Avaliação citológica em base líquida de fármacos moduladores estrogênicos

Hormone therapy is an important tool in the treatment of breast cancer and tamoxifen represents one of the most important drugs used in this type of treatment. Recently other drugs based on the inhibition of aromatase had been developed, this enzyme is responsible for the synthesis of estrogenic esteroids from the androgenic ones. The objective of this study would be the development of a quantitative cytological model of murine estral analysis that allowed the characterization of different hormone drugs effect over vaginal epithelium. The technique of monochromatic staining with Evans blue (C.I. 23860) showed to be efficient in the qualitative and quantitative classification of the cycle. It had been observed differences in the cytological standard of animals submitted to the studied drugs; tamoxifen presented a widening of phases of lesser maturation (diestrais), while anastrozole and exemestane increased the duration of the phases of larger maturation (estrais). The data were analysed through a cubical non linear regression (spline) which allowed a better characterization of the drugs, suggesting a proper cytological profile to the antagonism of the estrogen receptor (tamoxifen), aromatase competition (anastrozole) and inhibition of the enzyme (exemestane)

Ativação local da rota da quinurenina por moduladores inflamatórios durante a meningite bacteriana.

Activation of the kynurenine (KYN) pathway (KP) by modulators of immune system has been observed during several neurological diseases. Here we assessed the association of chemo-/cytokine levels with the concentration of KP metabolites in cerebrospinal fluid (CSF) and plasma samples from patients with bacterial meningitis (BM). All samples were collected from 42 patients diagnosed with acute bacterial meningitis (ABM), aseptic meningitis, tuberculous meningitis and patients without infection neurological disorders. CSF and plasma concentration of metabolites from the KP was assessed by high pressure liquid chromatography (HPLC) and cytokines and chemokines by Bio-plex 200 suspension array system. Concentrations of the KP metabolites KYN and kynurenic acid (KYNA) were significantly higher in CSF of patients with ABM compared to other groups. Tryptophan (TRP), anthranilic acid (AA), 3-hydroxykynurenine (3HK) and 3-hydroxyanthranilic acid (3HAA) did not show statistical significance, although some of them presented a good accumulation during ABM. The expression of TNF-alpha, IL-6, IL-1beta, IFN-gamma, IL-10, IL-1 receptor antagonist (IL-1Ra), MIP-1alpha, MIP-1beta, MCP-1 and G-CSF was about 100-fold higher in CSF from ABM patients than other infected groups. In all CSF and plasma samples, the concentration of IL-2, IL-12(p70), IL-4, IL-8 and GM-CSF was not significant. ABM still showed significant concentrations of IL-6, IL-10, IL-1Ra and MCP-1 in plasma samples. Based on the comparison of KP metabolites concentrations between plasma and CSF samples we conclude that the activation of the tryptophan pathway upon BM occurs within the brain. This increase in KP metabolites is most due to activation of the KP by molecules as IFN-gamma and TNF-alpha in response to infection.

Estudo da angiogênese pelo CD105 e FvW no carcinoma epidermóide oral e sua relação com o estadiamento clínico do tumor

The purpose of this study was to assess the immunohistochemical expression of CD105 and FvW antibodies in the angiogenesis of oral epidermoid carcinoma (OEC), correlating it with the TNM clinical staging system, seeking a better understanding of its biological behavior and use as an indicator of prognosis.The sample consisted of 30 epidermoid carcinoma (EC) cases, 10 of the floor of the mouth, 10 of the retromolar region and 10 of the tongue, in addition to 10 cases of pyogenic granuloma, which made up the control group. The results showed that mean microvessel counts (MVC) were correspondingly higher in the pyogenic granuloma group (CD105 = 57.26 vessels and FvW = 39.64) than in the EC group (CD105 = 10.09 and FvW = 12.20) and that the differences were statistically significant between the groups for each of the angiogenic biomarkers (p = 0.002 for CD105 and p< 0.001 for FvW). CD105 had better positivity in the pyogenic granuloma group (mean = 57.26 vessels) and for EC, FvW had the highest expression (mean = 12.20 vessels). With respect to EC, the most affected age group was between 51 and 70 years (n = 14; 46.7%), with a representative MVC for both markers. No statistically significant difference was found between the sexes for any of the markers (p = 0.967 for CD105 and p = 0.744 for FvW). Mean CD105 levels were much higher in patients with stage T3 and T4 (17.13) and lower in those with stage N+ (6.36). Mean FvW levels were higher in the patients with stage T1 and T2 (12.23) and lower in patients with T3 and T4 (12.10), but without a statistically significant difference. In regard to anatomic location, a statistically significant difference was observed between FvW sites, with a statistically significant difference between floor of the mouth cases and those located in the retromolar region (p =0.013). Therefore, this study suggests that CD105 expression in OEC angiogenesis, in contrast to other types of malignant neoplasias, may not be correlated with prognosis and tumor aggressiveness, whereas FvW was a more effective antibody for staining this lesion

