Olanzapine attenuates 5-HT2cR and GHSR1a interaction to increase orexigenic hypothalamic NPY: Implications for neuronal molecular mechanism of metabolic side effects of antipsychotics.

The main cause of second-generation antipsychotic (SGA)-induced obesity is considered due to the antagonism of serotonin 2c receptors (5-HT2cR) and activation of ghrelin receptor type 1a (GHSR1a) signalling. It is reported that 5-HT2cR interacted with GHSR1a, however it is unknown whether one of the SGA olanzapine alters the 5-HT2cR/GHSR1a interaction, affecting orexigenic neuropeptide signalling in the hypothalamus. We found that olanzapine treatment increased average energy intake and body weight gain in mice; olanzapine treatment also increased orexigenic neuropeptide (NPY) and GHSR1a signaling molecules, pAMPK, UCP2, FOXO1 and pCREB levels in the hypothalamus. By using confocal fluorescence resonance energy transfer (FRET) technology, we found that 5-HT2cR interacted/dimerised with the GHSR1a in the hypothalamic neurons. As 5-HT2cR antagonist, both olanzapine and S242084 decreased the interaction between 5-HT2cR and GHSR1a and activated GHSR1a signaling. The 5-HT2cR agonist lorcaserin counteracted olanzapine-induced attenuation of interaction between 5-HT2cR and GHSR1a and inhibited activation of GHSR1a signalling and NPY production. These findings suggest that 5-HT2cR antagonistic effect of olanzapine in inhibition of the interaction of 5-HT2cR and GHSR1a, activation GHSR1a downstream signaling and increasing hypothalamic NPY, which may be the important neuronal molecular mechanism underlying olanzapine-induced obesity and target for prevention metabolic side effects of antipsychotic management in psychiatric disorders.

Investigating the Therapeutic Potential of Plants and Plant-Based Medicines: Relevance to Antioxidant and Neuroprotective Effects.

Oxidative stress is a common characteristic of psychiatric, neurological, and neurodegenerative disorders. Therefore, compounds that are neuroprotective and reduce oxidative stress may be of interest as novel therapeutics. Phenolic, flavonoid and anthocyanin content, ORAC and DPPH free radical scavenging, and Cu2+ and Fe2+ chelating capacities were examined in variations (fresh/capsule) of Queen Garnet plum (QGP, Prunus salicina), black pepper (Piper nigrum) clove (Syzygium aromaticum), elderberry (Sambucus nigra), lemon balm (Melissa officinalis) and sage (Salvia officinalis), plus two blends (Astralagus membranaceus-lemon balm-rich, WC and R8). The ability of samples to prevent and treat H2O2-induced oxidative stress in SH-SY5Y cells was investigated. Pre-treatment with WC, elderberry, QGP, and clove prevented the oxidative stress-induced reduction in cell viability, demonstrating a neuroprotective effect. Elderberry increased cell viability following oxidative stress induction, demonstrating treatment effects. Clove had the highest phenolic and flavonoid content, DPPH, and Cu2+ chelating capacities, whereas QGP and elderberry were highest in anthocyanins. Black pepper had the highest ORAC and Fe2+ chelating capacity. These findings demonstrate that plant extracts can prevent and treat oxidative stress-induced apoptosis of neuron-like cells in vitro. Further research into phytochemicals as novel therapeutics for oxidative stress in the brain is needed.

Brief literature review and comprehensive bioinformatics analytics unravel the potential mechanism of curcumin in the treatment of periodontitis.

