M344 promotes nonamyloidogenic amyloid precursor protein processing while normalizing Alzheimer's disease genes and improving memory.

Alzheimer's disease (AD) comprises multifactorial ailments for which current therapeutic strategies remain insufficient to broadly address the underlying pathophysiology. Epigenetic gene regulation relies upon multifactorial processes that regulate multiple gene and protein pathways, including those involved in AD. We therefore took an epigenetic approach where a single drug would simultaneously affect the expression of a number of defined AD-related targets. We show that the small-molecule histone deacetylase inhibitor M344 reduces beta-amyloid (Aß), reduces tau Ser396 phosphorylation, and decreases both ß-secretase (BACE) and APOEε4 gene expression. M344 increases the expression of AD-relevant genes: BDNF, α-secretase (ADAM10), MINT2, FE65, REST, SIRT1, BIN1, and ABCA7, among others. M344 increases sAPPα and CTFα APP metabolite production, both cleavage products of ADAM10, concordant with increased ADAM10 gene expression. M344 also increases levels of immature APP, supporting an effect on APP trafficking, concurrent with the observed increase in MINT2 and FE65, both shown to increase immature APP in the early secretory pathway. Chronic i.p. treatment of the triple transgenic (APPsw/PS1M146V/TauP301L) mice with M344, at doses as low as 3 mg/kg, significantly prevented cognitive decline evaluated by Y-maze spontaneous alternation, novel object recognition, and Barnes maze spatial memory tests. M344 displays short brain exposure, indicating that brief pulses of daily drug treatment may be sufficient for long-term efficacy. Together, these data show that M344 normalizes several disparate pathogenic pathways related to AD. M344 therefore serves as an example of how a multitargeting compound could be used to address the polygenic nature of multifactorial diseases.

Pediatric Obesity Prevention and Treatment Among Hispanics: A Systematic Review and Meta-Analysis.

INTRODUCTION: The rates of pediatric obesity in the U.S. are highest among Hispanics. There is no existing meta-analysis of the effects of obesity interventions among Hispanic youth. This systematic review and meta-analysis assesses the effects of obesity prevention and treatment interventions on Hispanic youth's weight status and lifestyle behaviors. METHODS: PubMed, PsycINFO, and Scopus were searched between January 1, 2000 and October 30, 2020. Interventions with ≥50% Hispanic youth aged 0-18 years were included. Using a weighted inverse-variance procedure, fixed-effects and random-effects models were run for an overall effect size on the basis of the Qtotal test statistic. Hedges' g was calculated for outcomes of interest between baseline and postintervention separately for studies with multiple versus single conditions. Continuous and categorical moderators were also examined. RESULTS: A total of 1,103 articles were screened, of which 117 were included in the narrative synthesis and 105 in the meta-analysis (n=49,276 youth). The overall effects for RCT/quasi-experimental studies on BMI status (g= -0.15, SE=0.03, 95% CI= -0.20, -0.10), waist circumference (g= -0.15, SE=0.10, 95% CI= -0.35, -0.05), physical activity (g=0.12, SE=0.05, 95% CI=0.03, 0.22), fruit and vegetable intake (g=0.08, SE=0.02, 95% CI=0.03, 0.12), and sugar-sweetened beverage intake (g= -0.07, SE= 0.03, 95% CI= -0.13, -0.01) were small. Intervention effects varied by participant developmental stage, SES, study setting, and lifestyle behavior target. DISCUSSION: Beyond developing more impactful interventions to address obesity among Hispanic youth, findings highlight the need for targeted policies and more easily disseminable interventions that can spread small effects across a population for maximal public health impact.

Intergenerational cardiovascular disease risks among Hispanics living in the United States.

BACKGROUND: Few studies have assessed intergenerational associations of obesity and cardiovascular disease risks from parents to their children among Hispanic Americans. OBJECTIVES: To assess intergenerational cardiovascular associations among Hispanic families. METHODS: Using baseline data from an obesity-focused efficacy trial targeting Hispanic adolescents (n = 280) and their parents, we conducted a series of logistic regression analyses to investigate the effects of parental BMI and blood pressure on adolescents' BMI and blood pressure, respectively. RESULTS: After adjusting for significant socio-demographic variables and adolescents' lifestyle behaviours, adolescents were more than twice as likely to be in the severely obese versus overweight range when their parents had obesity (vs. non-obese; OR = 2.55, 95% CI = 1.20, 5.39) and more than twice as likely to be in the severely obese versus obese weight range (OR = 2.44, 95% CI = 1.22, 4.87) when their parents had obesity. When compared to those with normal blood pressure, adolescents who had parents with elevated blood pressure/hypertension were more than twice as likely to have elevated blood pressure (OR = 2.05, 95% CI = 1.04, 4.00) or be classified as hypertensive stage 1/2 (OR = 2.81, 95% CI = 1.31, 6.01). CONCLUSIONS: Both severe obesity and elevated blood pressure are highly associated among Hispanic parent-child dyads. Findings underscore the potential benefits of intervening with the family system.