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Free Wanderer Powder regulates AMPA receptor homeostasis in chronic restraint stress-induced rat model of depression with liver-depression and spleen-deficiency syndrome.

ABSTRACT: Free Wanderer Powder (FWP) is a classic formula for depression with digestive dysfunctions, i.e., liver-depression and spleen-deficiency syndrome (LDSDS) in Chinese Medicine. But its protective mechanism has not been fully clarified. Here a chronic restraint stress (CRS) induced rat model showed depression with LDSDS in food intake, metabolism, and behaviour tests. Then 75 rats were randomly divided, and received CRS and different treatment with behaviour tests. Expressions of c-Fos and AMPA-type glutamate receptor subunits GluR1-3 in hippocampus CA1, CA3, DG and amygdala BLA were detected by immunohistochemistry, western blot and RT-PCR, respectively. In CRS rats, FWP alleviated depressive behaviour and c-Fos expression. FWP suppressed the increasement of GluR1 in CA1 and DG, p-GluR1 in CA1, and p-GluR2 and GluR3 in BLA. FWP also blocked the decrease of GluR1 and Glur2/3 in CA3, p-GluR1 in CA3, and p-GluR2 in CA1 and CA3. Furthermore, constituents of FWP and their potential targets were explored using UHPLC-MS and systematic bioinformatics analysis. There were 23 constituents identified in FWP, 9 of which regulated glutamatergic synapse. Together, these results suggest that FWP contains effective constituents and alleviates depression with LDSDS by regulating AMPA-type glutamate receptor homeostasis in amygdala and hippocampus.

SUBMITTER: Xi S

PROVIDER: S-EPMC7732332 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Free Wanderer Powder regulates AMPA receptor homeostasis in chronic restraint stress-induced rat model of depression with liver-depression and spleen-deficiency syndrome.

Xi Shengyan S Yue Guangxin G Liu Yueyun Y Wang Yanan Y Qiu Yingkun Y Li Zhigeng Z Ma Pei P Liu Tiegang T Jiang Youming Y Liang Yuan Y Liu Qun Q Shi Jing J Chen Jiaxu J Yue Lifeng L

Aging 20201014 19

Free Wanderer Powder (FWP) is a classic formula for depression with digestive dysfunctions, i.e., liver-depression and spleen-deficiency syndrome (LDSDS) in Chinese Medicine. But its protective mechanism has not been fully clarified. Here a chronic restraint stress (CRS) induced rat model showed depression with LDSDS in food intake, metabolism, and behaviour tests. Then 75 rats were randomly divided, and received CRS and different treatment with behaviour tests. Expressions of c-Fos and AMPA-typ ...[more]

PMID: 33052137

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Project description:BackgroundDysregulation of gut microbiota-host bile acid (BA) co-metabolism is a critical pathogenic factor of diarrhea-predominant irritable bowel syndrome (IBS-D). Traditional Chinese Medicine (TCM), instructed by pattern differentiation, is effective in treating IBS-D, in which liver depression and spleen deficiency (LDSD) is the most prevalent pattern. Still, it is unclear the linkage between the LDSD pattern and the BA metabolic phenotype.PurposeThis study aimed to uncover the biological basis of the LDSD pattern from the BA metabolic perspective.MethodsPatients with IBS-D completed questionnaires regarding the irritable bowel severity scoring system (IBS-SSS), stool frequency, Stool Bristol scale, and Self-Rating Scales of mental health. Fasting blood and morning feces were collected to analyze the gut metagenome and BA-related indices/metabolites.ResultsIBS-D patients with LDSD had a higher incidence of BA overexcretion (41% vs. 23% non-LDSD) with significant elevations in fecal total BAs and serum BA precursor 7α-hydroxy-4-cholesten-3-one levels. Compared to controls or non-LDSD patients, LDSD patients had a featured fecal BA profile, with higher proportions of deoxycholic acid (DCA), 7-ketodeoxycholic acid, and lithocholic acid. It is consistent with the BA-metabolizing genomic changes in the LDSD gut microbiota characterized by overabundances of 7-dehydroxylating bacteria and BA-inducible genes (baiCD/E/H). The score of bowel symptoms (stool frequency and abdominal pain) showing greater severity in the LDSD pattern were positively correlated with bai-expressing bacterial abundances and fecal DCA levels separately.ConclusionWe clarified a differed BA metabolic phenotype in IBS patients with LDSD, which closely correlates with the severity of bowel symptoms. It demonstrates that gut microbiota and host co-metabolism of BAs would provide crucial insight into the biology of the LDSD pattern and its internal relationship with IBS progression.

Project description:BACKGROUND & AIMS:Disruption to endoplasmic reticulum (ER) calcium homeostasis has been implicated in obesity, however, the ability to longitudinally monitor ER calcium fluctuations has been challenging with prior methodologies. We recently described the development of a Gaussia luciferase (GLuc)-based reporter protein responsive to ER calcium depletion (GLuc-SERCaMP) and investigated the effect of a high fat diet on ER calcium homeostasis. METHODS:A GLuc-based reporter cell line was treated with palmitate, a free fatty acid. Rats intrahepatically injected with GLuc-SERCaMP reporter were fed a cafeteria diet or high fat diet. The liver and plasma were examined for established markers of steatosis and compared to plasma levels of SERCaMP activity. RESULTS:Palmitate induced GLuc-SERCaMP release in vitro, indicating ER calcium depletion. Consumption of a cafeteria diet or high fat pellets correlated with alterations to hepatic ER calcium homeostasis in rats, shown by increased GLuc-SERCaMP release. Access to ad lib high fat pellets also led to a corresponding decrease in microsomal calcium ATPase activity and an increase in markers of hepatic steatosis. In addition to GLuc-SERCaMP, we have also identified endogenous proteins (endogenous SERCaMPs) with a similar response to ER calcium depletion. We demonstrated the release of an endogenous SERCaMP, thought to be a liver esterase, during access to a high fat diet. Attenuation of both GLuc-SERCaMP and endogenous SERCaMP was observed during dantrolene administration. CONCLUSIONS:Here we describe the use of a reporter for in vitro and in vivo models of high fat diet. Our results support the theory that dietary fat intake correlates with a decrease in ER calcium levels in the liver and suggest a high fat diet alters the ER proteome. Lay summary: ER calcium dysregulation was observed in rats fed a cafeteria diet or high fat pellets, with fluctuations in sensor release correlating with fat intake. Attenuation of sensor release, as well as food intake was observed during administration of dantrolene, a drug that stabilizes ER calcium. The study describes a novel technique for liver research and provides insight into cellular processes that may contribute to the pathogenesis of obesity and fatty liver disease.

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Free Wanderer Powder regulates AMPA receptor homeostasis in chronic restraint stress-induced rat model of depression with liver-depression and spleen-deficiency syndrome.

Publications

Free Wanderer Powder regulates AMPA receptor homeostasis in chronic restraint stress-induced rat model of depression with liver-depression and spleen-deficiency syndrome.

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