Pathways Related to the Anti-Cancer Effects of Metabolites Derived from Cerrado Biome Native Plants: An Update and Bioinformatics Analysis on Oral Squamous Cell Carcinoma.

BACKGROUND: Oral cancer is a significant health problem worldwide. Oral squamous cell carcinoma (OSCC) is a malignant neoplasm of epithelial cells that mostly affects different anatomical sites in the head and neck and derives from the squamous epithelium or displays similar morphological characteristics. Generally, OSCC is often the end stage of several changes in the stratified squamous epithelium, which begin as epithelial dysplasia and progress by breaking the basement membrane and invading adjacent tissues. Several plant-based drugs with potent anti-cancer effects are considered inexpensive treatments with limited side effects for cancer and other diseases. OBJECTIVE: The aim of this review is to explore whether some Brazilian plant extracts or constituents exhibit anti-tumorigenic activity or have a cytotoxic effect on human oral carcinoma cells. METHODS: Briefly, OSCC and several metabolites derived from Brazilian plants (i.e., flavonoids, vinblastine, irinotecan, etoposide and paclitaxel) were used as keywords to search the literature on PubMed, GenBank and GeneCards. RESULTS: The results showed that these five chemical compounds found in Cerrado Biome plants exhibit anti-neoplastic effects. Evaluating the compounds revealed that they play a main role in the regulation of cell proliferation. CONCLUSION: Preserving and utilising the biodiversity of our planet, especially in unique ecosystems, such as the Cerrado Biome, may prove essential to preserving and promoting human health in modern contexts.

Gene expression profiling in the developing secondary palate in the absence of Tbx1 function.

BACKGROUND: Microdeletion of chromosome 22q11 is associated with significant developmental anomalies, including disruption of the cardiac outflow tract, thymic/parathyroid aplasia and cleft palate. Amongst the genes within this region, TBX1 is a major candidate for many of these developmental defects. Targeted deletion of Tbx1 in the mouse has provided significant insight into the function of this transcription factor during early development of the cardiac and pharyngeal systems. However, less is known about its role during palatogenesis. To assess the influence of Tbx1 function on gene expression profile within the developing palate we performed a microarray screen using total RNA isolated from the secondary palate of E13.5 mouse embryos wild type, heterozygous and mutant for Tbx1. RESULTS: Expression-level filtering and statistical analysis revealed a total of 577 genes differentially expressed across genotypes. Data were clustered into 3 groups based on comparison between genotypes. Group A was composed of differentially expressed genes in mutant compared to wild type (n = 89); Group B included differentially expressed genes in heterozygous compared to wild type (n = 400) and Group C included differentially expressed genes in mutant compared to heterozygous (n = 88). High-throughput quantitative real-time PCR (RT-PCR) confirmed a total of 27 genes significantly changed between wild type and mutant; and 27 genes between heterozygote and mutant. Amongst these, the majority were present in both groups A and C (26 genes). Associations existed with hypertrophic cardiomyopathy, cardiac muscle contraction, dilated cardiomyopathy, focal adhesion, tight junction and calcium signalling pathways. No significant differences in gene expression were found between wild type and heterozygous palatal shelves. CONCLUSIONS: Significant differences in gene expression profile within the secondary palate of wild type and mutant embryos is consistent with a primary role for Tbx1 during palatogenesis.

Oncogenic signalling pathways in benign odontogenic cysts and tumours.

The first step towards the prevention of cancer is to develop an in-depth understanding of tumourigenesis and the molecular basis of malignant transformation. What drives tumour initiation? Why do most benign tumours fail to metastasize? Oncogenic mutations, previously considered to be the hallmark drivers of cancers, are reported in benign cysts and tumours, including those that have an odontogenic origin. Despite the presence of such alterations, the vast majority of odontogenic lesions are benign and never progress to the stage of malignant transformation. As these lesions are likely to develop due to developmental defects, it is possible that they harbour quiet genomes. Now the question arises - do they result from DNA replication errors? Specific candidate genes have been sequenced in odontogenic lesions, revealing recurrent BRAF mutation in the case of ameloblastoma, KRAS mutation in adenomatoid odontogenic tumours, PTCH1 mutation in odontogenic keratocysts, and CTNNB1 (Beta-catenin) mutation in calcifying odontogenic cysts. Studies on these benign and rare entities might reveal important information about the tumorigenic process and the mechanisms that hinder/halt neoplastic progression. This is because the role of relatively common oncogenic mutations seems to be context dependent. In this review, each mutation signature of the odontogenic lesion and the affected signalling pathways are discussed in the context of tooth development and tumorigenesis. Furthermore, behavioural differences between different types of odontogenic lesions are explored and discussed based on the molecular alteration described. This review also includes the employment of molecular results for guiding therapeutic approaches towards odontogenic lesions.

Mannose-binding lectin gene (MBL-2) polymorphism in oral lichen planus.

