Publications by authors named "Xu-Feng Huang"

242 Publications

The kynurenine pathway in major depression: What we know and where to next.

Neurosci Biobehav Rev 2021 May 23;127:917-927. Epub 2021 May 23.

School of Medicine and Molecular Horizons, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, 2522, Australia; Illawarra Health and Medical Research Institute, Wollongong, New South Wales, 2522, Australia. Electronic address:

Major depression is a serious psychiatric disorder, occurring in up to 20 % of the population. Despite its devastating burden, the neurobiological changes associated with depression are not fully understood. A growing body of evidence suggests the kynurenine pathway is implicated in the pathophysiology of depression. In this review, we bring together the literature examining elements of the kynurenine pathway in depression and explore the implications for the pathophysiology and treatment of depression, while highlighting the gaps in the current knowledge. Current research indicates an increased potential for neurotoxic activity of the kynurenine pathway in peripheral blood samples but an increased activation of the putative neuroprotective arm in some brain regions in depression. The disconnect between these findings requires further investigation, with a greater research effort on elucidating the central effects of the kynurenine pathway in driving depression symptomology. Research investigating the benefits of targeting the kynurenine pathway centred on human brain findings and the heterogenous subtypes of depression will help guide the identification of effective drug targets in depression.
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http://dx.doi.org/10.1016/j.neubiorev.2021.05.018DOI Listing
May 2021

Cannabidiol regulates CB1-pSTAT3 signaling for neurite outgrowth, prolongs lifespan, and improves health span in Caenorhabditis elegans of Aβ pathology models.

FASEB J 2021 May;35(5):e21537

Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE), New Lambton Heights, NSW, Australia.

Cannabidiol (CBD), a phytocannabinoid from the Cannabis sativa plant, exhibits a broad spectrum of potential therapeutic properties for neurodegenerative diseases. An accumulation of amyloid-β (Aβ) protein is one of the most important neuropathology in neurodegenerative diseases like Alzheimer's disease (AD). Data on the effect of CBD on the amelioration of Aβ-induced neurite degeneration and its consequences of life and health spans is sparse. This study aimed to investigate the effects of CBD on neurite outgrowth in cells and lifespan and health span in Caenorhabditis elegans (C. elegans). In human SH-SY5Y neuronal cells, CBD prevented neurite lesion induced by Aβ and increased the expression of fatty acid amide hydrolase (FAAH) and cannabinoid receptor 1 (CB1R). Furthermore, CBD both protected the reduction of dendritic spine density and rescued the activity of synaptic Ca /calmodulin-dependent protein kinase II (CaMKII) from Aβ toxicity in primary hippocampal neurons. In C. elegans, we used the transgenic CL2355 strain of C. elegans, which expresses the human Aβ peptide throughout the nervous system and found that CBD treatment extended lifespan and improved health span. The neuroprotective effect of CBD was further explored by observing the dopaminergic neurons using transgenic dat-1: GFP strains using the confocal microscope. This study shows that CBD prevents the neurite degeneration induced by Aβ, by a mechanism involving CB1R activation, and extends lifespan and improves health span in Aβ-overexpressing worms. Our findings support the potential therapeutic approach of CBD for the treatment of AD patients.
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http://dx.doi.org/10.1096/fj.202002724RDOI Listing
May 2021

Olanzapine-Induced Activation of Hypothalamic Astrocytes and Toll-Like Receptor-4 Signaling via Endoplasmic Reticulum Stress Were Related to Olanzapine-Induced Weight Gain.

Front Neurosci 2020 13;14:589650. Epub 2021 Jan 13.

School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China.

The antipsychotic drug olanzapine is associated with serious obesity side effects. Hypothalamic astrocytes and associated toll-like receptor-4 (TLR4) signaling play an essential role in obesity pathogenesis. This study investigated the effect of olanzapine on astrocytes and TLR4 signaling both and in the rat hypothalamus and their potential role in olanzapine-induced weight gain. We found that olanzapine treatment for 24 h dose-dependently increased cell viability, increased the protein expression of astrocyte markers including glial fibrillary acidic protein (GFAP) and S100 calcium binding protein B (S100B), and activated TLR4 signaling . In rats, 8- and 36-day olanzapine treatment caused weight gain accompanied by increased GFAP and S100B protein expression and activated TLR4 signaling in the hypothalamus. These effects still existed in pair-fed rats, suggesting that these effects were not secondary effects of olanzapine-induced hyperphagia. Moreover, treatment with an endoplasmic reticulum (ER) stress inhibitor, 4-phenylbutyrate, inhibited olanzapine-induced weight gain and ameliorated olanzapine-induced changes in hypothalamic GFAP, S100B, and TLR4 signaling. The expression of GFAP, S100B, and TLR4 correlated with food intake and weight gain. These findings suggested that olanzapine-induced increase in hypothalamic astrocytes and activation of TLR4 signaling were related to ER stress, and these effects may be related to olanzapine-induced obesity.
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http://dx.doi.org/10.3389/fnins.2020.589650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874166PMC
January 2021

β-Glucan from Lentinula edodes prevents cognitive impairments in high-fat diet-induced obese mice: involvement of colon-brain axis.

J Transl Med 2021 02 4;19(1):54. Epub 2021 Feb 4.

Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.

Background: Long-term high fat (HF) diet intake can cause neuroinflammation and cognitive decline through the gut-brain axis. (1, 3)/(1, 6)-β-glucan, an edible polysaccharide isolated from medical mushroom, Lentinula edodes (L. edodes), has the potential to remodel gut microbiota. However, the effects of L. edodes derived β-glucan against HF diet-induced neuroinflammation and cognitive decline remain unknown. This study aimed to evaluate the neuroprotective effect and mechanism of dietary L edodes β-glucan supplementation against the obesity-associated cognitive decline in mice fed by a HF diet.