Avaliação da angiogênese em lesões de líquen plano oral e pênfigo vulgar

Oral lichen planus and pemphigus vulgaris are chronic diseases mucous membrane immune of unknown aetiology that can be observed affecting to the oral mucous. A relevant as regards neoplasies the role angiogenesis in the inflammatory chronic disease pathogenesis as it provides a substancial interest can be considered as being an activity diseases marker; besides being through specialised research of this angiogenic process to improve of understanding pathogenic mechanism. This research proposes to assess angiogenic active through of antibody immunohistochemistry expression antiCD34 antibody in 26 OLP of reticular cases, 14 OLP erosives cases, 18 of PV cases and 15 specimens of normal oral mucosa. The result was submitted non-parametric tests of 5% significance level. It is not statistically significant correlacion was seen regarding between average vessels. However, only be effectively observed the median of OLP cases was larger than pemphigus vulgaris in fact proved average larger than oral normal mucosa (p=0,280). Regarding the microvascular count of CD34 concerning clinic form oral lichen planus (reticular and erosion) increased emphasis is more cross-border average for the form erosion clinic. Despite of the statistic tests could not be more effective (p=0,720). Even though, the results of the research is not sufficient to enable to consider of angiogenic process in the pathogenesis and lesions progression of oral lichen planus and pemphigus vulgaris, we suggest this process is present in both forms lesion, however, more studies must be made in the near future in order to prepare a well-founded proposal

Um dermatam sulfato antitrombótico do camarão Litopenaeus vanammei inibe a inflamação e angiogênese

Inflammation is combined of a vascular and a cellular reaction, resulting in different cells and tissue responses, both the intravascular and extravascular environment. As the inflammatory process occurs, coagulation proteases, in particular thrombin (FIIa), are able to initiate various cellular responses in vascular biology and therefore is often observed activation of other biological systems, leading to complications during an event inflammatory, such as thrombosis and angiogenesis. Thus, antagonists molecules of these events are interesting models for the development of novel anti-inflammatory drugs. Thereby, it is worth stressing the glycosaminoglycans (GAGs), which are able to interact with several proteins involved in important biological processes, including inflammation and coagulation. Therefore, this study aimed to evaluate the anti-inflammatory, antithrombotic and anti-angiogenic potentials, as well anticoagulant of a dermatan sulfate-like GAG (DS) extracted from the Litopenaeus vannamei cephalotorax. The compound was obtained after proteolysis and purification by ion-exchange chromatography. After total digestion by DS-like compounds digesting lyases (chondroitinase ABC), the DS-like nature was revealed, and then called DSL. The shrimp compound showed reduced anticoagulant effect by the aPTT assay, but high anti-IIa activity, directly and through heparin cofactor II. On inflammation, the compound had a significant inhibitory effect with the reduction of proinflammatory cytokines. Potential Inhibitory were reported in the antithrombotic and anti-angiogenic assay, the latter being dose dependent. As for anti-hemostatic activity, the polysaccharides did not induced significant bleeding effect. Thus, the results shown by the shrimp DS-like compound indicate this glycosaminoglycan as a biotechnology target with prospects for the development of new multipotent drugs.

