Influence of Periodontal Disease Treatment on Serum Levels of Sirtuin 1 and Mannose-binding Lectin in Individuals With Coronary Artery Disease
Phase: NA
Conditions: Periodontal Diseases
Sponsor: InCor Heart Institute

 
 
Influence of treatment of periodontal disease on sirtuin 1 and mannose-binding 
lectin in individuals with coronary artery disease 
 
 
Pérola Michelle Vasconcelos Caribé 1,2 
Antonio de Padua Mansur 1 
 
 
1. Clinical Department, Heart Institute (InCor), University of São Paulo Medical 
School, São Paulo, Brazil  
2. Division of Periodontology, Stomatology Department, Dental School, 
University of São Paulo, São Paulo, Brazil 
 
 
 
This study is the result of a doctoral thesis presented at the Faculty of Medicine 
of the University of São Paulo (2016- Nov.2018). 
  
Advisor: Prof. Dr. Antonio de Pádua Mansur 
 
 
 
São Paulo 15 november 2018 
 
 
The present study does not have NCT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
Abstract 
Introduction: Increased levels of periodontal pathogens disrupt the homeostasis 
between the host and its microbiota and increase susceptibility to periodontal 
disease (PD). PD increases the serum concentration of mannose binding lectin 
(MBL), which exacerbates local inflammatory processes. In animal studies, 
sirtuin-1 (SIRT1) was associated with protection against inflammation. This 
study analyzed the influence of nonsurgical treatment of PD on serum levels of 
MBL and SIRT1. 
Methods: Forty patients with PD and 38 without PD (aged 45-79 years) were 
evaluated. PD was confirmed by the presence of at least 6 teeth with at least 
one noncontiguous interproximal site with probing pocket depth and clinical 
attachment loss ≥ 5 mm, 30% of sites with probing pocket depth and clinical 
attachment loss ≥ 4 mm, and bleeding on probing. MBL and SIRT1 
concentrations were analyzed by ELISA. 
Results: For all patients, an inverse correlation was observed between the 
serum concentrations of MLB and SIRT1 (r = -0.30; p = 0.006). PD treatment 
reduced the serum concentration of MBL from 1099.35 ± 916.59 to 861.42 ± 
724.82 ng/mL (p <0.001), and CRP showed a reduction from 6.05 ± 8.99 to 2.49 
± 2.89 mg/L (p=0.009). By contrast, PD increased the serum SIRT1 
concentration from 1.06 ± 1.03 to 1.66 ± 1.64 ng/mL (p<0.001). 
Conclusion: PD treatment was associated with decreased serum concentrations 
of MBL and CRP and increased serum levels of SIRT1. Prospective studies are 
needed to assess the impact of these biomarkers on the progression and 
prognosis of PD. 
 
Keywords: periodontal disease, atherosclerosis, mannose binding protein, 
sirtuin, periodontitis, inflammation. 
 
 
 
 

Clinical Relevance 
 
Periodontal disease (PD) or periodontitis is a highly prevalent chronic 
inflammatory disease that affects the protective and supporting structures of the 
teeth. 1 Clinically, PD is characterized by the presence of bleeding, edema and 
reabsorption of alveolar bone tissue. These changes result from the 
inflammatory activity of bacteria, endotoxins and the cellular/humoral response 
of the host, which is mediated by polymorphonuclear leukocytes, lymphocytes, 
immunoglobulins and the complement system. 2 The delicate balance between 
the host and oral bacteria is controlled by salivary immunoglobulins and 
lactoferrin, antimicrobial peptides in the epithelium and the oxidative and 
nonoxidative death systems of neutrophils, as well as the classical complement 
system pathway with its lectin, which form the first line of defense against 
bacteria. 3, 4 Mannose binding protein (MBL) is a serum protein synthesized in 
the liver 5 and can bind mannose residues or other carbohydrates commonly 
present in various pathogens. 6 After binding, MBL activates the complement 
system via lectins and mediates phagocytosis. 7 Unlike other collectins, MBL 
can activate the complement system in the absence of antibodies. Important 
periodontal pathogens, such as Aggregatibacter actinomycetemcomitans and 
Porphyromonas gingivalis, present mannose rich polysaccharides on their cell 
surfaces that are potentially capable of binding MBL and undergoing 
phagocytosis. Thus, MBL promotes defense against invading pathogens, but at 
high levels, it can be harmful, causing too much local and systemic 
inflammation through the activation of the complement system, aggravating 
inflammatory diseases and increasing tissue damage. 8 

