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Schizophrenia is a devastating neuropsychiatric disorder affecting 1% of the world population and ranks as one of the disorders providing the most severe burden for society. Schizophrenia etiology remains obscure involving multi-risk factors, such as genetic, environmental, nutritional, and developmental factors. Complex interactions of genetic and environmental factors have been implicated in the etiology of schizophrenia. This review provides an overview of the historical origins, pathophysiological mechanisms, diagnosis, clinical symptoms and corresponding treatment of schizophrenia. In addition, as schizophrenia is a polygenic, genetic disorder caused by the combined action of multiple micro-effective genes, we further detail several approaches, such as candidate gene association study (CGAS) and genome-wide association study (GWAS), which are commonly used in schizophrenia genomics studies. A number of GWASs about schizophrenia have been performed with the hope to identify novel, consistent and influential risk genetic factors. Finally, some schizophrenia susceptibility genes have been identified and reported in recent years and their biological functions are also listed. This review may serve as a summary of past research on schizophrenia genomics and susceptibility genes (NRG1, DISC1, RELN, BDNF, MSI2), which may point the way to future schizophrenia genetics research. In addition, depending on the above discovery of susceptibility genes and their exact function, the development and application of antipsychotic drugs will be promoted in the future., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Schizophrenia is a complex and devastating psychiatric disorder with a strong genetic background. However, much uncertainty still exists about the role of genetic susceptibility in the pathophysiology of schizophrenia. TEA domain transcription factor 1 (TEAD1) is a transcription factor associated with neurodevelopment and has modulating effects on various nervous system diseases. In the current study, we performed a case-control association study in a Northeast Chinese Han population to explore the characteristics of pathogenic TEAD1 polymorphisms and potential association with schizophrenia., Methods: We recruited a total of 721 schizophrenia patients and 1,195 healthy controls in this study. The 9 single nucleotide polymorphisms (SNPs) in the gene region of TEAD1 were selected and genotyped., Results: The genetic association analyses showed that five SNPs (rs12289262, rs6485989, rs4415740, rs7113256, and rs1866709) were significantly different between schizophrenia patients and healthy controls in allele or/and genotype frequencies. After Bonferroni correction, the association of three SNPs (rs4415740, rs7113256, and rs1866709) with schizophrenia were still evident. Haplotype analysis revealed that two strong linkage disequilibrium blocks (rs6485989-rs4415740-rs7113256 and rs16911710-rs12364619-rs1866709) were globally associated with schizophrenia. Four haplotypes (C-C-C and T-T-T, rs6485989-rs4415740-rs7113256; G-T-A and G-T-G, rs16911710-rs12364619-rs1866709) were significantly different between schizophrenia patients and healthy controls., Conclusion: The current findings indicated that the human TEAD1 gene has a genetic association with schizophrenia in the Chinese Han population and may act as a susceptibility gene for schizophrenia.

