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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.

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: χ2= 11.5217, P= 0.0032); rs11765480 (genotype: χ2= 10.6620, P= 0.0049); rs1473355 (genotype: χ2= 8.3902, P= 0.0151); rs322246 (allele: χ2= 5.5954, P= 0.0180); rs322240 (genotype: χ2= 8.8429, P= 0.0121; allele: χ2= 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: χ2= 9.0290, P= 0.0110; A-G: χ2= 8.985, P= 0.0027; C-A: χ2= 5.814, P= 0.0159). Our present results indicate PTNas a susceptibility gene for schizophrenia.

Nine new monoterpenoid indole alkaloids, uncarialins A–I (1–9), were isolated from Uncaria rhynchophyllaas 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 22displayed significant agonistic effects against the 5-HT1Areceptor with EC50values 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-HT1Areceptor 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.

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-perfusion injury (IRI). In vitro and in vivo FXR activation was determined by 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 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 IR-induced AKI in WT mice but not in FXR-/-mice. Our results demonstrate that ABA can activate renal FXR to exert renoprotection against IRI-induced AKI. Therefore, ABA may represent a potential therapeutic agent in the treatment of ischemic AKI.