Methods: C57BL/6J male mice were fed with either a lab chow (LC), HF or HF with L. edodes β-glucan supplementation diets for 7 days (short-term) or 15 weeks (long-term). Cognitive behavior was examined; blood, cecum content, colon and brain were collected to evaluate metabolic parameters, endotoxin, gut microbiota, colon, and brain pathology.

Results: We reported that short-term and long-term L. edodes β-glucan supplementation prevented the gut microbial composition shift induced by the HF diet. Long-term L. edodes β-glucan supplementation prevented the HF diet-induced recognition memory impairment assessed by behavioral tests (the temporal order memory, novel object recognition and Y-maze tests). In the prefrontal cortex and hippocampus, the β-glucan supplementation ameliorated the alteration of synaptic ultrastructure, neuroinflammation and brain-derived neurotrophic factor (BDNF) deficits induced by HF diet. Furthermore, the β-glucan supplementation increased the mucosal thickness, upregulated the expression of tight junction protein occludin, decreased the plasma LPS level, and inhibited the proinflammatory macrophage accumulation in the colon of mice fed by HF diet.

Conclusions: This study revealed that L. edodes β-glucan prevents cognitive impairments induced by the HF diet, which may occur via colon-brain axis improvement. The finding suggested that dietary L. edodes β-glucan supplementation may be an effective nutritional strategy to prevent obesity-associated cognitive decline.
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http://dx.doi.org/10.1186/s12967-021-02724-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863530PMC
February 2021

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

Sci Rep 2020 11 5;10(1):19185. Epub 2020 Nov 5.

Illawarra Health and Medical Research Institute and School of Medicine, University of Wollongong, Wollongong, NSW, 2522, Australia.

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 (O) and mitochondrial mass. NAC (10 mM) was used to reverse the effects of olanzapine (100 µM) on O, 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.
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http://dx.doi.org/10.1038/s41598-020-75356-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644715PMC
November 2020

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

Data Brief 2020 Dec 11;33:106406. Epub 2020 Oct 11.

ARC Centre of Excellence for Electromaterials Science, Intelligent Polymer Research Institute, Australian Institute for Innovative Materials, Innovation Campus, University of Wollongong, Squires Way, North Wollongong, NSW 2519, Australia.

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-TS, 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.
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http://dx.doi.org/10.1016/j.dib.2020.106406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567922PMC
December 2020

β-glucan attenuates cognitive impairment via the gut-brain axis in diet-induced obese mice.

Microbiome 2020 10 2;8(1):143. Epub 2020 Oct 2.

Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW, 2522, Australia.

Background: "Western" style dietary patterns are characterized by a high proportion of highly processed foods rich in fat and low in fiber. This diet pattern is associated with a myriad of metabolic dysfunctions, including neuroinflammation and cognitive impairment. β-glucan, the major soluble fiber in oat and barley grains, is fermented in the lower gastrointestinal tract, potentially impacting the microbial ecosystem and thus may improve elements of cognition and brain function via the gut-brain axis. The present study aimed to evaluate the effect of β-glucan on the microbiota gut-brain axis and cognitive function in an obese mouse model induced by a high-fat and fiber-deficient diet (HFFD).

Results: After long-term supplementation for 15 weeks, β-glucan prevented HFFD-induced cognitive impairment assessed behaviorally by object location, novel object recognition, and nesting building tests. In the hippocampus, β-glucan countered the HFFD-induced microglia activation and its engulfment of synaptic puncta, and upregulation of proinflammatory cytokine (TNF-α, IL-1β, and IL-6) mRNA expression. Also, in the hippocampus, β-glucan significantly promoted PTP1B-IRS-pAKT-pGSK3β-pTau signaling for synaptogenesis, improved the synaptic ultrastructure examined by transmission electron microscopy, and increased both pre- and postsynaptic protein levels compared to the HFFD-treated group. In the colon, β-glucan reversed HFFD-induced gut barrier dysfunction increased the thickness of colonic mucus (Alcian blue and mucin-2 glycoprotein immunofluorescence staining), increased the levels of tight junction proteins occludin and zonula occludens-1, and attenuated bacterial endotoxin translocation. The HFFD resulted in microbiota alteration, effects abrogated by long-term β-glucan supplementation, with the β-glucan effects on Bacteroidetes and its lower taxa particularly striking. Importantly, the study of short-term β-glucan supplementation for 7 days demonstrated pronounced, rapid differentiating microbiota changes before the cognitive improvement, suggesting the possible causality of gut microbiota profile on cognition. In support, broad-spectrum antibiotic intervention abrogated β-glucan's effects on improving cognition, highlighting the role of gut microbiota to mediate cognitive behavior.

Conclusion: This study provides the first evidence that β-glucan improves indices of cognition and brain function with major beneficial effects all along the gut microbiota-brain axis. Our data suggest that elevating consumption of β-glucan-rich foods is an easily implementable nutritional strategy to alleviate detrimental features of gut-brain dysregulation and prevent neurodegenerative diseases associated with Westernized dietary patterns. Video Abstract.
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http://dx.doi.org/10.1186/s40168-020-00920-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532656PMC
October 2020

Decreased serum NCAM is positively correlated with hippocampal volumes and negatively correlated with positive symptoms in first-episode schizophrenia patients.

J Psychiatr Res 2020 12 14;131:108-113. Epub 2020 Sep 14.

Illawarra Health and Medical Research Institute and School of Medicine, University of Wollongong, NSW, 2522, Australia. Electronic address:

Background: Neural cell adhesion molecule (NCAM) plays an important role in neurodevelopmental processes and regulates hippocampal plasticity. This study investigated the relationship between the serum NCAM concentrations and hippocampal volume and psychotic symptoms in first-episode drug naïve schizophrenia (FES) patients.