Introduction: As a devastating neurological disease, spinal cord injury (SCI) results in severe tissue loss and neurological dysfunction. Pregnane X receptor (PXR) is a ligand-activated nuclear receptor with a major regulatory role in xenobiotic and endobiotic metabolism and recently has been implicated in the central nervous system. In the present study, we aimed to investigate the role and mechanism of PXR in SCI., Methods: The clip-compressive SCI model was performed in male wild-type C57BL/6 (PXR +/+ ) and PXR-knockout (PXR -/- ) mice. The N2a H 2 O 2 -induced injury model mimicked the pathological process of SCI in vitro. Pregnenolone 16α-carbonitrile (PCN), a mouse-specific PXR agonist, was used to activate PXR in vivo and in vitro. The siRNA was applied to knock down the PXR expression in vitro. Transcriptome sequencing analysis was performed to discover the relevant mechanism, and the NRF2 inhibitor ML385 was used to validate the involvement of PXR in influencing the NRF2/HO-1 pathway in the SCI process., Results: The expression of PXR decreased after SCI and reached a minimum on the third day. In vivo, PXR knockout significantly improved the motor function of mice after SCI, meanwhile, inhibited apoptosis, inflammation, and oxidative stress induced by SCI. On the contrary, activation of PXR by PCN negatively influenced the recovery of SCI. Mechanistically, transcriptome sequencing analysis revealed that PXR activation downregulated the mRNA level of heme oxygenase-1 (HO-1) after SCI. We further verified that PXR deficiency activated the NRF2/HO-1 pathway and PXR activation inhibited this pathway in vitro., Conclusion: PXR is involved in the recovery of motor function after SCI by regulating NRF2/HO-1 pathway., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Renal fibrosis is a common pathological feature of chronic kidney disease (CKD) with various etiologies, which seriously affects the structure and function of the kidney. Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily and plays a critical role in regulating the genes related to xenobiotic and endobiotic metabolism in mammals. Previous studies show that PXR is expressed in the kidney and has protective effect against acute kidney injury (AKI). In this study, we investigated the role of PXR in CKD. Adenine diet-induced CKD (AD) model was established in wild-type and PXR humanized (hPXR) mice, respectively, which were treated with pregnenolone-16α-carbonitrile (PCN, 50 mg/kg, twice a week for 4 weeks) or rifampicin (RIF, 10 mg·kg -1 ·d -1 , for 4 weeks). We showed that both PCN and RIF, which activated mouse and human PXR, respectively, improved renal function and attenuated renal fibrosis in the two types of AD mice. In addition, PCN treatment also alleviated renal fibrosis in unilateral ureter obstruction (UUO) mice. On the contrary, PXR gene deficiency exacerbated renal dysfunction and fibrosis in both adenine- and UUO-induced CKD mice. We found that PCN treatment suppressed the expression of the profibrotic Wnt7a and β-catenin in AD mice and in cultured mouse renal tubular epithelial cells treated with TGFβ1 in vitro. We demonstrated that PXR was colocalized and interacted with p53 in the nuclei of tubular epithelial cells. Overexpression of p53 increased the expression of Wnt7a, β-catenin and its downstream gene fibronectin. We further revealed that p53 bound to the promoter of Wnt7a gene to increase its transcription and β-catenin activation, leading to increased expression of the downstream profibrotic genes, which was inhibited by PXR. Taken together, PXR activation alleviates renal fibrosis in mice via interacting with p53 and inhibiting the Wnt7a/β-catenin signaling pathway., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

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., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Sidestep cutting is a critical movement in sports. However, biomechanical research on sidestep cutting has not hitherto reached a consensus. In order to investigate the effects of limb dominance and movement direction on ankle and subtalar joints during sidestep cutting, twelve physically active male participants were recruited in the present study. Trajectory and ground reaction force data were collected by the motion capture system and force platform. Kinematics, kinetics, and muscle forces information were obtained by running OpenSim. Two-way repeated measures ANOVA was performed with movement direction and limb dominance as independent variables. We found that movement direction had a significant effect on ankle dorsiflexion angle. In contrast, the factor of limb dominance had no effect on ankle and subtalar joints angles. For ankle joint moment, the plantarflexion moment was greater by performing a 45° sidestep cutting or using the dominant limb, while the subtalar joint moment was not affected by these two variables. In terms of muscle forces, the soleus of the dominant limb generated greater plantarflexion muscle force on the sagittal plane, while the non-dominant limb tended to contract more strongly (peroneus longus and peroneus brevis) on the frontal plane to stabilize the subtalar joint. Meanwhile, a smaller sidestep cutting angle made participants generate greater plantarflexion muscle forces (soleus and gastrocnemius). In conclusion, our findings indicated that participants should take limb dominance and movement direction into consideration for enhancing athletic performance and reducing the risk of injury during sidestep cutting., Competing Interests: Declaration of Competing Interest The authors certify that there are no conflicts of interest to be declared., (Copyright © 2022 IPEM. Published by Elsevier Ltd. All rights reserved.)

As a member of the nuclear receptor (NR) superfamily, pregnane X receptor (PXR; NR1I2) is a ligand-activated transcription factor that plays a crucial role in the metabolism of xenobiotics and endobiotics in mammals. The tissue distribution of PXR is parallel to its function with high expression in the liver and small intestine and moderate expression in the kidney, stomach, skin, and blood-brain barrier, which are organs and tissues in frequent contact with xenobiotics. PXR was first recognized as an exogenous substance receptor regulating metabolizing enzymes and transporters and functioning in detoxification and drug metabolism in the liver. However, further research revealed that PXR acts as an equally important endogenous substance receptor in the metabolism and homeostasis of endogenous substances. In this review, we summarized the functions of PXR in metabolism of different substances such as glucose, lipid, bile acid, vitamin, minerals, and endocrines, and also included insights of the application of PXR ligands (drugs) in specific diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lv, Luo, Ren, Li, Xiang and Luan.)

