Background: With the growing importance of research about the association between neuroinflammation and major depressive disorder (MDD), anti-inflammatory agents have been used as a new antidepressant therapy in clinical practice. We conducted a network meta-analysis (NMA) with up-to-date evidence to compare different anti-inflammatory agents for improving the treatment of MDD patients.Methods: To identify eligible randomized clinical trials, four databases (i.e, the Cochrane Library, Web of Science, PubMed and Embase) were searched from inception date to May 31, 2020. Anti-inflammatory agents were defined as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, cytokine inhibitors, statins, pioglitazone, minocycline, N-acetylcysteine (NAC) and omega-3 fatty acid (Omega-3 FA). The main outcomes of this NMA were efficacy, acceptability and remission rate. Risk ratio (RR) was adopted for dichotomous outcomes, and the confidence interval (CI) was set at 95%. STATA 14.0 and R 3.6.3 were used to conduct the NMA. The study protocol was registered with PROSPERO (CRD42020182531).Results: A total of 39 studies, involving 2871 participants, were included in quantitative data synthesis. For efficacy, NSAIDs (RR=0.50, 95%CI: 0.26-0.73) and pioglitazone (RR=0.45, 95%CI: 0.20-0.84) were more favorable than placebo. With respect to acceptability, NSAIDs were more acceptable than placebo (RR=0.89, 95%CI: 0.77-0.99) and minocycline (RR=1.22, 95%CI: 1.03-1.49). For remission, NSAIDs were more superior than placebo (RR=0.48, 95%CI: 0.27-0.79) and Omega-3 FA (RR=2.01, 95%CI: 1.09-3.90), while NACs were more favorable than placebo (RR=0.39, 95%CI: 0.13-0.99). Based on the surface under the cumulative ranking curve (SUCRA) value, corticosteroids (0.86) were the best anti-inflammatory agent for MDD patients in terms of efficacy, but the head-to-head comparisons for the efficacy of glucocorticoids and other agents were not statistically significant. As for acceptability, NSAIDs (0.81) were much better than other anti-inflammatory agents. Besides, NAC (0.80) was the best anti-inflammatory agent in the terms of remission.Conclusions: In summary, we found that corticosteroids were more superior than other agents in terms of efficacy according to the SUCRA value. However, this result must be interpreted with caution because the head-to-head comparisons for the efficacy of glucocorticoids and other agents did not reach statistical significance. NSAIDs were recommended for acceptability and NAC for remission rate.

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Calcified aortic valve disease (CAVD), the most common valvular heart disease, lacks pharmaceutical treatment options because its pathogenesis remains unclear. This disease with a complex macroenvironment characterizes notable cellular heterogeneity. Therefore, a comprehensive understanding of cellular diversity and cell-to-cell communication are essential for elucidating the mechanisms driving CAVD progression and developing therapeutic targets. In this study, we used single-cell RNA sequencing (scRNA-seq) analysis to describe the comprehensive transcriptomic landscape and cell-to-cell interactions. The transitional valvular endothelial cells (tVECs), an intermediate state during the endothelial-to-mesenchymal transition (EndMT), could be a target to interfere with EndMT progression. Moreover, matrix valvular interstitial cells (mVICs) with high expression of midkine (MDK) interact with activated valvular interstitial cells (aVICs) and compliment-activated valvular interstitial cells (cVICs) through the MK pathway. Then, MDK inhibited calcification of VICs that calcification was validated by Alizarin Red S staining, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting assays in vitro. Therefore, we speculated that mVICs secreted MDK to prevent VICs’ calcification. Together, these findings delineate the aortic valve cells’ heterogeneity, underlining the importance of intercellular cross talk and MDK, which may offer a potential therapeutic strategy as a novel inhibitor of CAVD.

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