Methods: Forty-four FES patients and forty-four healthy controls (HC) were recruited in this study. Serum concentrations of NCAM were measured by ELISA. Psychiatric symptoms were assessed by the positive and negative syndrome scale (PANSS). Brain structural images were obtained using a 3T MRI Scanner and obtained T1 images were processed in order to determine hippocampal grey matter volumes.

Results: Schizophrenia patients revealed significantly decreased serum NCAM concentrations (p = 0.017), which were positively correlated with the left (r = 0.523, p < 0.001) and right (r = 0.449, p = 0.041) hippocampal volumes, but negatively correlated with the PANSS positive symptom scores (r = -0.522 p = 0.001). However, no such correlations existed in the HC group.

Conclusions: This is the first time to report that decreased serum NCAM concentrations were associated with hippocampal volumes and symptom severity in FES patients. Our data indicate that the low NCAM is possible neuropathology that is associated with the decreased hippocampus in FES patients.
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http://dx.doi.org/10.1016/j.jpsychires.2020.09.012DOI Listing
December 2020

Prevention of Neurite Spine Loss Induced by Dopamine D2 Receptor Overactivation in Striatal Neurons.

Front Neurosci 2020 23;14:642. Epub 2020 Jun 23.

Illawarra Health and Medical Research Institute (IHMRI) and School of Medicine, University of Wollongong, Wollongong, NSW, Australia.

Psychosis has been considered a disorder of impaired neuronal connectivity. Evidence for excessive formation of dopamine D2 receptor (D2R) - disrupted in schizophrenia 1 (DISC1) complexes has led to a new perspective on molecular mechanisms involved in psychotic symptoms. Here, we investigated how excessive D2R-DISC1 complex formation induced by D2R agonist quinpirole affects neurite growth and dendritic spines in striatal neurons. Fluorescence resonance energy transfer (FRET), stochastic optical reconstruction microscopy (STORM), and cell penetrating-peptide delivery were used to study the cultured striatal neurons from mouse pups. Using these striatal neurons, our study showed that: (1) D2R interacted with DISC1 in dendritic spines, neurites and soma of cultured striatal neurons; (2) D2R and DISC1 complex accumulated in clusters in dendritic spines of striatal neurons and the number of the complex were reduced after application of TAT-D2pep; (3) uncoupling D2R-DISC1 complexes by TAT-D2pep protected neuronal morphology and dendritic spines; and (4) TAT-D2pep prevented neurite and dendritic spine loss, which was associated with restoration of expression levels of synaptophysin and PSD-95. In addition, we found that Neuropeptide Y (NPY) and GSK3β were involved in the protective effects of TAT-D2pep on the neurite spines of striatal spiny projection neurons. Thus, our results may offer a new strategy for precisely treating neurite spine deficits associated with schizophrenia.
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http://dx.doi.org/10.3389/fnins.2020.00642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324769PMC
June 2020

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

Life Sci 2020 Sep 2;257:118036. Epub 2020 Jul 2.

Illawarra Health and Medical Research Institute and School of Medicine, University of Wollongong, NSW2522, Australia; Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China. Electronic address:

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 β-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.
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http://dx.doi.org/10.1016/j.lfs.2020.118036DOI Listing
September 2020

Curdlan Prevents the Cognitive Deficits Induced by a High-Fat Diet in Mice via the Gut-Brain Axis.

Front Neurosci 2020 14;14:384. Epub 2020 May 14.

Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China.

A high-fat (HF) diet is a major predisposing factor of neuroinflammation and cognitive deficits. Recently, changes in the gut microbiota have been associated with neuroinflammation and cognitive impairment, through the gut-brain axis. Curdlan, a bacterial polysaccharide widely used as food additive, has the potential to alter the composition of the microbiota and improve the gut-brain axis. However, the effects of curdlan against HF diet-induced neuroinflammation and cognitive decline have not been investigated. We aimed to evaluate the neuroprotective effect and mechanism of dietary curdlan supplementation against the obesity-associated cognitive decline observed in mice fed a HF diet. C57Bl/6J male mice were fed with either a control, HF, or HF with curdlan supplementation diets for 7 days (acute) or 15 weeks (chronic). We found that acute curdlan supplementation prevented the gut microbial composition shift induced by HF diet. Chronic curdlan supplementation prevented cognitive declines induced by HF diet. In addition, curdlan protected against the HF diet-induced abnormities in colonic permeability, hyperendotoxemia, and colonic inflammation. Furthermore, in the prefrontal cortex (PFC) and hippocampus, curdlan mitigated microgliosis, neuroinflammation, and synaptic impairments induced by a HF diet. Thus, curdlan-as a food additive and prebiotic-can prevent cognitive deficits induced by HF diet via the colon-brain axis.
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http://dx.doi.org/10.3389/fnins.2020.00384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239995PMC
May 2020

A synergistic effect between family intervention and rTMS improves cognitive and negative symptoms in schizophrenia: A randomized controlled trial.

J Psychiatr Res 2020 07 28;126:81-91. Epub 2020 Apr 28.

The First Affiliated Hospital/Zhengzhou University, Zhengzhou, China; Biological Psychiatry International Joint Laboratory of Henan, Zhengzhou University, Zhengzhou, China; Henan Psychiatric Transformation Research Key Laboratory, Zhengzhou University, Zhengzhou, China. Electronic address:

Objective: The present study explored an efficient new therapy that combined repetitive transcranial magnetic stimulation (rTMS) and family intervention in addition to risperidone to improve schizophrenia.

Methods: A randomized controlled trial (January 2016-September 2017) involving 200 patients, of which 188 patients completed the 12-week study, and 50 controls were conducted in the research. The patients were randomly assigned to 12 weeks of treatment with risperidone alone (risperidone group), rTMS and risperidone (rTMS group), family intervention and risperidone (family intervention group), rTMS and risperidone plus family intervention (combined group). MATRICS Consensus Cognitive Battery (MCCB) and the Positive and Negative Symptoms Scale (PANSS) were used to evaluate treatment efficacy. Repeated measures analysis of variance (RMANOVA) were performed to evaluate different treatment efficacy between four groups after 12 weeks of treatment.