Schizophrenia stands out as one of the most devastating psychiatric disorders. Previous findings have shown that schizophrenia is a polygenic genetic disorder. Thus, abnormal neurodevelopment and neurogenesis may be associated with the etiology of schizophrenia, so genes which affect these processes may be potential candidate genes of schizophrenia. Mitogen-activated protein kinase kinase kinase 4 (MAP3K4) gene is a member of the mitogen-activated protein kinase family. Taking into account previous findings, MAP3K4 plays a crucial role in the fundamental pathology of various nervous system diseases. In the present study, we aim to explore the association of MAP3K4 and schizophrenia in an independent case-control sample including 627 schizophrenic patients and 1175 healthy controls from a Northeast Chinese Han population. Both the allelic and genotypic association analyses showed that 6 SNPs in MAP3K4 were significantly associated with schizophrenia (rs590988, rs625977, rs9295134, rs12110787, rs1001808 and rs9355870). After rigorous Bonferroni correction, 4 SNPs (rs9295134, rs12110787, rs1001808 and rs9355870) were still significantly associated with the disease. The haplotype composed of these four SNPs also showed significantly global and individual association with schizophrenia. These results suggest that MAP3K4 is a susceptibility gene for schizophrenia in the Northeast Chinese Han population., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

As a major social and economic burden for the healthcare system, kidney diseases contribute to the constant increase of worldwide deaths. A deeper understanding of the underlying mechanisms governing the etiology, development and progression of kidney diseases may help to identify potential therapeutic targets. As a superfamily of ligand-dependent transcription factors, nuclear receptors (NRs) are critical for the maintenance of normal renal function and their dysfunction is associated with a variety of kidney diseases. Increasing evidence suggests that ligands for NRs protect patients from renal ischemia/reperfusion (I/R) injury, drug-induced acute kidney injury (AKI), diabetic nephropathy (DN), renal fibrosis and kidney cancers. In the past decade, some breakthroughs have been made for the translation of NR ligands into clinical use. This review summarizes the current understanding of several important NRs in renal physiology and pathophysiology and discusses recent findings and applications of NR ligands in the management of kidney diseases., Competing Interests: Declaration of interests The authors declare that they have no competing interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Intestinal commensal fungi are vital to human health, and their metabolites play a key role in the reciprocal relationship. In the present work, eighteen alkaloids and seven monoterpenoids were isolated from the fermentation of the human intestinal fungus Penicillium oxalicum SL2, including seven undescribed alkaloids (penicilloxalines A-G), three undescribed monoterpenoids (penicilloxalines H-J), and fifteen reported compounds. The structures of the isolated compounds were identified by HRESIMS, 1D and 2D NMR, electronic circular dichroism spectra and quantum chemical calculations. Some metabolites displayed moderate agonistic effects against the pregnane X receptor (PXR), whereas (6R)3,7-dimethyl-6,7-dihydroxy-2(Z)-octenoic acid displayed a significant agonistic effect against the farnesoid X receptor (FXR) with an EC 50 value of 0.43 μM, which was verified by investigating FXR downstream target genes and proteins, such as small heterodimer partner 1 (SHP1), fibroblast growth factor (FGF), and bile salt export pump (BSEP)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The ligand-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating renal function. Activation of FXR by its specific agonists exerts renoprotective action in animals with acute kidney injury (AKI). In the present study, we aimed to identify naturally occurring agonists of FXR with potential as therapeutic agents in renal ischemia-reperfusion injury. In vitro and in vivo FXR activation was determined by a dual-luciferase assay, docking analysis, site-directed mutagenesis, and whole kidney transcriptome analysis. Wild-type (WT) and FXR knockout ( FXR -/- ) mice were used to determine the effect of potential FXR agonist on renal ischemia-reperfusion injury (IRI). We found that alisol B 23-acetate (ABA), a major active triterpenoid extracted from Alismatis rhizoma , a well-known traditional Chinese medicine, can activate renal FXR and induce FXR downstream gene expression in mouse kidney. ABA treatment significantly attenuated renal ischemia-reperfusion-induced AKI in WT mice but not in FXR -/- mice. Our results demonstrate that ABA can activate renal FXR to exert renoprotection against ischemia-reperfusion injury-induced AKI. Therefore, ABA may represent a potential therapeutic agent in the treatment of ischemic AKI. NEW & NOTEWORTHY In the present study, we found that alisol B 23-acetate (ABA), an identified natural farnesoid X receptor (FXR) agonist from the well-known traditional Chinese medicine Alismatis rhizoma , protects against ischemic acute kidney injury (AKI) in an FXR-dependent manner, as reflected by improved renal function, reduced renal tubular apoptosis, ameliorated oxidative stress, and suppressed inflammatory factor expression. Therefore, ABA may have great potential as a novel therapeutic agent in the treatment of AKI in the future.

