CYP450 polymorphisms and clinical pharmacogenetics of ibuprofen after lower third molar extraction.

PURPOSE: This study hypothesized that drugs accumulate in the bloodstream of poor-metabolizing patients and may have more adverse effects and different pain perceptions and aimed to investigate the influence of CYP450 polymorphisms on acute postoperative pain, swelling, and trismus controlled by ibuprofen (600 mg) in 200 volunteers after dental extraction. In addition, surgical outcomes can determine pain, edema, and trismus and indicate inflammatory reactions after oral surgeries. METHODS: Genetic sequencing was performed to identify CYP450 polymorphisms and the surgical parameters evaluated: pre and postoperative swelling, trismus, and temperature; self-reported postoperative pain with visual analog scale (VAS); rescue medication consumed; and severity of adverse reactions. RESULTS: A multiple linear regression model with independent variables [single nucleotide polymorphisms (SNPs), BMI (body mass index), duration, and difficulty of surgery] and dependent variables [postoperative pain by sum of pain intensity difference (SPID), trismus, and swelling] was used for analysis. The duration of surgery was a predictor for pain at 8 h and 96 h after surgery, and BMI was a predictor for both swelling and trismus on the 2nd postoperative day. When evaluating CYP2C8 and C9 genotyped SNPs, it was observed that normal metabolizers showed higher pain levels than the intermediate/poor metabolizers on the postoperative periods as compared with time 0 h. In another analysis, the poor metabolizers for CYP2C8 and C9 presented lower levels of postoperative pain after 8 h and used rescue medication earlier than normal metabolizers. CONCLUSION: Ibuprofen 600 mg was very effective in controlling inflammatory pain after lower third molar surgeries, without relevant adverse reactions; although in a very subtle way, patients with poor metabolism had higher levels of pain in the first hours, and no longer after 8 h, and used pain relief medication earlier. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov ID (NCT03169127), on March 16th, 2017.

Dexamethasone Does Not Inhibit Treadmill Training-Induced Angiogenesis in Myocardium: Role of MicroRNA-126 Pathway.

Dexamethasone (DEX) has important anti-inflammatory activities; however, it induces hypertension and skeletal muscle microcirculation rarefaction. Nevertheless, nothing is known about DEX outcomes on cardiac microcirculation. By contrast, exercise training prevents skeletal and cardiac microvessel loss because of microRNA expression and a better balance between their related angiogenic and apoptotic proteins in spontaneously hypertensive rats. The purpose of this study was to investigate whether DEX and/or exercise training could induce microRNA alterations leading to cardiac angiogenesis or microvascular rarefaction. Animals performed 8 weeks of exercise training and were treated with DEX (50 µg/kg per day, subcutaneously) for 14 days. Cardiovascular parameters were measured, and the left ventricle muscle was collected for analyses. DEX treatment increased arterial pressure and did not cause cardiac microcirculation rarefaction. Treadmill training prevented the DEX-induced increase in arterial pressure. In addition, training, regardless of DEX treatment, increased microRNA-126 expression, phospho-protein kinase B/protein kinase B, and endothelial nitric oxide synthase levels associated with cardiac angiogenesis. In conclusion, this study suggests, for the first time, that treadmill training induces myocardial angiogenesis because of angiogenic pathway improvement associated with an increase in microRNA-126. Furthermore, DEX, per se, did not cause capillary density alterations and did not attenuate cardiac angiogenesis induced by training.

Novel rare variations in IRF6 in subjects with non-syndromic cleft lip and palate and dental agenesis.