Results: (1) There were no significant differences in sex, age, education, cognitive function, or PANSS scores between the four groups at baseline (p's > 0.05). (2) There was a significant decrease in the PANSS scores and an increase in the MCCB scores after 12 weeks of treatment in all groups (time effect p's < 0.001). (3) The improvements in positive symptoms and negative symptoms were more obvious in the combined group than in other groups (p's < 0.05). (4) The combined group showed the superior effect in cognition function after 12 weeks. (5) And, interestingly, a remarkable synergistic effect between rTMS and family intervention therapy was observed.

Conclusion: There was a synergistic effect between rTMS and the family intervention as an effective combined therapy in improving schizophrenia. This study is registered with Chictr.org, number ChiCTR1900024422 (http://www.chictr.org.cn/edit.aspx?pid=34285&htm=4).
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http://dx.doi.org/10.1016/j.jpsychires.2020.04.009DOI Listing
July 2020

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

J Neuroinflammation 2020 Mar 4;17(1):77. Epub 2020 Mar 4.

Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.

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-pGSK3β-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.
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http://dx.doi.org/10.1186/s12974-020-01760-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055120PMC
March 2020

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

Psychoneuroendocrinology 2020 04 25;114:104594. Epub 2020 Jan 25.

Illawarra Health and Medical Research Institute and Molecular Horizons, School of Medicine, University of Wollongong, NSW, 2522, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.psyneuen.2020.104594DOI Listing
April 2020

Risperidone stimulates food intake and induces body weight gain via the hypothalamic arcuate nucleus 5-HT2c receptor-NPY pathway.

CNS Neurosci Ther 2020 05 27;26(5):558-566. Epub 2019 Dec 27.

Department of Cardiology, Southwest Hospital, Third Military Medical University (Currently Army Medical University), Chongqing, China.

Aims: Many patients taking risperidone for the treatment of psychiatric disorders experience substantial body weight gain. Researchers have speculated that risperidone induces obesity by modulating central signals; however, the precise central mechanisms involved remain to be fully elucidated.

Methods: Twenty-four C57BL/6J mice were divided into four groups: a control group; a risperidone-treated group; a lorcaserin-treated group; and a combined risperidone + lorcaserin-treated group. The mice were received the corresponding treatments for 4 weeks, and their brains were collected for in situ hybridization analysis. A subset of C57BL/6J mice was administrated with risperidone or placebo, and brains were collected 60 minutes post-treatment for determination of c-fos activity. In addition, brains of NPY-GFP mice treated with or without risperidone were collected to perform colocalization of NPY and c-fos, as well as NPY and 5-HT2c receptor using immunohistochemistry.

Results: There was significantly elevated c-fos expression in the hypothalamic arcuate nucleus (Arc) of risperidone-treated mice. More than 68% c-fos-positive neurons were NPY-expressing neurons. Furthermore, in situ hybridization revealed that Arc NPY mRNA expression was significantly increased in the risperidone-treated group compared with control group. Moreover, we identified that 95% 5-HT2c receptors were colocalized with NPY positive neurons, and increased Arc NPY mRNA expression induced by risperidone was markedly reduced by cotreatment with lorcaserin, a specific 5-HT2c receptor agonist.

Conclusion: Our findings provide critical insight into the mechanisms underlying antipsychotic-induced obesity, which may assist the development of therapeutic strategies to address metabolic side effects of risperidone.
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http://dx.doi.org/10.1111/cns.13281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163792PMC
May 2020

Patients With Drug-Naive Bipolar Disorder in Remission After 8 Weeks of Treatment Had Decreased Serum Uric Acid Concentrations.

Front Psychiatry 2019 31;10:767. Epub 2019 Oct 31.

Illawarra Health and Medical Research Institute and School of Medicine, University of Wollongong, Wollongong, NSW, Australia.

Evidence indicates that the serum concentration of uric acid (UA) in patients may relate both to the pathophysiology and therapeutics of bipolar disorder (BPD). The purpose of this study was to examine the changes and clinical significance of serum UA concentrations in first-episode manic patients suffering from BPD. Seventy-six drug-naive patients with first-episode bipolar mania and 76 age- and gender-matched healthy subjects were recruited. Young Mania Rating Scale and Hamilton Depression Rating Scale were used to assess clinical symptoms. We tested serum UA concentrations by sandwich enzyme-linked immunosorbent assay at baseline and at the end of 8-week treatment in BPD patients and in the control group. After 8-week quetiapine and sodium valproate treatment, this study revealed that the serum UA concentrations in remitted patients were significantly lower than nonremitted patients; however, those remitted patients still had higher serum UA than healthy controls. We discovered that the baseline UA concentration was higher in nonremitted than remitted patients after 8 weeks of treatment. Finally, a positive association was found between serum UA and symptom relief in the first episode of manic disorder patients. Patients with first-episode BPD had high levels of serum UA, which responds to treatment mainly in remitted patients. Our results suggest that serum UA concentrations might present potentially a trait marker in bipolar patients.
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http://dx.doi.org/10.3389/fpsyt.2019.00767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6837074PMC
October 2019

Increased translocator protein (TSPO) binding throughout neurodevelopment in the perinatal phencyclidine rodent model of schizophrenia.

Schizophr Res 2019 10 13;212:243-245. Epub 2019 Aug 13.

Illawarra Health and Medical Research Institute, Wollongong, Australia; Molecular Horizons and School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales 2522, Australia.

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http://dx.doi.org/10.1016/j.schres.2019.07.041DOI Listing
October 2019

[Reproductive characteristics and habitat factors of Acanthopanax giraldii].