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.

Background: Accumulating evidence demonstrates that certain microRNAs play critical roles in epileptogenesis. Our previous studies found microRNA (miR)-129-2-3p was induced in patients with refractory temporal lobe epilepsy (TLE). In this study, we aimed to explore the role of miR-129-2-3p in TLE pathogenesis., Method: By bioinformatics, we predicted miR-129-2-3p may target the gene GABRA1 encoding the GABA type A receptor subunit alpha 1. Luciferase assay was used to investigate the regulation of miR-129-2-3p on GABRA1 3'UTR. The dynamic expression of miR-129-2-3p and GABRA1 mRNA and protein levels were measured in primary hippocampal neurons and a rat kainic acid (KA)-induced seizure model by quantitative reverse transcription-polymerase chain reaction (qPCR), Western blotting, and immunostaining. MiR-129-2-3p agomir and antagomir were utilized to explore their role in determining GABRA1 expression. The effects of targeting miR-129-2-3p and GABRA1 on epilepsy were assessed by electroencephalography (EEG) and immunostaining., Results: Luciferase assay, qPCR, and Western blot results suggested GABRA1 as a direct target of miR-129-2-3p. MiR-129-2-3p level was significantly upregulated, whereas GABRA1 expression downregulated in KA-treated rat primary hippocampal neurons and KA-induced seizure model. In vivo knockdown of miR-129-2-3p by antagomir alleviated the seizure-like EEG findings in accordance with the upregulation of GABRA1. Furthermore, the seizure-suppressing effect of the antagomir was partly GABRA1 dependent., Conclusions: The results suggested GABRA1 as a target of miR-129-2-3p in rat primary hippocampal neurons and a rat kainic acid (KA) seizure model. Silencing of miR-129-2-3p exerted a seizure-suppressing effect in rats. MiR-129-2-3p/GABRA1 pathway may represent a potential target for the prevention and treatment of refractory epilepsy., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

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.

Analysis and diagnosis according to the collected physical data are an important part in the physical examination. Through the data analysis of the physical examination results and expert diagnoses, the physical condition of a specific physical examination unit can be achieved which may guide individual health development. However, in general, the application of physical examination data is insufficient in most of the current physical examination organizations. Therefore, in the present study, statistical analysis and intelligent diagnosis were applied to maximize the utilization of physical examination data. The physical examination data collected from different departments of Dalian University of Technology were statistically analyzed and then synthesized for stimulating the thinking mode and knowledge framework of medical experts by a learning model on machine, resulting in the construction of an intelligent physical examination diagnosis method with 93.4% accuracy confirmed by experts. In conclusion, a potential artificial intelligence model of psychical examination data on health analysis and intelligent diagnosis was established, which may become more and more accurate with data accumulation in the near future., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Xiao-Ling Wang et al.)

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.)