OBJECTIVE: Subjects with cleft lip and palate (CLP) present high prevalence of dental agenesis. Among candidate genes for these phenotypes is IRF6. However, genetic studies do not analyze dental agenesis as a phenotype associated with cleft. Therefore, we investigated the frequency of rare and novel variations in IRF6 in subjects with non-syndromic unilateral cleft lip and palate (NSUCLP), with and without dental agenesis. SUBJECTS AND METHODS: Genomic DNA samples of 100 subjects with NSUCLP with and without dental agenesis and 50 controls were sequenced. IRF6 mutational screening was conducted by direct sequencing. RESULTS: Ten new and rare missense variations were identified, two in the group cleft with agenesis and eight in the group cleft without agenesis, and none were found in control group. In silico analysis revealed four variations as potentially deleterious, being two in the group with cleft and agenesis and two in the group with cleft without agenesis. CONCLUSION: The study identified novel IFR6 variations in subjects with NSUCLP with or without associated dental agenesis. The hypothesis of a higher frequency of deleterious variations in the subjects with cleft associated with dental agenesis, when compared to the group of cleft without agenesis and control without cleft, was not supported.

CCR5Δ32 (rs333) polymorphism is associated with decreased risk of chronic and aggressive periodontitis: A case-control analysis based in disease resistance and susceptibility phenotypes.

Chronic and aggressive periodontitis are infectious diseases characterized by the irreversible destruction of periodontal tissues, which is mediated by the host inflammatory immune response triggered by periodontal infection. The chemokine receptor CCR5 play an important role in disease pathogenesis, contributing to pro-inflammatory response and osteoclastogenesis. CCR5Δ32 (rs333) is a loss-of-function mutation in the CCR5 gene, which can potentially modulate the host response and, consequently periodontitis outcome. Thus, we investigated the effect of the CCR5Δ32 mutation over the risk to suffer periodontitis in a cohort of Brazilian patients (total N=699), representative of disease susceptibility (chronic periodontitis, N=197; and aggressive periodontitis, N=91) or resistance (chronic gingivitis, N=193) phenotypes, and healthy subjects (N=218). Additionally, we assayed the influence of CCR5Δ32 in the expression of the biomarkers TNFα, IL-1ß, IL-10, IL-6, IFN-γ and T-bet, and key periodontal pathogens P. gingivalis, T. forsythia, and T. denticola. In the association analysis of resistant versus susceptible subjects, CCR5Δ32 mutant allele-carriers proved significantly protected against chronic (OR 0.49; 95% CI 0.29-0.83; p-value 0.01) and aggressive (OR 0.46; 95% CI 0.22-0.94; p-value 0.03) periodontitis. Further, heterozygous subjects exhibited significantly decreased expression of TNFα in periodontal tissues, pointing to a functional effect of the mutation in periodontal tissues during the progression of the disease. Conversely, no significant changes were observed in the presence or quantity of the periodontal pathogens P. gingivalis, T. forsythia, and T. denticola in the subgingival biofilm that could be attributable to the mutant genotype.

Exercise Training Prevents Dexamethasone-induced Rarefaction.

Dexamethasone (DEX) causes rarefaction. In contrast, training (T) prevents rarefaction and stimulates angiogenesis. This study investigated the mechanisms responsible for the preventive role of T in DEX-induced rarefaction. Rats underwent T or were kept sedentary (8 weeks) and were treated with DEX or saline during the following 14 days. Tibialis anterior muscle was used for measurements of capillary density (CD), capillary-to-fiber ratio (C:F ratio), superoxide dismutase CuZn (SOD-1), superoxide dismutase MnSOD (SOD-2), catalase (CAT) mRNA as well as SOD-1, SOD-2, CAT, vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGF-R2), cyclooxygenase-2 (COX-2), B-cell lymphoma 2 (Bcl-2), Bd-2-like protein 4 (Bax), p-Bax, and caspase-3 cleaved protein levels. DEX decreased CD (-38.1%), C:F ratio (-30.0%), VEGF (-19.0%), VEGFR-2 (-20.1%), COX-2 (-22.8%), Bcl-2 (-20.5%), Bcl-2/Bax ratio (-13.7%), p-Bax/Bax (-20.0%) and increased SOD-2 (+41.6%) and caspase-3 cleaved (+24.1%). Conversely, T prevented reductions in CD (+54.2%), C:F ratio (+32.9%), VEGF (+25.3%), VEGFR-2 (+22.2%), COX-2 (+31.5%), Bcl-2 (+35.5%), Bcl-2/Bax ratio (+19.9%), p-Bax/Bax (+32.1%), and caspase-3 cleaved increase (-7.8%). T increased CAT mRNA (+21.5%) in the DEX-treated group. In conclusion, T prevented the DEX-induced rarefaction by increasing antioxidant enzymes resulting in a better balance between apoptotic and anti-apoptotic protein levels.

