RESUMEN
BACKGROUND: Sonic Hedgehog (SHH) is a fundamental signaling pathway that controls tissue reconstruction, stem cell biology, and differentiation and has a role in gut tissue homeostasis and development. Dysregulation of SHH leads to the development of HCC. METHODS, AND RESULTS: The present study was conducted to compare the effects of mesenchymal stem cells (MSCs) and curcumin on SHH molecular targets in an experimental model of HCC in rats. One hundred rats were divided equally into the following groups: control group, HCC group, HCC group received MSCs, HCC group received curcumin, and HCC group received MSCs and curcumin. Histopathological examinations were performed, and gene expression of SHH signaling target genes (SHH, PTCH1, SMOH, and GLI1) was assessed by real-time PCR in rat liver tissue. Results showed that SHH target genes were significantly upregulated in HCC-untreated rat groups and in MSC-treated groups, with no significant difference between them. Administration of curcumin with or without combined administration of MSCs led to a significant down-regulation of SHH target genes, with no significant differences between both groups. As regards the histopathological examination of liver tissues, both curcumin and MSCs, either through separate use or their combined use, led to a significant restoration of normal liver pathology. CONCLUSIONS: In conclusion, SHH signaling is upregulated in the HCC experimental model. MSCs do not inhibit the upregulated SHH target genes in HCC. Curcumin use with or without MSCs administration led to a significant down-regulation of SHH signaling in HCC and a significant restoration of normal liver pathology.
Asunto(s)
Carcinoma Hepatocelular , Curcumina , Proteínas Hedgehog , Neoplasias Hepáticas , Células Madre Mesenquimatosas , Transducción de Señal , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/genética , Animales , Curcumina/farmacología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Transducción de Señal/efectos de los fármacos , Ratas , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Trasplante de Células Madre Mesenquimatosas/métodos , Masculino , Modelos Animales de Enfermedad , Receptor Patched-1/genética , Receptor Patched-1/metabolismo , Proteína con Dedos de Zinc GLI1/metabolismo , Proteína con Dedos de Zinc GLI1/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hígado/efectos de los fármacosRESUMEN
The current study was conducted to determine the precise mechanisms of Sirtuin-1 (Sirt-1), TGF- ß (Transforming Growth Factor-ß), and long non-coding RNA Metastasis Associated Lung Adenocarcinoma Transcript 1 (LncRNA MALAT-1) in signaling pathways in doxorubicin (DOX)-induced nephrotoxicity. The potential therapeutic effect of Resveratrol and Pirfenidone in DOX toxicity was also assessed. Thirty-six male adult rats were evenly distributed into four groups: Group 1: control rats. Group 2: DOX exposed rats' group, each animal received 7.5â¯mg/kg DOX as a single intravenous dose, Group 3: DOX exposed group subjected to oral resveratrol (20â¯mg/kg/daily for two weeks), Group 4: DOX exposed group subjected to oral Pirfenidone (200â¯mg/kg once daily for 10 days). At the planned time, animals were sacrificed. Renal tissue was collected to assess matrix metalloproteinase-9 (MMP9), inflammatory and apoptotic markers: tumor necrosis factor-alpha (TNF- ß, caspase-3, cyclo-oxygenase-2 (COX-2), and oxidative stress markers: nitric oxide (NO), Glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD). Sirtuin-1 (Sirt-1), TGF-ß, and LncRNA MALAT-1 were quantitatively assessed by real-time RT-PCR in the whole blood. Results showed that the DOX group exhibited a significant increase in oxidative stress markers, and inflammatory, and apoptotic markers in the renal tissue. Histologically, the renal tubule lining cells exhibited vacuolar alterations in the cytoplasm, glomerular atrophy, and vascular congestion. Furthermore, renal degeneration was evident, as confirmed by the heightened immuno-expression of MMP9. Exposure to DOX resulted in a significant decrease in Sirtuin-1 (Sirt-1) with a significant increase in the TGFß, and LncRNA MALAT-1 gene expression. However, pre-treatment with either resveratrol/or Pirefenidone ameliorated the histological renal alterations, regulated the pathways of Sirt-1, TGFß, and LncRNA MALAT-1, and decreased all oxidative stress, inflammatory and apoptotic markers. In conclusion, DOX exposure leads to renal toxicity by inducing renal degeneration, oxidative stress, and apoptosis. Administration of either resveratrol or Pirfenidone counteracted these changes and protected the kidney against DOX-induced renal damage.