Zhongguo Zhong Yao Za Zhi 2019 May;44(9):1781-1788

Pharmacy College,Chengdu University of Traditional Chinese Medicine Chengdu 611137,China.

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.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20190301.011DOI Listing
May 2019

Cannabidiol improves behavioural and neurochemical deficits in adult female offspring of the maternal immune activation (poly I:C) model of neurodevelopmental disorders.

Brain Behav Immun 2019 10 19;81:574-587. Epub 2019 Jul 19.

Neuropharmacology and Molecular Psychiatry Laboratory, School of Medicine, University of Wollongong, Wollongong, NSW 2522, Australia; Centre for Translational Neuroscience, Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia; Molecular Horizons, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia; Australian Centre for Cannabinoid Clinical and Research Excellence, New Lambton Heights, NSW 2305, Australia. Electronic address:

Cognitive impairment is a major source of disability in schizophrenia and current antipsychotic drugs (APDs) have minimal efficacy for this symptom domain. Cannabidiol (CBD), the major non-intoxicating component of Cannabis sativa L., exhibits antipsychotic and neuroprotective properties. We recently reported the effects of CBD on cognition in male offspring of a maternal immune activation (polyinosinic-polycytidilic acid (poly I:C)) model relevant to the aetiology of schizophrenia; however, the effects of CBD treatment in females are unknown. Sex differences are observed in the onset of schizophrenia symptoms and response to APD treatment. Furthermore, the endogenous cannabinoid system, a direct target of CBD, is sexually dimorphic in humans and rodents. Therefore, the present work aimed to assess the therapeutic impact of CBD treatment on behaviour and neurochemical signalling markers in female poly I:C offspring. Time-mated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg; i.v.) or saline (control) on gestational day 15. From postnatal day 56, female offspring received CBD (10 mg/kg, i.p.) or vehicle treatment for approximately 3 weeks. Following 2 weeks of CBD treatment, offspring underwent behavioural testing, including the novel object recognition, rewarded alternation T-maze and social interaction tests to assess recognition memory, working memory and sociability, respectively. After 3 weeks of CBD treatment, the prefrontal cortex (PFC) and hippocampus (HPC) were collected to assess effects on endocannabinoid, glutamatergic and gamma-aminobutyric acid (GABA) signalling markers. CBD attenuated poly I:C-induced deficits in recognition memory, social interaction and glutamatergic N-methyl-d-aspartate receptor (NMDAR) binding in the PFC of poly I:C offspring. Working memory performance was similar between treatment groups. CBD also increased glutamate decarboxylase 67, the rate-limiting enzyme that converts glutamate to GABA, and parvalbumin protein levels in the HPC. In contrast to the CBD treatment effects observed in poly I:C offspring, CBD administration to control rats reduced social interaction, cannabinoid CB1 receptor and NMDAR binding density in the PFC, suggesting that CBD administration to healthy rats may have negative consequences on social behaviour and brain maturation in adulthood. Overall, the findings of this study support the therapeutic benefits of CBD on recognition memory and sociability in female poly I:C offspring, and provide insight into the neurochemical changes that may underlie the therapeutic benefits of CBD in the poly I:C model.
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http://dx.doi.org/10.1016/j.bbi.2019.07.018DOI Listing
October 2019

Tacrine-Hydrogen Sulfide Donor Hybrid Ameliorates Cognitive Impairment in the Aluminum Chloride Mouse Model of Alzheimer's Disease.

ACS Chem Neurosci 2019 08 20;10(8):3500-3509. Epub 2019 Jun 20.

Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy , Xuzhou Medical University , Xuzhou , Jiangsu 221004 , China.

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by progressive loss of memory and cognitive function, and is associated with the deficiency of synaptic acetylcholine, as well as chronic neuroinflmmation. Tacrine, a potent acetylcholinesterase (AChE) inhibitor, was previously a prescribed clinical therapeutic agent for AD, but it was recently withdrawn because it caused widespread hepatotoxicity. Hydrogen sulfide (HS) has neuroprotective, hepatoprotective, and anti-inflammatory effects. In this study, we synthesized a new compound, a tacrine-HS donor hybrid (THS) by introducing HS-releasing moieties (ACS81) to tacrine. Subsequently, pharmacological and biological evaluations of THS were conducted in the aluminum trichloride (AlCl)-induced AD mice model. We found that THS (15 mmol/kg) improved cognitive and locomotor activity in AD mice in the step-through test and open field test, respectively. THS showed strong AChE inhibitory activity in the serum and hippocampus of AD mice and induced increased hippocampal HS levels. Furthermore, THS reduced mRNA expression of the proinflammatory cytokines, TNF-α, IL-6, and IL-1β and increased synapse-associated proteins (synaptophysin and postsynaptic density protein 95) in the hippocampus of AD mice. Importantly, THS, unlike tacrine, did not increase liver transaminases (alanine transaminase and aspartate transaminase) or proinflammatory cytokines, indicating THS is much safer than tacrine. Therefore, the multifunctional effects of this new hybrid compound of tacrine and HS indicate it is a promising compound for further research into the treatment of AD.
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http://dx.doi.org/10.1021/acschemneuro.9b00120DOI Listing
August 2019

Effect of cannabidiol on endocannabinoid, glutamatergic and GABAergic signalling markers in male offspring of a maternal immune activation (poly I:C) model relevant to schizophrenia.

Prog Neuropsychopharmacol Biol Psychiatry 2019 12 14;95:109666. Epub 2019 Jun 14.