High-intensity resistance training attenuates dexamethasone-induced muscle atrophy.

INTRODUCTION: In this study we investigated the effects of high-intensity resistance training (RT) on dexamethasone (DEX)-induced muscle atrophy in flexor hallucis longus (FHL), tibialis anterior (TA), and soleus (SOL) muscles. METHODS: Rats underwent either high-intensity RT or were kept sedentary. In the last 10 days they received either DEX (0.5 mg/kg/day, intraperitoneally) or saline. RESULTS: DEX reduced body weight (-21%), food intake (-28%), FHL and TA muscle mass (-20% and -18%, respectively), and increased muscle-specific ring finger 1 (MuRF-1) protein level (+37% and +45.5%). RT attenuated FHL muscle atrophy through a combination of low increase in MuRF-1 protein level (-3.5%) and significant increases in mammalian target of rapamycin (mTOR) (+63%) and p70S6K (+46% and +49% for control and DEX, respectively) protein levels. CONCLUSION: RT attenuated DEX-induced muscle atrophy through a combination of increases in mTOR and p70S6K protein levels and a low increase in MuRF-1 protein level.

Taurodontism, Root Dilaceration, and Tooth Transposition: A Radiographic Study of a Population With Nonsyndromic Cleft Lip and/or Palate.

OBJECTIVES: In an effort to contribute to proper dental planning and define possible dental phenotypes of nonsyndromic cleft lip and/or palate (CL/P), this study aimed to investigate the occurrence of taurodontism, root dilaceration, and tooth transposition in persons with nonsyndromic CL/P, specifically analyzing the differences among gender, cleft types, and the most affected teeth. DESIGN: This retrospective study analyzed 974 panoramic x-rays from nonsyndromic Brazilians older than 16 years and categorized into the following four groups: group 1, 250 persons with unilateral cleft lip and palate; group 2, 250 persons with unilateral cleft lip; group 3, 224 persons with cleft palate; and a control group of 250 persons without clefts. Radiographs were digitalized with a scanner and analyzed. RESULTS: In the Brazilian population studied, the prevalence of taurodontism was 60.4% in group 1, 62.4% in group 2, 67.0% in group 3, and 42.8% in the control group. Root dilacerations had a prevalence of 31.2% in group 1, 29.6% in group 2, 26.3% in group 3, and 27.2% in the control group. The teeth most affected by taurodontism were 17 and 27; whereas root dilacerations were most common in teeth 38 and 48. No tooth transpositions were found in any radiograph analyzed. CONCLUSIONS: Taurodontism is significantly more prevalent in Brazilians with nonsyndromic CL/P than in persons without clefts; whereas the prevalence of root dilaceration no different from that in the control group. However, root dilacerations in anterior teeth were increased in groups 1 and 2 when compared to the control group.

Comparison of epinephrine and felypressin pressure effects in 1K1C hypertensive rats treated or not with atenolol.

PURPOSE: Epinephrine is considered the gold standard vasoconstrictor for hypertensive patients, but few studies report felypressin's effects. The present study aimed to analyze and compare the effects of these two vasoconstrictors, injected by the intravenous route, on the arterial pressure of normotensive, hypertensive and atenolol-treated hypertensive rats. METHOD: The hypertension model was one-kidney-one-clip (1K1C): the main left renal artery was partially constricted and the right kidney was surgically removed in 45-day-old male Wistar rats. 1K1C hypertensive rats received atenolol (90 mg/kg/day) by gavage for 2 weeks. 28-35 days after hypertension induction, a catheter was inserted into the left carotid artery to record direct blood pressure values. The following parameters were recorded: minimal hypotensive response, maximal hypertensive response, response duration and heart rate. RESULTS: Epinephrine, but not felypressin, exerted an important hypotensive action; non-treated hypertensive rats showed more pronounced vasodilation. Treated and non-treated rats showed hypertensive responses of the same magnitudes in all groups; 1K1C atenolol rats showed reduced hypertensive responses to both vasoconstrictors. Felypressin's response duration was longer than that of epinephrine in all groups. Epinephrine increased heart rate while felypressin reduced this parameter only in the normotensive group. CONCLUSIONS: Our results suggest that felypressin has equipotent pressure responses when compared with epinephrine, showing a greater extent of action. Atenolol's reduction of hypertensive effects surprisingly suggests that atenolol ß-blockade may also be important for felypressin's cardiovascular effect, as is widely known for epinephrine. Our data suggest that felypressin is safe for hypertensive subjects, in particular those receiving atenolol.

