Combination Therapy with N-Acetylserotonin and Aflibercept Activated the Akt/Nrf2 Pathway to Inhibit Apoptosis and Oxidative Stress in Rats with Retinal Ischemia-Reperfusion Injury.

PURPOSE: N-acetylserotonin (NAS) can reduce retinal ischemia-reperfusion injury (RIRI) by inhibiting the TLR4/NF-κB/NLRP3 signaling pathway. Aflibercept is an anti-VEGF drug used to treat a variety of eye diseases. This study was performed to investigate the effect of combination therapy with N-acetylserotonin and aflibercept on RIRI and its mechanism. METHODS: The RIRI model was established by elevating the intraocular pressure. H&E staining was used to observe the pathological changes in the retinal tissue. Cell apoptosis was evaluated by TUNEL. The expression of cleaved caspase-3 in the retina was detected by immunofluorescence and western blotting. The levels of SOD, GSH-Px, and MDA in retinal tissue were measured by ELISA. The protein expression of cytoplasmic Nrf2, nuclear Nrf2, HO-1, Akt, and p-Akt was determined by western blotting. RESULTS: The results showed that combination therapy with NAS and aflibercept significantly alleviated retinal histopathological damage, decreased retinal thickness (from 335.49 ± 30.50 µm to 226.16 ± 17.20 µm, p < 0.001) and the rate of retinal apoptosis (from 28.27 ± 0.39% to 7.87 ± 0.19%, p < 0.001), and downregulated protein expression (from 2.42 ± 0.03 to 1.39 ± 0.03, p < 0.001) and positive expression (from 31.88 ± 0.52 to 25.36 ± 0.58, p < 0.001) of cleaved caspase-3. In addition, combination therapy with NAS and aflibercept also upregulated the levels of SOD (from 20.31 ± 0.18 to 29.66 ± 0.83, p < 0.001) and GSH-Px (from 13.62 ± 0.36 to 19.31 ± 0.82, p < 0.001) and downregulated the level of MDA (from 0.51 ± 0.01 to 0.41 ± 0.01, p < 0.001) to inhibit oxidative stress. Finally, combination therapy with NAS and aflibercept increased the protein expression of cytoplasmic Nrf2 (from 0.10 ± 0.002 to 0.85 ± 0.01, p < 0.001), nuclear Nrf2 (from 0.43 ± 0.01 to 0.88 ± 0.04, p < 0.001), and HO-1 (from 0.45 ± 0.03 to 0.91 ± 0.04, p < 0.001) and the p-Akt/Akt ratio (from 0.45 ± 0.02 to 0.81 ± 0.07, p < 0.001). CONCLUSIONS: Overall, combination therapy with NAS and aflibercept attenuated RIRI, and its mechanism may be related to inhibiting apoptosis and oxidative stress and activating the Akt/Nrf2 pathway.

Relationship between preoperative external ventricular drainage and preoperative rebleeding in aneurysmal subarachnoid hemorrhage: A meta-analysis.

OBJECTIVE: To analyze published evidence on the relationship between preoperative external ventricular drainage (preop-EVD) and preoperative rebleeding (preop-rebleeding) in aneurysmal subarachnoid hemorrhage (aSAH). METHOD: A comprehensive search of three databases (PubMed, Ovid EMBASE, and The Cochrane Library) was conducted from their commencement to March 31, 2022. We collected studies reporting preop-EVD of rupture aneurysms while preop-rebleeding events were documented in these studies. We also extracted information on risk factors for preop-rebleeding from the studies and used Review Manager version 5.3 software to analyze. RESULTS: A total of 3671 cases from 14 articles were enrolled in this meta-analysis. Preop-rebleeding rate was 11.04 % (106/960) and 9.22 % (250/2711) in preop-EVD group and control group, respectively. The study lacked power to conclude a clinically significant increase in preop-rebleeding risk (OR=1.60, 95 %CI:0.82-3.22). Fisher> 2 (OR=1.86), modified Fisher> 2 (OR=7.57), World Federation of Neurological Surgeons (WFNS)> 2 (OR=4.39) and aneurysm size > 1 cm (OR=3.01) were risk factors of preop-rebleeding. Patients with Hunt-Hess (HH)> 2 showed a higher preop-rebleeding trend compared to HH≤ 2, but the result did not reach a statistical difference (OR=6.79, P = 0.06). No difference in preop-rebleeding risk between anterior circulation aneurysms and posterior circulation aneurysms. Hydrocephalus had also been shown to be unrelated to higher preop-rebleeding rate. CONCLUSIONS: Current evidence does not support that preop-EVD significantly increases the risk of rebleeding prior to aneurysm repair. Patients with poorer clinical status on admission and aneurysms size > 1 cm are at a higher risk of preop-rebleeding.