Procoagulant state after raloxifene therapy in postmenopausal women

AZEVEDO, George Dantas de et al. Procoagulant state after raloxifene therapy in postmenopausal women. Fertility and Sterility, Estados Unidos, v.84, n.6, p.1680-1684, 2005

Efeitos do fator de crescimento de fibroblasto Básico (FCFß) na cicatrização de anastomoses do esôfago

Os fatores de crescimento são substâncias moduladoras do processo de cicatrização. O fator de crescimento de fibroblastos básico (FCFß) liberado pelas plaquetas, macrófagos e pelos próprios fibroblastos, estimulam a proliferação celular, a produção de colágeno e de outros elementos da matriz celular, favorecendo o processo da cicatrização, mesmo em situações adversas, como diabetes e uso de corticosteróides. O presente estudo objetivou determinar a influência do FCFb no processo de cicatrização de anastomoses esofageanas em modelo de experimentação animal, avaliando-se a resistência à pressão,formação de tecido de granulação e deposição de colágeno. Método: Foram estudados dois grupos A e B,ambos com 10 ratos de linhagem Wistar, separados de forma aleatória, todos submetidos à secção e anastomose do esôfago por via abdominal. Nos animais do grupo A, foi feita aplicação tópica na linha de sutura de 10ng de FCFb. No grupo B (controle) foi aplicado igual volume de solução salina. Os animais foram sacrificados no 7º dia, o esôfago ressecado para teste de resistência da anastomose, estudo qualitativo do aporte de células inflamatórias, da angiogênese e quantificação do colágeno na zona da anastomose, através de sistema digital. Resultados: A densidade média dos parâmetros histológicos do grupo A foi 9095,51±1284,5, maior que no grupo B, que teve densidade 7162,4±1273,19 (p=0,013). A resistência da anastomose do grupo A teve a média 210±18,88 mmHg, significativamente maior que no grupo B, que atingiu o valor 157±29,55 mmHg (p=0,0024). Conclusão: Este estudo concluiu que o FCFß atuou melhorando a cicatrização e aumentando significativamente a resistência de anastomoses do esôfago realizadas em ratos

Aspectos estruturais, farmacológicos e biológicos de fucanas da alga marrom sargassum vulgare

The present study examines the chemical composition and their effects on free radicals, inflammation, angiogenesis, coagulation, VEGF effects and cellular proliferation of a polysaccharides from alga Sargassum vulgare. The sulfated polysaccharide was extracted from brown seaweed by proteolysis with enzymes maxataze. The presence of proteins and sugars were observed in crude polysaccharides. Fractionation of this crude extract was made with growing concentration of acetone (0.3-1.5 v) and produced four groups of polysaccharides. Anionic polysaccharides from brown seaweed Sargassum vulgare, SV1and PSV1 were fractionated (SV1) and purified (PSV1), and displayed with high total sugars and sulfate content and very low level of protein. This fucan SV1 contains low levels of protein and high carbohydrate and sulfate content. This polysaccharides prolonged activated partial thromboplastin time (aPTT) at 50 μg (>240 s). SV1 was found to have no effect on prothrombin time (PT), corresponding to the extrinsic pathway of coagulation. SV1 exhibits high antithrombotic action in vivo, with a concentration ten times higher than heparin. Polysaccharides from S. vulgare promoted direct inhibition enzymatic activity of thrombin and stimulated enzymatic activity of FXa. SV1 showed optimal inhibitory activity of thrombin (50.2±0.28%) at a concentration of 25 μg/mL. Its antioxidant action on scavenging radicals by DPPH was (22%), indicating the polymer has no cytotoxic action (hemolytic) on ABO and Rh blood types in different erythrocyte groups and displays strong anti-inflammatory action on all concentrations tested in the carrageenan-induced paw edema model, demonstrated by reduced edema and cellular infiltration. Angiogenesis is a dynamic process of proliferation and differentiation. It requires endothelial proliferation, migration, and tube formation. In this context, endothelial cells are a preferred target for several studies and therapies. The antiangiogenic efficacy of polysaccharides was examined in vivo in the chick chorioallantoic membrane (CAM) model by using fertilized eggs. Decreases in the density of the capillaries were assessed and scored. The results showed that SV1 and PSV1 have an inhibitory effect on angiogenesis. These results were also confirmed by inhibition tubulogenesis in rabbit aorta endothelial cell (RAEC) in matrigel. These compounds were assessed in Apoptosis assay (Annexin V - FITC / PI) and cell viability by MTT assay of RAEC. These polysaccharides do not affect the viability and do not have apoptotic or necrotic action. RAEC cell when incubated with SV1 and PSV1showed inhibition of VEGF secretion, observed when compounds were incubated at 25, 50 and 100 μg/μL. The VEGF secretion with the RAEC cell line for 24 h, was more effective for PSV1 at 50 μg/μL(71.4%) than SV1 100 μg/μL (75.9%). SV1 and PSV1 had an antiproliferative action (47%) against tumor cell line HeLa. Our results indicate that these sulfated polysaccharides have antiangiogenic and antitumoral actions