Neuropharmacology and Molecular Psychiatry Laboratory, School of Medicine, University of Wollongong, Wollongong, NSW 2522, Australia; Centre for Translational Neuroscience, Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia; Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia; Australian Centre for Cannabinoid Clinical and Research Excellence, New Lambton Heights, NSW 2305, Australia. Electronic address:

The mainstay treatment for schizophrenia is antipsychotic drugs (APDs), which are mostly effective against the positive symptoms (e.g. hallucinations), but provide minimal benefits for the negative symptoms (e.g. social withdrawal) and cognitive deficits. We have recently shown that treatment with the non-intoxicating phytocannabinoid, cannabidiol (CBD), can improve cognition and social interaction deficits in a maternal immune activation (MIA) model relevant to the aetiology of schizophrenia, however, the mechanisms underlying this effect are unknown. An imbalance in the main excitatory (glutamate) and inhibitory (GABA) neurotransmitter systems in the brain plays a role in the pathophysiology of schizophrenia. Therefore, the endocannabinoid system could represent a therapeutic target for schizophrenia as a regulator of glutamate and GABA release via the CB1 receptor (CB1R). This study investigated the effects of chronic CBD treatment on markers of glutamatergic, GABAergic and endocannabinoid signalling in brain regions implicated in social behaviour and cognitive function, including the prefrontal cortex (PFC) and hippocampus (HPC). Time-mated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg, i.v.) or saline (control) on gestational day 15. Male offspring were injected with CBD (10 mg/kg, i.p.) or vehicle twice daily from postnatal day 56 for 3 weeks. The prefrontal cortex (PFC) and hippocampus (HPC) were collected for post-mortem receptor binding and Western blot analyses (n = 8 per group). CBD treatment attenuated poly I:C-induced deficits in cannabinoid CB1 receptor binding in the PFC and glutamate decarboxylase 67, the enzyme that converts glutamate to GABA, in the HPC. CBD treatment increased parvalbumin levels in the HPC, regardless of whether offspring were exposed to poly I:C in utero. Conversely, CBD did not affect N-methyl-d-aspartate receptor and gamma-aminobutyric acid (GABA) A receptor binding or protein levels of fatty acid amide hydrolase, the enzyme that degrades the endocannabinoid, anandamide. Overall, these findings show that CBD can restore cannabinoid/GABAergic signalling deficits in regions of the brain implicated in schizophrenia pathophysiology following maternal poly I:C exposure. These findings provide novel evidence for the potential mechanisms underlying the therapeutic effects of CBD treatment in the poly I:C model.
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http://dx.doi.org/10.1016/j.pnpbp.2019.109666DOI Listing
December 2019

Nano-sunscreens - a double-edged sword in protecting consumers from harm: viewing Australian regulatory policies through the lenses of the European Union.

Crit Rev Toxicol 2019 02 5;49(2):122-139. Epub 2019 Apr 5.

School of Chemistry and Molecular Bioscience, University of Wollongong , Wollongong , Australia.

Nanotechnology has the potential to bring about revolutionary changes in manufacturing products, including sunscreens. However, a knowledge gap between benefits and detriments of engineered nano-materials used in sunscreens exists, which gives rise to safety concerns. This article is concerned with the protection of consumers without impairing the embellishment of this promising technology. It is widely argued that the harm associated with nano-sunscreens may only occur under certain conditions related mainly to users skin vulnerability, which can be avoided by informed and careful use of such a product. We thus recognize the need for fostering the growth of nanotech simultaneously with preventing potential harm. We revisit the Australian sunscreens regulatory policies, which embrace a "wait and see" approach, through the lens of regulatory policies in the European Union (EU) that are influenced by a "precautionary principle." We highlight the importance of informing consumers about the sunscreen they are using and recommend that product labels should disclose the presence of nano-ingredients in line with the EU disclosure requirements. This will allow users to carefully apply the product in order to avoid any potential harm and to protect manufacturers from possible costly litigation in future. This can be achieved through a combined collaborative effort of regulators, supply chain entities, and end users.
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http://dx.doi.org/10.1080/10408444.2019.1579780DOI Listing
February 2019

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

Psychoneuroendocrinology 2019 06 21;104:286-299. Epub 2019 Mar 21.

School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, Hubei, China; State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan, Hubei, China. Electronic address:

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 β- nuclear factor kappa B (IKKβ-NFκB) signaling pathway in olanzapine-induced weight gain in female rats. In this study, we found that olanzapine significantly activated PERK-eIF2α and IKKβ-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 IKKβ-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 IKKβ-NFκB signaling in the hypothalamus. These results suggested that hypothalamic ER stress may play an important role in antipsychotic-induced weight gain.
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http://dx.doi.org/10.1016/j.psyneuen.2019.03.017DOI Listing
June 2019

The gut microbiota promotes the pathogenesis of schizophrenia via multiple pathways.

Biochem Biophys Res Commun 2019 04 18;512(2):373-380. Epub 2019 Mar 18.

The First Affiliated Hospital/Zhengzhou University, Zhengzhou, China; Biological Psychiatry International Joint Laboratory of Henan/Zhengzhou University, Zhengzhou, China; Henan Psychiatric Transformation Research Key Laboratory/Zhengzhou University, Zhengzhou, China. Electronic address:

Schizophrenia is a severe mental disorder with unknown etiology. Many mechanisms, including dysregulation of neurotransmitters, immune disturbance, and abnormal neurodevelopment, are proposed for the pathogenesis of schizophrenia. The significance of communication between intestinal flora and the central nervous system through the gut-brain axis is increasingly being recognized. The intestinal microbiota plays an important role in regulating neurotransmission, immune homeostasis, and brain development. We hypothesize that an imbalance in intestinal flora causes immune activation and dysfunction in the gut-brain axis, contributing to schizophrenia. In this review, we examine recent studies that explore the intestinal flora and immune-mediated neurodevelopment of schizophrenia. We conclude that an imbalance in intestinal flora may reduce protectants and increase neurotoxin and inflammatory mediators, causing neuronal and synaptic damage, which induces schizophrenia.
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http://dx.doi.org/10.1016/j.bbrc.2019.02.152DOI Listing
April 2019

Alterations to the microbiota-colon-brain axis in high-fat-diet-induced obese mice compared to diet-resistant mice.