Sirtuins are a class of proteins that regulate a variety of cellular functions, such 
as genome integrity and cellular metabolism, and are associated with longevity. 
9 Most sirtuins (SIRT1, SIRT2, SIRT3 and SIRT5) catalyze NAD+ deacetylation 
that is dependent on protein lysine residues. SIRT1 is the most studied sirtuin 
and is involved in several central metabolic pathways. 10 The beneficial effects 
of SIRT1 on inflammation have been well documented in preclinical and animal 
studies. 11 Mansur et al. 12 showed an increase in serum levels of SIRT1 in 
normal 
subjects 
undergoing 
caloric 
restriction 
and 
after 
resveratrol 
administration. According to Moschen et al., 13 weight loss that increases the 
expression of SIRT1 is probably a consequence of reduced inflammation. 
Several studies have suggested that metabolic dysfunction in obesity is 
associated with inflammation in adipose tissue. 14 Our present study is the first 
to assess the impact of PD treatment on serum levels of SIRT1. In vitro, Lee et 
al. 15 identified the role of SIRT1 in human periodontal ligament cells by 
measuring the gene expression and SIRT1 protein during the process of human 
periodontal ligament cell formation. These authors used pieces of periodontal 
ligament obtained from extracted dental roots and studied the effects of 
overexpression and lower expression of SIRT1 during the differentiation of 
human periodontal ligament cells, as well as the signaling mechanisms 
involved. Lee and colleagues concluded that SIRT1 is a potent regulator of the 
differentiation of human periodontal ligament cells and may have clinical 
implications for periodontal bone regeneration. 
In our study, we utilized periodontal treatment focused on the elimination of 
pathological oral microorganisms that avoided exacerbation of inflammatory 

processes, with the aim of increasing the levels of SIRT1 and reducing serum 
levels of MBL. 
Methods 
This prospective study analyzed 78 patients (aged 45-79 years old, 38 
women and 42 men) from October 2016 to September 2018. Patients were 
distributed in two groups according to the presence (N=40) or absence of PD 
(N=38). The inclusion criteria for PD were the presence of at least 15 teeth 
(excluding third molars) and clinical diagnosis of PD. This diagnosis was 
confirmed by the presence of at least 6 teeth with at least one noncontiguous 
interproximal site with probing pocket depth (PPD) and clinical attachment loss 
(CAL) ≥ 5 mm, as well as 30% of sites with PPD and CAL ≥ 4 mm and bleeding 
on probing (BOP).16 PD is currently classified as Stage III Degree B. 17 
Individuals who presented a periodontium without loss of insertion, with PPD ≤3 
mm, BOP in less than 10% of sites and no radiographic bone loss were 
classified as periodontal healthy. 18 
The exclusion criteria of the study were uncontrolled diabetes, chronic renal 
disease, smoking, HIV and hepatitis B and C, pregnancy, edentulous jaws, 
orthodontic brachytherapy using specific drugs known to affect periodontal 
tissues, previous periodontal treatment (minimum of 6 months), anti-
inflammatory drugs and corticosteroids, and allergies to the antibiotics 
prescribed in this protocol. The study was approved by the Ethics Committee for 
Analysis of Research Projects-CAPPesq, Hospital das Clínicas, Faculty of 
Medicine, 
University 
of 
São 
Paulo 
(HC-FMUSP), 
CAAE: 
55556116.0.0000.0068. All participants signed a consent form. 
 

