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Acute kidney injury (AKI) is a pathological condition characterized by a rapid decrease in glomerular filtration rate and nitrogenous waste accumulation during hemodynamic regulation. Alisol B, from Alisma orientale, displays anti-tumor, anti-complement, and anti-inflammatory effects. However, its effect and action mechanism on AKI is still unclear. Herein, alisol B significantly attenuated cisplatin (Cis)-induced renal tubular apoptosis through decreasing expressions levels of cleaved-caspase 3 and cleaved-PARP and the ratio of Bax/Bcl-2 depended on the p53 pathway. Alisol B also alleviated Cis-induced inflammatory response (e.g. the increase of ICAM-1, MCP-1, COX-2, iNOS, IL-6, and TNF-α) and oxidative stress (e.g. the decrease of SOD and GSH, the decrease of HO-1, GCLC, GCLM, and NQO-1) through the NF-κB and Nrf2 pathways. In a target fishing experiment, alisol B bound to soluble epoxide hydrolase (sEH) as a direct cellular target through the hydrogen bond with Gln384, which was further supported by inhibition kinetics and surface plasmon resonance (equilibrium dissociation constant, K D = 1.32 μM). Notably, alisol B enhanced levels of epoxyeicosatrienoic acids and decreased levels of dihydroxyeicosatrienoic acids, indicating that alisol B reduced the sEH activity in vivo. In addition, sEH genetic deletion alleviated Cis-induced AKI and abolished the protective effect of alisol B in Cis-induced AKI as well. These findings indicated that alisol B targeted sEH to alleviate Cis-induced AKI via GSK3β-mediated p53, NF-κB, and Nrf2 signaling pathways and could be used as a potential therapeutic agent in the treatment of AKI.

Main observation and conclusion: Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history. After investigation of U. rhynchophylla, eleven monoterpene indole alkaloids, including four new compounds uncarialins J—M (1—4) and seven known analogues (5—11), were isolated and identified. Their structural characterization was conducted using HRESIMS, 1D and 2D NMR, electronic circular dichroism (ECD) spectra, and quantum chemical computations. Compounds 1, 2, 7, and 9—11 displayed significant agonistic effects towards 5‐HT1A receptor, and their EC50 values were 7.86, 7.32, 2.24, 1.18, 1.52, and 3.75 μmol/L, respectively. Furthermore, in vivo experimental results fully revealed that hirsuteine (7) displayed a significant antidepression effect in unpredictable chronic mild stress (UCMS)‐induced depression mice mainly via regulating 5‐HT1A signaling pathway. Molecular docking and site‐directed amino acid mutation verified that amino acid residues Asp116 and Asn386 were the binding sites of hirsuteine (7) with 5‐HT1A receptor. In addition, pre‐treatment of mice with WAY 100635 also blocked the anti‐depression effect of hirsuteine (7), which further demonstrated that 5‐HT1A receptor was a potential target of hirsuteine (7) to effectively treat depression. These findings indicated the therapeutic material basis of U. rhynchophylla and the anti‐depression underlying mechanism of hirsuteine (7), and further provided the useful guidance for the development of hirsuteine (7) as a potential antidepressant candidate. [ABSTRACT FROM AUTHOR]

Background: Depression is a pervasive or persistent mental disorder that causes mood, cognitive and memory deficits. Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history, although its efficacy and potential mechanism are still uncertain.Purpose: The present study aimed to investigate anti-depression effect and potential mechanism of U. rhynchophylla extract (URE).Study Design and Methods: A mouse depression model was established using unpredictable chronic mild stress (UCMS). Effects of URE on depression-like behaviours, neurotransmitters, and neuroendocrine hormones were investigated in UCMS-induced mice. The potential target of URE was analyzed by transcriptomics and bioinformatics methods and validated by RT-PCR and Western blot. The agonistic effect on 5-HT1A receptor was assayed by dual-luciferase reporter system.Results: URE ameliorated depression-like behaviours, and modulated levels of neurotransmitters and neuroendocrine hormones, including 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), corticosterone (CORT), corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH), in UCMS-induced mice. Transcriptomics and bioinformatics results indicated that URE could regulate glutamatergic, cholinergic, serotonergic, and GABAergic systems, especially neuroactive ligand-receptor and cAMP signaling pathways, revealing that Htr1a encoding 5-HT1A receptor was a potential target of URE. The expression levels of downstream proteins of 5-HT1A signaling pathway 5-HT1A, CREB, BDNF, and PKA were increased in UCMS-induced mice after URE administration, and URE also displayed an agonistic effect against 5-HT1A receptor with an EC50 value of 17.42 μg/ml.Conclusion: U. rhynchophylla ameliorated depression-like behaviours in UCMS-induced mice through activating 5-HT1A receptor. [ABSTRACT FROM AUTHOR]

Farnesoid X receptor (FXR) has been identified as an inhibitor of platelet function and an inducer of fibrinogen protein complex. However, the regulatory mechanism of FXR in hemostatic system remains incompletely understood. In this study, we aimed to investigate the functions of FXR in regulating antithrombin III (AT III). C57BL/6 mice and FXR knockout (FXR KO) mice were treated with or without GW4064 (30 mg/kg per day). FXR activation significantly prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), lowered activity of activated factor X (FXa) and concentrations of thrombin-antithrombin complex (TAT) and activated factor II (FIIa), and increased level of AT III, whereas all of these effects were markedly reversed in FXR KO mice. In vivo, hepatic AT III mRNA and protein expression levels were up-regulated in wild-type mice after FXR activation, but down-regulated in FXR KO mice. In vitro study showed that FXR activation induced, while FXR knockdown inhibited, AT III expression in mouse primary hepatocytes. The luciferase assay and ChIP assay revealed that FXR can bind to the promoter region of AT III gene where FXR activation increased AT III transcription. These results suggest FXR activation inhibits coagulation process via inducing hepatic AT III expression in mice. The present study reveals a new role of FXR in hemostatic homeostasis and indicates that FXR might act as a potential therapeutic target for diseases related to hypercoagulation.

