A nucleosomal protein, high mobility group box 1 (HMGB1) is known to be a late mediator of sepsis. Dabrafenib is a B-Raf inhibitor and initially used for the treatment of metastatic melanoma therapy. Inhibition of HMGB1 and renewal of vascular integrity is appearing as an engaging therapeutic strategy in the administration of severe sepsis or septic shock. Here, we examined the effects of dabrafenib (DAB) on the modulation of HMGB1-mediated septic responses. DAB inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses by enhancing the expressions of cell adhesion molecules (CAMs) in human endothelial cells. In addition, treatment with DAB inhibited the HMGB1 secretion by CLP and sepsis-related mortality and pulmonary injury. This study demonstrated that DAB could be alternative therapeutic options for sepsis or septic shock via the inhibition of the HMGB1 signaling pathway. [BMB Reports 2016; 49(4): 214-219]

A blood–brain barrier (BBB) opening induced by focused ultrasound (FUS) has been widely studied as an effective way of treating brain diseases. We investigate the effect of ultrasound’s incidence angle at caudate putamen (Cp) and thalamus (Th) of the rat brain by inducing the same power of focused ultrasound that corresponds to the acoustic pressure of 0.65 MPa in free field. The BBB permeability (Ktrans) was quantitatively evaluated with dynamic contrast-enhanced magnetic resonance imaging. The group averaged (n = 11) maximum Ktrans at Cp (0.021 ± 0.012 min−1) was 1.39 times smaller than the Ktrans of Th (0.029 ± 0.01 min−1) with p = 0.00343. The group averaged (n = 6) ultrasound’s incidence angles measured using the computed tomography image of rat skulls were compared with the maximum Ktrans and showed a negatively linear relation R2 = 0.7972). The maximum acoustic pressure computed from the acoustic simulation showed higher average acoustic pressures at Th (0.37 ± 0.02 MPa) compared to pressures at Cp (0.32 ± 0.01 MPa) with p = 0.138 × 10−11. More red blood cell were observed at the Th region compared to the Cp region in the tissue staining. These results indicate that localized characteristics of the sonication target within the subject should be considered for safer and more efficient BBB disruption induced by FUS.

Cyclopia subternata is a medicinal plant commonly used in traditional medicine to relieve pain. Here, the anticoagulant effects of scolymoside, an active compound in C. subternata, were examined by monitoring activated partial thromboplastin time (aPTT), prothrombin time (PT), and the activities of thrombin and activated factor X (FXa). The effects of scolymoside on plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) expression were evaluated in tumor necrosis factor (TNF)-α-activated human endothelial cells. Treatment with scolymoside resulted in prolonged aPTT and PT and the inhibition of thrombin and FXa activities and production. In addition, scolymoside inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. Scolymoside also elicited anticoagulant effects in mice, including a significant reduction in the PAI-1 to t-PA ratio. Collectively, these findings indicate that scolymoside possesses anticoagulant activities and could be developed as a novel anticoagulant. [BMB Reports 2015; 48(10): 577-582]

No abstract

Diketopiperazine is a naturally occurring cyclic dipeptide found from diverse living organisms. The compounds in this structure class have been known with a broad spectrum of bioactivities including anti-inflammatory activities. Transforming growth factor β-induced protein (TGFBIp) is an extracellular matrix protein whose expression in several cell types is greatly increased by TGF-β. TGFBIp is released by human umbilical vein endothelial cells and functions as a mediator of experimental sepsis. Here, three (1-3) of diketopiperazines were isolated from two strains of marine-derived bacteria and we hypothesized that 1-3 could reduce TGFBIp-mediated severe inflammatory responses in human endothelial cells and mice. Here, we investigated the anti-septic effects and underlying mechanisms of 1-3 against TGFBIp-mediated septic responses. 1-3 effectively inhibited lipopolysaccharide-induced release of TGFBIp and suppressed TGFBIp-mediated septic responses. In addition, 1-3 suppressed cecal ligation and puncture (CLP)-induced sepsis lethality and pulmonary injury. In conclusion, 1-3 suppressed TGFBIp-mediated and CLP-induced septic responses. Therefore, 1-3 could be a potential therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the TGFBIp signaling pathway.

Vicenin-2 and scolymoside possess anti-inflammatory functions by inhibiting hyperpermeability,expression of CAMs, and adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases.

No abstract

Salicornia herbacea is an annual halophytic glasswort that has been employed as a culinary vegetable, salad, and traditional medicinal resource. Chemical investigation of the aerial parts of S. herbacea led to the isolation of two new (1, 2) and known (3) flavanones as well as a new nature-derived (4) and two known chromone derivatives (5, 6). These purified compounds were evaluated for their suppressive potentials against the release of high-mobility group box 1 protein (HMGB1), which has captured attention as a viable target for alleviating serious septic manifestations or septicemia. The phenolic compounds improved the survival rates of cecal ligation and puncture operation (CLP) in murine models, simulating severe septic shock and its related complications, to 40-60%. These results collectively validate that flavanone- and chromone-based secondary metabolites may serve as prospective prodrugs or food additives that may be commercialized for the control of septic complications and lethality.