ABSTRACT
Differences in the features of aggressiveness of non-melanoma skin cancer (NMSC) subtypes, between basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are relevant characteristics. Comparing the characteristics between NMSC subtypes might help identify molecules associated with cancer metastasis and invasion. Considering these facts, the current study aimed to identify a molecular target for inhibiting skin cancer metastasis and invasion. Proteomic analysis suggested that heat shock protein 90 kDa, alpha, class B member 1 (HSP90AB1), pentaxin (PTX3), caspase-14 (CASP14), S100, actin-1, and profilin were the primary targets related to metastasis and invasion. However, after a differential expression comparison between BCC and SCC, HSP90AB1 was identified as the best target to repress metastasis and invasion. Based on molecular docking results, gallic acid (GA) was selected to inhibit HSP90AB1. A specific Hsp90ab1 siRNA targeting was designed and compared to GA. Interestingly, GA was more efficient in silencing HSP90AB1 than siRNAhsp90ab1. Hence, our data suggest that HSP90AB1 is a crucial biomarker for identifying invasion and metastasis and that its inhibition may be a viable strategy for treating skin cancer.
Subject(s)
Carcinoma, Basal Cell , Carcinoma, Squamous Cell , Skin Neoplasms , Humans , Heat-Shock Proteins , Gallic Acid/pharmacology , Proteomics , Molecular Docking Simulation , Carcinoma, Basal Cell/metabolism , Carcinoma, Squamous Cell/pathology , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , HSP90 Heat-Shock Proteins/geneticsABSTRACT
The present study aimed to evaluate the effects of resveratrol, a nutraceutical polyphenol, and Lactococcus lactis (bacteria probiotic), on metabolic parameters and hepatic proinflammatory markers expression. C57BL/6 mice were divided into 4 groups: Standard (ST), Lactococcus lactis (LL), Resveratrol (RSV), and Lactococcus lactis plus resveratrol (LL + RSV). Lactococcus lactis and resveratrol were administered by orogastric gavage. Blood parameters were assessed (total cholesterol, triglycerides, ALT and AST). IL-6 mRNA expression was evaluated by Real-time PCR and TNF-α protein expression was assessed by immunohistochemistry. The main findings showed that resveratrol and Lactococcus lactis association decreased body weight, aspartate aminotransferase and total cholesterol levels. LL and LL + RSV decreased triglycerides levels and IL-6 and TNF-α expression. These results open a perspective of using resveratrol and Lactococcus lactis to improve metabolic parameters and Lactococcus lactis in preventing inflammation and the hepatic diseases development.
Subject(s)
Gene Expression Regulation/drug effects , Lactococcus lactis/metabolism , Liver/drug effects , Probiotics/pharmacology , Resveratrol/pharmacology , Administration, Oral , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Body Weight/drug effects , Body Weight/physiology , Cholesterol/blood , Computational Biology , Female , Gene Expression Regulation/genetics , Gene Ontology , Immunohistochemistry , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/microbiology , Interleukin-6/genetics , Interleukin-6/metabolism , Liver/metabolism , Liver/pathology , Mice , Mice, Inbred C57BL , Resveratrol/administration & dosage , Triglycerides/blood , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: Solanum lycocarpum is a medicinal plant used in Brazil with hypoglycemic activity by its fruits use. However, the fruits production is restricted in some periods of the year, differently of leaves. OBJECTIVE: To evaluate the effects of hydroalcoholic extracts of S. lycocarpum leaves in alloxan-induced diabetic mice. METHODS: Hydroalcoholic extract of S. lycocarpum was characterized by phytochemical and GCMS analysis. The Antidiabetic activity was assessed following treatment for 22 days with S. lycocarpum extract at 125, 250, and 500 mg/kg. Bodyweight, water, and food intake, glycemia, biochemical parameters, anatomy-histopathology of the pancreas, liver and kidney, and expression of target genes were analyzed. In addition, oral acute toxicity was evaluated. RESULTS: Animals treated showed a significant reduction (p < 0.05) in glycemia following a dose of 125 mg/kg. Food intake remained similar for all groups. Decreased polydipsia symptoms were observed after treatment with 250 (p < 0.001) and 500 mg/kg (p < 0.01) compared with diabetic control, although normal rates were observed when 125 mg/kg was administered. A protective effect was also observed in the pancreas, liver, and kidneys, through the regeneration of the islets. Hypoglycemic activity can be attributed to myo-inositol, which stimulates insulin secretion, associated with α-tocopherol, which prevents damage from oxidative stress and apoptosis of ß-pancreatic cells by an increased Catalase (CAT) and Glutathione peroxidase 4 (GPX4) mRNA expression. The toxicological test demonstrated safe oral use of the extract under the present conditions. CONCLUSION: Hydroalcoholic extract of S. lycocarpum promotes the regulation of diabetes in the case of moderate glycemic levels, by decreasing glycemia and exerting protective effects on the islets.