As a severely and highly heritable psychotic disorder, schizophrenia has become a serious public health problem in modern society. Pleiotrophin (PTN) is a secreted cell cytokine associated with the extracellular matrix and acts as a growth factor. PTN is mainly expressed in neuroectodermal and mesodermal tissues, indicating its effect in neuron migration and epithelium-mesenchyme interactions. Whereas PTN is associated with some neurodegenerative diseases and has modulating effects on them. In this study, we aimed to investigate the association between PTN polymorphisms and schizophrenia in an independent case-control sample-set including 738 schizophrenia patients and 1085 healthy controls. Of the 13 selected single nucleotide polymorphisms (SNPs), five showed significant differences in allele or/and genotype frequencies between patients and controls: rs3959914 (genotype: χ = 11.5217, P = 0.0032); rs11765480 (genotype: χ = 10.6620, P = 0.0049); rs1473355 (genotype: χ = 8.3902, P = 0.0151); rs322246 (allele: χ = 5.5954, P = 0.0180); rs322240 (genotype: χ = 8.8429, P = 0.0121; allele: χ = 8.7802, P = 0.0031). The haplotype analysis of the selected SNPs showed different haplotype frequencies for one block (rs322240, rs322246) between cases and controls (global: χ = 9.0290, P = 0.0110; A-G: χ = 8.985, P = 0.0027; C-A: χ = 5.814, P = 0.0159). Our present results indicate PTN as a susceptibility gene for schizophrenia.

Objective: Schizophrenia is one of the most devastating neuropsychiatric disorders. Genetic epidemiological studies have confirmed that schizophrenia is a genetic disease. Genes promoting neurodevelopment may be potential candidates for schizophrenia. As an adaptor linking a number of tyrosine kinase receptors in multiple intracellular signaling cascades, Src homology 2 domain containing transforming protein 3 (SHC3) is a member of the Shc-like adaptor protein family, and expressed predominantly in the mature neurons of the central nervous system (CNS). In the present study, we aimed to investigate the association of SHC3 and schizophrenia., Methods: An independent case-control association study was performed in a sample including 710 schizophrenia patients and 1314 healthy controls from a Northeast Chinese Han population., Results: The allelic and genotypic association analyses showed that four SNPs in SHC3 significantly associated with schizophrenia (rs2316280, rs4877041, rs944485 and rs7021743). The haplotype composing of these four SNPs also showed significantly individual and global association with schizophrenia., Conclusion: Our present results suggest SHC3 as a susceptibility gene for schizophrenia.

Pulmonary fibrosis is a progressive, irreversible, and fatal fibrotic lung disease with a high mortality and morbidity, and commonly nonresponsive to conventional therapy. Inula japonica Thunb. is a traditional Chinese medicine, known as "Xuan Fu Hua" in Chinese, and has been widely applied to relieve cough and dyspnea and eliminate retained phlegm with a long history. In this study, we aimed to evaluate the anti-fibrosis effect and action mechanism of I. japonica extract (IJE) for the treatment of bleomycin (BLM)-induced pulmonary fibrosis in mice. IJE treatment significantly restored BLM-induced alterations in body weight loss and lung function decline, decreased the collagen deposition induced by BLM in lung tissues, and inhibited fibrotic and inflammatory factors, such as α-SMA, TGF-β1, TNF-α, IL-6, COX-2, NF-κB, and GSK3β, in a dose-dependent manner. We found that IJE could enhance the concentration of 8,9-epoxyeicosatrienoic acid (8,9-EET) and decrease concentrations of 8,9-dihydroxyeicosatrienoic acid (8,9-DHET), 11,12-DHET, and 14,15-DHET in BLM-induced mice. Meanwhile, IJE suppressed protein and mRNA expression levels of soluble epoxide hydrolase (sEH), and significantly displayed the inhibition of sEH activity with an IC 50 value of 0.98 μg/mL. Our results indicated that IJE exerted remarkable anti-fibrosis effect on BLM-induced pulmonary fibrosis in mice via inhibiting sEH activity, resulting in the regulation of GSK3β signaling pathway. Our findings revealed the underlying action mechanism of I. japonica, and suggested that I. japonica could be regarded as a candidate resource for the treatment of pulmonary fibrosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Diverse and circumstantial evidence suggests that schizophrenia is a neurodevelopmental disorder. Genes contributing to neurodevelopment may be potential candidates for schizophrenia. The human SOX11 gene is a member of the developmentally essential SOX (Sry-related HMG box) transcription factor gene family and mapped to chromosome 2p, a potential candidate region for schizophrenia., Methods: Our previous genome-wide association study (GWAS) implicated an involvement of SOX11 with schizophrenia in a Chinese Han population. To further investigate the association between SOX11 polymorphisms and schizophrenia, we performed an independent replication case-control association study in a sample including 768 cases and 1348 controls., Results: After Bonferroni correction, four SNPs in SOX11 distal 3'UTR significantly associated with schizophrenia in the allele frequencies: rs16864067 (allelic P = .0022), rs12478711 (allelic P = .0009), rs2564045 (allelic P = .0027), and rs2252087 (allelic P = .0025). The haplotype analysis of the selected SNPs showed different haplotype frequencies for two blocks (rs4371338-rs7596062-rs16864067-rs12478711 and rs2564045-rs2252087-rs2564055-rs1366733) between cases and controls. Further luciferase assay and electrophoretic mobility shift assay (EMSA) revealed the schizophrenia-associated SOX11 SNPs may influence SOX11 gene expression, and the risk and non-risk alleles may have different affinity to certain transcription factors and can recruit divergent factors., Conclusions: Our results suggest SOX11 as a susceptibility gene for schizophrenia, and SOX11 polymorphisms and haplotypes in the distal 3'UTR of the gene might modulate transcriptional activity by serving as cis-regulatory elements and recruiting transcriptional activators or repressors. Also, these SNPs may potentiate as diagnostic markers for the disease., (© 2020 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals, Inc.)