Exercise-induced angiogenesis is attenuated by captopril but maintained under perindopril treatment in hypertensive rats.

Angiogenesis is an important exercise-induced response to improve blood flow and decrease vascular resistance in spontaneously hypertensive rats (SHR), but some antihypertensive drugs attenuate this effect. This study compared the effects of captopril and perindopril on exercise-induced cardiac and skeletal muscle angiogenesis. Forty-eight Wistar rats and 48 SHR underwent 60 days of aerobic training or were kept sedentary. During the last 45 days, rats were treated with captopril, perindopril or water (Control). Blood pressure (BP) measurements were taken and histological samples from the tibialis anterior (TA) and left ventricle (LV) muscles were analyzed for capillary density (CD) and vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2) and endothelial nitric oxide synthase (eNOS) protein level. Exercise increased vessel density in Wistar rats due to higher VEGFR-2 (+17%) and eNOS (+31%) protein level. Captopril and perindopril attenuated exercise-induced angiogenesis in Wistar rats, but the attenuation was small in the perindopril group, and this response was mediated by higher eNOS levels in the Per group compared to the Cap group. Exercise increased myocardial CD in Wistar rats in all groups and treatment did not attenuate it. Both exercise and pharmacological treatment reduced BP of SHR similarly. Rarefaction was found in TA of SHR compared to Wistar, due to lower levels of VEGF (-26%) and eNOS (-27%) and treatment did not avoid this response. Exercise prevented these reductions in control SHR. While rats treated with perindopril showed angiogenesis in the TA muscle after training, those rats treated with captopril showed attenuated angiogenesis (-18%). This response was also mediated by lower eNOS levels in Cap group compared with Per and control group. Myocardial CD was reduced in all sedentary hypertensive compared with Wistar and training restored the number of vessels compared with sedentary SHR. In conclusion, taken into account only the aspect of vessel growth, since both pharmacological treatments reduced BP in SHR, the result of the present study suggests that perindopril could be a drug of choice over captopril for hypertensive practitioners of aerobic physical exercises, especially considering that it does not attenuate angiogenesis induced by aerobic physical training in skeletal and cardiac muscles.

Blockade of Inflammatory Markers Attenuates Cardiac Remodeling and Fibrosis in Rats with Supravalvular Aortic Stenosis.

Since cardiac inflammation has been considered an important mechanism involved in heart failure, an anti-inflammatory treatment could control cardiac inflammation and mitigate the worsening of cardiac remodeling. This study evaluated the effects of dexamethasone (DEX) and ramipril treatment on inflammation and cardiac fibrosis in an experimental model of heart failure induced by supravalvular aortic stenosis. Wistar rats (21d) were submitted to an aortic stenosis (AS) protocol. After 21 weeks, an echocardiogram and a maximal exercise test were performed, and after 24 weeks, rats were treated with DEX, ramipril or saline for 14d. The left ventricle (LV) was removed for histological and inflammatory marker analyses. The AS group showed exercise intolerance (-32% vs. Sham), higher relative wall thickness (+63%), collagen deposition and capillary rarefaction, followed by cardiac disfunction. Both treatments were effective in reducing cardiac inflammation, but only DEX attenuated the increased relative wall thickness (-17%) and only ramipril reduced LV fibrosis. In conclusion, both DEX and ramipril decreased cardiac inflammatory markers, which probably contributed to the reduced cardiac fibrosis and relative wall thickness; however, treated AS rats did not show any improvement in cardiac function. Despite the complex pharmacological treatment of heart failure, treatment with an anti-inflammatory could delay the patient's poor prognosis.

