Moreover, a comparison with other therapeutic agents having common features unveiled the peculiar ability of suramin to optimize the binding to the peptide sequence. The newly discovered suramin action is hoped to inspire the elaboration of novel repurposing strategies aimed to reduce LL-37 cytotoxicity under pathological conditions.Selective liver X receptor (LXR) agonists have been extensively pursued as therapeutics for Alzheimer's disease and related dementia (ADRD) and, for comorbidities such as type 2 diabetes (T2D) and cerebrovascular disease (CVD), disorders with underlying impaired insulin signaling, glucose metabolism, and cholesterol mobilization. The failure of the LXR-focused approach led us to pursue a novel strategy to discover nonlipogenic ATP-binding cassette transporter A1 (ABCA1) inducers (NLAIs) screening for ABCA1-luciferase activation in astrocytoma cells and counterscreening against lipogenic gene upregulation in hepatocarcinoma cells. Beneficial effects of LXRβ agonists mediated by ABCA1 include the following control of cholesterol and phospholipid efflux to lipid-poor apolipoproteins forming beneficial peripheral HDL and HDL-like particles in the brain and attenuation of inflammation. While rare, ABCA1 variants reduce plasma HDL and correlate with an increased risk of ADRD and CVD. In secondary assays, NLAI hits enhanced cholesterol mobilization and positively impacted in vitro biomarkers associated with insulin signaling, inflammatory response, and biogenic properties. In vivo target engagement was demonstrated after oral administration of NLAIs in (i) mice fed a high-fat diet, a model for obesity-linked T2D, (ii) mice administered LPS, and (iii) mice with accelerated oxidative stress. The lack of adverse effects on lipogenesis and positive effects on multiple biomarkers associated with T2D and ADRD supports this novel phenotypic approach to NLAIs as a platform for T2D and ADRD drug discovery.The lymph node is a highly organized and dynamic structure that is critical for facilitating the intercellular interactions that constitute adaptive immunity. Most ex vivo studies of the lymph node begin by reducing it to a cell suspension, thus losing the spatial organization, or fixing it, thus losing the ability to make repeated measurements. Live murine lymph node tissue slices offer the potential to retain spatial complexity and dynamic accessibility, but their viability, level of immune activation, and retention of antigen-specific functions have not been validated. Here we systematically characterized live murine lymph node slices as a platform to study immunity. Live lymph node slices maintained the expected spatial organization and cell populations while reflecting the 3D spatial complexity of the organ. Slices collected under optimized conditions were comparable to cell suspensions in terms of both 24-h viability and inflammation. Slices responded to T cell receptor cross-linking with increased surface marker expression and cytokine secretion, in some cases more strongly than matched lymphocyte cultures. Furthermore, slices processed protein antigens, and slices from vaccinated animals responded to ex vivo challenge with antigen-specific cytokine secretion. In summary, lymph node slices provide a versatile platform to investigate immune functions in spatially organized tissue, enabling well-defined stimulation, time-course analysis, and parallel read-outs.Simultaneous determination of the content of six alkaloids (aconitine, hypoaconitine, mesaconitine, benzoylaconine, benzoylhypaconine, and benzoylmesaconine) in rat plasma is enabled by HPLC-MS/MS combined with microsolid phase extraction (micro-SPE). To study its pharmacokinetics in rat plasma, the extracted plasma sample was passed through a C18 extraction column and eluted with acetonitrile. The six alkaloids in the Radix aconiti Preparata extract can be completely separated as peaks with good shape. The six components in the plasma sample showed a good linear relationship within their respective linear ranges (R 2 > 0.997). The analysis of the six alkaloids can be completed within 20 min. This method has high intraday and interday precision, and the room temperature stability and freeze-thaw stability are good. The matrix effect of the plasma samples is between 86.4 and 114%. The metabolism of the six Aconitum alkaloids in plasma is analyzed using a two-compartment model, which is characterized by fast absorption, slow elimination, and good linear fit, R 2 > 0.99. The peak time (T max) for aconitine, hypaconitine, and neoaconitine ranged from 29.95 to 42.07 min, while the peak time (T max) for benzoaconitine, benzohypaconitine, and benzoxinaconitine ranged from 42.88 to 73.08 min. With the increased dosage, the bioavailability of Aconitum alkaloids decreased gradually. The method for the determination of Aconitum alkaloids in rat plasma by high performance liquid chromatography-tandem mass spectrometry is sensitive and accurate, which is suitable for rat plasma analysis. The results provide a scientific basis for metabolic study of Aconitum alkaloids in vivo, and pave the way for clinical use of Aconitum medicinal materials and extracts.Diabetic foot ulcers (DFUs) are a common complication of diabetes that are recalcitrant to healing due to persistent inflammation. The majority of DFUs have bacterial biofilms, with Staphylococcus epidermidis as a predominant bacterium, requiring infection control with antibiotics before treatment of the wound. Matrix metalloproteinases (MMPs) play roles in the pathology and repair of DFUs. However, defining the roles of the 24 human MMPs has been challenging due to the presence of three forms for each MMP, of which only one is catalytically competent, and the lack of convenient methods to distinguish among the three forms of MMPs. https://www.selleckchem.com/products/harringtonine.html Using an affinity resin that binds only to the active forms of MMPs, with identification and quantification by mass spectrometry, we found that infected wounds in mice had increased levels of active MMP-9 compared to uninfected ones, paralleling infected human DFUs. MMP-9 activity prevents diabetic wounds from healing. We evaluated the efficacy of the selective small-molecule MMP-9 inhibitor, (R)-ND-336, in the infected diabetic mouse model of wound healing and showed that (R)-ND-336 alone or in combination with the antibiotic linezolid improves wound healing by inhibiting the detrimental MMP-9, mitigating macrophage infiltration to diminish inflammation, and increasing angiogenesis to restore the normal wound healing process.