New insights about the antidepressant-like effects of riparin A in a chronic murine model of depression.

Riparin A is a synthetic form of natural riparins. Acute scale studies that take into consideration the structure-activity relationship have shown preliminary evidence of antidepressant and anxiolytic effects of riparin A, similar to that already known for other riparins. However, for better pharmacological characterization of this new compound, further studies are required. The aim of this work was to evaluate the effect of chronic treatment with riparin A (10 mg/kg; intraperitoneally) on depressive-like behavior in the forced swimming test and tail suspension test, as well as the reduction of anhedonia in the sucrose preference test, and on anxiety-like behavior in the open field and elevated plus maze apparatus, triggered in rats previously subjected to unpredictable chronic mild stress by 4 weeks. In addition, a pentobarbital-induced sleep time test was also used. Riparin A reduced the duration of immobility in both the forced swimming test and tail suspension test, as well as attenuated the anhedonia in the sucrose preference test. Furthermore, riparin A appears to produce anxiolytic effects in rats exposed to an open field and elevated plus maze, while increasing the alertness/vigilance in rats submitted to pentobarbital-induced sleep time test, without altering their locomotor integrity. Our results suggest that chronic riparin A appears to be a potential pharmacological target for new studies on the control of depression- and anxiety-like behaviors in stressed rats.

Histological implications of high-power laser use in the oral soft tissue lesions: a systematic review.

The objective of this study was to describe the histological artifacts caused by high-power laser use compared to cold scalpel surgery in oral soft tissue lesions. Clinical studies that evaluated and compared histological artifacts resulting from the use of high-power lasers and cold scalpels in oral soft tissue lesions biopsies were retrieved from seven databases and four grey literatures, up to July 2022. The risk of bias was investigated using the ROBINS-I tool. The certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Seven studies were eligible for qualitative analysis. Based on the results obtained, those four studies had a low risk of bias, and three studies had an unclear risk of bias. The certainty of the evidence was classified as low. Limited evidence showed that epithelial artifacts such as loss of intraepithelial and subepithelial adhesions, accompanied by pyknotic, fusiform, and/or hyperchromic nuclei, were more common when a high-power laser device was used. Four articles reported that the use of high-power lasers did not interfere with the histopathological diagnosis of oral soft tissue lesions. Due to the heterogeneity of the data, a meta-analysis was not performed. Compared to the use of cold scalpels, histological artifacts, particularly those observed in epithelial tissue, are more common when high-powered lasers are used in oral lesions biopsies. The eligibility criteria and adequate indications of high-power lasers in different oral soft tissue lesion treatments must be respected to avoid tissue artifacts that impair precise histopathological diagnosis.

Antidepressant activity of Riparin A in murine model.

Depression and anxiety are common neuropsychiatric disorders that usually appear as comorbidities. The development of new drugs is crucial for safer and more effective clinical management of both disorders. Riparin A is a synthetic chemical analog of riparins that naturally occur in several medicinal plants. Marked pharmacological effects such as anxiolytic and antidepressant properties characterize this class of compounds. However, little is known about the potential anxiolytic and antidepressant effects of Riparin A. In this work, we showed that, unlike other riparins, Riparin A exerts only a very mild anxiolytic-like effect as demonstrated by the results of classical behavioral tests such as the elevated plus-maze, light-dark box and open-field tests in rats. However, all doses of Riparin A (2.5; 5.0 and 10 mg/kg; intraperitoneal) have shown significant antidepressant activity in rats submitted to forced swimming test. In addition to this interesting pharmacological property, Riparin A did not promote any important alterations in the locomotor performance of the animals as specifically demonstrated by the rotarod test. Furthermore, Riparin A did not induce sedation in treated animals; instead, this compound appears to increase the animal's state of alertness as measured by the latency time to loss of reflexes and time to recovery from sleep in rats submitted to the pentobarbital-induced sleep time test. The present results point to an antidepressant effect of Riparin A and reinforce the pharmaceutical interest in the group of riparins, particularly their high potential for use in new studies investigating the structure-activity relationships between member compounds.

