate the functional outcomes and radiographic results of flexible fixation for treatment of ILL injuries. CONCLUSION: The conclusion of this study will provide evidence for judging whether flexible fixation is superior to screw fixation for treatment of ILL injuries.

Managing the medical resources of a national insurance program: lessons based on China's NCMS.

BACKGROUND: The security of medical insurance fund is very important to health equity. In China, the expenditure of medical insurance fund has increased sharply year after year, and the balance of local medical insurance fund is difficult to sustain. To realize the equitable distribution of the medical insurance burden, the central government has to continuously increase transfer payments, which causes regional unfairness in the distribution of central financial resources. This paper explores the influence of central transfer payments on the balance of medical insurance fund, influential mechanisms, and the strategic behavior of local governments. METHODS: First, we constructed a dynamic game model between central government and local governments and analyzed the mechanism of central transfer payments affecting the balance of local medical insurance fund. Then, based on the provincial panel data of 28 provincial administrative regions in China from 2004 to 2014, an empirical test was made. The spatial regression model was constructed, and the transfer payments obtained by neighboring provinces in the previous year were taken as instrumental variables. RESULTS: Central transfer payments led to strategic behaviors by local governments that resulted in increased local health insurance fund expenditures and lower balance rates. Moreover, the central transfer payments demonstrated "path dependence". Central transfer payments had a significant negative influence on the local NCMS fund balance rate. The local government subsidy and per capita GDP had a significant positive impact on the local NCMS fund balance rate. The obtained transfer payments of local governments had a significant space correlation. This study based on NCMS data remains valid. CONCLUSIONS: Central transfer payments induced the strategic behavior of local governments, which neglected to supervise the expenditure of medical insurance fund, reducing the efficiency of medical insurance fund management and use. The financial resources of medical insurance fund are unevenly distributed among provinces. Measures such as strengthening the supervision ability and initiatives of local governments, refining the central transfer payment mechanism, promoting the economic growth of western regions, and increasing rates for individual contributions appropriately can ensure that the medical insurance fund are used well and distributed equitably.