Daniel Droguett

Chronic Restraint Stress in Oral Squamous Cell Carcinoma

Pathogenic processes have been identified that could associate chronic stress and cancer, but these findings have not been observed in oral cancer. This study examined the role of chronic restraint stress on the incidence and severity of OSCC induced with 4-nitroquinoline-1-oxide (4-NQO) in the tongues of CF-1 mice. One hundred twenty CF-1 male mice were divided into 4 groups: (A) received two treatments — restraint stress and induction of chemical carcinogenesis (n = 50); (B) induction of chemical carcinogenesis, without restraint stress (n = 50); (C) restraint stress (n = 10); and (D) control (n = 10). After 30 weeks, tongues were dissected and analyzed by conventional histopathology. The severity of OSSC was analyzed according to the International Histological Classification of Tumors and Bryne’s Multifactorial Grading System for the Invasive Tumor Front (ITF). Chronic stress induction was confirmed by plasma corticosterone levels. Results showed that chronic stress was induced with movement restriction (p ≤ 0.05, Mann-Whitney U-test). However, chronic stress did not increase the incidence (p > 0.05, Chi-square) or severity (p > 0.05, Mann-Whitney U-test) of the 4-NQO-induced OSSC in the tongues of CF-1 mice. These results suggest that there is no relationship between chronic stress (induced in mice by restraint) and the incidence and severity of OSSC.

Synthesis and pharmacological activity of diterpenylnaphthoquinone derivatives.

New diterpenylquinones, combining a diterpene diacid and a naphthoquinone, were prepared from junicedric acid and lapachol. The new derivatives were assessed as gastroprotective agents by the HCl-EtOH-induced gastric lesions model in mice as well as for basal cytotoxicity on the following human cell lines: Normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), and hepatocellular carcinoma (Hep G2). Several of the new compounds were significantly active as antiulcer agents and showed selective cytotoxicity against AGS cells.

Synthesis, gastroprotective effect and cytotoxicity of new amino acid diterpene monoamides and diamides.

Following our studies on the gastroprotective effect and cytotoxicity of terpene derivatives, new amides were prepared from the diterpene 8(17)-labden-15,19-dioic acid (junicedric acid) and its 8(9)-en isomer with C-protected amino acids (amino acid esters). The new compounds were evaluated for their gastroprotective effect in the ethanol/HCl-induced gastric lesions model in mice, as well as for cytotoxicity using the following human cell lines: normal lung fibroblasts (MRC-5), gastric adenocarcinoma cells (AGS) and liver hepatocellular carcinoma (Hep G2). A dose-response experiment showed that at 25 mg/kg the C-15 leucyl and C-15,19-dileucylester amides of junicedric acid reduced gastric lesions by about 65.6 and 49.6%, respectively, with an effect comparable to lansoprazole at 20 mg/kg (79.3% lesion reduction). The comparison of the gastroprotective effect of 18 new amino acid ester amides was carried out at a single oral dose of 25 mg/kg. Several compounds presented a strong gastroprotective effect, reducing gastric lesions in the 70.9-87.8% range. The diprolyl derivative of junicedric acid, the most active product of this study (87.8% lesion reduction at 25 mg/kg) presented a cytotoxicity value comparable with that of the reference compound lansoprazole. The structure-activity relationships are discussed.

Progressive Extracellular Matrix Disorganization in Chemically Induced Murine Oral Squamous Cell Carcinoma

Introduction. Oral squamous cell carcinoma (OSCC) is one of the ten most common cancers affecting the human population. Tumor pathogenesis implies a multistep process in which cells acquire features that enable them to become tumorigenic and ultimately malignant. The process of OSCC carcinogenesis can be reproduced in animal models, the OSCC induction with 4-nitroquinoline-1-oxide (4NQO) in mice is a widely used tool for studying tumor pathogenesis. Objective. The aim of the present study was to determine the progressive changes in basal lamina and connective tissue remodeling during 4NQO-induced OSCC carcinogenesis. Material and Methods. Samples were classified according to “International Histological Classification of tumors” in mild, moderate, and severe dysplasia and invasive carcinoma. Five samples of each pathologic entity and control healthy tongues were used. Immunohistochemical analysis of collagen IV as well as histochemical analysis of glycosylated molecules (PAS) and collagen I (Picro Sirius red) were performed. Results. During experimental-induced carcinogenesis by 4NQO a progressive basal lamina destruction and collagen I disorganization in adjacent connective tissue can be observed. Conclusion. Our results confirm previous studies that show alterations in extracellular matrix (ECM) in malignant lesions, validating the experimental carcinogenesis induced by 4NQO.

New gastroprotective labdeneamides from (4S,9R,10R) methyl 18-carboxy-labda-8,13(E)-diene-15-oate.