Biological Activities of Extracts from Ageratum fastigiatum: Phytochemical Study and In Silico Target Fishing Approach.

In the present study, the ethanolic extract from aerial parts of Ageratum fastigiatum was evaluated in vitro against epimastigote forms of Trypanosoma cruzi (Y strain), promastigote forms of Leishmania amazonensis (PH8 strain), and L. chagasi (BH400 strain). The extract was also evaluated against Staphylococcus aureus (ATCC 25 923), Escherichia coli (ATCC 11 775), Pseudomonas aeruginosa (ATCC 10 145), and Candida albicans (ATCC 36 802). The phytochemical screening was performed by thin-layer chromatography and high-performance liquid chromatography. The extract was fractionated using flash preparative chromatography. The ethanolic extract showed activity against T. cruzi, L. chagasi, and L. amazonensis and antimicrobial activity against S. aureus, E. coli, P. aeruginosa, and C. albicans. The phytochemical screening revealed coumarins, terpenes/sterols, and flavonoids in the ethanolic extract. In addition, the coumarin identified as ayapin was isolated from this extract. We also performed in silico prediction of potential biological activities and targets for compounds previously found in A. fastigiatum. Several predictions were confirmed both retrospectively and prospectively by experimental results described here or elsewhere. Some activities described in the in silico target fishing approach were validated by the ethnopharmacological use and known biological properties. Some new activities and/or targets were predicted and could guide future studies. These results suggest that A. fastigiatum can be an interesting source of substances with antiparasitic and antimicrobial activities.

Efficacy and safety in the treatment of hyperprolactinemia: A systematic review and network meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Hyperprolactinemia is a neuroendocrine disease that is responsible for a quarter of cases of secondary amenorrhea, which can lead to infertility in women. Dopaminergic agonists (bromocriptine, cabergoline, quinagolide) can be used in the treatment. However, there is a lack of secondary studies that compare their efficacy and safety, especially through a network meta-analysis. Thus, to contribute to the decision-making, a systematic review and network meta-analyses (NMA) were performed to evaluate the efficacy and safety of dopaminergic agonists in the treatment of hyperprolactinemia. METHODS: Randomized clinical trials (RCT) were retrieved through PubMed, Web of Science and Scopus databases. The efficacy and safety of the drugs were compared, considering the following outcomes: prolactin (PRL) levels, number of patients with galactorrhoea, menstrual irregularities and adverse drug reactions. NMA was built for each outcome. Results were reported as odds ratios (OR) with 95% credibility intervals. Ranking probabilities were calculated by surface under the cumulative ranking analysis (SUCRA) and Stochastic multicriteria acceptability analysis (SMAA). RESULTS AND DISCUSSION: Seventeen RCTs were included in the systematic review and fifteen in the meta-analyses. The drugs had similar efficacy, considering the PRL levels. The SUCRA analysis showed that quinagolide (0.075 and 0.05 mg/day) was superior for reducing irregular menstruation, whereas bromocriptine was the best (97%) for galactorrhoea. Cabergoline proved to be the safest drug, except for abdominal pain at a dose of 1 mg/week. The SMAA demonstrated similar results to SUCRA. WHAT IS NEW AND CONCLUSION: This is the first network meta-analysis that evaluated the efficacy and safety of dopaminergic agonists in the treatment of hyperprolactinemia. The results of this review revealed that these drugs have similar efficacy, but cabergoline has a better safety profile.

The relevance of miRNAs as promising biomarkers in lip cancer.