OBJECTIVE: Periodontitis is a chronic oral disease prevalent worldwide, and natural products are recommended as adjunctive therapy due to their minor side effects. Curcumin, a widely used ancient compound, has been reported to possess therapeutic effects in periodontitis. However, the exact mechanism underlying its activity remains unclear. In this context, the present study aimed to conduct computational simulations to uncover the potential mechanism of action of Curcumin in the treatment of periodontitis. MATERIALS AND METHODS: Single-cell analysis was conducted using a dataset (i.e., GSE164241) curated from the Gene Expression Omnibus (GEO) database through an R package "Seurat package." Bulk RNA sequencing data were curated from GSE10334 and GSE16134 and processed by R package "Limma." Then, the marker genes in the single-cell transcriptome and differentially expressed genes (DEGs) in the bulk transcriptome were integrated. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were also carried out to reveal their functionalities. Key targets were mined from their protein-protein interaction (PPI) network topologically. Afterward, molecular docking was performed. The top-ranked pose was subjected to molecular dynamics simulations to investigate the stability of the docking result. RESULTS: FOS, CXCL1, CXCL8, and IL1B, were filtered after a series of selected processes. The results of molecular modeling suggested that except for IL1B, the Vena Scores of the rest exceeded -5 kcal/mol. Furthermore, the molecular dynamic simulation indicated that the binding of the CXCL8-Curcumin complex was stable over the entire 100 ns simulation. CONCLUSION: The present study unlocked the binding modes of CXCL1, FOS, and CXCL8 with the Curcumin molecule, which were relatively stable, especially for CXCL8, hindering its promising potential to serve as the critical targets of Curcumin in periodontitis treatment.

Cannabidiol as a Treatment for Neurobiological, Behavioral, and Psychological Symptoms in Early-Stage Dementia: A Double-Blind, Placebo-Controlled Clinical Trial Protocol.

Rationale: The slowing of disease progression in dementia in the early stages of diagnosis is paramount to improving the quality of life for those diagnosed and their support networks. Accumulating evidence suggests that CBD, a constituent of Cannabis sativa, is associated with neuroprotective, neuroendocrine, and psychotherapeutic effects, suggesting that it may be beneficial to dementia treatment. However, no published human study to date has examined this possibility. This trial aims to determine whether daily treatment with CBD over a 12-week period is associated with improved neurobiological, behavioral, and psychological outcomes in individuals living with early-stage dementia. Methods: Sixty participants with early-stage dementia will be recruited for a randomized, double-blind, placebo-controlled clinical trial. Participants will be randomized into either 99.9% pure CBD or placebo treatment conditions and administered two capsules per day for 12 weeks. Participants will commence a 200 mg/day dose for 2 weeks before escalating to 300 mg/day for the remaining 10 weeks. Neuroimaging and blood-based neuroendocrine profiles will be assessed at baseline and post-treatment. Psychological and behavioral symptoms will be assessed at baseline, 6 weeks, and post-treatment. Monitoring of health and side-effects will be conducted through weekly home visits. Discussion: This study is among the first to investigate the effects of isolated CBD in improving neuroanatomical and neuroendocrine changes, alongside psychological symptoms, during the early stages of dementia diagnosis. The outcomes of this trial have the capacity to inform a potential novel and accessible treatment approach for individuals living with early-stage dementia, and in turn, improve quality of life, prognoses, and treatment outcomes. Trial Registration: This trial has been registered with the Therapeutic Goods Administration (CT-2020-CTN-03849-1v2) and the Australian and New Zealand Clinical Trials Registry (ACTRN12621001364864).

Butyrate Attenuates Hepatic Steatosis Induced by a High-Fat and Fiber-Deficient Diet via the Hepatic GPR41/43-CaMKII/HDAC1-CREB Pathway.

SCOPE: Hepatic steatosis is a major health issue that can be attenuated by a healthy diet. This study investigates the effects and molecular mechanisms of butyrate, a dietary fiber metabolite of gut microbiota, on lipid metabolism in hepatocytes. METHODS AND RESULTS: This study examines the effects of butyrate (0-8 mM) on lipid metabolism in primary hepatocytes. The results show that butyrate (2 mM) consistently inhibits lipogenic genes and activates lipid oxidation-related gene expression in hepatocytes. Furthermore, butyrate modulates lipid metabolism genes, reduces fat droplet accumulation, and activates the calcium/calmodulin-dependent protein kinase II (CaMKII)/histone deacetylase 1 (HDAC1)-cyclic adenosine monophosphate response element binding protein (CREB) signaling pathway in the primary hepatocytes and liver of wild-type (WT) mice, but not in G-protein-coupled receptor 41 (GPR41) knockout and 43 (GPR43) knockout mice. This suggests that butyrate regulated hepatic lipid metabolism requires GPR41 and GPR43. Finally, the study finds that dietary butyrate supplementation (5%) ameliorates hepatic steatosis and abnormal lipid metabolism in the liver of mice fed a high-fat and fiber-deficient diet for 15 weeks. CONCLUSION: This work reveals that butyrate improves hepatic lipid metabolism through the GPR41/43-CaMKII/HDAC1-CREB pathway, providing support for consideration of butyrate as a dietary supplement to prevent the progression of NAFLD induced by the Western-style diet.

