Protective Effects of CISD2 and Influence of Curcumin on CISD2 Expression in Aged Animals and Inflammatory Cell Model

Abstract

Background: Inflammation and mitochondrial dysfunction have been linked to trauma, neurodegeneration, and aging. Impairment of CISD2 expression may trigger the aforementioned pathological conditions in neural cells. We previously reported that curcumin attenuates the downregulation of CISD2 in animal models of spinal cord injury and lipopolysaccharide (LPS)-treated neuronal cells. In this study, we investigate (1) the role of CISD2 and (2) how curcumin regulates CISD2 in the aging process. Materials and methods: The serial expression of CISD2 and the efficacy of curcumin treatment were evaluated in old (104 weeks) mice and long-term cultures of neural cells (35 days in vitro, DIV). LPS-challenged neural cells (with or without siCISD2 transfection) were used to verify the role of curcumin on CISD2 underlying mitochondrial dysfunction. Results: In the brain and spinal cord of mice aged P2, 8, 25, and 104 weeks, we observed a significant decrease in CISD2 expression with age. Curcumin treatment in vivo and in vitro was shown to upregulate CISD2 expression; attenuate inflammatory response in neural cells. Moreover, curcumin treatment elevated CISD2 expression levels and prevented mitochondrial dysfunction in LPS-challenged neural cells. The beneficial effects of curcumin in either non-stressed or LPS-challenged cells that underwent siCISD2 transfection were significantly lower than in respective groups of cells that underwent scrambled siRNA-transfection. Conclusions: We hypothesize that the protective effects of curcumin treatment in reducing cellular inflammation associated trauma, degenerative, and aging processes can be partially attributed to elevated CISD2 expression. We observed a reduction in the protective effects of curcumin against injury-induced inflammation and mitochondrial dysfunction in cells where CISD2 expression was reduced by siCISD2.

Wild Bitter Melon Exerts Anti-Inflammatory Effects by Upregulating Injury-Attenuated CISD2 Expression following Spinal Cord Injury

“…LPS-stimulated ALT cells were used as an in vitro model of cellular injuries. This model recapitulates SCI-associated aberrant astrocyte activation and inflammation [ 25 , 26 , 30 ]. The cells were treated with 20 μ g/mL LPS for 24 h and subjected to qRT-PCR and western blotting.…”

“…In addition to mitochondrial dysfunction, CISD2 mitigates CNS injury-induced inflammatory response. Aging, neurodegeneration, and trauma are associated with downregulated CISD2 expression, which enhances the inflammatory response and exacerbates mitochondrial dysfunction [ 25 , 26 ]. Therefore, therapeutic targeting of CISD2 can aid in preventing the exacerbation of inflammation and mitochondrial dysfunction.…”

“…Furthermore, CISD2 is an outer mitochondrial membrane structural protein that may be degraded during the pathological process of primary injury (in acute trauma) or secondary injury (in chronic inflammation) associated with CNS injury or disease. CISD2 is downregulated under nonstressed and injured conditions [ 25 ]. Insult-induced CISD2 downregulation results in the inhibition of NF- κ B activity in the cytoplasm and mitochondria.…”

“…CDGSH iron sulfur domain 2 (CISD2), known to be associated with aging, has been reported to be involved in conferring protection against mitochondrial dysfunction-induced inflammatory responses and apoptosis. Previously, we had demonstrated that CISD2 was significantly downregulated under conditions of CNS injury and disease, such as aging mouse brain [ 25 ] and hemisection injury to the spinal cord in rats [ 26 ]. Injury-induced CISD2 downregulation leads to neuroinflammation and mitochondrial dysfunction.…”

CISD2 Attenuates Inflammation and Regulates Microglia Polarization in EOC Microglial Cells—As a Potential Therapeutic Target for Neurodegenerative Dementia

“…High inflammation due to microglial activation has been demonstrated underlying the pathogenesis of various neurodegenerative diseases in the CNS and neurodegenerative dementia (Thomas et al, 2015;Raz et al, 2016). In our previous study, we demonstrated that the attenuated CISD2 expression is associated with the aging process and leads to the inflammatory response (Lin et al, 2015(Lin et al, , 2019. Hence, we sought to determine whether CISD2 deficiency in microglia results in the inflammatory cascade as well as the likelihood that these detrimental insults influence microglia polarization.…”