Salivary immunity in elderly individuals presented with Candida-related denture stomatitis.

OBJECTIVES: Elderly individuals with Candida-related denture stomatitis (DS) present with a reduced defence against Candida albicans. This study evaluated levels of antimicrobial mediators in the elderly DS saliva and salivary neutrophils' activation characteristics compared with elderly and young without DS. METHODS: Salivary peroxidases (SPO) and elastase activities (ELA), nitric oxide (NO), transforming growth factor beta (TGF-ß), IL-6 and CCL3 production were determined in saliva from elderly with or without DS, and young control individuals. TLR4, CXCR1, CD11b, CD16 and CD32 expression on salivary neutrophils were evaluated. Correlations between number and apoptosis rate of salivary neutrophils, enzymatic activities and cytokine levels were determined. RESULTS: Elderly DS individuals exhibited the lowest SPO and ELA activities. Also, the activity of both enzymes was low in elderly without DS. Although both elderly groups showed higher salivary NO and TGF-ß levels compared to young control groups, elderly DS presented the highest salivary NO, TGF-ß, IL-6 and CCL3 levels. Decreased percentages of salivary TLR4(+) and CD16(+) neutrophils were detected in both elderly groups. Although these damages could influence the establishment and persistence of DS, the highest levels of salivary IL-6 and CCL3 in elderly DS could be preventing more serious complications.

Dexamethasone and Training-Induced Cardiac Remodeling Improve Cardiac Function and Arterial Pressure in Spontaneously Hypertensive Rats.

INTRODUCTION: Dexamethasone (DEX)-induced hypertension and cardiac remodeling are still unclear, especially in spontaneously hypertensive rats (SHR). On the other side, exercise training is a good strategy to control hypertension. Therefore, this study investigated the effects of DEX treatment and physical training on arterial pressure and cardiac remodeling in SHR. MATERIAL AND METHODS: SHR underwent treadmill training (5 days/week, 1h/session, at 50-60% of maximal capacity, 0% degree, 75 days) and received low-dose of DEX (50µg/kg, s.c.) during the last 15 days. Sedentary Wistar rats (W) were used as control. Echocardiography and artery catheterization were performed for cardiac remodeling and function, arterial pressure and autonomic nervous system analyses. In addition, left ventricle (LV) capillary density, myocyte diameter and collagen deposition area were analyzed using specific histological staining. RESULTS: Low-dose of DEX treatment did not exacerbate arterial pressure of SHR and trained groups had lower values, regardless of DEX. DEX and training decreased relative left ventricle wall thickness (RWT) and determined LV angiogenesis (+19%) and lower collagen deposition area (-22%). In addition, it determined increased left ventricular diastolic diameter. These changes were followed by improvements on systolic and diastolic function, since it was observed increased posterior wall shortening velocity (PWSV) and reduced isovolumetric relaxation time (IVRT). CONCLUSION: In conclusion, this study is unique to indicate that low-dose of DEX treatment does not exacerbate arterial pressure in SHR and, when associated with training, it improves LV systolic and diastolic function, which may be due to LV angiogenesis and reduction of wall collagen deposition area.

Training counteracts DEX-induced microvascular rarefaction by improving the balance between apoptotic and angiogenic proteins.