The High Risk Factors and Preventive Measures of Percutaneous Nephrolithotomy under the Guidance of B-Ultrasound in the Treatment of Postoperative Renal Calculi.

Objective: The aim of this study is to explore and analyze the high risk factors and preventive measures of percutaneous nephrolithotomy under the guidance of B-ultrasound in the treatment of postoperative renal calculi. Methods: The clinical data of 220 patients with renal calculi admitted to our hospital from 2018 to October 2021 were retrospectively analyzed. All patients were treated with percutaneous nephrolithotomy n = 36) and nonbleeding group (n = 184), comparing the personal data, disease-related data, surgical operation related data of the two groups of patients, single factor and logistic multifactor regression analysis to explore the influence of B-guided percutaneous. Nephrolithotomy is a high-risk factor for postoperative bleeding in patients with kidney stones, and preventive measures are based on high-risk factors. Results: There was no significant difference in the proportion of patients with different genders, whether they had renal surgery, whether they had hypertension, and those with postoperative hepatic insufficiency in the hemorrhagic group and the nonbleeding group (p > 0.05). There was no significant difference in age and body mass index between the bleeding group and the nonbleeding group (p > 0.05). The proportion of patients with diabetes in the bleeding group was higher than that in the nonbleeding group, and the difference between the groups was statistically significant (p < 0.05). Compared with the nonbleeding group, the bleeding group had a higher proportion of patients with calculus diameter ≥2 cm. The proportion of patients with staghorn calculi in the bleeding group was higher than that in the nonbleeding group. The difference between the groups was statistically significant (p < 0.05). There was no significant difference in the proportion of patients with hemorrhage, single or multiple renal stones, and ureteral stones in the hemorrhage group compared with the nonbleeding group (p > 0.05). Compared with the nonbleeding group, the proportion of patients with bleeding in the first stage was higher, and the proportion of patients with operation time >90 min was higher. The difference between the groups was statistically significant (p < 0.05). There was no significant difference in the proportion of patients in the bleeding group compared with the nonbleeding group (p > 0.05). Using Logic multifactorial regression analysis, independent risk factors for bleeding after percutaneous nephrolithotomy under ultrasound-guided bovery include diabetes mellitus, stone diameter, staghorn kidney stones, surgical timing, and staging surgery (p < 0.05). Conclusion: The independent high-risk factors affecting bleeding after percutaneous nephrolithotomy guided by B-ultrasound include diabetes, stone diameter, staghorn type kidney stones, operation time, and staged surgery. According to this, effective preventive measures can effectively reduce the operation and the occurrence of postbleeding.

Data on enhanced wireless cell stimulation using soft and improved bipolar electroactive conducting polymer templates.

Data in this article is associated with our research article "Enhanced wireless cell stimulation using soft and improved bipolar electroactive conducting polymer templates" Qin et al. (2022). Primarily, the present article shows the data of PPy-PMAS/FTO, PPy-PMAS-collagen/FTO and PPy-PMAS-DS-collagen/FTO in conventional electrochemical process and bipolar electrochemical process along with in situ spectrometry for comprehensive supplement and comparison to help with better developing modified conducting polymers based bipolar electrochemistry. Secondly, the presented the complete dataset useful for modelling the soft and improved bipolar electroactive conducting polymers focusing on wireless cell (animal and human) stimulation, which are reported in the main article. All data reported were analysed using Origin 2019b 64Bit.

Expression of LncRNA-BCYRN1 in pediatric asthma and related factors of disease induction.