OBJECTIVES: This study aimed to analyze the expression of miR-181b, miR-21, miR-31, and miR-345 in actinic cheilitis with and without epithelial dysplasia and lower lip squamous cell carcinomas, and to verify if the deregulated expression of these miRNAs would be indicative of malignant transformation. MATERIALS AND METHODS: The sample was selected from formalin-fixed paraffin-embedded tissues of 19 actinic cheilitis without epithelial dysplasia, 32 actinic cheilitis with epithelial dysplasia, 42 lower lip squamous cell carcinomas, and 10 nonaltered oral mucosa of the lip. The microRNA (miR, miRNA) expression was quantified by real-time RT-PCR and the expression of the selected miRNAs among the groups of actinic cheilitis and lower lip cancer was compared by chi-square. RESULTS: A higher expression of miR-181b, miR-31, and miR-345 was found in actinic cheilitis without epithelial dysplasia in comparison to that in actinic cheilitis with epithelial dysplasia and with lower lip cancer. There were no differences in miR-21 expression between actinic cheilitis and lower lip cancer. Hierarchical clustering analysis showed a tendency for a downregulation of miR-181b, miR-21, miR-31, and miR-345 in most patients with lower lip cancers. CONCLUSIONS: The upregulation of miR-181b, miR-31, and miR-345 expression in actinic cheilitis without epithelial dysplasia and the decrease in the expression of these miRNAs in actinic cheilitis with epithelial dysplasia and in lower lip cancer are potential biomarkers of malignant progression. CLINICAL RELEVANCE: This miRNA signature can help to identify actinic cheilitis with potential to progress to lip cancer.

Association of lymph vessel density with occult lymph node metastasis and prognosis in oral squamous cell carcinoma.

BACKGROUND: The aims of this study were to determine intra (ILVD) and peritumoral (PLVD) lymphatic vessel density (LVD), and to investigate the relationship of LVD with occult metastasis and prognosis. METHODS: Eighty-seven oral squamous cell carcinomas, in clinical stages I or II, arising in the tongue or floor of the mouth were stained with podoplanin. Lymphatic vessels were quantified in intra and peritumoral areas by sequential analysis and hot spot evaluation. Associations of the ILVD and PLVD with clinicopathologic parameters were determined by Chi-square or Fisher's exact test. The 5 and 10-year survival rates were calculated by the Kaplan-Meier and compared using the log-rank test. RESULTS: No significant association was observed between ILVD or PLDV and clinicopathologic variables including occult lymph node metastasis, or clinical follow-up. However, ILVD showed a significant association with regional recurrence (p = 0.040). The perineural invasion was associated with PLVD (p = 0.041). Disease-specific (p = 0.044) and disease-free survivals (p = 0.016) had significant association with PLVD. CONCLUSIONS: The intra or peritumoral lymphatic vessel density had no predictive value for occult lymph node metastasis in the early stages of oral cancer arising in the tongue or floor of mouth.

Latex proteins downregulate inflammation and restores blood-coagulation homeostasis in acute Salmonella infection.

BACKGROUND: Calotropis procera latex protein fraction (LP) was previously shown to protect animals from septic shock. Further investigations showed that LP modulate nitric oxide and cytokines levels. OBJECTIVES: To evaluate whether the protective effects of LP, against lethal bacterial infection, is observed in its subfractions (LPPII and LPPIII). METHODS: Subfractions (5 and 10 mg/kg) were tested by i.p. administration, 24 h before challenging with lethal injection (i.p.) of Salmonella Typhimurium. LPPIII (5 mg/kg) which showed higher survival rate was assayed to evaluate bacterial clearance, histopathology, leukocyte recruitment, plasma coagulation time, cytokines and NO levels. FINDINGS: LPPIII protected 70% of animals of death. The animals given LPPIII exhibited reduced bacterial load in blood and peritoneal fluid after 24 h compared to the control. LPPIII promoted macrophage infiltration in spleen and liver. LPPIII restored the coagulation time of infected animals, increased IL-10 and reduced NO in blood. MAIN CONCLUSIONS: LPPIII recruited macrophages to the target organs of bacterial infection. This addressed inflammatory stimulus seems to reduce bacterial colonisation in spleen and liver, down regulate bacterial spread and contribute to avoid septic shock.

Molecular method for the semiquantitative identification of gastrointestinal nematodes in domestic ruminants.