Starting from the diterpene (4S,9R,10R) methyl 18-carboxy-labda-8,13(E)-dien-15-oate (PMD) and its 8(9)-en isomer [PMD 8(9)-en], 11 amides were prepared and assessed for a gastroprotective effect in the ethanol/HCl-induced gastric lesions model in mice. Basal cytotoxicity of the compounds was determined on the following human cell lines: normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), and hepatocellular carcinoma (Hep G2). All compounds are described for the first time. At the single oral dose of 0.1 mg/kg, compounds 1, 10, and 11 presented a strong gastroprotective effect, at least comparable with that of the reference compound lansoprazole at 1 mg/kg, reducing gastric lesions by 76.7, 67.7, and 77.2 %, respectively. The leucyl amide methyl ester 3, tryptophanyl amide methyl ester 5, and benzyl amide 6 of PMD presented a selective basal cytotoxicity on Hep G2 cells with IC₅₀ values of 136.8, 105.3, and 94.2 µM, respectively, while the IC₅₀ values towards AGS cells were 439.5, 928.0, and 937.3 µM, respectively. The three compounds did not affect fibroblast viability with IC₅₀ values > 1000 µM. Compounds 7, 8, 10, and 11 showed no toxic effect against the three selected cell lines.

Oral mucosal lesions in a Chilean elderly population: A retrospective study with a systematic review from thirteen countries.

Background The oral examination is an essential part of the multidisciplinary medical care in elderly people. Oral mucosal lesions and normal variations of oral anatomy (OMLs) are very common in this people, but few studies have examined the frequency and prevalence of these conditions worldwide and less in Chile. The aim of this research was to evaluate the frequency of OMLs in a Chilean elderly population. Material and Methods It was conducted a retrospective study (Talca, Chile). Two hundred seventy-seven OMLs were classified in groups and anatomical sites. In order to contextualize our numbers, we made a systematic review using Publish or Perish software, Google Scholar and InteractiVenn. Results The most prevalent OMLs groups were soft tissue tumors, epithelial pathology, facial pain and neuromuscular diseases, and dermatologic diseases. The most frequent OMLs included irritation fibroma (30 patients, 10.8%), hemangioma (20, 7.2%), burning mouth syndrome (20 cases, 7.2%), oral lichen planus (12, 4.3%) and epulis fissuratum (12, 4.3%). In the systematic review, 75 OMLs were relevant and the more studied pathologies were traumatic ulcerations (11 of 15 articles), oral lichen planus (10/15), irritation fibroma, melanotic pigmentations, and recurrent aphthous stomatitis (9/10, respectively). Considering all included articles, most frequent OMLs in elderly people included denture-related stomatitis (13.3%), irritation fibroma (8.7%) and fissured tongue (6.3%). Conclusions The results reflect the frequency of OMLs diagnosed in a specialized service in south of Chile and many countries around the world. These numbers will allow the establishment of preventive politics and adequacy of the clinical services. Key words:Oral mucosal lesions, elderly people, Chilean population, frequency, systematic review.

Oral diseases: a 14-year experience of a Chilean institution with a systematic review from eight countries

Background Retrospective studies to assess the distribution of oral diseases (ODs) are helpful in estimating the prevalence of oral diagnoses in the population, and thus help in preventive and curative services. Prevalence and frequency data for ODs are available from many countries, but information from Chile is scarce. Material and Methods This study investigated the frequency of ODs in a Chilean population. For this, we included all patients treated at the University of Talca (UTALCA, Chile) between 2001 and 2014. Patient characteristics were retrieved from medical files. To contextualize our results, we conducted a systematic review (SystRev) using Publish or Perish software (PoP), Google Scholar and MEDLINE/PubMed. Results One hundred sixty-six ODs were diagnosed, and the most prevalent groups were soft tissue tumours, epithelial pathology and salivary gland pathology. Individually, irritation fibroma, oral lichen planus (OLP) and mucocele were the most common diagnoses. ODs frequently affected unspecified parts of the mouth (including cheek, vestibule and retromolar area), gum, lips, tongue and palate. In the SystRev, the more studied diagnoses were leukoplakia, OLP and recurrent aphthous stomatitis; prevalent lesions included Fordyce’s spots, recurrent aphthous stomatitis and fissured tongue. Chilean patients and SistRev shared almost all ODs. Conclusions The results reflect ODs diagnosed in a specialized service of oral pathology and medicine in Chile and will allow the establishment of preventive/curative policies, adequate health services and dentistry curriculum. Key words:Stomatognathic diseases, mouth diseases, oral mucosal lesions, epidemiology, Chilean population, retrospective cohort study.