The study aimed to investigate the expression of lncRNA-BCYRN1 in serum of pediatric asthma patients and the related factors of disease induction. For this purpose, a total of 95 patients were randomly selected from the outpatient department of pediatrics of a hospital affiliated with the medical university from October 2018 to October 2019, including 25 intermittent episodes, 25 mild persistent episodes, 20 moderate persistent episodes, and 20 severe persistent episodes. In addition, serum samples from 30 healthy control children were selected for comparison. The expression levels of lncRNA-BCYRN1 and the inflammatory factors IL-4, IL-12, IL-37, 25-(OH)D in serum were detected by real-time quantitative fluorescence PCR(qrt-PCR), and the influence of the expression of lncRNA-BCYRN1 on the prognosis of children and its correlation with the expression of TNF-a and IgE were analyzed. Results: the expression of LncRNA BCYRN1 was positively correlated with the expression of TNF-α and IgE (r=0.712, 0.748, all P<0.001). Serum IL-4 levels in each group were 21.06±2.93pg/ml, 23.88±3.91pg/ ml, 25.85±4.02pg/ml, and 17.74±1.77pg/ml, respectively. Serum IL-4 levels in each group were higher than those in the normal control group, and the difference was statistically significant (P<0.001). The levels of IL-12, IL-37 and 25-(OH)D in all the affected groups were decreased compared with the normal control group, while the serum levels of IL-37 were negatively correlated with IL-4 and positively correlated with IL-12 and 25-(OH)D. Conclusion: serum IL-4 level of children in the disease group was increased, indicating hyperexpression of Th2 cell function, and serum IL-12 and IL-37 levels were decreased, suggesting decreased Th1 cell function, indicating Th1/Th2 imbalance in children with asthma. The low serum vitamin D level of children in the disease group was negatively correlated with serum IL-4 level and positively correlated with IL-12 and IL-37 levels, which may be the trigger factor of inflammation in asthmatic diseases and should be supplemented in clinical treatment. The expression level of lncRNA-BCYRN1 is related to the severity of pediatric asthma, which can be used as a prognostic indicator and has a certain effect on the prognosis of clinical pediatric asthma.

Mechanistic insight of the potential of geraniol against Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) as a neurodegenerative disease occupies 3/5-4/5 cases among patients with dementia, yet its pathogenetic mechanism remains unclear. Geraniol, on the other hand, is a well-known extract from essential oils of aromatic plants and has been proven that it has outstanding neuroprotective effects as well as ameliorating influence in memory impairment. Therefore, the present study aims to elucidate the potential of geraniol against AD by network pharmacology-based approach combined with molecular modeling study. MATERIALS AND METHODS: Firstly, we evaluated the druggability of geraniol by ADME method. Then, we obtained the geraniol targets and AD-related targets from multiple open data sources. Afterward, we calculated the intersection through a Venn diagram to find common targets, and via Panther classification system to categorize them. In order to gain a macroscopic understanding of these common targets, we carried out GO terms and KEGG pathways enrichment analyses, according to which we constructed a compound-target-pathway-disease network. In addition, we built a preliminary PPI network which was further analyzed both functionally and topologically. Consequently, five hub targets were sorted out. Finally, we conducted molecular docking and molecular dynamic simulation to validate our findings. RESULTS: In the present study, the pharmacological properties of geraniol were assessed according to ADME and Lipinski's rule, which demonstrate promising druggability. Then, from 10,972 AD-related targets and 33 geraniol targets, 29 common targets were identified, among which 38.1% of them are metabolite interconversion enzymes, 23.8% are protein modifying enzymes, 33.3% are transmembrane receptors, and the rest are transporters. Enrichment analyses hint that geraniol is involved in cholinergic synapse, serotonergic synapse, and neuroactive ligand-receptor interaction. We also built a preliminary PPI network to investigate the interplay between these targets and their extensive interactions. Then, by functionally clustering the preliminary PPI network, we gained a cluster of proteins which formed a subnetwork with score of 8.476, and 22 nodes. Its results of GO terms and KEGG pathways enrichment analyses once again suggests that geraniol actively participates in cholinergic synapse, serotonergic synapse, and neuroactive ligand-receptor interaction, which are believed to be strongly associated with AD pathogenesis. Besides, topological analyses of the preliminary PPI network helped find 5 hub targets (i.e., CHRM3, PRKCA, PRKCD, JAK1, JAK2). To verify their interaction with geraniol molecule, we conducted molecular docking, and found that CHRM3 possesses the highest affinity in binding, indicating that geraniol molecules are closely bound to each hub target, and CHRM3 may serve as a key target of geraniol against AD. It was then further confirmed by molecular dynamic simulation, the result of which supports our hypothesis. CONCLUSION: The present study shares a mechanistic insight of the potential of geraniol against AD, giving a reference to future experimental studies.

