TRPV1 signaling of perirenal adipose tissue promotes DOCA-Salt-induced hypertension and kidney injury.

BACKGROUND: Denervation of renal or perirenal adipose tissue (PRAT) can reduce arterial blood pressure in various hypertensive experimental models. Trpv1 (transient receptor potential vanillin 1) channel is highly expressed in the renal sensory nerves and the dorsal root ganglias (DRGs) projected by PRAT. However, it is currently unclear whether Trpv1 in DRGs projected from PRAT can regulate renal hypertension. METHODS: We used resintoxin (RTX) to block the afferent sensory nerves of rat PRAT. We also constructed Trpv1-/- mice and Trpv1+/- mice or used the injection of AAV2-retro-shTrpv1 to detect the effects of Trpv1 knockout or knockdown of PRAT-projected DRGs on deoxycorticosterone acetate (DOCA)-Salt-induced hypertension and kidney injury. RESULTS: Blocking the afferent sensory nerves of PRAT with RTX can alleviate DOCA-Salt-induced hypertension and renal injury in rats. And this blockade reduces the expression of Trpv1 in the DRGs projected by PRAT. Injecting AAV2-retro-shTrpv1 into the PRAT of DOCA-Salt mice also achieved the same therapeutic effect. However, DOCA-Salt-induced hypertension and renal injury can be treated in Trpv1+/- mice but not alleviated or even worsened in Trpv1-/- mice, possibly because of compensatory increase of Trpv5 in DRG of Trpv1-/- mice. CONCLUSION: Reducing, rather than eliminating, Trpv1 in DRG from PRAT-projection can reduce blood pressure and kidney damage in DOCA-Salt in rats or mice. Trpv1 in PRAT-DRGs may serve as a therapeutic target for salt-sensitive hypertension and its renal complications.

Targeting of G protein-coupled receptor 39 alleviates angiotensin II-induced renal damage by reducing ribonucleotide reductase M2.

Renal fibrosis, apoptosis and autophagy are the main pathological manifestations of angiotensin II (Ang II)-induced renal injury. G protein-coupled receptor 39 (GPR39) is highly expressed in various tissues including the kidney, but its role in the kidney is entirely unclear. This study was performed to investigate the underlying mechanism by which knockdown of GPR39 alleviated Ang II-induced renal injury. In vivo, GPR39 knockout (KO) mice were constructed and infused with Ang II for 4 weeks, followed by renal function tests. In vitro, Ang II-induced cells were treated with si-GPR39 for 48 h. Fibrosis, apoptosis and autophagy were detected in both cells and mice. The underlying mechanism was sought by mRNA transcriptome sequencing and validated in vitro. GPR39 was upregulated in renal tissues of mice with Ang II-mediated renal injury. Knockdown of GPR39 ameliorated renal fibrosis, apoptosis, and autophagy, and decreased the expression of ribonucleotide reductase M2 (RRM2). In vitro, knockdown of GPR39 was also identified to improve the Ang II-induced cell fibrosis, apoptosis, and autophagy. mRNA transcriptome results showed that knockout of GPR39 reduced the expression of RRM2 in Ang II-induced kidney tissue. Activation of RRM2 could reverse the therapeutic effect of GPR39 knockout, and the inhibitor of RRM2 could improve the cell fibrosis, apoptosis and autophagy caused by GPR39 agonist. These results indicated that targeting of GPR39 could alleviate Ang II-induced renal fibrosis, apoptosis, and autophagy via reduction of RRM2 expression, and GPR39 may serve as a potential target for Ang II-induced renal injury.

In Silico Investigations on the Synergistic Binding Mechanism of Functional Compounds with Beta-Lactoglobulin.

Piceatannol (PIC) and epigallocatechin gallate (EGCG) are polyphenolic compounds with applications in the treatment of various diseases such as cancer, but their stability is poor. ß-lactoglobulin (ß-LG) is a natural carrier that provides a protective effect to small molecule compounds and thus improves their stability. To elucidate the mechanism of action of EGCG, PIC, and palmitate (PLM) in binding to ß-LG individually and jointly, this study applied molecular docking and molecular dynamics simulations combined with in-depth analyses including noncovalent interaction (NCI) and binding free energy to investigate the binding characteristics between ß-LG and compounds of PIC, EGCG, and PLM. Simulations on the binary complexes of ß-LG + PIC, ß-LG + EGCG, and ß-LG + PLM and ternary complexes of (ß-LG + PLM) + PIC, (ß-LG + PLM) + EGCG, ß-LG + PIC) + EGCG, and (ß-LG + EGCG) + PIC were performed for comparison and characterizing the interactions between binding compounds. The results demonstrated that the co-bound PIC and EGCG showed non-beneficial effects on each other. However, the centrally located PLM was revealed to be able to adjust the binding conformation of PIC, which led to the increase in binding affinity with ß-LG, thus showing a synergistic effect on the co-bound PIC. The current study of ß-LG co-encapsulated PLM and PIC provides a theoretical basis and research suggestions for improving the stability of polyphenols.

Traditional Chinese medicine for post-stroke depression: A systematic review and network meta-analysis (Protocol).

BACKGROUND: Post-stroke depression (PSD) is common in stroke survivors, with significantly negative effects and serious impairments in terms of personal and social functioning. While both pharmacological and traditional Chinese medicine (TCM) interventions have been administered for PSD, there is still uncertainty about the balance between these and what treatment strategy should be preferred in clinical practice. Therefore, we aim to compare and rank, describing the protocol of a systematic review and network meta-analysis (NMA), the commonly used TCM interventions for PSD. METHODS AND ANALYSIS: We will search CENTRAL (the Cochrane Central Register of Controlled Trials), CINAHL, Embase, PubMed, CBM and PsycINFO, the US National Institutes of Health and the World Health Organisation International Trials Registry Platform search portal from inception to November 2018. There will be no restrictions on language, publication year or publication type. Only randomized clinical trials (RCTs) accessing any TCM treatments against active comparator or other controls for PSD will be included. The primary outcomes will be efficacy (the total number of participants, declining more than 50% on the total score between baseline) and acceptability of treatment (dropout rate due to any cause). A Bayesian NMA will be performed to compare all relative outcome of different TCM interventions. we will conduct the network meta-regression meta-analyses of data on the sex ratio, the types of stroke and the treatment duration of TCM interventions. Potential explanations in extra subgroup analyses according to the results of heterogeneity and inconsistency will be explored, and sensitivity analyses will be conducted to assess the robustness of the findings. TRIALS REGISTRATION NUMBER: PROSPERO CRD42018082400. CONCLUSION: Our study will generate evidence for TCM in the treatment of PSD and help to reduce the uncertainty about the effectiveness of PSD management, which will encourage further suggestions for TCM clinical practice or guideline.