Caracterização físico-química e ações farmacológicas hepatoprotetora, antiinflamatória, pró-angiogênica, antioxidante e anticoagulante da fração rica em fucana 0,8FRF 0,8 da alga marrom Lobophora variegata

This study examines the physical and chemical composition and the pharmacological effects of brown seaweed FRF 0.8 Lobophora variegata. Fractionation of the crude extract was done with the concentration of 0.8 volumes of acetone, obtaining the FRF 0.8. The physicochemical characterization showed that it was a fucana sulfated. Anti-inflammatory activity was assessed by paw edema model by the high rates of inhibition of the edema and the best results were in the fourth hour after induction (100 ± 1.4% at the dose of 75 mg / kg) and by the strong inhibitory activity of the enzyme myeloperoxidase (91.45% at the dose of 25 mg / kg). The hepataproteção was demonstrated by measurements of enzymatic and metabolic parameters indicative of liver damage, such as bilirubin (reduction in 68.81%, 70.68% and 68.21% for bilirubin total, direct and indirect, respectively at a dose of 75 mg / kg), ALT, AST and γ-GT (decrease of 76.93%, 44.58% and 50% respectively at a dose of 75 mg / kg) by analysis of histological slides of liver tissue, confirming that hepatoprotective effect the polymers of carbohydrates, showing a reduction in tissue damage caused by CCl4 and the inhibition of the enzyme complex of cytochrome P 450 (increasing sleep time in 54.6% and reducing the latency time in 71.43%). The effectiveness of the FRF 0.8 angiogenesis was examined in chorioallantoic membrane (CAM) of fertilized eggs, with the density of capillaries evaluated and scored, showing an effect proangigênico at all concentrations tested FRF (10 mg- 1000 mg). The FRF showed antioxidant activity on free radicals (by inhibiting Superoxide Radical in 55.62 ± 2.10%, Lipid Peroxidation in 100.15 ± 0.01%, Hydroxyl Radical in 41.84 ± 0.001% and 71.47 Peroxide in ± 2.69% at concentration of 0.62 mg / mL). The anticoagulant activity was observed with prolongation of activated partial thromboplastin time (aPTT) at 50 mg (> 240 s), showing that its action occurs in the intrinsic pathway of the coagulation cascade. Thus, our results indicate that these sulfated polysaccharides are an important pharmacological target

Polissacarídeos sulfatados de interesse farmacológico no camarão litopenaeus schimitti

Sulfated Polysaccharides with unique chemical structures and important biological activities has been found in a diversity of sea invertebrates. For that, to exist a huger interest on the biotechnology field in the research theses sulfated compounds isolated from sea organisms. Despite the privileged brazilian position for these compounds attainment, there are still a few scientific informations about the isolated substances and their biological activities. A head the displayed, the present work has for objectives, to evaluate the pharmacological properties of the glycosaminoglycans isolated from the sea shrimp Litopenaeus schimitti on homeostasis, blood coagulation, leukocytes migration and platelet/leukocyte adhesion. For this, yhe glycosaminoglycans were extracted from crustacean tissues by proteolysis, fractionation with acetone and later submitted to pharmacological assays. The crustacean tissues showed compounds heparin-like, with anticoagulant activity of 45 IU/mg and 90 IU/mg, respectively. These molecules showed low residual hemorrhagic effects in the tested concentration (100 µg/mL), when compared to unfractionated commercial heparin (UFH). Another dermatan sulfate-like compound, predominately constituted for disulfated disaccharides, was isolated from crustacean abdomen. This compound showed an efficient effect on leukocytes migration inhibition, in the concentration of 15 µg/mL, reducing the cellular infiltration in 65% when compared to the controlled animals. In this same concentration, the DS reduced in 60% the protein concentration of the peritoneal exudates. In the concentration, this compound of 0.5 mg/mL, it was capable to reduce in 40% platelet/leukocytes adhesion. Our data demonstrate that these sulfated polysaccharides isolated from the shrimp L. schimitti will can be used as bioactive compounds, appearing as active principles for pharmacological development, anticoagulants and inflammatory response regulators