Network Pharmacology-Based Approach Combined with Bioinformatic Analytics to Elucidate the Potential of Curcumol against Hepatocellular Carcinoma.

PURPOSE: Modern, open-source databases provide an unprecedented wealth of information to help drug development. By combining data available in these databases with the proper bioinformatical tools, we can elucidate the molecular targets of natural compounds. One such molecule is curcumol, a guaiane-type sesquiterpenoid hemiketal isolated from Rhizoma Curcumae, which is used for a broad range of diseases in traditional Chinese and Indian medicine. It has been reported to exert anti-tumor activity, but the intrinsic molecular mechanism in hepatocellular carcinoma (HCC) is unclear. Therefore, the present study was designed to reveal the predictive targets and biological mechanisms of curcumol against HCC via a network pharmacology-based approach combined with bioinformatic analytics and to provide proof of concept for further similar investigations. METHODS: Data available from open-source databases (Traditional Chinese Medicine Systems Pharmacology, Comparative Toxicogenomic Database, The Cancer Genome Atlas, the Human Protein Atlas project) was processed with the help of a variety of open-source tools (SwissADME, SwissTargetPrediction, JVenn, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, GeneMANIA, Cytoscape). RESULTS: In the present study, the potential of curcumol against HCC was unraveled by network pharmacology-based elucidation. It suggests that curcumol shows exciting druggability with 44 potent homo sapiens biotargets against HCC. The GO terms and KEGG pathways enrichment analyses, curcumol-targets-pathways-HCC network, PPI network, and corresponding in-depth topological analyses, as well as survival analysis, molecular docking simulation indicate that the potential mechanism of curcumol against HCC is complicated, as it may act in various ways, mainly by inducing apoptosis and modulating the inflammatory response, increasing presentation of HCC-specific protein. CONCLUSION: The present study highlights the potential of curcumol against HCC, giving reference to further experimental study. It also presents a roadmap that can be followed to conduct in silico prescreening of other compounds of interest.

N-acetylcysteine prevents olanzapine-induced oxidative stress in mHypoA-59 hypothalamic neurons.

Olanzapine is a second-generation antipsychotic (AP) drug commonly prescribed for the treatment of schizophrenia. Recently, olanzapine has been found to cause brain tissue volume loss in rodent and primate studies; however, the underlying mechanism remains unknown. Abnormal autophagy and oxidative stress have been implicated to have a role in AP-induced neurodegeneration, while N-acetylcysteine (NAC) is a potent antioxidant, shown to be beneficial in the treatment of schizophrenia. Here, we investigate the role of olanzapine and NAC on cell viability, oxidative stress, mitochondrial mass and mitophagy in hypothalamic cells. Firstly, cell viability was assessed in mHypoA-59 and mHypoA NPY/GFP cells using an MTS assay and flow cytometric analyses. Olanzapine treated mHypoA-59 cells were then assessed for mitophagy markers and oxidative stress; including quantification of lysosomes, autophagosomes, LC3B-II, p62, superoxide anion (O2-) and mitochondrial mass. NAC (10 mM) was used to reverse the effects of olanzapine (100 µM) on O2-, mitochondrial mass and LC3B-II. We found that olanzapine significantly impacted cell viability in mHypoA-59 hypothalamic cells in a dose and time-dependent manner. Olanzapine inhibited mitophagy, instigated oxidative stress and prompted mitochondrial abnormalities. NAC was able to mitigate olanzapine-induced effects. These findings suggest that high doses of olanzapine may cause neurotoxicity of hypothalamic neurons via increased production of reactive oxygen species (ROS), mitochondrial damage and mitophagy inhibition. This could in part explain data suggesting that APs may reduce brain volume.

Data on the bipolar electroactive conducting polymers for wireless cell stimulation.