Standard diagnostic methods currently in use for the identification of helminth infections in ruminants are based on the morphological analysis of immature and adult stages of parasites. This paper describes a method for the semiquantitative identification of nematodes, mainly Trichostrongyloidea, at species-level resolution. The method is based on amplification and fragment analysis followed by minisequencing of the ITS-2 region (internal transcribed spacer 2) of the ribosomal DNA of parasite eggs or larvae. This method allows for the identification of seven genera (Chabertia, Cooperia, Haemonchus, Oesophagostomum, Ostertagia, Teladorsagia, and Trichostrongylus) and 12 species (Chabertia ovina, Cooperia curticei, Cooperia punctata, Cooperia oncophora/Cooperia surnabada, Haemonchus contortus, Haemonchus placei, Haemonchus longistipes, Oesophagostomum asperum, Oesophagostomum radiatum, Ostertagia ostertagi, Trichostrongylus axei, and Trichostrongylus colubriformis) of infectious nematodes of domestic ruminants. The concordance between the morphological and molecular analyses in the detection of genera ranged from 0.84 to 0.99, suggesting the proposed detection method is specific, semiquantitative, less laborious, and highly cost-efficient.

A function for the pleurogram in physically dormant seeds.

BACKGROUND AND AIMS: Different structures have been shown to act as a water gap in seeds with physical dormancy (PY), and in Fabaceae they are commonly located in the hilar region. However, the function of the pleurogram, a structure in the extra-hilar region that is common in legume seeds, remains unknown. Our aims were to review the literature for occurrence of the pleurogram in Fabaceae, determine if the pleurogram can open, and compare the functional morpho-anatomy of water gaps in seeds of 11 Senna species. METHODS: Imbibition tests showed that all 11 species had PY. Structural features of the hilar and extra-hilar regions of the seeds were investigated using light and scanning electron microscopy, and dye-tracking was performed to trace the pathways of water through the seed coat. KEY RESULTS: A pleurogram has been reported for 37 legume genera. Water gaps differed among Senna species, with lens, hilum, micropyle and pleurogram taking up water after PY was broken. In Senna alata seeds, only the pleurogram acted as a water gap, whereas in S. reniformis and S. silvestris water entered the seed through both the pleurogram and the hilar region. In the pleurogram of S. alata and S. reniformis, the palisade layer moved outward, exposing the hourglass cells, whereas in S. silvestris the palisade layer was broken. CONCLUSIONS: The pleurogram acts as a water gap in some of the 11 Senna species examined, but it is non-functional in others. Opening the pleurogram occurs due to the formation of a linear slit in the palisade layer. The pleurogram is of functional significance by creating a wide opening, whereby water can reach the embryo and start germination. This is the first report of the pleurogram functioning as a water gap. Because this structure is shared by at least 37 genera, it also may be a water gap in many other legume species.

Myofibroblastic lesions in the oral cavity: Immunohistochemical and ultrastructural analysis.

OBJECTIVE: To immunohistochemically characterize a group of oral myofibroblastic lesions (MLs) and to evaluate the ultrastructural features of myofibroblasts. MATERIAL AND METHODS: Using a tissue microarray technique (TMA), cases of myofibroma (MF), of nodular fasciitis (NF), of desmoplastic fibroma (DF), and of myofibroblastic sarcoma (MS) from the Universidad Autónoma Metropolitana Xochimilco, and a Private Oral Pathology Service in Mexico City were stained with antibodies against alpha-smooth muscle actin (α-SMA), H-caldesmon, vimentin, desmin, ß-catenin, CD34, anaplastic lymphoma protein kinase (ALK-1), and Ki-67. RESULTS: Nineteen of the 22 MF cases, 2/5 of the NF cases, 1/10 of the DF cases, and 1/2 of the MS cases were positive for α-SMA. 1/2 of the MS cases were positive for desmin; 6/10 of the DF cases were positive for ß-catenin, and 2 of the MF cases were positive for ALK-1. All of the MLs were positive for vimentin and negative for H-caldesmon and CD-34. The Ki-67 labeling index in all of the 8/22 MF, 3/5 NF, and 2/2 MS cases was ≥10%. For all of the MLs evaluated, ultrastructural analysis revealed spindle-shaped cells containing endoplasmic reticulum and peripheral actin filament bundles. CONCLUSION: In certain myofibroblastic lesions, the use of auxiliary techniques (such as immunohistochemistry) can be critical for differential diagnosis.