Nonsurgical Periodontal Therapy 
 
Nonsurgical periodontal treatment was performed, including oral hygiene 
education, scaling, smoothing and coronal-radicular polishing (RAR). Six sites 
were 
evaluated 
in 
each 
tooth 
(mesiobuccal, 
buccal, 
distobuccal, 
distolingual/palatal, lingual/palatal and mesiolingual/palatal surfaces). Scaling 
and root planing were performed using mechanical devices—ultrasound and 
manual instruments. The treatment was administered with local anesthesia, 3% 
lidocaine with a vasoconstrictor, for PPD ≥ 5 mm. The objective of each session 
was to achieve a smooth surface devoid of biofilm and calculus. 
The following parameters were evaluated during clinical examination: PPD, 
distance of the enamel-cementum line at the gingival margin, CAL, plaque index 
(IP)19 and BOP.20 PPD and CAL measurements were rounded to the nearest 
millimeter using a North Carolina periodontal probe (Hu-Friedy, Chicago, IL, 
USA). Patients in this study also received the antibiotics metronidazole (1.2 
g/d/14 days) and amoxicillin (1.5 g/d/14 days). 
The calibration of the examiner was aimed at establishing consistency and 
obtaining confidence in the results of periodontal exams. After performing two 
periodontal exams in 10 individuals with a one-week interval, the result was 
submitted to the intraclass correlation test. The intraexaminer agreement of 
CAL was verified by the examination of 1074 sites of 8 patients in 2 exams with 
an interval of 2 weeks. Reproducibility was assessed using the intraclass 
correlation coefficient (Table 1). 

A significant correlation was found between the two exams [(R = 0.95 (95% CI: 
0.94-0.96, p <0.001).) According to Evans, 21 a correlation between 0.80 and 
1.0 is considered strong. 
Laboratory Tests 
A 10 ml sample of blood from the peripheral vein was collected at baseline and 
at the end of the study after 8-12 hours of fasting. Laboratory tests analyzed 
triglycerides, total cholesterol, HDL-cholesterol, glucose and CRP. Plasma 
glucose, triglycerides and HDL-cholesterol were obtained by a commercial 
calorimetry-enzymatic method. Measurements were performed with Dimension 
RxL (Siemens Healthcare Diagnostic Inc., Newark, DE, USA) with dedicated 
reagents. The LDL-cholesterol value was calculated by the Friedewald 
equation. The determination of ultrasensitive C-reactive protein was performed 
by immunonephelometry with dedicated reagents on Siemens Healthcare BN-II 
equipment (Marburg, Hessen, Germany). Serum MBL levels were determined 
by enzyme linked immunosorbent assay (ELISA) using anti-MBL monoclonal 
antibody HYB 131-01 (BioPorto Diagnostics A/S, Copenhagen, Denmark). Sirt1 
concentrations were determined using an ELISA kit (Usin Life Science, Wuhan, 
Hubei, China). Before and after interventions, SIRT1 samples were analyzed in 
duplicate on the same ELISA plate using a Multiscan FC plate reader (Thermo 
Scientific), with a coefficient of variation of 12%, according to the manufacturer's 
instructions. 
Statistical Analyses 
Sample size was calculated by the difference in serum levels of SIRT1 pre- and 
postperiodontal treatment. The difference between the means for the control 
group was 1 mg, and the standard deviation was 1 mg. For the group of 

patients with PD, the difference was 2 mg, with a standard deviation of 1 mg. 
The power of the test was β = 0.90 and α = 0.05. The estimated sample was 20 
individuals for each group. The expected values were based on a previous 
study performed in our service in normal individuals.22 The Chi-square test (χ2) 
was used for categorical variables. Correlations between studied variables were 
performed by the Spearman correlation test. Paired Student’s t test was used 
for intragroup analysis between the initial and final values of the protocol. 
Unpaired Student’s t test was used for comparisons between groups. Student's 
t test was performed for variables with a normal distribution, which was verified 
by analysis of the equality of variances (folded F method). Depending on the 
result of this analysis, we used the pooled method (variances with p ≥ 0.05) or 
the Satterthwaite method (variances with p <0.05). The SAS statistical program 
(version 9.2, Institute, Inc., Cary, NC) was used. 
 
RESULTS 
 
Eighty-eight individuals were included in the study. Of these individuals, 8 were 
lost to follow-up, and 2 were on dialysis and were excluded. The study follow-up 
time was 80.4 ± 63.3 days. The age, body mass index, and laboratory tests of 
the 78 patients are shown in Table 1. Of the 78 patients who participated in the 
study, 40 (51%) were male. 
 
