Although only a small number of venom peptides have successfully progressed to the clinic, there is reason to be optimistic about their development as anti-epileptic drugs, notwithstanding the challenges associated with development of any class of peptide drug.Small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched to offer anticancer oral treatment modalities. Different small molecules have been designed, such as BMS-202 and BMS-1166 which potently bind to PD-L1, sequestering the protein dimer and thus preventing cancer cells to escape antitumor immune responses. A (top → down) deconvolution of BMS compounds has characterized their central biphenyl unit as the minimal element required for PD-L1 protein binding. On this basis, we searched for approved drugs containing a similar biphenyl unit and endowed with immune modulatory activities. We identified the biphenyl anti-inflammatory drug flurbiprofen (FLB) as a potential candidate for PD-L1 interaction, and then proposed a (bottom → up) convolution to select similar molecules, used in Human, susceptible to engage stable interactions with PD-L1. The hypothesis was tested by molecular modeling using the crystal structure of BMS-202 bound to the PD-L1 dimer. The calculations suggest that both (R) and (S) isomers of FLB can form stable complexes with PD-L1, penetrating deep into the cylindric pocket at the interface of the protein dimer. However, the potential energy of interaction (ΔE) is reduced by ~40% for FLB compared to BMS compounds. Then, we identified three FLB analogues (diflunisal, CHF-5074 and HCT1026) forming stable complexes with PD-L1. The longer FLB derivative HCT1026 appears as a suitable binder of the PD-L1 dimer, sliding well along the BMS binding cavity. Our approach proposes a new strategy to discover PD-L1-binding small molecules and raises the intriguing possibility that FLB can bind transiently to PD-L1, thus possibly explaining some of its biological effects. Our study opens new perspectives for the use of FLB (and analogs) as an immune modulator in oncology and other therapeutic domains.Several studies have shown that 17β-estradiol (E2) exerted beneficial effects on liver disease, and it has a protective impact on brain damage after traumatic brain injury (TBI). TBI-induced liver injury is associated with the activation of TLR4. However, it remains unknown whether E2 can modulate TBI-induced liver injury through TLR4. The objective of this study was to determine the role of TLR4 in hepatoprotective mechanisms of E2 after TBI. Diffuse TBI induced by the Marmarou model in male rats. TAK-242 as a selective antagonist of TLR4 (3 mg/kg) and E2 (33.3 μg/kg) were injected (i.p) respectively 30 min before and 30 min after TBI. The results showed that E2 and TAK-242 markedly inhibited TBI-induced liver injury, which was characterized by decreased aminotransferase activities, inhibition of the oxidative stress, and reduced levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and IL-17 in the liver. Sodium L-ascorbyl-2-phosphate We also found that TBI induced significant upregulation of TLR4 in the liver, with peak expression occurring 24 h after TBI, and that treatment with E2 significantly inhibited the upregulation of TLR4. Also, both classic [Estrogen receptors alpha (ERα) and beta (ERβ)] and non-classic (G protein-coupled estrogen receptor GPER) E2 receptors are involved in modulating the expression of TLR4. These results suggested that the hepatoprotective effects of estradiol after TBI may be mediated via the downregulation expression of TLR4.MitoNEET is a mitochondrial outer membrane protein that hosts a redox active [2Fe-2S] cluster in the C-terminal cytosolic domain. Increasing evidence has shown that mitoNEET has an essential role in regulating energy metabolism in human cells. Previously, we reported that the [2Fe-2S] clusters in mitoNEET can be reduced by the reduced flavin mononucleotide (FMNH2) and oxidized by oxygen or ubiquinone-2, suggesting that mitoNEET may act as a novel redox enzyme catalyzing electron transfer from FMNH2 to oxygen or ubiquinone. Here, we explore the FMN binding site in mitoNEET by using FMN analogs and find that lumiflavin, like FMN, at nanomolar concentrations can mediate the redox transition of the mitoNEET [2Fe-2S] clusters in the presence of flavin reductase and NADH (100 μM) under aerobic conditions. The electron paramagnetic resonance (EPR) measurements show that both FMN and lumiflavin can dramatically change the EPR spectrum of the reduced mitoNEET [2Fe-2S] clusters and form a covalently bound complex with mitoNEET under blue light exposure, suggesting that FMN/lumiflavin has specific interactions with the [2Fe-2S] clusters in mitoNEET. In contrast, lumichrome, another FMN analog, fails to mediate the redox transition of the mitoNEET [2Fe-2S] clusters and has no effect on the EPR spectrum of the reduced mitoNEET [2Fe-2S] clusters under blue light exposure. Instead, lumichrome can effectively inhibit the FMNH2-mediated reduction of the mitoNEET [2Fe-2S] clusters, indicating that lumichrome may act as a potential inhibitor to block the electron transfer activity of mitoNEET.Purpose Myocardial ischemia/reperfusion injury (IRI) induces cardiomyocytes death and leads to loss of cardiac function. Circular RNAs (circRNA) have gain increasing interests in modulating myocardial IRI. In this study, we aim to investigate the role and exact mechanism of circTLK1 in the pathogenesis of myocardial IRI. Methods Myocardial IRI was developed in mice with measuring hemodynamic parameters and the activity of serum myocardial enzymes to evaluate cardiac function. HE and TTC staining were performed to assess infarct area. Expression patterns of circTLK1 and miR-214 were investigated using qRT-PCR assay. Gene expression of circTLK1, miR-214 or RIPK was altered by transfecting with their overexpression or knockdown vectors. The apoptosis of cardimyocytes was assessed by TUNEL staining and Caspase-3 activity analysis. Apoptosis-related markers Bcl-2, Bax, and caspase3, as well as TNF-α signals were determined by western blotting. The interactions of circTLK1/miR-214 and miR-214/RIPK1 were verified using luciferase reporter assay.