Hypothalamic histamine H1 receptor-AMPK signaling time-dependently mediates olanzapine-induced hyperphagia and weight gain in female rats

Although second-generation antipsychotics induce severe weight gain and obesity, there is a lack of detailed knowledge about the progressive development of antipsychotic-induced obesity. This study examined the hypothalamic histamine H1 receptor and AMP-activated protein kinase (H1R-AMPK) signaling at three distinctive stages of olanzapine-induced weight gain (day 1-12: early acceleration, day 13-28: middle new equilibrium, and day 29-36: late heavy weight maintenance). At the early acceleration stage, the rats were hyperphagic with an underlying mechanism of olanzapine-increased H1R mRNA expression and AMPK phosphorylation (pAMPK), in which pAMPK levels positively correlated with H1R mRNA expression and food intake. At the middle stage, when the rats were no longer hyperphagic, the changes in H1R-AMPK signaling vanished. At the late stage, olanzapine increased H1R mRNA expression but decreased pAMPK which were positively and negatively correlated with weight gain, respectively. These data suggest a time-dependent change of H1R-AMPK signaling, where olanzapine activates AMPK by blocking the H1Rs and causing hyperphagia in the acute phase. The chronic blockade of H1R may contribute to the late stage of olanzapine-induced heavy weight maintenance. However, pAMPK was no longer elevated and actually decreased. This indicates that AMPK acts as an energy sensor and negatively responds to the positive energy balance induced by olanzapine. Furthermore, we showed that an H1R agonist, 2-(3-trifluoromethylphenyl) histamine, can significantly inhibit olanzapine-induced hyperphagia and AMPK activation in the mediobasal hypothalamus in a dose dependent manner. Therefore, lowering H1R-AMPK signaling is an effective treatment for the olanzapine-induced hyperphagia associated with the development of obesity

Olanzapine reduced brown adipose tissue thermogenesis and locomotor activity in female rats

Excessive weight gain has been identified as a serious metabolic side-effect of second-generation antipsychotics (SGAs), including olanzapine. While hyperphagia has been suggested to be the main contributor for this side-effect in the short term, reduced energy expenditure, in particular thermogenesis and locomotor activity, has been considered to contribute to the maintenance of heavy weight under long-term SGA treatments. Recent studies have identified metabolically active brown adipose tissues (BAT) in adult humans, suggesting potential clinical significance for the involvement of BAT thermogenesis in SGA-induced weight gain. However, to date there has been little research elucidating the central neuronal pathways affecting BAT thermogenesis or the morphological changes of the BAT. The present study aimed to investigate the role of BAT thermogenesis and locomotor activity in olanzapine-induced weight gain during the prolonged time courses of olanzapine treatment in an established female rat model. Although short- to mid-term olanzapine treatment had no effect on BAT temperature, we observed that long-term olanzapine treatment (from day 18 to 34) induced a significant reduction in BAT temperature, with an acute effect being observed between 45 and 150 min post-treatment in the long-term cohort. Additionally, in the long-term olanzapine group, the reduced BAT temperature was accompanied by decreased UCP1 and PGC-1α expressions in the BAT. Moreover, TH mRNA expressions in both hypothalamus and brainstem were also downregulated after mid- to long-term olanzapine treatment. Further, olanzapine led to reduced percentage of brown adipocytes in BAT during mid- to long-term treatments. Finally, locomotor activity was reduced throughout the three treatment cohorts. In summary, our results suggest that the reduction of BAT thermogenesis plays an important role during the long-term of olanzapine-induced weight gain, which was accompanied by an earlier onset of BAT adipocyte morphological changes and biochemical changes in the hypothalamus and the brainstem, while locomotor activity contributes to the entire olanzapine treatment courses

Hypothalamic ghrelin signalling mediates olanzapine-induced hyperphagia and weight gain in female rats

Excessive weight gain is a major metabolic side effect of second-generation antipsychotics (SGAs) in the treatment of schizophrenia. Ghrelin is an orexigenic hormone secreted mainly from the stomach, which can induce weight gain and hyperphagia through regulating neuropeptides at the hypothalamus. Accumulating evidence implicates a relationship between ghrelin signalling and SGA-induced hyperphagia and weight gain. We report that olanzapine (a SGA with high weight gain liability) potently and time-dependently up-regulate ghrelin and ghrelin signalling, leading to hyperphagia and weight gain in female Sprague-Dawley rats, an action reversed by i.c.v. injection of a ghrelin receptor (GHS-R1a) antagonist. These findings indicate a crucial role of ghrelin signalling in hyperphagia induced by olanzapine, supporting the notion that GHS-R1a antagonist may be useful for pharmacological treatment of SGA-induced weight gain resulted from hyperphagia

PSANet: Pyramid Splitting and Aggregation Network for 3D Object Detection in Point Cloud

3D object detection in LiDAR point clouds has been extensively used in autonomous driving, intelligent robotics, and augmented reality. Although the one-stage 3D detector has satisfactory training and inference speed, there are still some performance problems due to insufficient utilization of bird’s eye view (BEV) information. In this paper, a new backbone network is proposed to complete the cross-layer fusion of multi-scale BEV feature maps, which makes full use of various information for detection. Specifically, our proposed backbone network can be divided into a coarse branch and a fine branch. In the coarse branch, we use the pyramidal feature hierarchy (PFH) to generate multi-scale BEV feature maps, which retain the advantages of different levels and serves as the input of the fine branch. In the fine branch, our proposed pyramid splitting and aggregation (PSA) module deeply integrates different levels of multi-scale feature maps, thereby improving the expressive ability of the final features. Extensive experiments on the challenging KITTI-3D benchmark show that our method has better performance in both 3D and BEV object detection compared with some previous state-of-the-art methods. Experimental results with average precision (AP) prove the effectiveness of our network

Monooxygenase, a novel beta-cypermethrin degrading enzyme from Streptomyces sp.