An unusual clinical manifestation of oral melanocytic nevus.

Melanocytic nevi are acquired or congenital benign neoplasms, often found in skin but rarely in the oral mucosa. This article reports an atypical case of oral hypopigmented melanocytic nevus in a 39-year-old woman referred for evaluation of a well-circumscribed papule with discrete brownish spots in the buccal mucosa. An excisional biopsy was performed, the results of which led to a clinical diagnosis of inflammatory fibrous hyperplasia. The histopathologic analysis resulted in a diagnosis of hypopigmented intramucosal melanocytic nevus. This unusual clinical manifestation of melanocytic nevus reinforces the importance of including nonpigmented or hypopigmented melanocytic nevi in the differential diagnosis of papules arising in the oral mucosa. A biopsy and subsequent histologic examination of the specimen are recommended to establish an accurate diagnosis.

Moesin expression by tumor cells is an unfavorable prognostic biomarker for oral cancer.

BACKGROUND: Moesin is a member of the ERM (ezrin, radixin and moesin) proteins that participate in cell migration and tumor invasion through transductional signals sent to actin filaments by glycoproteins, such as podoplanin. METHODS: This study aimed to evaluate the participation of moesin and podoplanin in the invasive tumor front of oral squamous cell carcinomas, and their influence on patients' prognosis. Podoplanin and moesin immunoexpressions were evaluated by a semi-quantitative score method, based on the capture of 10 microscopic fields, at 400X magnification, in the invasive tumor front of oral squamous cell carcinomas. The association of moesin and podoplanin expression with clinicopathological variables was analyzed by the chi-square, or Fisher's exact test. The 5 and 10 years survival rates were calculated by the Kaplan-Meier method and the survival curves were compared by using the log-rank test. RESULTS: The immunohistochemical expression of moesin in the invasive front of oral squamous cell carcinomas was predominantly strong, homogenously distributed on the membrane and in the cytoplasm of tumor cells. The expression of moesin was not associated with clinical, demographic and microscopic features of the patients. Otherwise, podoplanin expression by malignant epithelial cells was predominantly strong and significantly associated with radiotherapy (p = 0.004), muscular invasion (p = 0.006) and lymph node involvement (p = 0.013). Strong moesin expression was considered an unfavorable prognostic factor for patients with oral squamous cell carcinomas, clinical stage II and III (p = 0.024). CONCLUSIONS: These results suggested that strong moesin expression by malignant cells may help to determine patients with oral squamous cell carcinoma and poor prognosis.

The role of mitochondrial DNA damage at skeletal muscle oxidative stress on the development of type 2 diabetes.

Reduced cellular response to insulin in skeletal muscle is one of the major components of the development of type 2 diabetes (T2D). Mitochondrial dysfunction involves in the accumulation of toxic reactive oxygen species (ROS) that leads to insulin resistance. The aim of this study was to verify the involvement of mitochondrial DNA damage at ROS generation in skeletal muscle during development of T2D. Wistar rats were fed a diet containing 60% fat over 8 weeks and at day 14 a single injection of STZ (25 mg/kg) was administered (T2D-induced). Control rats received standard food and an injection of citrate buffer. Blood and soleus muscle were collected. Abdominal fat was quantified as well as glucose, triglyceride, LDL, HDL, and total cholesterol in plasma and mtDNA copy number, cytochrome b (cytb) mRNA, 8-hydroxyguanosine, and 8-isoprostane (a marker of ROS) in soleus muscle. T2D-induced animal presented similar characteristics to humans that develop T2D such as changes in blood glucose, abdominal fat, LDL, HDL and cholesterol total. In soleus muscle 8-isoprostane, mtDNA copy number and 8-hydroxyguanosine were increased, while cytb mRNA was decreased in T2D. Our results suggest that in the development of T2D, when risks factors of T2D are present, intracellular oxidative stress increases in skeletal muscle and is associated with a decrease in cytb transcription. To overcome this process mtDNA increased but due to the proximity of ROS generation, mtDNA remains damaged by oxidation leading to an increase in ROS in a vicious cycle accounting to the development of insulin resistance and further T2D.