Table 1 
 

In the 78 patients studied, SIRT1 and MBL mean concentrations were 0.92 
ng/mL and 899.8 ng/mL, respectively, at the beginning of the protocol and 1.30 
ng/mL and 905.5 ng/mL, respectively, at the end of the study. 
An inverse correlation was observed between concentration changes (final 
minus initial values) in MLB and SIRT1 (r = -0.30; p = 0.006). There was also a 
positive correlation between MBL concentrations and changes in total 
cholesterol (r = 0.30 and p = 0.006), non-HDL (r = 0.27 and p = 0.014) and LDL 
(r = 0.25 and p = 0.024). There was a significant difference in glucose (126.21 ± 
56.12 vs. 114.66 ± 32.72 mg/dL, p = 0.025) and triglycerides (155.42 ± 105, 71 
vs. 128.42 ± 80.51, p = 0.016) between the initial and final time points of the 
protocol (Table 2). In the group without PD, an increased MBL concentration (p 
= 0.014) was observed at the end of the study. No significant changes in SIRT1 
values were observed between the initial and final time points of the group 
without PD (p = 0.324). 
 
Table 2 
 
In the group with PD, the serum concentration of SIRT1 increased from 1.06 ± 
1.03 to 1.66 ± 1.64 ng/mL, p <0.001), and the serum concentration of MBL 
decreased from 1099.35 ± 916.59 to 861.42 ± 724.82 ng/mL (p <0.001) from 
the initial and final time points of periodontal treatment. After periodontal 
treatment, there was a reduction in the IP (63.9% ± 5.7% vs. 37.8% ± 10.5%, p 
<0.001), BOP (34.2% ± 6.9% vs. 16.9% ± 5.1%, p <0.001), CAL (5.9 ± 0.7 vs. 
4.5 ± 0.8 mm; p <0.001) and PPD (5.3 ± 0.8 vs. 3.3 ± 0.7 mm, p <0.001). 
 

 
There was also a significant reduction in the serum concentration of total 
cholesterol (191.28 ± 52.14 vs. 175.78 ± 53.17 mg/dL, p = 0.001), LDL (111.28 
± 44.48 vs. 102, 90 ± 45.19 mg/dL, p = 0.044), non-HDL (139.20 ± 47.02 vs. 
125.68 ± 48.90 mg/dL, p = 0.003), triglycerides (138.25 ± 78.66 vs. 117, 40 ± 
65.38 mg/dL, p = 0.048) and CRP (6.05 ± 8.99 vs. 2.44 ± 2.89 mg/L, p = 0.009) 
(Table 3). In these individuals, there was an inverse correlation between MBL 
and CRP values (r = -0.418; p = 0.009). 
 
Table 3 
 

DISCUSSION 
 
In our study, we observed a significant reduction in the IP, BOP, CAL and PPD 
in patients who received periodontal treatment. Compared to surgical 
approaches, nonsurgical treatment, comprising scaling and root planning, was 
proven effective in PD. 23 According to a previous study, both techniques 
promoted a reduction in PPD and an increase in CAL. 24 In our study, we chose 
antibiotic therapy in association with nonsurgical treatment of PD due to the 
results of recent articles that showed the additional efficacy of antibiotic therapy 
in nonsurgical treatment of PD. 25, 26, 27 Moreover, our study showed that 
nonsurgical treatment of PD was associated with a reduction in the serum 
concentration of MBL and increased serum concentration of SIRT1. After PD 
treatment, a reduced serum concentration of CRP was also observed for mean 
values lower than 3 mg/dL. In our study, PD treatment was associated with a 
significant reduction in MBL serum levels. Periodontal treatment contributed to 
up to a 25% reduction in the initial MBL concentration. In contrast to our present 
findings, Maffei et al. 28 did not show elevated serum levels of MBL in 
periodontitis, and MBL deficiency was also not related to increased 
susceptibility to PD. However, these authors defined MBL deficiency arbitrarily 
as serum levels of MBL below 800 ng/ml. By contrast, in most studies, serum 
MBL levels below 100 ng/ml are defined as deficiency. 29, 30, 31, 32, 33 Additionally, 
in a study by Louropoulou et al., 34 PD was associated with increased serum 
MBL levels in individuals deficient in MBL production. Similarly, our study 
showed that PD treatment was associated with reduced serum MBL levels. 
These results are consistent with those of previous studies in which MBL was 