Data in this article is associated with our research article "Bipolar Electroactive Conducting Polymers for Wireless Cell Stimulation" [1]. Primarily, the present article shows the data of PPy-pTS, PPy-DS and PPy-DS/collagen in conventional electrochemical process and bipolar electrochemical process for comprehensive supplement and comparison to help with better understanding and developing conducting polymers based bipolar electrochemistry. Secondly, the presented data of bipolar electrostimulation (BPES) protocol development constitute the complete dataset useful for modeling the bipolar electroactive conducting polymers focusing on wireless cell stimulation, which are reported in the main article. All data reported were analysed using Origin 2018b 64Bit.

DHA reduces hypothalamic inflammation and improves central leptin signaling in mice.

AIMS: Anti-obesity effects and improved leptin sensitivity from n-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported in diet-induced obese animals. This study sought to determine the beneficial central effects and mechanism of docosahexaenoic acid (DHA, 22:6 n-3) in high-fat (HF) diet fed mice. MAIN METHODS: Male C57BL/6J mice were given HF diet with or without intracerebroventricular (icv) injection of docosahexaenoic acid (DHA, 22:6 n-3) for two days. Central leptin sensitivity, hypothalamic inflammation, leptin signaling molecules and tyrosine hydroxylase (TH) were examined by central leptin sensitivity test and Western blot. Furthermore, the expression of hepatic genes involved in lipid metabolism was examined by RT-PCR. KEY FINDINGS: We found that icv administration of DHA not only reduced energy intake and body weight gain but also corrected the HF diet-induced hypothalamic inflammation. DHA decreased leptin signaling inhibitor SOCS3 and improved the leptin JAK2-Akt signaling pathways in the hypothalamus. Furthermore, icv administration of DHA improved the effects of leptin in the regulation of mRNA expression of enzymes related to lipogenesis, fatty acid ß-oxidation, and cholesterol synthesis in the liver. DHA increased leptin-induced activation of TH in the hypothalamus. SIGNIFICANCE: Therefore, increasing central DHA concentration may prevent the deficit of hypothalamic regulation, which is associated with disorders of energy homeostasis in the liver as a result of a high-fat diet.

Supplement of microbiota-accessible carbohydrates prevents neuroinflammation and cognitive decline by improving the gut microbiota-brain axis in diet-induced obese mice.

BACKGROUND: Western pattern diets induce neuroinflammation and impair cognitive behavior in humans and animals. Neuroinflammation and cognitive impairment have been associated with microbiota dysbiosis, through the gut-brain axis. Furthermore, microbiota-accessible carbohydrates (MACs) found in dietary fiber are important in shaping the microbial ecosystem and have the potential to improve the gut-brain-axis. However, the effects of MACs on neuroinflammation and cognition in an obese condition have not yet been investigated. The present study aimed to evaluate the effect of MACs on the microbiota-gut-brain axis and cognitive function in obese mice induced by a high-fat and fiber deficient (HF-FD) diet. METHODS: C57Bl/6 J male mice were fed with either a control HF-FD or a HF-MAC diet for 15 weeks. Moreover, an additional group was fed with the HF-MAC diet in combination with an antibiotic cocktail (HF-MAC + AB). Following the 15-week treatment, cognitive behavior was investigated; blood, cecum content, colon, and brain samples were collected to determine metabolic parameters, endotoxin, gut microbiota, colon, and brain pathology. RESULTS: We report MACs supplementation prevented HF-FD-induced cognitive impairment in nesting building and temporal order memory tests. MACs prevented gut microbiota dysbiosis, including increasing richness, α-diversity and composition shift, especially in Bacteroidetes and its lower taxa. Furthermore, MACs increased colonic mucus thickness, tight junction protein expression, reduced endotoxemia, and decreased colonic and systemic inflammation. In the hippocampus, MACs suppressed HF-FD-induced neuroglia activation and inflammation, improved insulin IRS-pAKT-pGSK3ß-pTau synapse signaling, in addition to the synaptic ultrastructure and associated proteins. Furthermore, MACs' effects on improving colon-cognitive parameters were eliminated by wide spectrum antibiotic microbiota ablation. CONCLUSIONS: These results suggest that MACs improve cognitive impairments via the gut microbiota-brain axis induced by the consumption of an HF-FD. Supplemental MACs to combat obesity-related gut and brain dysfunction offer a promising approach to prevent neurodegenerative diseases associated with Westernized dietary patterns and obesity.