An update of 77 cases diagnosed as oral hemangiomas based on GLUT-1 positivity.

OBJECTIVES: To evaluate cases diagnosed as "oral hemangiomas" based on the immunohistochemical expression of human glucose transporter protein (GLUT-1) and on histopathological features, and to investigate whether the classification proposed by the ISSVA was used correctly to classify these lesions. MATERIAL AND METHODS: All cases stored in the archives of an Oral Pathology Service and diagnosed as "oral hemangiomas" were reviewed. Seventy-seven cases were analyzed regarding the expression of GLUT-1. GLUT-1(+) specimens were classified as true infantile hemangioma (IH) and GLUT-1(-) specimens were reclassified based on their histopathological features. The nomenclature of these lesions was evaluated and some cases were reclassified. RESULTS: Only 26 (33.8%) of the specimens were indeed IHs. Among the GLUT-1(-) specimens, 20 (26.0%) were reclassified as pyogenic granulomas (PGs) and 31 (40.2%) as vascular malformations. Considering the previously applied nomenclature, only 47.5% of the cases initially diagnosed as "hemangiomas" were IHs. In the group of "capillary hemangiomas", most cases (56.2%) were PGs. Among the three "cellular hemangiomas", two were PGs and one was IH. Most (88.8%) "cavernous hemangiomas" were vascular malformations. CONCLUSION: Careful and parameterized review of cases of vascular anomalies is necessary using auxiliary tools such as GLUT-1, since the exclusive use of histopathological findings might be insufficient to differentiate some anomalies. CLINICAL RELEVANCE: Accurate clinical examination and the use of biomarkers such as GLUT-1 are essential for the diagnosis.

Podoplanin, ezrin, and Rho-A proteins may have joint participation in tumor invasion of lip cancer.

INTRODUCTION: Podoplanin and ezrin connection through Rho-A phosphorylation have been suggested as part of the activation pathway, in the process of tumor invasion and cell movement in oral squamous cell carcinomas. OBJECTIVE: The aim of this study was to evaluate the correlation among podoplanin, ezrin, and Rho-A immunoexpressions in 91 squamous cells carcinomas of the lower lip and their influence in patient's prognosis. MATERIAL AND METHODS: The immunoexpressions of podoplanin, ezrin, and Rho-A were evaluated through a semi-quantitative score method, based on the capture of 10 microscopic fields at the front of tumor invasion. The association and correlation of these proteins with the clinicopathological features were verified by Fischer's exact test and Spearman's test. The prognostic values were analyzed by Kaplan-Meier method and log-rank test. RESULTS: A statistically significant association between strong cytoplasmic podoplanin expression and alcohol (p = 0.024), loco-regional recurrences (p = 0.028), and lymph node metastasis (pN+) (p = 0.010) was found. The membranous (p = 0.000 and r = 0.384) and cytoplasmic (p = 0.000 and r = 0.344) podoplanin expression was statistically correlated with ezrin expression. Also, membranous podoplanin was significantly correlated with Rho-A expression (p = 0.006 and r = 0.282). The expressions of podoplanin, ezrin, and Rho-A were not significant prognostic factors for patients with squamous cell carcinomas of the lower lip. CONCLUSIONS: Therefore, our results confirm a correlation among podoplanin, ezrin, and Rho-A expressions in squamous cell carcinoma of the lip suggesting a cooperative participation of these proteins in cell movement and invasion. CLINICAL RELEVANCE: Furthermore, strong cytoplasmic podoplanin expression could be helpful to identify patients with squamous cell carcinoma of the lip and lower risk of loco-regional recurrences.

An Uncommon Occurrence of Three-Fourth Molars Concomitant to Hypodontia in a Nonsyndromic Patient.

Bilaterally mandibular and maxillary fourth molars, concomitant to hypodontia, are uncommon. These dental anomalies, called hypohyperdontia, are rare and etiology is not well defined. Several complications may occur as a consequence of supernumerary teeth, such as teeth impaction, resorption of adjacent teeth, and development of cysts and tumors. The authors present an uncommon occurrence of three-fourth molars concomitant to hypodontia and dentigerous cyst associated with impacted mandibular second and third molars in a nonsyndromic patient. The authors attempt to discuss the occurrence of bilaterally fourth molars and reinforce the importance of clinical approach, considering risks and benefits for the patient.

