Hypothalamic NPFFR2 attenuates central insulin signaling and its knockout diminishes metabolic dysfunction in mouse models of diabetes mellitus.

BACKGROUND: The hypothalamus is a crucial brain region that mediates the effects of insulin and leptin signals on peripheral metabolic functions. Previous research has shown that insulin signals in the hypothalamus act via multiple neuronal circuits and anabolic/catabolic pathways that converge on the vagus nerve and sympathetic fibers to coordinate energy metabolism in peripheral organs. Additionally, neuropeptide FF (NPFF) has been identified as a regulator of feeding behaviors and energy homeostasis in the hypothalamus, but the mechanisms underlying its involvement in metabolic control remain unclear. This study aims to explore the underlying mechanisms of NPFF in modulating metabolic disorders. METHODS: In this study, we investigated the physiological role of NPFF in insulin-related energy homeostasis and metabolic health. First, we evaluated the effects of NPFF and its receptors on central insulin signaling using mouse hypothalamic cell lines and Npffr2-overexpressing mice. To further explore the effects of NPFFR2 on insulin-related metabolic disorders, such as diabetes mellitus, we used Npffr2-deleted mice in combination with the streptozotocin (STZ)-induced type 1 diabetes and high-fat diet/STZ-induced type 2 diabetic mouse models. The impacts of central NPFFR2 were demonstrated specifically through Npffr2 overexpression in the hypothalamic arcuate nucleus, which subsequently induced type 2 diabetes. RESULTS: We found that stimulating NPFFR2 in the hypothalamus blocked hypothalamic insulin activity. Npffr2 deletion improved central and peripheral metabolic symptoms in both mouse models of diabetes mellitus, exerting effects on central and systemic insulin resistance, feeding behaviors, glucose and insulin intolerance, lipid metabolism, liver steatosis, and inflammation of white adipose tissues. The overexpression of ARC Npffr2 augmented the metabolic dysregulation in the mouse model of type 2 diabetes. CONCLUSIONS: Our findings demonstrate that hypothalamic NPFFR2 negatively regulates insulin signaling in the central nervous system and plays an important role in maintaining systemic metabolic health, thereby providing valuable insights for potential clinical interventions targeting these health challenges.

What Could Highly Engaged Workers Gain From Mental Health Promotion Programs?: An Exploratory Analysis of Secondary Outcomes of Brief Daily Workplace Well-being Programs.

OBJECTIVE: The current study aims to examine the effects of mental health programs on well-being among highly engaged workers. METHODS: Participants were randomly allocated to body-mind-spiritual or peer support program. Of the whole sample, we examined participants' work engagement and positive affect from the highest quarter and the lowest quarter of work engagement at baseline. Measures were taken at baseline and 1-month intervals during 3-month programs and 3-month follow-up. RESULTS: The programs had decreasing effects on work engagement in the HWE subgroup. There is an increasing trend of positive affect on the HWE group only in the body-mind-spiritual program. The trajectories of work engagement in the HWE group moved toward a moderate level. CONCLUSION: Our results suggest that the work engagement's decrease in the HWE group could be a sign of recovery and relaxation.

Study protocol of guided mobile-based perinatal mindfulness intervention (GMBPMI) - a randomized controlled trial.

BACKGROUND: Psychological distress is a common occurrence among women during the perinatal period. Maternal psychological distress (MPS) can also have a negative influence on neonatal outcomes such as infant health, child development or mother-child interaction. Hence, interventions to improve mental wellbeing during this period are vital. Mindfulness based intervention (MBI) has been found to be effective in reducing psychological distress. Delivery of MBI via the internet, making it accessible and inexpensive, is showing a promising positive effect in reducing psychological distress. A randomized control trial with sufficient power is required to confirm its positive effect among pregnant women. The positive effects of MBI have been found to be associated with heart rate variability (HRV) biofeedback; however, the efficacy of MBI on HRV has been rarely studied among pregnant women. Also, the potential association of HRV with MBI and psychological wellbeing needs further examination. This research aims to test the effectiveness of guided mobile-based perinatal mindfulness intervention (GMBPMI) among pregnant women experiencing psychological distress during the pre- and post-natal period, as well as examining the efficacy of GMBPMI on HRV. METHOD: This study is a randomized controlled trial that follows a parallel design. Consenting pregnant women in their second trimester (between 12th and 20th week gestation) will be randomly assigned to an intervention group (GMBPMI) or a control group (psychoeducation). The intended sample size is 198, with 99 participants in each group. Three levels of outcomes will be measured at baseline, post intervention in both the intervention and control groups, and at 36-week gestation and five-week postpartum. The primary outcomes include maternal psychological stress, mindfulness and positive appraisal HRV. Secondary outcomes are psychological and physical wellbeing. Tertiary outcomes include obstetric and neonatal outcomes, and social support. Analyses will follow an intention-to-treat method and repeated measures MANOVA will be conducted to compare changes in primary and secondary outcomes. A series of mixed-effects models will be fitted to assess the mediation effects. DISCUSSION: This trial expects to increase understanding of GMBPMI on HRV and psychological wellbeing for pregnant women, with extended support in both pre-and post-natal periods. The study could also potentially provide evidence for delivery of cost-effective and accessible services to pregnant women. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04876014, registered on 30 March 2021. Protocol Version 1.0., 10 May 2021.