J Nutr Biochem 2019 03 1;65:54-65. Epub 2018 Sep 1.

Department of Pathogen Biology and Immunology, Xuzhou Medical University and Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou, Jiangsu 221004, China. Electronic address:

Obesity is underpinned by both genetic and environmental factors, including a high-saturated-fat diet. Some mice develop diet-induced obesity (DIO), but others remain diet resistant (DR) despite intake of the same high-saturated-fat diet, a phenomenon that mimics characteristics of the human obese phenotype. Microbiota-colon-brain axis regulation is important for energy metabolism and cognition. Using DIO and DR mouse models, this study aimed to examine gut microbiota, colonic inflammation and cognitive function to elucidate the role of microbiota-gut-brain regulation in DIO. C57Bl6/J mice fed a chronic saturated-palmitic-acid diet for 22 weeks showed significant body weight gain differences, with the top one third gaining 48% heavier body weight than the lower one third. There was significant reduction in gut microbiota richness and diversity in DIO mice but not in DR mice. At the phylum level, DIO mice had increased abundance of Firmicutes and Antinobacteria, and decreased abundance of Bacterioides and Proteobacteria in gut microbiota. DIO mice exhibited reduced tight junction proteins, increased plasma endotoxin lipopolysaccharide (LPS) and increased inflammation in the colon and liver. Recognition memory and spatial memory were impaired in DIO mice, associated with decreased Bacteroidetes. Further examination showed that hippocampal brain-derived neurotrophic factor was significantly decreased in DIO mice (vs. DR). Conversely, DR mice showed no changes in the above parameters measured. Therefore, gut microbiota, colon inflammation and circulating LPS may play a major role in the development of the obese phenotype and cognitive decline associated with a chronic high-saturated-palmitic-acid diet.
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http://dx.doi.org/10.1016/j.jnutbio.2018.08.016DOI Listing
March 2019

Aripiprazole and haloperidol protect neurite lesions via reducing excessive D2R-DISC1 complex formation.

Prog Neuropsychopharmacol Biol Psychiatry 2019 06 28;92:59-69. Epub 2018 Dec 28.

Illawarra Health and Medical Research Institute (IHMRI) and School of Medicine, University of Wollongong, NSW 2522, Australia; Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Jiangsu 221004, China. Electronic address:

Dopamine D2 receptor (D2R) hyperactivity causes altered brain development and later produces onset of symptoms mimicking schizophrenia. It is known that D2R interacts with disrupted in schizophrenia 1 (DISC1); however, the effect of D2R-DISC1 interaction in intracellular signalling and neurite growth has not been studied. This study investigated the effect of D2R over-activation on Akt-GSK3β signalling and neurite morphology in cortical neurons. Over-activation of D2Rs caused neurite lesions, which were associated with decreased protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3β) phosphorylation in cortical neurons. The antipsychotic drug aripiprazole was more effective in the prevention of neurite lesions than haloperidol. Unlike haloperidol, aripiprazole prevented downregulation of phospho (p) Akt-pGSK3β induced by D2R hyperactivity, indicating involvement of different pathways. D2Rs were hyperactive in cortical neurons of mice with DISC1 mutation, which caused more severe neurite lesions in cortical neurons treated with quinpirole. Immunofluorescent staining for Ca/calmodulin-dependent protein kinase II (CaMKII) confirmed that cortical pyramidal neurons were involved in the D2R hyperactivity-induced neurite lesions. Using the fluorescence resonance energy transfer (FRET) technique, we provide direct evidence that D2R hyperactivity led to D2R-DISC1 complex formation, which altered pGSK3β signalling. This study showed that D2R hyperactivity-induced D2R-DISC1 complex formation is associated with decreased pAkt-pGSK3β signalling and in turn, caused neurite impairment. Aripiprazole and haloperidol prevented the impairment of neurite growth but appeared to do so via different intracellular signalling pathways.
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http://dx.doi.org/10.1016/j.pnpbp.2018.12.007DOI Listing
June 2019

Association between hyperuricemia and metabolic syndrome in patients suffering from bipolar disorder.

BMC Psychiatry 2018 12 18;18(1):390. Epub 2018 Dec 18.

Illawarra Health and Medical Research Institute and School of Medicine, University of Wollongong, Wollongong, NSW, 2522, Australia.

Background: Clinical studies have shown that bipolar patients have increased serum uric acid levels. High serum uric acid levels could play a role contributing to high prevalence of metabolic syndrome. Metabolic syndrome is known to increase the risk of developing a number of life threatening diseases including coronary heart disease, hypertension, and type 2 diabetes. This study investigated the association between hyperuricemia and metabolic syndrome and its components in individuals suffering from bipolar disorders.

Methods: This study recruited 318 inpatients suffering from bipolar disorders from Beijing Hui-Long-Guan Hospital in China and 160 healthy subjects from the same region as the controls. We used National Cholesterol Education Program Adult Treatment Panel III Adapted criteria (NCEP ATP-III A) for the diagnosis of metabolic syndrome. Hyperuricemia was determined as serum uric acid level above 420 μmol/L in men and 360 μmol/L in women (N Engl J Med 359(17):1811-1821, 2008).

Results: Among 318 bipolar patients, there was higher prevalence of metabolic syndrome (42.5%) and hyperuricemia (27.7%) than healthy controls (21.9 and 11.9%). Bipolar patients with metabolic syndrome had increased prevalence of hyperuricemia (OR = 3.0, CI95 [1.7-5.4]). Hypertriglyceridemia and larger waist circumference (WC) were associated with hyperunicemia (OR = 1.8, CI95 [1.1-3.1], OR = 1.9, CI95 [1.1-3.4]). Hyperuricemia was associated with metabolic syndrome in bipolar patients (p < 0.001) and especially with hypertriglyceridemia (OR = 1.9, CI95 [1.1-3.1] and increased WC (OR = 2.1 [1.2-4.0]). Bipolar patients over 50 years of age and hyperuricemia were highly prone to develop metabolic syndrome (OR = 14.0, CI95 [5.0-39.0]).