This work investigated the mechanisms induced by exercise training that may contribute to attenuate dexamethasone (DEX)-induced microvascular rarefaction and hypertension. Wistar rats underwent training protocol or were kept sedentary for 8 weeks. Dexamethasone was administered during the following 14-days and hemodynamic parameters were recorded at the end. Capillary density (CD) and capillary-to-fiber ratio (C:F ratio) were obtained in soleus muscle (SOL). Also, vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR-2), endothelial nitric oxide synthase (eNOS), B-cell lymphoma 2 (Bcl-2), Bcl-2-like protein 4 (Bax), p-BAX and caspase-3 cleaved protein levels were analyzed. DEX treatment significantly increased blood pressure (+14%), which was associated with reduced C:F ratio (-41.0%) and CD (-43.1%). Reduction of vessel density was associated with decreased VEGF (-15.6%), VEGFR-2 (-14.6%), Bcl-2 (-18.4%), Bcl-2/Bax ratio (-29.0%) and p-Bax/Bax (-25.4%), and also with increased caspase-3 cleaved protein level (25%). Training, on the other hand, prevented microvessels loss by mitigating all proteins changes induced by DEX. In addition, angiogenic and apoptotic proteins were significantly correlated with CD, which, in turn, was associated with blood pressure. Therefore, we may point out that exercise training is a good strategy to attenuate DEX-induced microvascular rarefaction in soleus muscle and this response involves a better balance between apoptotic and angiogenic proteins, which may contribute for the attenuation of hypertension.

MicroRNA-126 upregulation, induced by training, plays a role in controlling microcirculation in dexamethasone treated rats.

Microcirculation maintenance is associated with microRNAs. Nevertheless, the role of microRNAs induced by training in preventing dexamethasone (DEX)-induced microvascular rarefaction remains unknown. The study aim was to investigate if training-induced microRNAs are able to improve microcirculation proteins and prevent DEX-induced microvascular rarefaction. Rats underwent training for 8 weeks and then were treated with DEX (50 µg/kg per day, s.c.) for 14 days. Arterial pressure was measured and tibialis anterior (TA) muscle was collected for analyses. DEX induced hypertension concomitantly with capillary density loss (CD, -23.9%) and decrease of VEGF (-43.0%), p-AKT/AKT (-39.6%) and Bcl-2 (-23.0%) and an increase in caspase-3-cleaved protein level (+34.0%) in TA muscle. Training upregulated microRNA-126 expression (+13.1%), prevented VEGF (+61.4%), p-AKT/AKT (+37.7%), Bcl-2 (+7.7%) decrease and caspase-3-cleaved (-23.1%) increase associated with CD (+54.7%) reduction and hypertension prevention. MiRNA-126 upregulation, induced by training, plays a role in controlling microcirculation, which may be a potential target against DEX-induced microvascular rarefaction.

Passive Cigarette Smoking Impact on Blood Pressure Response to Epinephrine and Felypressin in 1K1C Hypertensive Rats Treated or not with Atenolol.

BACKGROUND: Cigarette smoking is usually associated with hypertension and may modify vasoconstrictor response. OBJECTIVE: The present study aimed to analyze and compare the interaction of passive cigarette smoking and hypertension on epinephrine and felypressin blood pressure effects after intravascular injection. METHOD: 45-day male Wistar rats had the main left renal artery partially constricted and the right kidney removed (1K1C model). Rats were placed in the chamber for exposition to passive cigarette smoking (10 cigarettes) during 10 min (6 days a week). Hypertensive rats received atenolol (90 mg/kg/day) by gavage for two weeks. Hypotensive and hypertensive response, response duration and heart rate were recorded from direct blood pressure values. The significance level was 5%. RESULTS: Passive cigarette smoking increased maximal hypertensive response to epinephrine in normotensive and 1K1C-atenolol treated rats and to felypressin only in 1K1C-atenolol treated rats; it also reduced epinephrine hypotensive response. Epinephrine increased heart rate in normotensive and hypertensive passive smokers or non-smoker rats. Comparing the two vasoconstrictors, epinephrine showed greater hypertensive response in normotensive smokers, 1K1C-atenolol treated smokers and non-smokers. However, in normotensive-nonsmoker rats, felypressin showed a greater and longer hypertensive effect. CONCLUSIONS: Our results suggest that passive cigarette smoking may reduce epinephrine vasodilation and increase hypertensive response when compared to felypressin. Therefore, felypressin may be safe for hypertensive patients to avoid tachycardia and atenolol interaction, but for normotensive and non-smoker patients, epinephrine may be safer than felypressin.

AT1 receptor antagonism promotes bone loss attenuation in experimental periodontitis, blocks inflammatory mediators, and upregulates antioxidant enzymes and bone formation markers.