[Study on pharmacokinetics of geniposide in mice administrated by xingnaojing microemulsion and mPEG2000-PLA modified xingnaojing microemulsion].

An HPLC method for the determination of geniposide concentration in mouse plasma was developed and the pharmacokinetics after intranasal administration of Xingnaojing microemulsion (XNJ-M) and mPEG2000-PLA modified Xingnaojing microemulsion (XNJ-MM) were investigated. Eighty mice were treated by XNJ-M and XNJ-MM nasally. The plasma samples were collected at different times and the drug in samples was detected by HPLC. The pharmacokinetic parameters were calculated by the software of Kinetica. The pharmacokinetic parameters of geniposide of XNJ-M were C(max) (4.36 +/- 2.69) mg x L(-1), t(max) 1 min, MRT (29.73 +/- 4.54) min, AUC (53.63 +/- 14.03) mg x L(-1) x min. The pharmacokinetic parameters of geniposide of XNJ-MM were C(max) (9.75 +/- 4.14) mg x L(-1), t(max) 1 min, MRT(22.34 +/- 2.90) min, AUC (131.87 +/- 40.13) mg x L(-1) x min. Geniposide can be absorbed into blood in a higher degree after intranasal administration with XNJ-MM compared to XNJ-M, which maybe caused by its less irritating and more absorption.

[Comparative study on rat in situ nasal absorption of geniposide of Xingnaojing nasal drop and Xingnaojing microemulsion].

Xingnaojing (XNJ) is an effective clinical drug used to treat acute stroke. Compared with injection administration, its nasal administration has better brain targeting. Therefore, through nasal administration, XNJ microemulsion could help solve the drug load of compound components of different polarities contained in large-dose and high-concentration traditional Chinese medicines, and reduce irritation to nasal mucosa In this study, the modified volume correction method and the improved rat in situ nasal perfusion model were adopted to compare the nasal absorption of geniposide contained in different XNJ preparations. The results showed that the constant absorption rate of geniposide (GE) in XNJ-D was (2.95 +/- 0.25) x 10(-3) min(-1), whereas the constant absorption rate of GE in XNJ-M was (2.16 +/- 0.21) x 10(-3) min(-1). This indicated that the rat nasal absorption of GE in different XNJ preparations complied with the first-order process and could be considered as passive absorption. GE in XNJ-D was absorbed faster than that in XNJ-M, which provided basis for the development of nasal preparations of XNJ.

[Study on tissue distribution of borneol in mice by intravenous and intranasal administrations].

OBJECTIVE: To develop a GC-FID method to determine borneol's concentration in mouse tissues, and to investigate the tissue distribution after intravenous and intranasal administrations of borneol. METHOD: Mouse brains, hearts, livers, spleens, lungs and kidneys were collected at 1, 3, 5, 10, 20, 30, 60, 90, 120 min after administration of borneol with the dose of 30.0 mg x kg(-1). The drug in tissues was extracted with ethyl acetate, and borneol's concentration detected by GC, with octadecane as the internal standard. RESULT: The calibration curve showed a good linear relationship. Extraction recoveries, inter-day and intra-day precisions and stability were in conformity with the analytical requirements of biological samples. Borneol was mainly distributed in most tissues, more in heart, brain and kidney, and less in liver, spleen and lung. CONCLUSION: The established GC-FID method is applicable for content determination of borneol in tissues. After intravenous and intranasal administrations in mice, borneol is mainly distributed in abundant blood-supply tissues. After intranasal administration, brain tissues showed the highest target coefficient and target effectiveness.

Functional characterizations of cocaine- and amphetamine-regulated transcript mRNA expression in rat hypothalamus.

Anatomical relationships of hypothalamic cocaine- and amphetamine-regulated transcript (CART) with other hypothalamic neuropeptides were examined by using in situ hybridization histochemistry and immunohistochemistry. CART mRNA was found in various regions in rat hypothalamus, including the periventricular nucleus, paraventricular nucleus, dorsomedial nucleus, perifornical regions, lateral nucleus, and the arcuate nucleus. In the paraventricular nucleus, CART mRNA is colocalized with vasopressin and corticotropin-releasing factor-containing neurons. Moreover, either fasting or diabetes attenuates CART mRNA expression in the hypothalamus, demonstrating that CART mRNA regulation is related to the fuel availability and peripheral hormonal status. Our findings suggest that the presence of CART mRNA in specific cell groups of the hypothalamus plays a role in hypothalamic regulation of neuroendocrine functions.