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Abstract Reperfusion therapy is critical for saving heart muscle after myocardial infarction, but the process of restoring blood flow can itself exacerbate injury to the myocardium. This phenomenon is known as myocardial ischemia-reperfusion injury (MIRI), which includes oxidative stress, inflammation, and further cell death. microRNA-146a (miR-146a) is known to play a significant role in regulating the immune response and inflammation, and has been studied for its potential impact on the improvement of heart function after myocardial injury. However, the delivery of miR-146a to the heart in a specific and efficient manner remains a challenge as extracellular RNAs are unstable and rapidly degraded. Milk exosomes (MEs) have been proposed as ideal delivery platform for miRNA-based therapy as they can protect miRNAs from RNase degradation. In this study, the effects of miR-146a containing MEs (MEs-miR-146a) on improvement of cardiac function were examined in a rat model of MIRI. To enhance the targeting delivery of MEs-miR-146a to the site of myocardial injury, the ischemic myocardium-targeted peptide IMTP was modified onto the surfaces, and whether the modified MEs-miR-146a could exert a better therapeutic role was examined by echocardiography, myocardial injury indicators and the levels of inflammatory factors. Furthermore, the expressions of miR-146a mediated NF-κB signaling pathway-related proteins were detected by western blotting and qRT-PCR to further elucidate its mechanisms. MiR-146 mimics were successfully loaded into the MEs by electroporation at a square wave 1000 V voltage and 0.1 ms pulse duration. MEs-miR-146a can be up-taken by cardiomyocytes and protected the cells from oxygen glucose deprivation/reperfusion induced damage in vitro. Oral administration of MEs-miR-146a decreased myocardial tissue apoptosis and the expression of inflammatory factors and improved cardiac function after MIRI. The miR-146a level in myocardium tissues was significantly increased after the administration IMTP modified MEs-miR-146a, which was higher than that of the MEs-miR-146a group. In addition, intravenous injection of IMTP modified MEs-miR-146a enhanced the targeting to heart, improved cardiac function, reduced myocardial tissue apoptosis and suppressed inflammation after MIRI, which was more effective than the MEs-miR-146a treatment. Moreover, IMTP modified MEs-miR-146a reduced the protein levels of IRAK1, TRAF6 and p-p65. Therefore, IMTP modified MEs-miR-146a exerted their anti-inflammatory effect by inhibiting the IRAK1/TRAF6/NF-κB signaling pathway. Taken together, our findings suggested miR-146a containing MEs may be a promising strategy for the treatment of MIRI with better outcome after modification with ischemic myocardium-targeted peptide, which was expected to be applied in clinical practice in future.

Abstract Patients with Parkinson’s disease and cognitive impairment (PD-CI) deteriorate faster than those without cognitive impairment (PD-NCI), suggesting an underlying difference in the neurodegeneration process. We aimed to verify brain age differences in PD-CI and PD-NCI and their clinical significance. A total of 94 participants (PD-CI, n = 27; PD-NCI, n = 34; controls, n = 33) were recruited. Predicted age difference (PAD) based on gray matter (GM) and white matter (WM) features were estimated to represent the degree of brain aging. Patients with PD-CI showed greater GM-PAD (7.08 ± 6.64 years) and WM-PAD (8.82 ± 7.69 years) than those with PD-NCI (GM: 1.97 ± 7.13, P adjusted = 0.011; WM: 4.87 ± 7.88, P adjusted = 0.049) and controls (GM: -0.58 ± 7.04, P adjusted = 0.004; WM: 0.88 ± 7.45, P adjusted = 0.002) after adjusting demographic factors. In patients with PD, GM-PAD was negatively correlated with MMSE (P adjusted = 0.011) and MoCA (P adjusted = 0.013) and positively correlated with UPDRS Part II (P adjusted = 0.036). WM-PAD was negatively correlated with logical memory of immediate and delayed recalls (P adjusted = 0.003 and P adjusted

BackgroundThe association between rheumatoid arthritis (RA) and osteoporotic fracture has garnered considerable attention; however, the causal relationships between diseases remain uncertain. Therefore, this study employed Mendelian randomization (MR) analysis to investigate the causal effects of RA on osteoporotic fracture.MethodsThe summary data for RA and osteoporotic fracture were extracted from the genome-wide association studies (GWAS) catalog and the Finn Biobank database. The database provides information about diseased and health control subjects. We searched the database for the following conditions: RA, osteoporosis (OP), and osteoporotic fractures. Entries were published by investigating centers, which had established definitions and diagnostic criteria. We downloaded and processed the data to obtain the single-nucleotide polymorphisms (SNPs) strongly associated with RA, OP, and osteoporotic fracture. RA genetic associations were obtained from the GWAS catalog, including 1961 cases and 454,387 controls. The osteoporosis of the GWAS catalog involved 991 cases and 455,357 controls, and the data of the Finn Biobank involved 8,017 cases and 391,037 controls. Genetic associations for osteoporotic fracture were taken from the Finn Biobank of 1822 cases and 311,210 controls. Independent SNPs that are significantly associated with meeting the criteria of p

Objective To compare and analyze the influence of traditional blood flow restriction (tBFR) and practical blood flow restriction (pBFR) on the immediate efficacy of upper limb muscles in military cadets, and explore the application effect of pBFR. Methods Ten well-trained healthy military cadets from Army Medical University were enrolled in this study. After the baseline measurement was completed, all of them were asked to do alternating dumbbell curl with dominant arm. Low-intensity (LI), low-intensity combined tBFR (LI-tBFR), high-intensity combined tBFR (HI-tBFR), low-intensity combined pBFR (LI-pBFR), and high-intensity combined pBFR (HI-pBFR) training were completed within 5 weeks. Each training mode of each subject was randomly generated until all 5 different training modes were completed, and the interval between 2 adjacent training sessions was 1 week. Surface electromyography (EMG) was conducted during the whole process of each training, and the muscle thickness and upper arm circumference were measured before and after each training. Subjective fatigue was evaluated by the participants after each training, and the results were recorded and analyzed statistically. Results Whether it is tBFR or pBFR, the root mean square (RMS) value of LI-BFR was significantly higher than that of LI, and that of HI-BFR was significantly higher than that of LI-BFR (P < 0.05). However, there were no obvious differences in RMS between LI-tBFR and LI-pBFR, and between HI-tBFR and HI-pBFR (P>0.05). In terms of muscle thickness (0.2~0.3 mm) and upper limb arm circumference (0.3~0.4 cm), certain increments were observed before and after combined BFR (P < 0.05), but no such significant difference was observed between tBFR and pBFR (P>0.05). The results of subjective fatigue evaluation indicated that the fatigue level was gradually elevated with load increasing, and there was no statistical difference in the level between tBFR and pBFR under the same load of training (P>0.05). Conclusion In immediate efficacy, pBFR has a similar effect as tBFR, and both of them can effectively promote the immediate activation effect of upper limb muscles and increase muscle hypertrophy in military cadets. For military cadets and even the general public, conducting pBFR training on their own without professional training venues and equipment is also a good choice. However, further verification is still needed for long-term effects.