Plasma free fatty acids levels are increased in subjects with obesity and type 2 diabetes, playing detrimental roles in the pathogenesis of atherosclerosis and cardiovascular diseases. Increasing evidence showing that dysfunction of the vascular endothelium, the inner lining of the blood vessels, is the key player in the pathogenesis of atherosclerosis. In this review, we aimed to summarize the roles and the underlying mechanisms using the evidence collected from clinical and experimental studies about free fatty acid-mediated endothelial dysfunction. Because of the multifaceted roles of plasma free fatty acids in mediating endothelial dysfunction, elevated free fatty acid level is now considered as an important link in the onset of endothelial dysfunction due to metabolic syndromes such as diabetes and obesity. Free fatty acid-mediated endothelial dysfunction involves several mechanisms including impaired insulin signaling and nitric oxide production, oxidative stress, inflammation and the activation of the renin-angiotensin system and apoptosis in the endothelial cells. Therefore, targeting the signaling pathways involved in free fatty acid-induced endothelial dysfunction could serve as a preventive approach to protect against the occurrence of endothelial dysfunction and the subsequent complications such as atherosclerosis.

Importance: Depression is the second most prevalent mental disorder among children and adolescents, yet only a small proportion seek or receive disorder-specific treatment. Physical activity interventions hold promise as an alternative or adjunctive approach to clinical treatment for depression.Objective: To determine the association of physical activity interventions with depressive symptoms in children and adolescents.Data Sources: PubMed, CINAHL, PsycINFO, EMBASE, and SPORTDiscus were searched from inception to February 2022 for relevant studies written in English, Chinese, or Italian.Study Selection: Two independent researchers selected studies that assessed the effects of physical activity interventions on depressive symptoms in children and adolescents compared with a control condition.Data Extraction and Synthesis: A random-effects meta-analysis using Hedges g was performed. Heterogeneity, risk of bias, and publication bias were assessed independently by multiple reviewers. Meta-regressions and sensitivity analyses were conducted to substantiate the overall results. The study followed the PRISMA reporting guideline.Main Outcomes and Measures: The main outcome was depressive symptoms as measured by validated depression scales at postintervention and follow-up.Results: Twenty-one studies involving 2441 participants (1148 [47.0%] boys; 1293 [53.0%] girls; mean [SD] age, 14 [3] years) were included. Meta-analysis of the postintervention differences revealed that physical activity interventions were associated with a reduction in depressive symptoms compared with the control condition (g = −0.29; 95% CI, −0.47 to −0.10; P = .004). Analysis of the follow-up outcomes in 4 studies revealed no differences between the physical activity and control groups (g = −0.39; 95% CI, −1.01 to 0.24; P = .14). Moderate study heterogeneity was detected (Q = 53.92; df = 20; P < .001; I² = 62.9% [95% CI, 40.7%-76.8%]). The primary moderator analysis accounting for total physical activity volume, study design, participant health status, and allocation and/or assessment concealment did not moderate the main treatment effect. Secondary analyses demonstrated that intervention (ie, <12 weeks in duration, 3 times per week, unsupervised) and participant characteristics (ie, aged ≥13 years, with a mental illness and/or depression diagnosis) may influence the overall treatment effect.Conclusions and Relevance: Physical activity interventions may be used to reduce depressive symptoms in children and adolescents. Greater reductions in depressive symptoms were derived from participants older than 13 years and with a mental illness and/or depression diagnosis. The association with physical activity parameters such as frequency, duration, and supervision of the sessions remains unclear and needs further investigation.

More than half of older adults worldwide report sleep disturbances, of whom between 20% and 40% report insomnia.¹ Insomnia and persistent sleep disturbance impair quality of life and prospectively increase mortality and morbidity.^2,3 The US National Health Interview Survey 2017 data reported that 29.8% of individuals with sleep problems used mind-body medicine to improve sleep.⁴

Apoptosis has been implicated in the regulation of denervation‐induced muscle atrophy. However, the activation of apoptotic signal transduction during muscle denervation has not been fully elucidated. The present study examined the apoptotic responses to denervation in rat gastrocnemius muscle. Following 14 days of denervation, the extent of apoptotic DNA fragmentation as determined by a cytosolic nucleosome ELISA was increased by 100% in the gastrocnemius muscle. RT‐PCR and immunoblot analyses indicated that Bax was dramatically upregulated while Bcl‐2 was modestly increased; however, the Bax/Bcl‐2 ratio was significantly increased in denervated muscles relative to control muscles. Analyses of ELISA and immunoblots from mitochondria‐free cytosol extracts showed a significant increase in mitochondria‐associated apoptotic factors, including cytochrome c, Smac/DIABLO and apoptosis‐inducing factor (AIF). In addition to the upregulation of caspase‐3 and ‐9 mRNA, pro‐/cleaved caspase protein and proteolytic activity levels, the X‐linked inhibitor of apoptosis (XIAP) protein level was downregulated. The cleaved product of poly(ADP‐ribose) polymerase (PARP) was detected in muscle samples following denervation. Although we did not find a difference in the inhibitor of DNA binding/differentiation‐2 (Id2) and c‐Myc protein contents between the denervated and control muscles, the protein content of tumour suppressor p53 was significantly increased in both the nuclear and the cytosolic fractions with denervation. Moreover, denervation increased the protein content of HSP70, whereas the MnSOD (a mitochondrial isoform of superoxide dismutase) protein content was diminished, which indicated that denervation might have induced cellular and/or oxidative stress. Our data show that mitochondria‐associated apoptotic signalling is upregulated during muscle denervation. We interpret these findings to indicate that apoptosis has a physiologically important role in regulating denervation‐induced muscle atrophy.

Although apoptosis has been demonstrated in soleus during hindlimb suspension (HS), it is not known whether apoptosis is also involved in the loss of muscles dominated by mixed fibers. Therefore, we examined the apoptotic responses in gastrocnemius muscles of young adult and aged Fischer 344 × Brown Norway rats after 14 days of HS. The medial gastrocnemius muscle wet weight significantly decreased by 30 and 32%, and muscle wet weight normalized to the animal body weight decreased by 11 and 15% in young adult and aged animals, respectively, after HS. The extent of apoptotic DNA fragmentation increased by 119 and 61% in suspended muscles from young and aged rats, respectively. Bax mRNA increased by 73% in young muscles after HS. Bax and Bcl-2 protein levels were greater in suspended muscles relative to control muscles in both age groups. The level of cytosolic mitochondria-housed apoptotic factor cytochrome c was significantly increased in the mitochondria-free cytosol of suspended muscles from young and aged rats. In contrast, the release/accumulation of AIF, a caspase-independent apoptogenic factor, was exclusively expressed in the suspended muscles from aged rats. Our data also show that aging favors the proapoptotic signaling in skeletal muscle by altering the contents of Bax, Bcl-2, Apaf-1, AIF, caspases, XIAP, Smac/DIABLO, and cytochrome c. Furthermore, these results indicate that apoptosis occurs not only in slow-twitch soleus muscle but also in the mixed-fiber (predominately fast fibered) gastrocnemius muscle. Our data are consistent with the hypothesis that apoptotic signaling differs in young adult and aged gastrocnemius muscles during HS.