Early childhood (1-5 years) obesity prevention: A systematic review of family-based multicomponent behavioral interventions.

INTRODUCTION: Globally 38.9 million children under age 5 have overweight or obesity, leading to type 2 diabetes, cardiovascular complications, depression, and poor educational outcomes. Obesity is difficult to reverse and lifestyle behaviors (healthy or unhealthy) can persist from 1.5 years of age. Targeting caregivers to help address modifiable behaviors may offer a viable solution. OBJECTIVE: Evaluate the impact of multicomponent family interventions on weight-based outcomes in early childhood and explore related secondary behavior outcomes. METHODS: Four databases were searched (1/2017-6/2022) for randomized controlled trials (RCTs) of obesity-prevention interventions for children (1-5 years). Eligible studies included an objectively measured weight-based outcome, family interventions targeting the caregiver or family, and interventions including at least two behavioral components of nutrition, physical activity, or sleep. RESULTS: Eleven interventions were identified consisting of four delivery modes: self-guided (n = 3), face-to-face group instruction (n = 3), face-to-face home visits (n = 2), and multiple levels of influence (n = 3). The reviewed studies reported almost no significant effects on child weight-based outcomes. Only two studies (one was an underpowered pilot study) resulted in significant positive child weight-management outcomes. Seven of the interventions significantly improved children's dietary intake. CONCLUSION: Except for one, the reviewed studies reported that family based interventions had no significant effects on child weight-based outcomes. Future studies of this type should include measurements of age and sex-based body mass index (BMI) and trajectories, and also examine other important benefits to the children and families.

Inhibition of the Na+/K+-ATPase by cardiac glycosides suppresses expression of the IDO1 immune checkpoint in cancer cells by reducing STAT1 activation.

Despite extensive basic and clinical research on immune checkpoint regulatory pathways, little is known about the effects of the ionic tumor microenvironment on immune checkpoint expression and function. Here we describe a mechanistic link between Na+/K+-ATPase (NKA) inhibition and activity of the immune checkpoint protein indoleamine-pyrrole 2',3'-dioxygenase 1 (IDO1). We found that IDO1 was necessary and sufficient for production of kynurenine, a downstream tryptophan metabolite, in cancer cells. We developed a spectrophotometric assay to screen a library of 31 model ion transport-targeting compounds for potential effects on IDO1 function in A549 lung and MDA-MB-231 breast cancer cells. This revealed that the cardiac glycosides ouabain and digoxin inhibited kynurenine production at concentrations that did not affect cell survival. NKA inhibition by ouabain and digoxin resulted in increased intracellular Na+ levels and downregulation of IDO1 mRNA and protein levels, which was consistent with the reduction in kynurenine levels. Knockdown of ATP1A1, the ɑ1 subunit of the NKA and target of cardiac glycosides, increased Na+ levels to a lesser extent than cardiac glycoside treatment and did not affect IDO1 expression. However, ATP1A1 knockdown significantly enhanced the effect of cardiac glycosides on IDO1 expression and kynurenine production. Mechanistically, we show that cardiac glycoside treatment resulted in curtailing the length of phosphorylation-mediated stabilization of STAT1, a transcriptional regulator of IDO1 expression, an effect enhanced by ATP1A1 knockdown. Our findings reveal cross talk between ionic modulation via cardiac glycosides and immune checkpoint protein expression in cancer cells with broad mechanistic and clinical implications.