Identification of novel inhibitors targeting TIRAP interactions with BTK and PKCδ in inflammation through an in silico approach.

Advanced computational tools focusing on protein-protein interaction (PPI) based drug development is a powerful platform to accelerate the therapeutic development of small lead molecules and repurposed drugs. Toll/interleukin-1 receptor (TIR) domain-containing adapter protein (TIRAP) and its interactions with other proteins in macrophages signalling are crucial components of severe or persistent inflammation. TIRAP activation through Bruton's tyrosine kinase (BTK) and Protein Kinase C delta (PKCδ) is essential for downstream inflammatory signalling. We created homology-based structural models of BTK and PKCδ in MODELLER 9.24. TIRAP interactions with BTK and PKCδ in its non-phosphorylated and phosphorylated states were determined by multiple docking tools including HADDOCK 2.4, pyDockWEB and ClusPro 2.0. Food and Drug Administration (FDA)-approved drugs were virtually screened through Discovery Studio LibDock and Autodock Vina tools to target the common TIR domain residues of TIRAP, which interact with both BTK and PKC at the identified interfacial sites of the complexes. Four FDA-approved drugs were identified and found to have stable interactions over a range of 100 ns MD simulation timescales. These drugs block the interactions of both kinases with TIRAP in silico. Hence, these drugs have the potential to dampen downstream inflammatory signalling and inflammation-mediated disease.

Protein kinase C-delta (PKCδ), a marker of inflammation and tuberculosis disease progression in humans, is important for optimal macrophage killing effector functions and survival in mice.

This corrects the article DOI: 10.1038/mi.2017.68.

Protein kinase C-delta (PKCδ), a marker of inflammation and tuberculosis disease progression in humans, is important for optimal macrophage killing effector functions and survival in mice.

We previously demonstrated that protein kinase C-δ (PKCδ) is critical for immunity against Listeria monocytogenes, Leishmania major, and Candida albicans infection in mice. However, the functional relevance of PKCδ during Mycobacterium tuberculosis (Mtb) infection is unknown. PKCδ was significantly upregulated in whole blood of patients with active tuberculosis (TB) disease. Lung proteomics further revealed that PKCδ was highly abundant in the necrotic and cavitory regions of TB granulomas in multidrug-resistant human participants. In murine Mtb infection studies, PKCδ-/- mice were highly susceptible to tuberculosis with increased mortality, weight loss, exacerbated lung pathology, uncontrolled proinflammatory cytokine responses, and increased mycobacterial burdens. Moreover, these mice displayed a significant reduction in alveolar macrophages, dendritic cells, and decreased accumulation of lipid bodies (lungs and macrophages) and serum fatty acids. Furthermore, a peptide inhibitor of PKCδ in wild-type mice mirrored lung inflammation identical to infected PKCδ-/- mice. Mechanistically, increased bacterial growth in macrophages from PKCδ-/- mice was associated with a decline in killing effector functions independent of phagosome maturation and autophagy. Taken together, these data suggest that PKCδ is a marker of inflammation during active TB disease in humans and required for optimal macrophage killing effector functions and host protection during Mtb infection in mice.

Structural secrets of multiferroic interfaces.

We present an experimental and theoretical study of the geometric structure of ultrathin BaTiO(3) films grown on Fe(001). Surface x-ray diffraction reveals that the films are terminated by a BaO layer, while the TiO(2) layer is next to the top Fe layer. Cations in termination layers have incomplete oxygen shells inducing strong vertical relaxations. Onset of polarization is observed at a minimum thickness of two unit cells. Our findings are supported by first-principles calculations providing a quantitative insight into the multiferroic properties on the atomic scale.

Effect of Solanum nigrum and Ricinus communis extracts on histamine and carrageenan-induced inflammation in the chicken skin.

We studied anti-inflammatory effect of ethanolic extract of Solanum nigrum leaves and Ricinus communis root bark using chicken skin as model. Leaves of these plants were dried under shade and powdered. 5% Ethanol extracts were prepared using Soxhlet and injected intraperitoneally (400 mg/kg) 1 hour prior to the induction of inflammation. Inflammatory lesion were induced by intradermal injection of 0.02 ml 0.05%w/v histamine (0-2 min, 15 min, 30 min, 1 hr and 6 hr) and 1% w/v carrageenan (0-2 min, 30 min, 1 hr, 6 hr, 12 hr and 48 hr) in different group of birds. Increase in vascular permeability was studied using Evans blue as a permeability marker both qualitatively and quantitatively. Cellular events were studied in skin lesions at various time intervals and cells were counted at high power objective under microscope. Both, extracts exhibited significant decrease in permeability response at an early stage (0-2 min) of histamine as well as in carrageenan induced inflammatory lesions. There was a significant (p< 0.05) suppression in the emigration of heterophils, monocytoid cells, basophils and total leukocytosis in Solanum nigrum and Ricinus communis pretreated chicken skin lesions as compared to the control. The present study suggested antihistamine and anti-inflammatory properties of ethanolic extract of Solanum nigrum and Ricinus communis.

Phase and amplitude recovery and diffraction image generation method: structure of Sb/Au(110)-radical3xradical3R54.7 degrees from surface X-ray diffraction.

The discovery that the phase problem of diffraction from non-periodic objects may be solved by oversampling the diffraction intensities in reciprocal space with respect to a Nyquist criterion has opened up new vistas for structure determination by diffraction methods. A similar principle may be applied to the problem of surface X-ray diffraction (SXRD), where, owing to the breaking of a crystal periodicity normal to its surface, diffraction data consist of a set of superstructure rods (SRs) due to scattering from the parts of the surface whose structure is different from that of the truncated bulk and of crystal truncation rods (CTRs), formed by interfering contributions from the surface and the bulk. A phase and amplitude recovery and diffraction image generation method (PARADIGM) is described that provides a prescription for finding the unmeasured amplitudes and phases of the surface contributions to the CTRs in addition to the phases of the SRs, directly from the diffraction data. The resulting ;diffraction image' is the basis of a determination of the previously unknown multidomain structure of Sb/Au(110)-radical3xradical3R54.7 degrees.