Synthesis, computational studies and antioxidant activity of some 3-(2-alkylamino-4-aminothiazole-5-oyl) pyridines

A series of thiazoloylpyridine derivatives has been synthesized and analyzed to confirm the structure of the product using IR, 1H and 13C NMR, mass spectra and analytical data. Optimized structural and electronic parameters of all the compounds have been calculated by using B3LYP/ 6-31G basis set. The Mulliken charges of all atoms have been evaluated. The calculated IR spectrum has been analyzed by comparing the experimental IR. All the synthesized compounds have been examined for antioxidant activities. The antioxidant activity of 3-(2-alkylamino-4-aminothiazol -5-oyl)pyridines have been analyzed using DPPH radical scavenging assay. The compounds 6a and 6b possess higher radical scavenging activity.

Synthesis, DFT calculations, NBO analysis and docking studies of 3-(2-arylamino-4-aminothiazol-5-oyl)pyridine derivatives

Electronic structure of 3-(2-arylamino-4-aminothiazol-5-oyl)pyridine derivatives are investigated theoretically using B3LYB/6-31G (d,p) method. The energy gap between HOMO-LUMO and several thermodynamic properties in the ground state are calculated by means of B3LYP hybrid density functional theory (DFT) method together with 6-31G basis sets. A series of pyridinyl thiazoles were synthesized and characterized. The molecular docking studies were done using PyRx virtual screening tool in the active site of Hepg-2 (PDB code 4mmh) to study the hydrogen bonding interaction of these analogs. ADME properties and the hydrophobicity are found to be critical for activity. It is observed that all the synthesized compounds can be used orally as good drug candidates and the docking scores are comparable to the standard compounds. The compound C3 is found to have the highest activity against the cancer (PDB code: 4mmh)  protein.

Expression of the G-CSF receptor in monocytic cells is sufficient to mediate hematopoietic progenitor mobilization by G-CSF in mice

Expression of the G-CSF receptor on bone marrow monocytes is sufficient to trigger HSC mobilization in response to G-CSF, in part via effects on osteoblast lineage cells

In-vivo anterior segment OCT imaging provides unique insight into cerulean blue-dot opacities and cataracts in Down syndrome

Down syndrome (DS) is frequently associated with cataract, but there remains scant information about DS cataract morphology. Supra-nuclear cataracts in DS have been proposed as indicative of beta-amyloid (Aβ) aggregation and thus potential biomarkers for Alzheimer’s (AD). This study employed anterior segment OCT (AS-OCT) and slit-lamp (SL) photography to image the crystalline lens in DS, compared with adult controls. Lens images were obtained post-dilation. Using MATLAB, AS-OCT images were analysed and lens opacities calculated as pixel intensity and area ratios. SL images were classified using LOCS III. Subjects were n = 28 DS (mean ± SD 24.1 ± 14.3years), and n = 36 controls (54.0 ± 3.4years). For the DS group, AS-OCT imaging revealed the frequent presence of small dot opacities (27 eyes, 50%) in the cortex and nucleus of the lens, covering an area ranging from 0.2–14%. There was no relation with age or visual acuity and these dot opacities (p > 0.5) and they were not present in any control lenses. However, their location and morphology does not coincide with previous reports linking these opacities with Aβ accumulation and AD. Four participants (14%) in the DS group had clinically significant age-related cataracts, but there was no evidence of early onset of age-related cataracts in DS

Synthesis, computational studies and antioxidant activity of some 3-(2-alkylamino-4-aminothiazole-5-oyl)pyridines

605-610A series of thiazoloylpyridine derivatives has been synthesized and analyzed to confirm the structure of the product using IR, 1H and 13C NMR, mass spectra and analytical data. Optimized structural and electronic parameters of all the compounds have been calculated by using B3LYP/ 6-31G basis set. The Mulliken charges of all atoms have been evaluated. The calculated IR spectrum has been analyzed by comparing the experimental IR. All the synthesized compounds have been examined for antioxidant activities. The antioxidant activity of 3-(2-alkylamino-4-aminothiazol -5-oyl)pyridines have been analyzed using DPPH radical scavenging assay. The compounds 6a and 6b possess higher radical scavenging activity

Synthesis, DFT calculations, NBO analysis and docking studies of 3-(2-arylamino-4-aminothiazol-5-oyl)pyridine derivatives

999-1006Electronic structure of 3-(2-arylamino-4-aminothiazol-5-oyl)pyridine derivatives are investigated theoretically using B3LYB/6-31G (d,p) method. The energy gap between HOMO-LUMO and several thermodynamic properties in the ground state are calculated by means of B3LYP hybrid density functional theory (DFT) method together with 6-31G basis sets. A series of pyridinyl thiazoles were synthesized and characterized. The molecular docking studies were done using PyRx virtual screening tool in the active site of Hepg-2 (PDB code 4mmh) to study the hydrogen bonding interaction of these analogs. ADME properties and the hydrophobicity are found to be critical for activity. It is observed that all the synthesized compounds can be used orally as good drug candidates and the docking scores are comparable to the standard compounds. The compound C3 is found to have the highest activity against the cancer (PDB code: 4mmh) protein

IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis

Psoriasis is an immune-mediated skin disorder associated with severe systemic comorbidities. Whereas IL-36 is a key disease driver, the pathogenic role of this cytokine has mainly been investigated in skin. Thus, its effects on systemic immunity and extracutaneous disease manifestations remain poorly understood. To address this issue, we investigated the consequences of excessive IL-36 activity in circulating immune cells. We initially focused our attention on generalized pustular psoriasis (GPP), a clinical variant associated with pervasive upregulation of IL-36 signaling. By undertaking blood and neutrophil RNA sequencing, we demonstrated that affected individuals display a prominent IFN-I signature, which correlates with abnormal IL-36 activity. We then validated the association between IL-36 deregulation and IFN-I over-expression in patients with severe psoriasis vulgaris (PV). We also found that the activation of IFN-I genes was associated with extracutaneous morbidity, in both GPP and PV. Finally, we undertook mechanistic experiments, demonstrating that IL-36 acts directly on plasmacytoid dendritic cells, where it potentiates toll-like receptor (TLR)-9 activation and IFN-α production. This effect was mediated by the upregulation of PLSCR1, a phospholipid scramblase mediating endosomal TLR-9 translocation. These findings identify an IL-36/ IFN-I axis contributing to extracutaneous inflammation in psoriasis.</p

Using Real-World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic-Pharmacodynamic Study.

Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (Emax ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes