Whereas urine and blood are typically targeted in clinical research, saliva represents an interesting alternative as its intrinsic metabolome is chemically diverse and reflective for various biological processes. Moreover, saliva collection is easy and non-invasive, which is especially valuable for cohorts in which sample collection is challenging, e.g. infants and children. With this rationale, we established a validated UHPLC-HRMS method for salivary metabolic profiling and fingerprinting. Hereby, 450 L of saliva was centrifuged and passed over a 0.45-m polyamide membrane filter, after which the extract was subjected to chromatographic analysis (HSS T3 column) and Q-Exactive TM Orbitrap-MS. For the majority of the profiled metabolites, good linearity (R 2 ≥ 0.99) and precision (coefficient of variance ≤ 15%) was achieved. The fingerprinting performance was evaluated based on the complete metabolome (11,385 components), whereby 76.8% was found compliant with the criteria for precision (coefficient of variance ≤ 30%) and 82.7% with linearity (R 2 ≥ 0.99). In addition, the method was proven fit-for-purpose for a cohort of 140 adolescents (6-16 years, stratified according to weight), yielding relevant profiles (45 obesity-related metabolites) and discriminative fingerprints (Q 2 of 0.784 for supervised discriminant analysis). Alternatively, LA-REIMS was established for rapid fingerprinting of saliva, thereby using a Nd:YAG laser and Xevo G2-XS QToF-MS. With an acquisition time of 0.5 min per sample, LA-REIMS offers unique opportunities for point-of-care applications. In conclusion, this work presents a platform of UHPLC-HRMS and LA-REIMS, complementing each other to perform salivary metabolomics.
The phytoestrogen resveratrol has been reported to possess cancer chemo-preventive activity on the basis of its effects on tumor cell lines and xenograft or carcinogen-inducible in vivo models. Here we investigated the effects of resveratrol on spontaneous mammary carcinogenesis using Δ16HER2 mice as HER2+/ERα+ breast cancer model. Instead of inhibiting tumor growth, resveratrol treatment (0.0001% in drinking water; daily intake of 4μg/mouse) shortened tumor latency and enhanced tumor multiplicity in Δ16HER2 mice. This in vivo tumor-promoting effect of resveratrol was associated with up-regulation of Δ16HER2 and down-regulation of ERα protein levels and was recapitulated in vitro by murine (CAM6) and human (BT474) tumor cell lines. Our results demonstrate that resveratrol, acting as a proteasome inhibitor, leads to Δ16HER2 accumulation which favors the formation of Δ16HER2/HER3 heterodimers. The consequential activation of downstream mTORC1/p70S6K/4EBP1 pathway triggers cancer growth and proliferation. This study provides evidence that resveratrol mechanism of action (and hence its effects) depends on the intrinsic molecular properties of the cancer model under investigation, exerting a tumor-promoting effect in luminal B breast cancer subtype models.
The persistent coexistence of stress and paediatric obesity involves interrelated psychophysiological mechanisms, which are believed to function as a vicious circle. Here, a key mechanistic role is assumed for stress responsiveness and eating behaviour. After a stress induction by the Trier Social Stress Test in youngsters (n = 137, 50.4% boys, 6–18 years), specifically those high in chronic stress level and overweight (partial η2 = 0.03–0.07) exhibited increased stress vulnerability (stronger relative salivary cortisol reactivity and weaker happiness recovery) and higher fat/sweet snack intake, compared to the normal-weight and low-stress reference group. Stress responsiveness seems to stimulate unhealthy and emotional eating, i.e., strong cortisol reactivity was linked to higher fat/sweet snack intake (β = 0.22) and weak autonomic system recovery was linked to high total and fat/sweet snack intake (β = 0.2–0.3). Additionally, stress responsiveness acted as a moderator. As a result, stress responsiveness and emotional eating might be targets to prevent stress-induced overweight.
Objective This study explored the role of emotion regulation (ER) as a moderator in the stressor–adjustment outcome relationship while identifying the relevant stressors. Methods In 214 adolescents (10–18 years; 51.4% boys), stressors (parent and peer relations, negative events), psychological outcomes (adolescent perceived stress, psychopathology symptoms, negative affect), and biological measures related to the stress response (hair cortisol [HC], heart rate variability [HRV]) as well as ER strategies—maladaptive (MalER), adaptive (AdER), and their ratio (Mal/AdER)—were measured and analyzed via linear regression, adjusted for age, sex, and socioeconomic status. Results Parental rejection and bullying were the stressors with the strongest association with psychological outcomes (β range = |0.217–0.352|, p < .05). In addition, parental rejection was associated with HC (β = 0.242, p = .035), whereas none of the stressors were associated with HRV. MalER was linked to all, and AdER to most psychological outcomes (β range = |0.21–0.49|, p < .05). MalER, but not AdER, was associated with HC (β = 0.25, p = .009), whereas none of the ER strategy types were associated with HRV. Moreover, several associations between stressors and psychological outcomes were moderated by MalER and Mal/AdER, whereas AdER’s role as a moderator was not confirmed. Conclusions The study confirmed that adolescents’ stressors are associated with both psychological and physiological outcomes and moderated by MalER or Mal/AdER. The lack of moderation by AdER directs toward the maladaptive shift theory. Investigations through a longitudinal, rather than a cross-sectional design, could further elucidate the current observations. Moreover, training in how to use ER effectively has a potential of increasing adolescents’ stress resilience.
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