Estudo do papel da proteína multifuncional APE1/Ref-1 sobre a resposta inflamatória na meningite bacteriana

Despite advances in antibiotic therapy, bacterial meningitis (BM) remains with high mortality and morbidity rates in worldwide. One important mechanism associated to sequels during disease is the intense inflammatory response which promotes an oxidative burst and release of reactive oxygen species, consequently leading to cell death. Activation of DNA repair enzymes during oxidative stress has been demonstrated in several neurological disorders. APE1/Ref-1 is a multifunctional protein involved in DNA repair and plays a redox function on transcription factors such as NFkB and AP-1.The aim of this study was assess the role of APE1/Ref-1 on inflammatory response and the possibility of its modulation to reduce the sequels of the disease. Firstly it was performed an assay to measure cytokine in cerebrospinal fluid of patients with BM due to Streptococcus pneumoniae and Neisseriae meningitides. Further, a cellular model of inflammation was used to observe the effect of the inhibition of the endonuclease and redox activity of APE1/Ref-1 on cytokine levels. Additionally, APE1/Ref-1 expression in cortex and hippocampus of rat with MB after vitamin B6 treatment was evaluated. Altogether, results showed a similar profile of cytokines in the cerebrospinal fluid of patients from both pathogens, although IFNy showed higher expression in patients with BM caused by S. pneumoniae. On the other hand, inhibitors of APE1/Ref-1 reduced cytokine levels, mainly TNF-α. Reduction of oxidative stress markers was also observed after introduction of inhibitors in the LPS-stimulated cell. In the animal model, BM increased the expression of the protein APE1/Ref-1, while vitamin B6 promoted reduction. Thereby, this data rise important factors to be considered in pathogenesis of BM, e.g., IFNy can be used as prognostic factor during corticosteroid therapy, APE1/Ref-1 can be an important target to modulate the level of inflammation and VIII oxidative stress, and vitamin B6 seems modulates several proteins related to cell death. So, this study highlights a new understanding on the role of APE1/Ref-1 on the inflammation and the oxidative stress during inflammation condition

Prevalência e determinantes de oclusopatias nas dentições decídua, mista e permanente na cidade do Natal/RN

This work is intended to bring a contribuition to the verification of the prevalance of malocclusion in the deciduous, permanent and mixed dentition in the student population in the city of Natal, Brazil. In this purpose, a sectional study of infantiles aging 5, 8 and 12 years old was carried out. The average prevalance of malocclusions in the group as a whole was 76,5%. Considering the different dentitions separately, the study showed malocclusion prevalence as follows: Deciduous Dentition 75,5%; Mixed Dentition 84% and Permanent Dentition 70,5%. The most common malocclusion cases found in the deciduous dentition were openbite (20.6%); overbite (16.6%) and maxillary overjet (14,7). Mixed Dentition: the most commonly found occlusional malfunctions in this dentitional phase were maxillary overjet (33,8%); crowding (28,3%), and mandillary discrepancy (19,9%). In the univaried analysis, he application of the Chi square test of independence, (significance 5%), has indicated a meaningful association of the variables social class (p=0,019), primata space (p = 0,036), habits (p= 0,002) and time-and-habit (P=0,03). The same test on the permanent dentition group revealed a significant association for the independent variables, as follows: Social class (p=O,OOO), School (p=O,OOI), Income (p=O,OOO), housing standard (p=0,001), facial pattem (p=0,004), caries record (p=0,031). No significant association was found in the mixed dentition. The Logistic Regression analysis on the deciduous dentition has shown that income, ethnicity, habit and canine relationship constitute factors of risk regardless of the other variables. As for the permanent dentition, only Facial Pattem was pointed as a factor of risk for the formation of malocclusion

Expressão imuno-histoquímica dos marcadores angiogênicos CD105 (endoglina) e CD34 em hemangiomas e granulomas piogênicos orais