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.

Farnesoid X receptor (FXR) is a key regulator in charge of bile acid synthesis, transport, and metabolism. Activation of FXR represses bile acid synthesis and increases its excretion and transport, consequently protecting the liver functions. Thus, FXR is considered as a critical therapeutic target of cholestasis and nonalcoholic steatohepatitis. Herein, we isolated and identified fourteen new protostane-type triterpenoids (1-14) and four known analogues (15-18) from Alisma orientale, and finally constructed a small library of protostane-type triterpenoids (1-70) to investigate their structure-activity relationship with FXR, further leading to obtain compound 15 with potent agonistic activity against FXR (EC 50  = 90 nM). Extensive in vitro investigation confirmed high efficacy of compound 15 against FXR in living cell, and revealed its underlying mechanism for FXR activation (amino acid residues Arg331 and Ser332) by molecular docking and site-directed mutagenesis technology., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

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.

Ten new triterpenoid compounds with structure diversity of the C-17 side-chain, including nine tirucallanes, named xylocarpols A⁻E ( 1 ⁻ 5 ) and agallochols A⁻D ( 6 ⁻ 9 ), and an apotirucallane, named 25-dehydroxy protoxylogranatin B ( 10 ), were isolated from the mangrove plants Xylocarpus granatum , Xylocarpus moluccensis , and Excoecaria agallocha . The structures of these compounds were established by HR-ESIMS and extensive one-dimensional (1D) and two-dimensional (2D) NMR investigations. The absolute configurations of 1 and 2 were unequivocally determined by single-crystal X-ray diffraction analyses, conducted with Cu K α radiation; whereas those of 4 , 6 ⁻ 8 were assigned by a modified Mosher's method and the comparison of experimental electronic circular dichroism (ECD) spectra. Most notably, 5 , 6 , 7 , and 9 displayed potent activation effects on farnesoid⁻X⁻receptor (FXR) at the concentration of 10.0 μM; 10 exhibited very significant agonistic effects on pregnane⁻X⁻receptor (PXR) at the concentration of 10.0 nM.

A novel 1(2), 2(18)-diseco indole diterpenoid, drechmerin H (1), was isolated from the fermentation broth of Drechmeria sp. together with a new indole diterpenoid, 2'-epi terpendole A (3), and a known analogue, terpendole A (2). Their structures were determined by HRESIMS, 1D and 2D NMR, ECD, and X-ray single crystal diffraction analyses as well as quantum chemical calculation. The abosulte configuration of terpendole A (2) was determined for the first time. Compound 1 displayed the significant agonistic effect on pregnane X receptor (PXR) with EC 50 value of 134.91 ± 2.01 nM, and its interaction with PXR was investigated by molecular docking. Meantime, a plausible biosynthetic pathway for compounds 1-3 is also discussed in the present work., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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.