Exerkine fibronectin type-III domain-containing protein 5/irisin-enriched extracellular vesicles delay vascular ageing by increasing SIRT6 stability.

AIMS: Exercise confers protection against cardiovascular ageing, but the mechanisms remain largely unknown. This study sought to investigate the role of fibronectin type-III domain-containing protein 5 (FNDC5)/irisin, an exercise-associated hormone, in vascular ageing. Moreover, the existence of FNDC5/irisin in circulating extracellular vesicles (EVs) and their biological functions was explored. METHODS AND RESULTS: FNDC5/irisin was reduced in natural ageing, senescence, and angiotensin II (Ang II)-treated conditions. The deletion of FNDC5 shortened lifespan in mice. Additionally, FNDC5 deficiency aggravated vascular stiffness, senescence, oxidative stress, inflammation, and endothelial dysfunction in 24-month-old naturally aged and Ang II-treated mice. Conversely, treatment of recombinant irisin alleviated Ang II-induced vascular stiffness and senescence in mice and vascular smooth muscle cells. FNDC5 was triggered by exercise, while FNDC5 knockout abrogated exercise-induced protection against Ang II-induced vascular stiffness and senescence. Intriguingly, FNDC5 was detected in human and mouse blood-derived EVs, and exercise-induced FNDC5/irisin-enriched EVs showed potent anti-stiffness and anti-senescence effects in vivo and in vitro. Adeno-associated virus-mediated rescue of FNDC5 specifically in muscle but not liver in FNDC5 knockout mice, promoted the release of FNDC5/irisin-enriched EVs into circulation in response to exercise, which ameliorated vascular stiffness, senescence, and inflammation. Mechanistically, irisin activated DnaJb3/Hsp40 chaperone system to stabilize SIRT6 protein in an Hsp70-dependent manner. Finally, plasma irisin concentrations were positively associated with exercise time but negatively associated with arterial stiffness in a proof-of-concept human study. CONCLUSION: FNDC5/irisin-enriched EVs contribute to exercise-induced protection against vascular ageing. These findings indicate that the exerkine FNDC5/irisin may be a potential target for ageing-related vascular comorbidities.

No difference in postoperative efficacy and safety between autograft and allograft in anterior cruciate ligament reconstruction: a retrospective cohort study in 112 patients.

Background: Arthroscopic anterior cruciate ligament reconstruction (ACLR) is the best treatment choice for returning to pre-injury activities following ACL rupture. Although allografts are considered an effective alternative to autografts, there is still controversy regarding the safety and effectiveness of this procedure, especially concerning the risk of postoperative infection and disease transmission. The purpose of this study was to compare the efficacy outcomes and safety between allografts and autografts in primary ACLR. Methods: The retrospective analysis involved 112 patients (58 patients received allogeneic tendons and 54 patients received autologous hamstring tendons) who underwent primary ACLR. All patients were followed up and evaluated on admission and at 1 week, 3 months, 6 months, and 1 year postoperatively. The efficacy outcome of the ACLR was evaluated by International Knee Documentation Committee (IKDC) score and physical examinations (Lachman test, anterior drawer test, and pivot shift test). The safety outcome of allografts and autografts was compared by investigating the occurrence of postoperative complications, including postoperative inflammation and potential disease transmission. The benefits of each operation for surgeons and patients were also analyzed, including the length of surgical incision and operative time. Results: There was no significant difference in the demographic and clinical characteristics between the allograft and autograft groups. The two cohorts proved to be similar in terms of the acute or chronic nature of the cruciate ligament and the incidence of concomitant meniscal surgery. Arthroscopic ACLR was performed in all patients. The physical examinations were all positive before surgery and negative immediately after the operation. The KT-1000 and IKDC scores of two groups significantly decreased than pre-operative ones (P<0.05), but the difference between the two groups was not statistically significant (P>0.05). At final follow-up, all patients had returned to their pre-injury activities. Allografts showed no increased risk for postoperative infection or potential disease transmission relative to autografts. Conclusions: The outcomes of reconstructed ACL with allografts were similar to those of autographs. Moreover, the safety of allografts showed to be comparable to that of autografts, especially concerning postoperative infection and disease transmission. Therefore, the surgical option should be chosen wisely according to the patient's condition.

Melatonin safeguards against fatty liver by antagonizing TRAFs-mediated ASK1 deubiquitination and stabilization in a ß-arrestin-1 dependent manner.

Melatonin has been previously shown to prevent nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms are poorly understood. Here, we identified a previously unknown regulatory action of melatonin on apoptosis signal-regulating kinase 1 (ASK1) signaling pathway in the pathogenesis and development of NAFLD. Although melatonin administration did not alter food intake, it significantly alleviated fatty liver phenotypes, including the body weight gain, insulin resistance, hepatic lipid accumulation, steatohepatitis, and fibrosis in a high-fat diet (HFD)-induced NAFLD mouse model (in vivo). The protection of melatonin against NAFLD was not affected by inactivation of Kupffer cell in this model. In NAFLD mice liver, ASK1 signal cascade was substantially activated, evidence by the enhancement of total ASK1, phospho-ASK1, phospho-MKK3/6, phospho-p38, phospho-MKK4/7, and phospho-JNK. Melatonin treatment significantly suppressed the ASK1 upregulation and the phosphorylation of ASK1, MKK3/6, MKK4/7, p38, and JNK. Mechanistically, we found that lipid stress triggered the interaction between ASK1 and TNF receptor-associated factors (TRAFs), including TRAF1, TRAF2, and TRAF6, which resulted in ASK1 deubiquitination and thereby increased ASK1 protein stability. Melatonin did not alter ASK1 mRNA level; however, it activated a scaffold protein ß-arrestin-1 and enabled it to bind to ASK1, which antagonized the TRAFs-mediated ASK1 deubiquitination, and thus reduced ASK1 protein stability. Consistent with these findings, knockout of ß-arrestin-1 in mice partly abolished the protection of melatonin against NAFLD. Taken together, our results for the first time demonstrate that melatonin safeguards against NAFLD by eliminating ASK1 activation via inhibiting TRAFs-mediated ASK1 deubiquitination and stabilization in a ß-arrestin-1 dependent manner.