Mycobacterium leprae infection causes bone lesions and osteoporosis, however, the effect of antileprosy drugs on the bone is unknown. We, therefore, set out to address it by investigating osteogenic differentiation from bone marrow (BM)-derived mesenchymal stem cells (MSCs). Out of 7 antileprosy drugs, only clofazimine (CFZ) reduced MSCs viability (IC50 ∼ 1 μM) and their osteogenic differentiation but increased adipogenic differentiation on a par with rosiglitazone, and this effect was blocked by a peroxisome proliferator-activated receptor gamma antagonist, GW9662. CFZ also decreased osteoblast viability and resulted in impaired bone regeneration in a rat femur osteotomy model at one-third human drug dose owing to increased callus adipogenesis as GW9662 prevented this effect. CFZ treatment decreased BM MSC population and homing of MSC to osteotomy site despite drug levels in BM being much less than its in vitro IC50 value. In adult rats, CFZ caused osteopenia in long bones marked by suppressed osteoblast function due to enhanced adipogenesis and increased osteoclast functions. A robust increase in marrow adipose tissue (MAT) by CFZ did not alter the hematologic parameters but likely reduced BM vascular bed leading to osteonecrosis (ON) characterized by empty osteocyte lacunae. However, CFZ had no effect on visceral fat content and was not associated with any metabolic and hematologic changes. Levels of unsaturated fatty acids in MAT were higher than saturated fatty acids and CFZ further increased the former. From these data, we conclude that CFZ has adverse skeletal effects and could be used for creating a rodent ON model devoid of extraskeletal effects.
The base-promoted
intramolecular cyclization of Ugi-azide adduct
has been demonstrated for the synthesis of highly substituted aziridinyl
glycoconjugates in one pot. The reactions are scalable and efficient
and have an operationally simple broad substrate scope. To gain insight
into the mechanism of aziridine formation, DFT and control experiments
show that the cyclization of the aziridine glycoconjugate pathway
was preferred, as it proceeds with a low activation energy barrier
(0.57 kcal mol–1), which supports our experimental
observation.
We report herein the first systematic crystal structural investigation of azaproline incorporated in homo‐ and heterochiral diprolyl peptides. The X‐ray crystallography data of peptides 1–5 illustrates that stereodynamic nitrogen in azaproline adopted the stereochemistry of neighbouring proline residue without depending on its position in the peptide sequence. Natural bond orbital analysis of crystal structures indicates OazPro−C′Pro of peptides 4 and 5 participating in n→π* interaction with stabilization energy about 1.21–1.33 kcal/mol. Density functional theory calculations suggested that the endo‐proline ring puckering favoured over exo‐conformation by 6.72–7.64 kcal/mol. NBO and DFT data reveals that the n→π* interactions and proline ring puckering stabilize azaproline chirality with the neighbouring proline stereochemistry. The CD, solvent titration, variable‐temperature and 2D NMR experimental results further supported the crystal structures conformation.
Zinc oxide (ZnO) nanoparticles (NPs) have been widely used in industry, cosmetics, drugs, bioimaging, and drug delivery. ZnO NPs have been found to interact and interfere with cellular physiology via macrophages, thereby resulting in macrophage polarization. The functional reprogramming of the cells is synchronized through cellular metabolic adaptations. The current study, therefore, aims to establish crosstalk between ZnO-NP-induced metabolic alterations and macrophage polarization in PMA-activated THP-1 cell lines. We observed moderate to heightened cytotoxic response in terms of cell viability and proliferation. The results also revealed increased Th1-type cytokine and chemokine expression. In order to characterize the changes in metabolite concentration in treatment groups, we employed multivariate data analysis (principal component analysis and partial least-squares discriminant analysis) of 1 H NMR spectra. The results revealed biologically relevant patterns and alterations in many metabolic pathways. These alterations and patterns were found to be in line across the immune−cytotoxic axis. Furthermore, the results also implicate the role of carbon metabolism toward the classical activation of macrophage polarization. The omics approach could identify the markers involved in NP-induced toxicity, thus elaborating our vision of cytotoxicity that is currently limited to end-point and cytokine assays. Also, it could be emphasized that metabolic reconfiguration upon NP stimulation could direct macrophage polarization toward classical activation.
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