Subject(s)
Diabetes Complications/drug therapy , Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/pharmacology , Plant Extracts/pharmacology , Solanum/chemistry , Alanine Transaminase/metabolism , Alkaline Phosphatase/metabolism , Alloxan/administration & dosage , Animals , Aspartate Aminotransferases/metabolism , Blood Glucose/metabolism , Body Weight/drug effects , Catalase/metabolism , Diabetes Complications/metabolism , Diabetes Complications/pathology , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Drinking/drug effects , Eating/drug effects , Hypoglycemic Agents/chemistry , Inositol/pharmacology , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Liver/drug effects , Liver/metabolism , Liver/pathology , Male , Mice , Pancreas/drug effects , Pancreas/metabolism , Pancreas/pathology , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Plant Extracts/chemistry , Plant Leaves/chemistry , alpha-Tocopherol/pharmacologyABSTRACT
Radiation Therapy (RT) is a treatment option for a large number of neoplasias. However, the effect of RT on the level of hypoxia markers is poorly understood. The present study aimed to investigate the effect of RT on the levels of hypoxic markers in Oral squamous cell carcinoma (OSCC). Evaluation of HIF-1α and miR-210 levels in OSCC was performed. Then a proteomic analysis was performed to identify candidate hypoxic targets of RT. To validate proteomic studies, the effect of RT on HIF-1α, miR-210, PDH-A and LDH-A levels under hypoxia was assessed by qRT-PCR. The impact of RT in hypoxia markers was evaluated in patients to confirm in vitro results. An increase in the HIF-1α levels was observed in OSCC. RT reduced OSCC cell proliferation and migration. Interestingly, hypoxia could revert the effect of radiation on OSCC phenotype. However, proteomics analyses suggested that LDH is one of the critical targets of RT even in hypoxia. Moreover, RT decreased HIF-1α, miR-210, and LDH even in hypoxia. The current study demonstrated that hypoxia could revert the effects of RT in the OSCC context. However, RT reduces the levels HIF-1α, miR-210 and LDH in vivo and in vitro. The consequences of RT in blood should be carefully investigated.
Subject(s)
Cell Hypoxia/radiation effects , Hypoxia-Inducible Factor 1, alpha Subunit/radiation effects , L-Lactate Dehydrogenase/radiation effects , MicroRNAs/radiation effects , Radiotherapy/adverse effects , Squamous Cell Carcinoma of Head and Neck/radiotherapy , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/blood , L-Lactate Dehydrogenase/blood , Male , MicroRNAs/blood , Middle Aged , Radiation Tolerance , Young AdultABSTRACT
Gallic acid is a polyphenolic compost appointed to interfere with neoplastic cells behavior. Evidence suggests an important role of leptin in carcinogenesis pathways, inducing a proliferative phenotype. We investigated the potential of gallic acid to modulate leptin-induced cell proliferation and migration of oral squamous cell carcinoma cell lines. The gallic acid effect on leptin secretion by oral squamous cell carcinoma cells, as well as the underlying molecular mechanisms, was also assessed. For this, we performed proliferation, migration, immunocytochemical and qPCR assays. The expression levels of cell migration-related genes (MMP2, MMP9, Col1A1, and E-cadherin), angiogenesis (HIF-1α, mir210), leptin signaling (LepR, p44/42 MAPK), apoptosis (casp-3), and secreted leptin levels by oral squamous cell carcinoma cells were also measured. Gallic acid decreased proliferation and migration of leptin-treated oral squamous cell carcinoma cells, and reduced mRNA expression of MMP2, MMP9, Col1A1, mir210, but did not change HIF-1α. Gallic acid decreased levels of leptin secreted by oral squamous cell carcinoma cells, accordingly with downregulation of p44/42 MAPK expression. Thus, gallic acid appears to break down neoplastic phenotype of oral squamous cell carcinoma cells by interfering with leptin pathway.
