Summary LRRK2 mutations are the most common genetic cause of Parkinson’s disease, but its normal physiological role in the brain is unclear. Here we show that inactivation of LRRK2 and its functional homologue LRRK1 results in earlier mortality and age-dependent, selective neurodegeneration. Loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and noradrenergic neurons in the locus coeruleus is accompanied with increases in apoptosis, whereas the cerebral cortex and cerebellum are unaffected. Furthermore, selective age-dependent neurodegeneration is only present in LRRK−/− but not LRRK1−/− or LRRK2−/− brains, and is accompanied with increases of α-synuclein and impairment of the autophagy-lysosomal pathway. Quantitative electron microscopy analysis revealed age-dependent increases of autophagic vacuoles in the SNpc of LRRK−/− mice before the onset of dopaminergic neuron loss. These findings revealed an essential role of LRRK in the survival of dopaminergic neurons and the regulation of the autophagy-lysosomal pathway in the aging brain.

The optimal aerobic exercise training (AET) protocol for patients following myocardial infarction (MI) has remained under debate. The present study therefore aimed to compare the effects of continuous moderate-intensity training (CMT) and high-intensity interval training (HIT) on cardiac functional recovery, and to investigate the potential associated mechanisms in a post-MI rat model. Female Sprague Dawley rats (8-10 weeks old) undergoing MI or sham surgery were subsequently submitted to CMT or HIT, or kept sedentary for eight weeks. Prior to and following AET, echocardiographic parameters and exercise capacity of the rats were measured. Western blotting was used to evaluate the levels of apoptosis and associated signaling pathway protein expression. The concentrations of biomarkers of oxidative stress were also determined by ELISA assay. Messenger (m)RNA levels and activity of the key enzymes for glycolysis and fatty acid oxidation, as well as the rate of adenosine triphosphate (ATP) synthesis, were also measured. Compared with the MI group, exercise capacity and cardiac function were significantly improved following AET, particularly following HIT. Left ventricular ejection fraction and fraction shortening were further improved in the MI-HIT group in comparison to that of the MI-CMT group. The two forms of AET almost equally attenuated apoptosis of the post-infarction myocardium. CMT and HIT also alleviated oxidative stress by decreasing the concentration of malondialdehyde and increasing the concentration of superoxide dismutase and glutathione peroxidase (GPx). In particular, HIT induced a greater increase in the concentration of GPx than that of CMT. AET, and HIT in particular, significantly increased the levels of mRNA and the maximal activity of phosphofructokinase-1 and carnitine palmitoyl transferase-1, as well as the maximal ratio of ATP synthesis. In addition, compared with the MI group, the expression of signaling proteins PI3K, Akt, p38mapk and AMPK was significantly altered in the MI-CMT and MI-HIT groups. HIT was superior to CMT in its ability to improve cardiac function and exercise capability in a post-MI rat model. HIT was also superior to CMT with regard to attenuating oxidative stress and improving glucolipid metabolism of the post-MI myocardium.

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The administration of intravenous vitamin C (IV‐VC) in treating patients with coronavirus disease 2019 (COVID‐19) is still highly controversial. There have been no previous studies on the effect of IV‐VC on the severity and mortality of COVID‐19. Hence, we conducted a systematic review and meta‐analysis to compare the disease severity and mortality in patients with COVID‐19 who promptly received IV‐VC treatment vs those who did not. We performed a comprehensive systematic search of seven health science databases, including PubMed, Embase, Cochrane Library, MEDLINE, Web of Science, China National Knowledge Infrastructure, and Wanfang Data, up to June 23, 2021. We identified a total of seven related articles, which were included in this study. This meta‐analysis showed that IV‐VC treatment did not affect disease severity compared with placebo treatment or usual care (odds ratio [OR], 0.70; 95% CI, 0.45 to 1.07; P = 0.10). In addition, no statistically significant difference in mortality was observed between patients who received IV‐VC treatment and those who did not (OR, 0.64; 95% CI, 0.41 to 1.00; P = 0.05). Moreover, the adjusted meta‐analysis revealed that the use of IV‐VC did not influence disease severity (OR, 0.67; 95% CI, 0.34 to 1.31; P = 0.242) or mortality (OR, 1.02; 95% CI, 0.75 to 1.40; P = 0.877) in comparison with a control group. The results of this meta‐analysis demonstrated that short‐term IV‐VC treatment did not reduce the risk of severity and mortality in patients with COVID‐19.