BmBlimp-1 gene encoding a C2H2 zinc finger protein is required for wing development in the silkworm Bombyx mori.

Cys2-His2 zinc finger (C2H2-ZF) proteins represent the most common class of transcription factors. These factors have great potential for the management of developmental progression by regulating the specific spatiotemporal expression of genes. In this study, we cloned one C2H2-ZF protein gene of Bombyx mori, BGIBMGA000319, that is orthologous to B-lymphocyte-induced maturation protein-1 (Blimp-1); we thus named it as Bombyx mori Blimp-1 (BmBlimp-1). In the silkworm, the BmBlimp-1 gene is specifically upregulated during day 2 of the pupal to adult stage and is highly expressed in wing discs on day 3 of the pupa. Knockdown of its expression level in the pupal stage results in a crumpled-winged silkworm moth. Using the predicted DNA-binding sequences of BmBlimp-1 to search the silkworm genome to screen target genes of BmBlimp-1, 7049 genes were identified to have at least one binding site of BmBlimp-1 on their 1 kb upstream and downstream genome regions. Comparisons of those genes with a reported pupal wing disc transcriptome data resulted in 4065 overlapping genes being retrieved. GO enrichment analysis of the overlapping genes showed that most of the genes were enriched in the binding term. Combining functional annotation and real-time quantitative PCR, 15 genes were identified as the candidate target genes of BmBlimp-1, including several wing cuticular protein genes, chitin synthase A, and wing disc development genes, such as Wnt1, cubitus interruptus (ci) and engrailed (en). Moreover, the amino acid sequence of the zinc finger motif of Blimp-1 gene was highly conserved among the 15 insect species. We propose that BmBlimp-1 is an important regulatory factor in silkworm wing development.

Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ-PI3Kδ Dual Inhibitors.

An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure-activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ-PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species.

Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (volitinib) as a highly potent and selective mesenchymal-epithelial transition factor (c-Met) inhibitor in clinical development for treatment of cancer.

HGF/c-Met signaling has been implicated in human cancers. Herein we describe the invention of a series of novel triazolopyrazine c-Met inhibitors. The structure-activity relationship of these compounds was investigated, leading to the identification of compound 28, which demonstrated favorable pharmacokinetic properties in mice and good antitumor activities in the human glioma xenograft model in athymic nude mice.

The molecular mechanisms involved in the cytotoxicity of alkannin derivatives.

In order to better understand the molecular aspects of the cytotoxic action mechanisms, the cytotoxicity of alkannin derivatives, 1-10, on five human tumor cell lines were examined and their standard redox potentials in aprotic medium were tested by means of cyclic voltammetry. It was suggested that the oxidative potential is closely related to the cytotoxicity. The more negative the oxidative potential of the hydroquinones, the higher cytotoxicity of these derivatives. The results of the compounds 5, 7, 9 and 10 with bad leaving groups, have higher cytotoxic action is not agreed with the bioreductive alkylation mechanism of quinones. It indicates that the molecular mechanism involving cytotoxicity of alkannin derivatives may favor the mechanism of production of reactive oxygen.