Epigenetic therapeutics attenuate kidney injury and fibrosis by restoring the expression of epigenetically reprogrammed fibrogenic genes and signaling pathways

Article

作者: Singh, Kamaleshwar P ; Warraich, Irfan ; Kandel, Ramji ; Acharya, Narayan ; Roy, Priti

Kidney fibrosis is a commonly observed pathological condition during development of chronic kidney disease. Therapeutic options currently available are effective only in slowing the progression of kidney fibrosis and there is no cure for this disease. Aberrant expression and excessive accumulation of extracellular matrix (ECM) proteins in the peritubular space is a characteristic pathological feature of fibrotic kidney. However, the molecular basis of aberrant regulation of fibrotic genes in kidneys is not clear. In this context, this study aimed to evaluate the role of epigenetic reprogramming in kidney fibrosis. Folic acid (FA)-induced acute kidney injury (AKI) and kidney fibrosis in mice as an in vivo model and long-term arsenic or FA-exposed fibrogenic HK-2 cells as an in vitro model were used to evaluate the role of DNA methylation and histone modifications in fibrosis. DNA demethylating agent 5aza2 deoxycytidine (5-aza-2-dC) and histone deacetylase inhibitor Trichostatin A (TSA) were used to treat FA-injected mice. Results of histopathological and immunofluorescence staining of kidney tissue, serum albumin- creatinine levels, body weight, and gene expression analysis revealed significant protective effects of 5-aza-2-dC and TSA in FA-induced AKI and fibrosis. Insignificant change in the expression of N-cadherin whereas a significant decrease in E-cadherin as well as an increase in the expression of Vimentin and α-SMA suggest partial EMT associated with fibrosis. Aberrant expression of epithelial-mesenchymal-transition (EMT) and ECM-regulators (MMP2, Smad7, and TIMP3) as well as fibrogenic signaling pathways (Notch, TGF-beta, and Wnt signaling), and their restoration by 5-aza-2-dC and TSA treatments suggest epigenetic reprogramming of these genes and signaling pathways during FA-induced fibrosis. In summary, this study provides new information on the role of epigenetic reprogramming of fibrogenic genes and signaling pathways during the development of kidney fibrosis. Attenuation of fibrosis after 5-aza-2-dC and TSA treatments suggest the promise of these epigenetic-based therapeutics in the clinical management of this disease.

2025-01-01·NEOPLASIA

5-Aza-2′-deoxycytidin (Decitabine) increases cancer-testis antigen expression in head and neck squamous cell carcinoma and modifies immune checkpoint expression, especially in CD39-positive CD8 and CD4 T cells

Article

作者: Betzler, Annika C ; Theodoraki, Marie-Nicole ; Schuler, Patrick J ; Grages, Ayla ; von Witzleben, Adrian ; Ezić, Jasmin ; Kors, Tsima Abou ; Brunner, Cornelia ; Hoffmann, Thomas K ; Fehn, Adrian ; Laban, Simon

Failure of immunotherapy in head and neck squamous cell carcinoma (HNSCC) patients represents an unmet need to augment leverage of adaptive immunity. Immunogenic cancer-testis antigen (CTA) expression as well as lymphocyte differentiation and function are regulated by DNA methylation. Therefore, epigenetic therapy via inhibition of DNA-Methyltransferases by 5-Aza-2'-deoxycytidine (DAC) serves a promising adjuvant in immunotherapy. We investigated the effects of DAC on CTA expression and proliferative capacity in HNSCC cell lines and on the expression of 12 immune checkpoint molecules (ICM) on lymphocytes of oropharyngeal squamous cell carcinoma (OPSCC) patients and healthy donors. In all cell lines CTA were upregulated accompanied by decreased proliferation. In lymphocytes pronounced alterations of the ICM repertoire were observed, influenced by donor type and subpopulation. On CD39+ CD4 and CD8 T cells, the expression of co-stimulatory ICM GITR and OX40 increased dose dependently, whereas expression decreased on CD39- CD4 T cells. PD1 expression increased primarily on CD39+ CD8 T cells and decreased on CD39- CD4 T cells. CD27 expression decreased primarily in CD8 T cells, but increased in CD39- CD4 T cells, whereas ICOS expression was lowered in both CD39+ and CD39- subsets of CD4 as well as CD8 T cells. DAC treatment increased immunogenicity and decreased proliferation in HNSCC cells while enhancing expression of co-stimulatory ICM GITR and OX40. We propose low dose DAC treatment as a adjuvant to immunotherapy.

2024-11-27·ONCOGENE

Editorial Expression of Concern: 5-Aza-2′-deoxycytidine and IFN-γ cooperate to sensitize for TRAIL-induced apoptosis by upregulating caspase-8

作者: Fulda, S. ; Debatin, K -M ; Fulda, S ; Debatin, K. -M.

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