TNF-α may be associated with the etiopathogenesis of oral lichen planus (OLP), and it has been suggested that polymorphism of mannose-binding lectin (MBL) increases the in vitro production of TNF- α. The aim of the present study was to assess the relevance of genetic diversity of MBL in OLP. The study sample comprised 90 individuals, 45 OLP patients and 45 healthy volunteers. MBL-2 gene was amplified using real-time PCR. Frequency of A/A genotype was 55.6% in OLP and 53.3% in healthy volunteers. Likewise, A/0 heterozygote genotype was found in 42.2% and 35.6%; 2.2% and 11.1%, had the recessive 0/0 genotype respectively. Frequencies of the "A" and "0" alleles were 77% and 23% in the OLP group and 71.2% in control group. There were no statistically significant differences regarding genotype frequency (p = 0.546) or allele frequency (p = 0.497). In conclusion, no significant association was found between polymorphism of MBL-2 gene and OLP.

Investigation of functional gene polymorphisms: IL-1B, IL-6 and TNFA in benign migratory glossitis in Brazilian individuals.

BACKGROUND: Benign migratory glossitis (BMG) is a very common immunological oral disease of unknown aetiology. METHODS AND SUBJECTS: Fifty-three consecutive subjects affected by BMG and 53 age- and sex-matched control subjects were genotyped for IL-1B, IL-6 and TNFA polymorphisms. Binary logistic regression models were fitted and values of P < 0.05 were considered significant. RESULTS: A significant difference in the distribution of IL-1B genotypes was observed in the group with BMG in univariate analyses (P = 0.01). The multivariate analyses showed that the CT genotype of the IL1-B gene was significantly associated with a high risk to develop BMG (P = 0.02, OR 2.76). The combined presence of IL-1beta high and intermediate producers genotypes was also associated with BMG in multivariate analyses (P = 0.01, OR 3.05). IL-6 and TNFA polymorphisms were not associated with BMG in the univariate and multivariate analyses. CONCLUSION: Our findings demonstrate that the polymorphism +3954 IL-1B is associated with an increased risk of BMG development and suggest a genetic basis for disease development.

Investigation of functional gene polymorphisms interleukin-1beta, interleukin-6, interleukin-10 and tumor necrosis factor in individuals with oral lichen planus.

Oral lichen planus (OLP) is a chronic inflammatory oral mucosal disease. There are some studies in the literature demonstrating association between cytokines genes polymorphisms and susceptibility to develop some immune-mediate conditions. The purpose of this study was to investigate cytokine gene polymorphisms in a sample of Brazilian patients with OLP. Fifty-three patients with OLP (mean age = 43.1 years; range 20-68 years) and 53 healthy volunteers (mean age = 42.9 years; range 21-67) were genotyped for IL-1beta +3954 (C/T), IL-6-174 (G/C), IL-10-1082 (G/A) and TNFA-308 (G/A) gene polymorphisms. Statistical analysis was based on the use of logistic regression (P-values below 0.05 were considered as significant). IL-6 and TNFA homozygous genotypes were significantly more often detected in OLP patients. These genotypes were associated with an increased risk of OLP development (OR 6.89 and 13.04, respectively). IL-1beta and IL-10 gene polymorphisms were not related to OLP development. Our findings clearly demonstrate an association between inheritance of IL-6 and TNFA gene polymorphisms and OLP occurrence, thus giving additional support for genetic basis of this disease.

Serotonin transporter gene polymorphism (5-HTTLPR) in patients with oral lichen planus.

BACKGROUND: Considerable evidence indicates that serotonergic mechanisms, particularly the serotonin transporter (5-HTT) may be involved in psychiatric alterations. Recent findings have demonstrated that depression and stress are influenced by polymorphism of the promoter region of 5-HTT (5-HTTLPR) and that the short allele (S) is associated with reduced transcriptional efficiency resulting in reduced serotonin expression and uptake. As psychiatric and genetic factors have been implicated in the pathogenesis of oral lichen planus (OLP), the purpose of the present study was to investigate 5-HTTLPR polymorphism in patients with OLP compared to control subjects. SUBJECTS AND METHODS: Fifty-four subjects affected by OLP and 54 healthy volunteers were genotyped at 5-HTTLPR. The chi-squared test was used for statistical analysis. To investigate the association between the single nucleotide polymorphisms and risk of OLP, binary logistic regression models were fitted. RESULTS: No statistical difference was observed between the genotype and allele frequency in the group of OLP and controls (p=0.51). Moreover no association between 5HTTLPR alleles and OLP was found in the multivariate analyses. CONCLUSION: Our study demonstrates that polymorphism on the 5-HTTLPR is not associated with OLP pathogenesis.

Systemic leukocyte activation in patients with central giant cell lesions.

BACKGROUND: Central giant cell lesion (CGCL) is a reactive lesion of the jaws with an associated inflammatory infiltrate. Since cell circulation allows for intense communication between different compartments in the body, we investigated whether the CGCL would lead to phenotypic and/or functional changes in circulating leukocytes. METHODS: We obtained lymphocytes and monocytes from CGCL patients and control subjects, to evaluate cytokine and adhesion molecule expression using flow cytometry. RESULTS: Our results revealed that CD4(+) T cells and CD14(+) monocytes from CGCL express elevated levels of CD11a and CD11b, respectively, when compared with controls. The frequencies of CD4(+) T cells expressing interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha and the frequencies of CD4(+) and CD14(+) cells expressing interleukin (IL)-10 were increased in CGCL group, when compared with controls. CONCLUSIONS: Our data indicate that, although CGCL is a localized lesion, the patients show systemic functional alterations in circulating leukocytes, suggesting their role in the inflammatory pathogenesis of CGCL.