The widely used insecticide beta-cypermethrin has become a public concern because of its environmental contamination and toxic effects on mammals. In this study, a novel beta-cypermethrin degrading enzyme designated as CMO was purified to apparent homogeneity from a Streptomyces sp. isolate capable of utilizing beta-cypermethrin as a growth substrate. The native enzyme showed a monomeric structure with a molecular mass of 41 kDa and pI of 5.4. The enzyme exhibited the maximal activity at pH 7.5 and 30°C. It was fairly stable in the pH range from 6.5-8.5 and at temperatures below 10°C. The enzyme activity was significantly stimulated by Fe(2+), but strongly inhibited by Ag(+), Al(3+), and Cu(2+). The enzyme catalyzed the degradation of beta-cypermethrin to form five products via hydroxylation and diaryl cleavage. A novel beta-cypermethrin detoxification pathway was proposed based on analysis of these products. The purified enzyme was identified as a monooxygenase by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry analysis (MALDI-TOF-MS) and N-terminal protein sequencing. Given that all the characterized pyrethroid-degrading enzymes are the members of hydrolase family, CMO represents the first pyrethroid-degrading monooxygenase identified from environmental microorganisms. Taken together, our findings depict a novel pyrethroid degradation mechanism and indicate that the purified enzyme may be a promising candidate for detoxification of beta-cypermethrin and environmental protection

Microstructural Evolution of Carbon Nanotube Fibers: Deformation and Strength Mechanism

A comprehensive investigation of the mechanical behavior and microstructural evolution of carbon nanotube (CNT) continuous fibers under twisting and tension is conducted using coarse-grained molecular dynamics simulations. The tensile strength of CNT fibers with random CNT stacking is found to be higher than that of fibers with regular CNT stacking. The factor dominating the mechanical response of CNT fibers is identified as individual CNT stretching. A simplified twisted CNT fiber model is studied to illustrate the structural evolution mechanisms of CNT fibers under tension. Moreover, it is demonstrated that CNT fibers can be reinforced by enhancing intertube interactions. This study would be helpful not only in the general understanding of the nano- and micro-scale factors affecting CNT fibers\u27 mechanical behavior, but also in the optimal design of CNT fibers\u27 architecture and performance

Extraction, Physicochemical Properties, Anti-Aging, and Antioxidant Activities of Polysaccharides from Industrial Hemp Residues

A large amount of hemp polysaccharides remain in industrial hemp residues (IHR) after cannabidiol extraction, resulting in the waste of resources. Therefore, the systematic study of hemp polysaccharides is beneficial to the development of IHR in the future. In this study, the extraction of industrial hemp residues polysaccharide (IHRPs) was optimized by single-factor experiment and orthogonal experimental design. The optimum heating extraction conditions were extraction temperature 98 degrees C, solid-liquid ratio 1:10, extraction time 1 h, number of successive extractions 2, and pH at 4. The extraction ratio and the polysaccharide content were 20.12 +/- 0.55% and 12.35 +/- 0.26% at the conditions, respectively. Besides, the best alcohol precipitation conditions were pumping with 2 L/h, stirring continuously, and ice-water bath for 4 h. The crude IHRPs was further purified by column chromatography and the polysaccharide/protein contents of purified IHRPs were 34.44% and 1.61%. IHRPs was mainly made up of ten monosaccharides and some non-sugar components including organic acids, flavonoids, steroids, and glycoside. The FT-IR demonstrated the polysaccharide skeleton of IHRPs. Moreover, the DPPH and ABTS scavenging rate of IHRPs were 76.00% and 99.05% at the concentrations of 1 mg/mL. IHRPs could promote the epidermal cells proliferation and healing of cell scratches. Meanwhile, IHRPs could promoted the expression of anti-aging-related genes. Overall, IHRPs could be a desirable natural source of antioxidants and anti-aging products in many aspects

Extraction, Physicochemical Properties, Anti-Aging, and Antioxidant Activities of Polysaccharides from Industrial Hemp Residues

A large amount of hemp polysaccharides remain in industrial hemp residues (IHR) after cannabidiol extraction, resulting in the waste of resources. Therefore, the systematic study of hemp polysaccharides is beneficial to the development of IHR in the future. In this study, the extraction of industrial hemp residues polysaccharide (IHRPs) was optimized by single-factor experiment and orthogonal experimental design. The optimum heating extraction conditions were extraction temperature 98 degrees C, solid-liquid ratio 1:10, extraction time 1 h, number of successive extractions 2, and pH at 4. The extraction ratio and the polysaccharide content were 20.12 +/- 0.55% and 12.35 +/- 0.26% at the conditions, respectively. Besides, the best alcohol precipitation conditions were pumping with 2 L/h, stirring continuously, and ice-water bath for 4 h. The crude IHRPs was further purified by column chromatography and the polysaccharide/protein contents of purified IHRPs were 34.44% and 1.61%. IHRPs was mainly made up of ten monosaccharides and some non-sugar components including organic acids, flavonoids, steroids, and glycoside. The FT-IR demonstrated the polysaccharide skeleton of IHRPs. Moreover, the DPPH and ABTS scavenging rate of IHRPs were 76.00% and 99.05% at the concentrations of 1 mg/mL. IHRPs could promote the epidermal cells proliferation and healing of cell scratches. Meanwhile, IHRPs could promoted the expression of anti-aging-related genes. Overall, IHRPs could be a desirable natural source of antioxidants and anti-aging products in many aspects