Conclusions: Hyperuricemia was highly associated with development of metabolic disorder particularly for aged patients suffering from bipolar disorders. Early prevention of hyperuricemia and metabolic syndrome may lead better life for bipolar patients when they get older.
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http://dx.doi.org/10.1186/s12888-018-1952-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299580PMC
December 2018

Obesity, altered oxidative stress, and clinical correlates in chronic schizophrenia patients.

Transl Psychiatry 2018 11 29;8(1):258. Epub 2018 Nov 29.

Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.

Antipsychotic pharmacotherapy is strongly obesogenic and is associated with increased oxidative stress in patients with schizophrenia. However, whether these changes reflect psychopathology, antipsychotic efficacy, or some other factor is not known. Our study aims to investigate the degree of oxidative stress in different BMI categories and to identify clinical symptomatology that may be paired with increased oxidative stress in a schizophrenia population. To this end, we performed a cross-sectional study and recruited 89 long-term inpatients with schizophrenia and collected the following variables: plasma malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), routine biochemical analysis, and psychopathology through the Positive and Negative Syndrome Scale (PANSS). The results indicate that the levels of the lipid peroxidation product, MDA, were significantly higher in the high BMI group than the low (normal) BMI group. As expected, high BMI was associated with an atherogenic lipid profile; however, it was also associated with fewer psychopathological symptoms. Multiple regression analysis found that MDA levels, the PANSS general psychopathology subscore, and triglyceride levels (all p < 0.05) were independent contributors to the BMI in patients. These results suggested that oxidative stress may play an important role in antipsychotic-induced weight gain. Further investigations using the longitudinal design in first-episode schizophrenia patients are needed to explore the beneficial effect of antioxidants on the abnormal lipid metabolism mediated by antipsychotic treatment.
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http://dx.doi.org/10.1038/s41398-018-0303-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265271PMC
November 2018

Propionate Protects Haloperidol-Induced Neurite Lesions Mediated by Neuropeptide Y.

Front Neurosci 2018 15;12:743. Epub 2018 Oct 15.

Illawarra Health and Medical Research Institute, School of Medicine, University of Wollongong, Wollongong, NSW, Australia.

Haloperidol is a commonly used antipsychotic drug for treating schizophrenia. Clinical imaging studies have found that haloperidol can cause volume loss of human brain tissue, which is supported by animal studies showing that haloperidol reduces the number of synaptic spines. The mechanism remains unknown. Gut microbiota metabolites, short chain fatty acids including propionate, are reported to have neuroprotective effect and influence gene expression. This study aims to investigate the effect and mechanism of propionate in the protection of neurite lesion induced by haloperidol. This study showed that 10 μM haloperidol (clinical relevant dose) impaired neurite length in human blastoma SH-SY5Y cells, which were confirmed by using primary mouse striatal spiny neurons. We found that haloperidol impaired neurite length were accompanied by a decreased neuropeptide Y (NPY) expression, but no effect on GSK3β signaling. Importantly, this project research found that propionate was capable of protecting against haloperidol-induced neurite lesions and preventing NPY reduction. To confirm this finding, we used specific siRNAs targeting NPY which blocked the protective effect of propionate on haloperidol-induced neurite lesions. Furthermore, since NPY is regulated by the nuclear transcription factor CREB, we measured pCREB that was decreased by haloperidol and was normalized by propionate. Therefore, propionate has a protective effect against pCREB-NPY mediated haloperidol-induced neurite lesions.
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http://dx.doi.org/10.3389/fnins.2018.00743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196753PMC
October 2018

Perinatal administration of phencyclidine alters expression of Lingo-1 signaling pathway proteins in the prefrontal cortex of juvenile and adult rats.

Neuronal Signal 2018 Sep 28;2(3):NS20180059. Epub 2018 Sep 28.

Centre for Medical and Molecular Bioscience, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia.

Postnatal administration of phencyclidine (PCP) in rodents causes major brain dysfunction leading to severe disturbances in behavior lasting into adulthood. This model is routinely employed to model psychiatric disorders such as schizophrenia, as it reflects schizophrenia-related brain disturbances including increased apoptosis, and disruptions to myelin and plasticity processes. Leucine-rich repeat and Immunoglobin-like domain-containing protein 1 (Lingo-1) is a potent negative regulator of both axonal myelination and neurite extension. The Nogo receptor (NgR)/tumor necrosis factor (TNF) receptor orphan Y (TROY) and/or p75 neurotrophin receptor (p75) complex, with no lysine (K) (WNK1) and myelin transcription factor 1 (Myt1) are co-receptors or cofactors in Lingo-1 signaling pathways in the brain. We have examined the developmental trajectory of these proteins in a neurodevelopmental model of schizophrenia using PCP to determine if Lingo-1 pathways are altered in the prefrontal cortex throughout different stages of life. Sprague-Dawley rats were injected with PCP (10 mg/kg) or saline on postnatal days (PN)7, 9, and 11 and killed at PN12, 5 or 14 weeks for measurement of Lingo-1 signaling proteins in the prefrontal cortex. Myt1 was decreased by PCP at PN12 (=0.045), and at 14 weeks PCP increased Lingo-1 (=0.037), TROY (=0.017), and WNK1 (=0.003) expression. This is the first study reporting an alteration in Lingo-1 signaling proteins in the rat prefrontal cortex both directly after PCP treatment in early development and in adulthood. We propose that Lingo-1 pathways may be negatively regulating myelination and neurite outgrowth following the administration of PCP, and that this may have implications for the cortical dysfunction observed in schizophrenia.
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http://dx.doi.org/10.1042/NS20180059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373234PMC
September 2018