Objective: To study the effect of the schizophrenia susceptible gene Sox11 on the migration of cortical neurons using mice as experimental animals. Methods: The real-time quantitative PCR and in situ hybridization were used to clarify the expression pattern of Sox11 in the cerebral cortex during development (E14.5, P0, P7, P14). The techniques of plasmid construction, transfection, in utero electroporation and immunostaining were used to explore the role of Sox11 in the neuronal radial migration by transfecting control shRNA plasmid, mSox11 shRNA plasmid and mSox11 shRNA post-interference recovery plasmid in mice of different ages (E17.5, P0, P4, P7). Results: Compared with control neurons, the migration of mSox11 shRNA transfected neurons was delayed significantly. When a part of the neurons in the control group had reached the surface of the neocortex, most of the neurons transfected with mSox11 shRNA remained in the middle area of the neocortex. After the rat Sox11 ( rSox11 ) gene overexpression vector was used to recuse the mouse Sox11 ( mSox11 ) gene interference in mice, the distribution of neurons after migration was basically the same as the control. The distribution of migrating neurons in the subventricular zone (SVZ), intermediate zone (IZ), and cortical plate (CP) was different significantly ( P ＜0.01) after Sox11 interference and recovery. Conclusion: Sox11 can promote the migration of cortical neurons, suggesting that Sox11 plays a crucial role in the migration process of mouse cortical neurons.

Background: Depression is a pervasive or persistent mental disorder that causes mood, cognitive and memory deficits. Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history, although its efficacy and potential mechanism are still uncertain., Purpose: The present study aimed to investigate anti-depression effect and potential mechanism of U. rhynchophylla extract (URE)., Study Design and Methods: A mouse depression model was established using unpredictable chronic mild stress (UCMS). Effects of URE on depression-like behaviours, neurotransmitters, and neuroendocrine hormones were investigated in UCMS-induced mice. The potential target of URE was analyzed by transcriptomics and bioinformatics methods and validated by RT-PCR and Western blot. The agonistic effect on 5-HT 1A receptor was assayed by dual-luciferase reporter system., Results: URE ameliorated depression-like behaviours, and modulated levels of neurotransmitters and neuroendocrine hormones, including 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), corticosterone (CORT), corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH), in UCMS-induced mice. Transcriptomics and bioinformatics results indicated that URE could regulate glutamatergic, cholinergic, serotonergic, and GABAergic systems, especially neuroactive ligand-receptor and cAMP signaling pathways, revealing that Htr1a encoding 5-HT 1A receptor was a potential target of URE. The expression levels of downstream proteins of 5-HT 1A signaling pathway 5-HT 1A , CREB, BDNF, and PKA were increased in UCMS-induced mice after URE administration, and URE also displayed an agonistic effect against 5-HT 1A receptor with an EC 50 value of 17.42 μg/ml., Conclusion: U. rhynchophylla ameliorated depression-like behaviours in UCMS-induced mice through activating 5-HT 1A receptor., (Copyright © 2020. Published by Elsevier GmbH.)

Nine new monoterpenoid indole alkaloids, uncarialins A-I ( 1 - 9 ), were isolated from Uncaria rhynchophylla as well as 14 known analogues ( 10 - 23 ). Their structures were determined by HRESIMS, 1D and 2D NMR, and experimental and calculated electronic circular dichroism data. Compounds 5 , 7 , 15 , and 22 displayed significant agonistic effects against the 5-HT 1A receptor with EC 50 values of 2.2 ± 0.1, 0.1 ± 0.1, 1.6 ± 0.3, and 2.0 ± 0.5 μM, respectively. The mechanisms of action of these four compounds with the 5-HT 1A receptor were investigated by molecular docking, and the results suggested that amino acid residues Asp116, Thr196, Asn386, and Tyr390 played critical roles in the observed activity of the above-mentioned compounds.

As a member of the nuclear receptor superfamily, the pregnane X receptor (PXR) is a ligand-activated transcription factor. PXR is highly expressed in liver and intestinal tissues, and also found in other tissues and organs, such as stomach and kidney. After heterodimerization with retinoid X receptor (RXR), PXR recruits numerous co-activating factors, and binds to specific DNA response elements to perform transcriptional regulation of the downstream target genes. As an acknowledged receptor for xenobiotics, PXR was initially considered as a nuclear receptor regulating drug metabolizing enzymes and transporters. However, nowadays, PXR has also been recognized as an important endobiotic receptor. Recent studies have shown that PXR activation can regulate glucose metabolism, lipid metabolism, steroid endocrine homeostasis, detoxification of cholic acid and bilirubin, bone mineral balance, and immune inflammation in vivo. This review focuses on the role of PXR in metabolism of endogenous substances.

Alismanin A (1), a novel aromatic triterpenoid with a C 34 skeleton, was isolated from Alisma orientale together with a rearranged nor-triterpenoid (2) and a 13,17-seco triterpenoid (3). Their structures were determined by a combination of HRESIMS, 2D NMR spectra, electronic circular dichroism (ECD), theoretical calculations, and X-ray diffraction analysis. Compounds 1 and 2 displayed significant activation effects on pregnane X receptor (PXR) at 10 nM. A plausible biosynthetic pathway for 1-3 is also discussed.