AIM OF THE STUDY: The study is aimed to investigate the anti-depressant effect and the molecular mechanism of G. elata in vitro and in vivo using PC12 cells and zebrafish model, respectively.
MATERIAL AND METHODS: Network pharmacology was performed to explore the potential active ingredients and action targets of G. elata Blume extracts (GBE) against depression. The cell viability and proliferation were determined by MTT and EdU assay, respectively. TUNEL assay was used to examine the anti-apoptotic effect of GBE. Immunofluorescence and Western blot were used to detect the protein expression level. In addition, novel tank diving test was used to investigate the anti-depressant effect in zebrafish depression model. RT-PCR was used to analyze the mRNA expression levels of genes.
RESULTS: G. elata against depression on the reticulon 4 receptors (RTN4R) and apoptosis-related targets, which were predicted by network pharmacology. Furthermore, GBE enhanced cell viability and inhibited the apoptosis in PC12 cells against CORT treatment. GBE relieved depression-like symptoms in adult zebrafish, included increase of exploratory behavior and regulation of depression related genes. Mechanism studies showed that the GBE inhibited the expression of RTN4R-related and apoptosis-related genes.
CONCLUSION: Our studies show the ameliorative effect of G. elata against depression. The mechanism may be associated with the inhibition of RTN4R-related and apoptosis pathways.
DESIGN: Double-masked, 100-week, multicenter, active-controlled, randomized trials.
METHODS: Subjects were randomized 1:1:1 to brolucizumab 3mg/6mg or aflibercept 2mg in KESTREL (N=566) or 1:1 to brolucizumab 6mg or aflibercept 2mg in KITE (N=360). Brolucizumab groups received 5 loading doses every 6 weeks (q6w) followed by q12w dosing, with optional adjustment to q8w if disease activity was identified at pre-defined assessment visits; aflibercept groups received 5xq4w followed by fixed q8w dosing. The primary endpoint was best-corrected visual acuity (BCVA) change from baseline at Week 52; secondary endpoints included the proportion of subjects maintained on q12w dosing, change in DRSS score and anatomical and safety outcomes.
RESULTS: At Week 52, brolucizumab 6mg was noninferior (NI margin 4 letters) to aflibercept in mean change in BCVA from baseline (KESTREL: +9.2 letters versus +10.5 letters; KITE: +10.6 letters versus +9.4 letters; p<0.001), more subjects achieved central subfield thickness (CSFT) <280µm and fewer had persisting subretinal and/or intraretinal fluid versus aflibercept, with >50% of brolucizumab 6mg subjects maintained on q12w dosing after loading. In KITE, brolucizumab 6mg showed superior improvements in change of CSFT from baseline over Week 40-Week 52 versus aflibercept (p=0.001). The incidence of ocular serious adverse events was 3.7% (brolucizumab 3mg), 1.1% (brolucizumab 6mg), 2.1% (aflibercept) in KESTREL; 2.2% (brolucizumab 6mg), 1.7% (aflibercept) in KITE.
CONCLUSION: Brolucizumab 6mg showed robust visual gains and anatomical improvements with an overall favorable benefit/risk profile in patients with DME.