Burkitt Lymphoma in Adult With Atypical Clinical Presentation Primarily Involving the Oral Soft Tissue.

Non-Hodgkin lymphoma is the second most common neoplasm of the head and neck after squamous cell carcinoma. However, it accounts for only 3.5% of all malignancies of the oral cavity. Oral lesions are often a component of disseminated disease process that may involve regional lymph nodes or may at times represent the primary extra nodal form of the disease. Although, isolated oral lymphoma in adults is extremely rare, this paper presents a patient with Burkitt lymphoma in an adult male with atypical clinical presentation primarily involving the oral soft tissue. It is believed that the prognosis of Burkitt lymphoma depends on the extent of the disease, the patient's age, and the timing of diagnosis. Therefore, the role of the dentist in the early diagnosis and prompt referral of patients with Burkitt lymphoma cannot be overemphasized.

Luteolin Impacts on the DNA Damage Pathway in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) exhibited high chemoresistance to current treatments. Here we aimed at identifying and repositioning approved drugs that could be selectively toxic toward OSCC cells. Through a cell-based drug screening of 1,280 chemical molecules, we selected compounds lethal to oral cancer SCC-25 cells, while sparing normal keratinocyte HaCaT cells. Within the chemical library, the natural flavonoid luteolin was identified as a potent cytotoxic agent against oral cancer cells in vitro, along with metixene hydrochloride and nitazoxanide. Of note, they exhibit low toxicity and high efficiency compared to the standard-of-care, such as cisplatin and the epidermal growth factor receptor inhibitor tyrphostin. From a molecular standpoint, luteolin causes phosphorylation of ataxia telangiectasia mutated (ATM) and H2AX in a DNA repair pathway and can be efficiently combined with a checkpoint kinase (CHK) pharmacological inhibitor. Thus, luteolin emerges as a potent cytotoxic and/or adjuvant therapy in oral cancer, as it is a natural compound presenting better effects in vitro compared to conventional chemotherapeutic agents. Future in vivo exploration is next required to provide the proof-of-concept that luteolin could be an efficient anticancer molecule.

M2 macrophages and inflammatory cells in oral lesions of chronic paracoccidioidomycosis.

BACKGROUND: Paracoccidioidomycosis (PCM) is a systemic fungal infection caused by Paracoccidioides brasiliensis (Pb) and associated with deficient cellular immune response, which is modulated by inflammatory cells, mainly macrophages, and cytokines. Recently, the comprehension of the macrophage polarization mediated by Th1 and Th2 cytokines has contributed to elucidate the immune response that takes part in some diseases. Thus, the aim of this study was to assess the presence of Th1- and Th2-immune response and also Pb counting in oral lesions of chronic PCM. METHODS: Forty-eight cases of chronic PCM oral lesions were included. All cases were classified as loose or dense granulomas. S100 protein, IL-1ß, IL-6, TNF-α, CD163 and CD68 immunoexpressions, and Pb localization were evaluated. The fungi present in the tissue were quantified by anti-Pb antibody. RESULTS: Most patients were white men with mean age of 47 years old and showed higher incidence of multiple lesions. Loose granulomas were predominant and exhibited a great amount of M2 macrophages, which were visualized with anti-CD163 antibody. The expression for CD163 and CD68 was similar (P = 0.05), highlighting the predominance of M2 macrophages in PCM. IL-1ß, IL-6, and TNF-α immunoexpression did not significantly change with CD163, CD68, and S100 protein. The number of fungi was significantly higher in cases with intense IL-1ß immunoexpression (P = 0.003). CONCLUSIONS: M2-activated macrophages were the majority among inflammatory cells in chronic PCM, characterizing the action of a Th2-immune response. Nevertheless, Th1 cytokines were also found; mainly IL-1ß, which was associated with fungi counting in oral lesions.