Olanzapine increases AMPK-NPY orexigenic signaling by disrupting H1R-GHSR1a interaction in the hypothalamic neurons of mice.

Second generation antipsychotics, particularly olanzapine, induce severe obesity, which is associated with their antagonistic effect on the histamine H1 receptor (H1R). We have previously demonstrated that oral administration of olanzapine increases the concentration of neuropeptide Y (NPY) in the hypothalamus of rats, accompanied by hyperphagia and weight gain. However, it is unclear if the increased NPY after olanzapine administration is due to its direct effect on hypothalamic neurons and its H1R antagonistic property. In the present study, we showed that with an inverted U-shape dose-response curve, olanzapine increased NPY expression in the NPY-GFP hypothalamic neurons; however, this was not the case in the hypothalamic neurons of H1R knockout mice. Olanzapine inhibited the interaction of H1R and GHSR1a (ghrelin receptor) in the primary mouse hypothalamic neurons and NPY-GFP neurons examined by confocal fluorescence resonance energy transfer (FRET) technology. Furthermore, an H1R agonist, FMPH inhibited olanzapine activation of GHSR1a downstream signaling pAMPK and transcription factors of NPY (pFOXO1 and pCREB) in the hypothalamic NPY-GFP cell. However, an olanzapine analogue (E-Olan) with lower affinity to H1R presented negligible enhancement of pCREB within the nucleus of NPY neurons. These findings suggest that the H1R antagonist property of olanzapine inhibits the interaction of H1R and GHSR1a, activates GHSR1a downstream signaling pAMPK-FOXO1/pCREB and increases hypothalamic NPY: this could be one of the important molecular mechanisms of H1R antagonism of olanzapine-induced obesity in antipsychotic management of psychiatric disorders.

[Reproductive characteristics and habitat factors of Acanthopanax giraldii].

The growth parameters,clonal propagation parameters and sexual reproduction parameters of Acanthopanax giraldii population were systematically investigated and analyzed by means of population ecology in this study. The correlation among the above mentioned parameters and the correlation among canopy density,topography and soil fertility factors were analyzed. It is clear that there was a significant correlation among the clonal ramets,the fruit production capacity of the cluster and the new shoot production capacity of the A. giraldii. Sexual reproduction and clonal reproduction played an important role in the continuation of the population. Illumination was the key ecological factor that determined growth type. The increase in canopy density changed the population from " group clonal growth" to " guerrilla clonal growth",and the higher stand closure degree and low-strength herb layer competition was a necessary condition for seed germination and colonization. Under the background of natural forest protection and sustainable development of resources,the reproductive characteristics of wild A. giraldii resulted in the decrease of its recoverable quantity.

Olanzapine-induced endoplasmic reticulum stress and inflammation in the hypothalamus were inhibited by an ER stress inhibitor 4-phenylbutyrate.

Antipsychotics are the most important treatment for schizophrenia. However, antipsychotics, particularly olanzapine and clozapine, are associated with severe weight gain/obesity side-effects. Although numerous studies have been carried out to identify the exact mechanisms of antipsychotic-induced weight gain, it is still important to consider other pathways. Endoplasmic reticulum (ER) stress signaling and its associated inflammation pathway is one of the most important pathways involved in regulation of energy balance. In the present study, we examined the role of hypothalamic protein kinase R like endoplasmic reticulum kinase- eukaryotic initiation factor 2α (PERK-eIF2α) signaling and the inflammatory IkappaB kinase ß- nuclear factor kappa B (IKKß-NFκB) signaling pathway in olanzapine-induced weight gain in female rats. In this study, we found that olanzapine significantly activated PERK-eIF2α and IKKß-NFκB signaling in SH-SY5Y cells in a dose-dependent manner. Olanzapine treatment for 8 days in rats was associated with activated PERK-eIF2α signaling and IKKß-NFκB signaling in the hypothalamus, accompanied by increased food intake and weight gain. Co-treatment with an ER stress inhibitor, 4-phenylbutyrate (4-PBA), decreased olanzapine-induced food intake and weight gain in a dose- and time-dependent manner. Moreover, 4-PBA dose-dependently inhibited olanzapine-induced activated PERK-eIF2α and IKKß-NFκB signaling in the hypothalamus. These results suggested that hypothalamic ER stress may play an important role in antipsychotic-induced weight gain.