BACKGROUND: The initiation and progression of periodontitis might involve a local renin-angiotensin system in periodontal tissue. This study hypothesized that Losartan treatment could promote protection to rats submitted to experimental periodontitis (EP) by attenuating alveolar bone loss due to reduction in inflammatory cytokines, better reactive oxidant species regulation and maintenance of the balance between bone formation and resorption factors. METHODS: One hundred and thirty rats were submitted to EP with a silk suture thread (4.0) placed around the lower right first molar for 1, 3, 7, and 14 consecutive days. The study comprised four groups: G1-control without EP; G2-animals with EP treated with water; G3-Losartan-treated animals (treatment started at the same day of EP induction), and G4-animals previously treated with Losartan for 30 days followed by induction of EP and continuity of treatment. RESULTS: G2 rats had greater bone loss volume, increased number, and thickness and decreased separation of trabeculae. On the other hand, G4 animals showed significant improvements in these parameters. Histological analysis revealed that EP favors inflammatory cell infiltration and junctional epithelium, cementum with alveolar bone crest destruction, but animals pretreated with Losartan (G4) did not show these features. Although the G3 animals did not demonstrate the improvements detected in G4, mRNA expression results were similar. In mandibular tissue, EP promoted mRNA increases for ACE, AT1 receptor, and inflammatory mediators as well as decreases for antioxidant enzymes. However, Losartan treatments attenuated these responses in addition to promoting an increase in bone formation markers and transcription factors. CONCLUSION: AT1 receptor modulates EP progression.

The broad effects of the functional IL-10 promoter-592 polymorphism: modulation of IL-10, TIMP-3, and OPG expression and their association with periodontal disease outcome.

Periodontal diseases are infectious diseases, in which periodontopathogens trigger chronic inflammatory and immune responses that lead to tissue destruction. It occurs through the generation of metalloproteinases and the activation of bone resorption mechanisms. Anti-inflammatory cytokines such as IL-10 seem to attenuate periodontal tissue destruction through the induction of tissue inhibitors of metalloproteinases (TIMPs) and the inhibitor of osteoclastogenesis osteoprotegerin (OPG). A high individual variation in levels of IL-10 mRNA is verified in periodontitis patients, which is possibly determined by genetic polymorphisms. In this study, the IL-10 promoter -592C/A single nucleotide polymorphism (SNP), which is associated with a decrease in IL-10 production, was analyzed by RFLP in 116 chronic periodontitis (CP) patients and 173 control (C) subjects, and the IL-10, TIMPs, and OPG mRNA expression levels in diseased gingival tissues were determined by real-time-PCR. The IL-10-592 SNP CA (P=0.0012/OR=2.4/CI:1.4-4.1), AA (P=0.0458/OR=2.3/CI:1.1-4.9), and CA+AA (P=0.0006/OR=2.4/CI:1.4-3.4) genotypes and the allele A (P=0.0036/OR=1.7/CI:1.2-2.4) were found to be significantly more prevalent in the CP group when compared with control subjects. Both CA and AA genotypes were associated with lower levels of IL-10, TIMP-3, and OPG mRNA expression in diseased periodontal tissues and were also associated with disease severity as mean pocket depth. Taken together, the results presented here demonstrate that IL10-592 SNP is functional in CP, being associated with lower levels of IL-10 mRNA expression, which is supposed to consequently decrease the expression of the downstream genes TIMP-3 and OPG, and influence periodontal disease outcome.

An interleukin-1beta (IL-1beta) single-nucleotide polymorphism at position 3954 and red complex periodontopathogens independently and additively modulate the levels of IL-1beta in diseased periodontal tissues.

