High urea induces depression and LTP impairment through mTOR signalling suppression caused by carbamylation.

BACKGROUND: Urea, the end product of protein metabolism, has been considered to have negligible toxicity for a long time. Our previous study showed a depression phenotype in urea transporter (UT) B knockout mice, which suggests that abnormal urea metabolism may cause depression. The purpose of this study was to determine if urea accumulation in brain is a key factor causing depression using clinical data and animal models. METHODS: A meta-analysis was used to identify the relationship between depression and chronic diseases. Functional Magnetic Resonance Imaging (fMRI) brain scans and common biochemical indexes were compared between the patients and healthy controls. We used behavioural tests, electrophysiology, and molecular profiling techniques to investigate the functional role and molecular basis in mouse models. FINDINGS: After performing a meta-analysis, we targeted the relevance between chronic kidney disease (CKD) and depression. In a CKD mouse model and a patient cohort, depression was induced by impairing the medial prefrontal cortex. The enlarged cohort suggested that urea was responsible for depression. In mice, urea was sufficient to induce depression, interrupt long-term potentiation (LTP) and cause loss of synapses in several models. The mTORC1-S6K pathway inhibition was necessary for the effect of urea. Lastly, we identified that the hydrolysate of urea, cyanate, was also involved in this pathophysiology. INTERPRETATION: These data indicate that urea accumulation in brain is an independent factor causing depression, bypassing the psychosocial stress. Urea or cyanate carbamylates mTOR to inhibit the mTORC1-S6K dependent dendritic protein synthesis, inducing impairment of synaptic plasticity in mPFC and depression-like behaviour. CKD patients may be able to attenuate depression only by strict management of blood urea.

Protective effects of astragaloside IV against ovalbumin-induced allergic rhinitis are mediated by T-box protein expressed in T cells/GATA-3 and forkhead box protein 3/retinoic acid-related orphan nuclear receptor γt.

3-O-ß-D-xylopyranosyl-6-O-ß-D-glucopyranosyl-cycloastragenol, or Astragaloside IV (AST), is one of the major active ingredients isolated from Astragalus membranaceous with distinct pharmacological effects, and possesses anti-inflammatory, immunoregulatory and antifibrotic properties. However, the effects of AST on allergic rhinitis remain to be elucidated. The present study aimed to examine the effects of AST on immunoglobulin (Ig) E­mediated allergic reactions in vivo, by using a mouse model of allergic rhinitis established via repetitive sensitization and intranasal challenge with ovalbumin (OVA). Intragastric administration of AST (25 mg/kg or 50 mg/kg) or dexamethasone (DEX; 3 mg/kg) significantly alleviated the inflammatory response, nasal symptoms and mucosa remodeling, and decreased the serum levels of OVA­specific IgE in allergic mice. Furthermore, treatment with AST or DEX significantly suppressed the mRNA and protein expression levels of the transcription factor GATA­3 and retinoic acid receptor­related orphan nuclear receptor (ROR)γt in tissue samples isolated from the spleen and nasal mucosa of mice with allergic rhinitis. Conversely, mRNA and protein expression levels of T­box protein expressed in T cells (T­bet) and forkhead box protein 3 (Foxp3) were upregulated in the spleen and nasal mucosa of mice with allergic rhinitis following treatment with AST or DEX, and spleen protein levels of signal transducer and activator of transcription 3 followed a similar trend. In addition, treatment with AST was associated with fewer adverse events compared with treatment with DEX. The present results suggested that treatment with AST may attenuate OVA­induced allergic rhinitis via regulating the expression of the transcription factors GATA­3, RORγt, T­bet and Foxp3, which commit T helper cells to the Th1 phenotype. Therefore, AST may represent an alternative therapeutic approach for the treatment of patients with allergic rhinitis.

20(S)-ginsenoside Rh2 inhibits the proliferation and induces the apoptosis of KG-1a cells through the Wnt/ß-catenin signaling pathway.

Previous research has shown that total saponins of Panax ginseng (TSPG) and other ginsenoside monomers inhibit the proliferation of leukemia cells. However, the effect has not been compared among them. Cell viability was determined by Cell Counting Kit-8 assay, and ultra-structural characteristics were observed under transmission electron microscopy. Cell cycle distribution and apoptosis were determined by flow cytometry (FCM). Real-time fluorescence quantitative­PCR, western blotting and immunofluorescence were used to measure the expression of ß-catenin, TCF4, cyclin D1 and NF-κBp65. ß-catenin/TCF4 target gene transcription were observed by ChIP-PCR assay. We found that 20(S)-ginsenoside Rh2 [(S)Rh2] inhibited the proliferation of KG-1a cells more efficiently than the other monomers. Moreover, (S)Rh2 arrested KG-1a cells in the G0/G1 phase and induced apoptosis. In addition, the levels of ß-catenin, TCF4, cyclin D1 mRNA and protein were decreased. The ChIP-PCR showed that (S)Rh2 downregulated the transcription of ß-catenin/TCF4 target genes, such as cyclin D1 and c-myc. These results indicated that (S)Rh2 induced cell cycle arrest and apoptosis through the Wnt/ß-catenin signaling pathway, demonstrating its potential as a chemotherapeutic agent for leukemia therapy.