RESUMO
Radiation-induced intestinal injury (RIII) constitutes a crucial clinical element of acute radiation syndrome with life-threatening implications posing challenges in devising effective medical countermeasures. Herein, we report the potential of 7, 8-diacetoxy-4-methylthiocoumarin (DAMTC) to mitigate RIII following total-body irradiation (TBI) in C57BL/6 mice and underlying mechanisms. Administration of DAMTC 24 hours post TBI facilitated structural reconstitution and restoration of functional absorption linked to alleviation of radiation-induced apoptotic death of intestinal crypt progenitor/stem (ICPS) and villus stromal cells through induction of Bcl-2 family-mediated anti-apoptotic signalling. Reduction in TBI-induced DNA damage accumulation coupled with inhibition of cell cycle arrest through stimulation of anti-p53- and anti-p21-dependent synergistic signalling protected ICPS cells from radiation injury. Enhanced proliferation of crypt stem cells, induction of anti-oxidant defence, subjugation of TBI-induced lipid peroxidation and phenotypic polarization of intestinal macrophages to anti-inflammatory M2 class underlie amelioration of RIII. Stimulation of multiple mitigative signalling processes by DAMTC appeared to be associated with enhanced protein acetylation, an important regulator of cellular responses to radiation damage. Our findings establish the mitigative potential of DAMTC against RIII by hyper-acetylation-mediated epigenetic regulation, which triggers axes of anti-apoptotic and pro-survival pathways, enabling proliferation and maintenance of ICPS cells leading to epithelial regeneration.
Assuntos
Anormalidades Induzidas por Radiação/tratamento farmacológico , Síndrome Aguda da Radiação/tratamento farmacológico , Cumarínicos/farmacologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/efeitos da radiação , Anormalidades Induzidas por Radiação/metabolismo , Síndrome Aguda da Radiação/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Feminino , Trato Gastrointestinal/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/efeitos da radiação , Irradiação Corporal Total/efeitos adversosRESUMO
Small molecule osmolytes, responsible for protecting stresses have long been known to rescue proteins and enzymes from loss of function. In addition to protecting macromolecules integrity, many osmolytes also act as potential antioxidant and also help to prevent protein aggregation, amyloid formation or misfolding, and therefore are considered promising molecules for neurodegenerative and many other genetic diseases. Osmolytes are also known to be involved in the regulation of several key immunological processes. In the present review we discuss in detail the effect of these compounds on important aspects of vaccines i.e., increasing the efficiency, production and purification steps. The present review therefore will help researchers to make a better strategy in vaccine production to formulation by incorporating specific and appropriate osmolytes in the processes.