Dihydroergotamine ameliorates liver fibrosis by targeting transforming growth factor β type Ⅱ receptor

BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway.AIM To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis.METHODS Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8(CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect.RESULTS We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine(DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson’s trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver.CONCLUSION DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.

A symmetry-based length model for characterizing the hypersonic boundary layer transition on a slender cone at moderate incidence

The hypersonic boundary layer(HBL)transition on a slender cone at moderate incidence is studied via a symmetry-based length model:the SED-SL model.The SED-SL specifies an analytic stress length function(which defines the eddy viscosity)describing a physically sound two-dimensional multi-regime structure of transitional boundary layer.Previous studies showed accurate predictions,especially on the drag coefficient,by the SED-SL for airfoil flows at different subsonic Mach numbers,Reynolds numbers and angles of attack.Here,the SED-SL is extended to compute the hypersonic heat transfer on a 7∘half-angle straight cone at Mach numbers 6 and 7 and angles of attack from 0∘to 6∘.It is shown that a proper setting of the multi-regime structure with three parameters(i.e.a transition center,an after-transition near-wall eddy length,and a transition width quantifying transition overshoot)yields an accurate description of the surface heat fluxes measured in wind tunnels.Uniformly good agreements between simulations and measurements are obtained from windward to leeward side of the cone,implying the validity of the multi-regime description of the transition independent of instability mechanisms.It is concluded that a unified description for the HBL transition of cone is found,and might offer a basis for developing a new transition model that is simultaneously of computational simplicity,sound physics and greater accuracy.

Investigation on cavitating turbulent flow for the twisted NACA66 hydrofoil using a PANS model with helicity modification

In the present paper,the unsteady cavitating turbulent flow over the twisted NACA66 hydrofoil is investigated based on an modified shear stress transfer k-ωpartially averaged Navier-Stokes(MSST PANS)model,i.e.,new MSST PANS(NMSST PANS)model,where the production term of kinetic energy in the turbulence model is modified with helicity.Compared with the experimental data,cavitation evolution and its characteristic frequency are satisfactorily predicted by the proposed NMSST PANS model.It is revealed that the interaction among the main flow,the reentrant jets,and sheet cavitation causes the formation of the primary shedding cavity near the mid-span and the secondary shedding cavity at each side of the twisted hydrofoil,and further induces the remarkable pressure gradient around shedding cavities.Along with the development of the primary and the secondary shedding cavities,the great pressure gradient associated with large cavity volume variation promotes the vortical flow generation and the spatial deformation of vortex structure during cavitation evolution,and results in the primary and the secondary U-type vortices.Further,dynamic mode decomposition(DMD)analysis is utilized to confirm the interaction among the main flow,the main reentrant jet and two side reentrant jets,and cavitation.These results indicate that the proposed NMSST PANS model is suitable to simulate the complicated cavitating turbulent flow for various engineering applications.