Inflammatory cytokines such as interleukin-1beta (IL-1beta) are involved in the pathogenesis of periodontal diseases. A high individual variation in the levels of IL-1beta mRNA has been verified, which is possibly determined by genetic polymorphisms and/or by the presence of periodontopathogens such as Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, and Aggregatibacter actinomycetemcomitans. In this study, we investigated the role of an IL-1beta promoter single-nucleotide polymorphism at position 3954 [IL-1beta(3954) SNP] and the presence of the periodontopathogens in the determination of the IL-1beta levels in the periodontal tissues of nonsmoking chronic periodontitis (CP) patients (n = 117) and control (C) subjects (n = 175) and the possible correlations with the clinical parameters of the disease. IL-1beta(3954) SNP was investigated by restriction fragment length polymorphism, while the IL-1beta levels and the presence of the periodontopathogens were determined by real-time PCR. Similar frequencies of IL-1beta(3954) SNP were found in the C and CP groups, in spite of a trend toward a higher incidence of T alleles in the CP group. The IL-1beta(3954) SNP CT and TT genotypes, as well as P. gingivalis, T. forsythia, and T. denticola, were associated with higher IL-1beta levels and with higher values of the clinical parameters of disease severity. Concomitant analyses demonstrate that IL-1beta(3954) and the red complex periodontopathogens were found to independently and additively modulate the levels of IL-1beta in periodontal tissues. Similarly, the concurrent presence of both factors was associated with increased scores of disease severity. IL-1beta(3954) genotypes and red complex periodontopathogens, individually and additively, modulate the levels of IL-1beta in the diseased tissues of nonsmoking CP patients and, consequently, are potentially involved in the determination of the disease outcome.

COX-2 inhibition decreases VEGF expression and alveolar bone loss during the progression of experimental periodontitis in rats.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a macromolecule of importance in inflammation that has been implicated in periodontitis. The aims of this study were to investigate VEGF expression during the progression of periodontal disease and to evaluate the effect of a preferential cyclooxygenase (COX)-2 inhibitor meloxicam on VEGF expression and alveolar bone loss in experimentally induced periodontitis. METHODS: A total of 120 Wistar rats were randomly separated into groups 1 (control) and 2 (meloxicam, 3 mg/kg/day, intraperitoneally, for 3, 7, 14, or 30 days). Silk ligatures were placed at the gingival margin level of the lower right first molar of all rats. VEGF expression was assessed by reverse transcription-polymerase chain reaction (RT-PCR), Western blot (WB), and immunohistochemical (IHC) analyses. The hemiarcades were processed for histopathologic analysis. RT-PCR and WB results were submitted to analysis of variance, the Tukey test, and Pearson correlation analysis (P <0.05). RESULTS: A reduction in alveolar bone resorption was observed in the meloxicam-treated group compared to the control group at all periods studied. There was a positive correlation between COX-2 mRNA and VEGF mRNA in the gingival tissues and periodontal disease (R = 0.80; P = 0.026). Meloxicam significantly reduced the increased mRNA VEGF expression in diseased tissues after 14 days of treatment (P = 0.023). Some alterations in VEGF receptor 1 mRNA expression were observed, but these were not statistically significant. VEGF protein expression in WB experiments was significantly higher in diseased sites compared to healthy sites (P <0.05). After 14 days of treatment with meloxicam, an important decrease in VEGF protein expression was detected in diseased tissues (P = 0.08). Qualitative IHC analysis revealed that VEGF protein expression was higher in diseased tissues and decreased in tissues from rats treated with meloxicam. CONCLUSIONS: The present data suggest an important role for VEGF in the progression of periodontal disease. Systemic therapy with meloxicam can modify the progression of experimentally induced periodontitis in rats by reducing VEGF expression and alveolar bone loss.

Management of a multiple dentoalveolar trauma in permanent dentition with avulsion of a canine: a 4-year follow-up.

Traumatic dental injuries are relatively frequent accidents that typically involve teeth in the maxillary anterior segment. The emergency treatment and the clinical decisions must be efficiently made at the time of injury, and there is a need for long-term follow-up because of the high incidence of complications. The aim of this article was to present the emergency and rehabilitation treatments of a multiple dentoalveolar trauma in the permanent dentition involving different extensions of enamel-dentin crown fracture, pulp exposure, and the avulsion of a canine. The treatment outcomes are reported up to the 4-year follow-up, and the clinical approaches and their rationale are discussed.