Dietary Galacto-Oligosaccharides and Resistant Starch Protect Against Altered CB1 and 5-HT1A and 2A Receptor Densities in Rat Brain: Implications for Preventing Cognitive and Appetite Dysfunction During a High-Fat Diet.

SCOPE: A high-fat, but low-fiber, diet is associated with obesity and cognitive dysfunction, while dietary fiber supplementation can improve cognition. METHODS AND RESULTS: This study examines whether dietary fibers, galacto-oligosaccharides (GOS) and resistant starch (RS), could prevent high-fat (HF)-diet-induced alterations in neurotransmitter receptor densities in brain regions associated with cognition and appetite. Rats are fed a HF diet, HF diet with GOS, HF diet with RS, or a low-fat (LF, control) diet for 4 weeks. Cannabinoid CB1 (CB1R) and 5HT1A (5HT1A R) and 5-HT2A (5HT2A R) receptor binding densities are examined. In the hippocampus and hypothalamus, a HF diet significantly increases CB1R binding, while HF + GOS and HF + RS diets prevented this increase. HF diet also increases hippocampal and hypothalamic 5-HT1A R binding, while HF + GOS and HF + RS prevented the alterations. Increased 5-HT2A binding is prevented by HF + GOS and HF + RS in the medial mammillary nucleus. CONCLUSIONS: These results demonstrate that increased CB1R, 5-HT1A R and 5-HT2A R induced by a HF diet can be prevented by GOS and RS supplementation in brain regions involved in cognition and appetite. Therefore, increased fiber intake may have beneficial effects on improving learning and memory, as well as reducing excessive appetite, during the chronic consumption of a HF (standard Western) diet.

RANKL Reduces Body Weight and Food Intake via the Modulation of Hypothalamic NPY/CART Expression.

The receptor activator of nuclear factor-κB ligand (RANKL) modulates energy metabolism. However, how RANKL regulates energy homeostasis is still not clear. This study aims to investigate the central mechanisms by which central administration of RANKL inhibits food intake and causes weight loss in mice. We carried out a systematic and in-depth analysis of the neuronal pathways by which RANKL mediates catabolic effects. After intracerebroventricle (i.c.v.) injection of RANKL, the expression of neuropeptide Y (NPY) mRNA in the Arc was significantly decreased, while the CART mRNA expression dramatically increased in the Arc and DMH. However, the agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) mRNA had no significant changes compared with control groups. Together, the results suggest that central administration of RANKL reduces food intake and causes weight loss via modulating the hypothalamic NPY/CART pathways.

[Study on photosynthesis and physiological characteristics of Acanthopanax giraldii on different light intensity].

This article is aimed to study the response mechanism of Acanthopanax giraldii on different shading intensity to guide its artificial cultivation. The cultivated A. giraldii in Maoxian was used as the research object, set up different shading treatment groups, analyzed photosynthesis, physiology, submicroscopic structure to explore the response mechanism of A. giraldii to different light intensity. Light was the main influencing factor to photosynthetic rate.During morning and afternoon periods,the Pn of the CK group reduced by stomatal limitation and non stomatal limitation factors respectively. While during 14：30-18：30 period, the Pn of A1 and A2 groups reduced by non stomatal limitation factors.LSP, LCP and Rd of A1 and A2 groups were significantly lower than those of CK group;The content of SS and SP of A1 and A2 groups were lower than those of CK group. The content of Pro of CK group were significantly higher than those of group A2.The activities of SOD and POD of them was higher than that of CK group,CAT activity of A1 and POD activity of A2 were relatively higher In their respective free radical scavenging system. Starch grain increased and base grana declined in the chloropalst of those group CK. The study results indicated that response mechanism of different shading conditions of A. giraldii under field cultivation conditions. Its could effectively adapt to environmental changes of the home cultivation,which provided a reference for ensuring yield and quality.