Angiogenesis, a fundamental mechanism in tumor development, is used for differential diagnosis and prognosis purposes in various neoplasias of the head and neck. This study proposes to assess angiogenic activity using immunohistochemical expression by anti-CD105 and anti-CD34 antibodies in 20 cases of hemangiomas and 20 cases of oral pyogenic granulomas, in addition to determining the usefulness of these markers as one of the differential diagnosis resources for these two oral lesions. The results showed no statistically significant difference between microvascular count (MVC) means determined by anti-CD105 (p = 0.803) and anti-CD34 (p = 0.279) antibodies. The mean number of vessels obtained by MVC in the oral hemangiomas immunostained by anti-CD105 and anti-CD34 was 18.75 and 59.72, respectively, whereas in the oral pyogenic granulomas, the mean number was 20.22 and 48.09 respectively. It was also shown that CD34 was more effective than CD105 in identifying blood vessels. However, it must be pointed out that the anti-CD105 antibody seems to be more related to vascular neoformation. Overall, this assay reinforces the role of angiogenic factors in the etiopathogenesis of hemangiomas and oral pyogenic granulomas, but the results showed that angiogenesis quantification cannot be used as a differential diagnosis parameter between the two lesions analyzed

Expressão imuno-histoquímica das proteínas MMP-9, VEGF e FVW em lesões centrais e periféricas de células gigantes

Central giant cell lesion (CGCL) and peripheral giant cell lesion (PGCL) of the jaws have a distinct clinical behavior, although they share histopathologic features. It is still unclear whether these clinical differences are supported by a distinct pattern of immunoexpression of markers for multinucleated giant cells (GC) and mononuclear cells (MC). The purpose of this study was to compare the immunohistochemical expression of VEGF, MMP-9 in CG and MC and measure the vascularization by vWF to check whether there are differences in expression of these biomarkers between CGCL and PGCL. Paraffin wax blocks of 20 cases of LCCG and 20 LPCG were retrieved. MMP-9 immunoreactivity was greater in the CM of PGCL compared to VEGF (p<0.05). VEGF expression was greater in the CM of CGCL compared to PGCL (p<0.05) and it was greater in the overall expression of CGCL compared to PGCL (p<0.05). Vascularity was quantified by microvascular counting (MVC). MVC was greater in the PGCL compared CGCL (p<0.05). MMP-9 showed a greater tendency of expression in CGCL, though was not significant (p>0.05). We tested correlation between the proteins studied in each group and found a significant negative correlation between VEGF and vWF in CGCL (p<0.05). These results suggest that there are differences in the expression of VEGF in CM and overall expression between the lesions, although no statistically significant difference in the overall expression of the MMP-9. Then, there was a trend in increased expression of MMP-9 and VEGF in CGCL, possibly by the involvement of both proteins in osteoclastogenesis. Additionally, the results of this study indicate a higher degree of vascularization in PGCL compared to CGCL, fact that can be directly linked to the reactive nature of the PGCL, where the inflammatory process with its rich angiogenesis contributes significantly to these findings.

Análise imuno-histoquímica das proteínas VEGF e HIF-1α na doença periodontal

Periodontal disease is a complex inflammatory and infectious condition that immune host, front of the microbial aggressions, can lead to disease progression, resulting in tissue destruction. The tissue damage induces the release of regulatory molecules, which protective roles and / or destructive, including proteins VEGF (vascular endothelial growth factor vascular) and HIF-1 α (hypoxia-induced factor α -1). Thus, this study investigated, quantitatively and comparatively, the immunohistochemical expression of VEGF (vascular endothelial growth factor) and HIF-1 α (hypoxia induced factor 1-α), proteins involved in inflammation, angiogenesis and hypoxia, in human gingival tissues. Therefore, 75 samples of gingival tissues were examined. Thirty samples were chronic periodontitis, 30 with chronic gingivitis and 15 healthy gingival. After sections analysis, positives and negatives inflammatory and endothelial cells in the connective tissue were counted and converted into percentage. Data were statistically analyzed using Kruskal-Wallis test and Spearman correlation. The results showed that both proteins marked. It was observed higher immunoreactivity for HIF-1 α at chronic gingivitis and periodontitis specimens compared to healthy sites, however, no statistically significant differences were observed among them (p>0.05). The VEGF immunostaining showed similarity among the cases of periodontitis, gingivitis and healthy gingiva. Moderate and positive correlation statistically significant differences were verified for the expressions of VEGF and HIF-1α in gingival health (r = 0,529, p = 0.04). Thus, it can be conclude that possibly the route of HIF-1 α, is activated in periodontal disease may have involvement of the protein in pathogenesis and progression of disease, and that activation of VEGF, can be in addition to being triggered transcription by HIF-1 α may be also influenced by other additional factors such as the action of periodontal microorganisms endotoxins