identified as an acute phase reagent. 35, 36, 37 This finding in part explains the 
reduction in serum MBL levels observed in our study after periodontal 
treatment. 
In our study, another finding showed that nonsurgical treatment of PD was 
associated with increased serum concentrations of SIRT1. The beneficial 
effects of SIRT1 on inflammation, lipid metabolism and atherosclerosis have 
been well documented in preclinical and animal studies. 11 Using the partial 
deletion of SIRT1 in atherosclerotic mice, Stein et al. 38 showed that SIRT1 
protects against atherosclerosis by reducing the formation of foam cells. SIRT1 
increases the production of nitric oxide and promotes vasodilation. 
39 
Interventions that increase SIRT1 production, such as caloric restriction and 
resveratrol, significantly attenuate age and inflammation-related vascular 
oxidative stress and improve endothelial function. 40 In obese rats, Zucker 
showed greater progression of periodontitis with increased oxidative stress 
induced by obesity. 41 In other animal studies, resveratrol and curcumin led to a 
reduction in experimentally induced periodontal degradation by reducing 
oxidative stress; these effects were possibly mediated by the activation of the 
sirtuin pathway. 42, 43, 44 Additionally, cell culture studies have shown a reduction 
in proinflammatory substances, such as matrix metalloproteinases and 
interleukins, mediated by SIRT1. 45, 46 However, this study is the first showing 
the interaction between the serum concentration of SIRT1 and the treatment of 
PD in humans. Increased serum SIRT1 concentrations were probably a 
consequence of PD treatment and may have had a positive influence on the PD 
treatment response. According to a recent study, SIRT1 is a potent regulator of 
the differentiation of human periodontal ligament cells and may have clinical 

implications in periodontal bone regeneration. Increased serum concentrations 
of SIRT1 reduce oxidative stress, and this increase may be beneficial in 
patients with PD. 15 Machida et al. 47 showed that a reduction in the clinical level 
of insertion is associated with a reduction in the plasma levels of reactive 
oxygen species and with less PD progression. 
In conclusion, PD treatment was associated with decreased serum MBL and 
CRP concentrations, as well increased serum SIRT1 levels. Nonetheless, 
prospective studies are needed to assess the impact of changes in these 
biomarkers on the progression and prognosis of PD. 
 
References 
                                               
 
1 Armitage GC. 2004. Periodontal diagnoses and classification of periodontal 
diseases. Periodontol. 34: 9-21. 
2 Beck JD, Offenbacher S. 2001.The association between periodontal diseases 
and cardiovascular diseases:  a state-of-the-science review. Ann Periodontol. 6: 
9-15.  
3 
Darveau 
RP. 2010. 
Periodontitis: 
a 
polymicrobial 
breach 
of 
host 
homeostasis. Nat Rev Microbiol. 8: 481-90. 
4 Haririan H, Andrukhov O, Bertl K, Lettner S, Kierstein S, Moritz A, Rausch-Fan 
X. 2014. Microbial analysis of subgingival plaque samples compared to that of 
whole saliva in patients with periodontitis. J Periodontol. 85: 819-28. 
5 Turner MW. 2003. The role of mannose-binding lectin in health and disease. 
Mol Immunol. 40: 423-29.  
6 Mattila, KJ. 1993. Dental infections as a risk factor for acute myocardial 
infarction. Eur Heart J. 14: 51-3. 
7 Jack DL, Klein NJ, Turner MW. 2001. Mannose-binding lectin:  targeting the 
microbial world for complement attack and opsonophagocytosis. Immunol Rev. 
180:  86–99. 

                                                                                                                                          
8 Liukkonen A, He Q, Gürsoy UK, Pussinen PJ, Gröndahl-Yli-Hannuksela K, 
Liukkonen J, Sorsa T, Suominen AL, Huumonen S, Könönen E. 2016. 
Mannose-binding lectin gene polymorphism in relation to periodontal infection. J 
Periodont Res. 14: 1-6. 
9 Zhang W, Huang Q, Zeng Z, Wu J, Zhang Y, Chen Z. 2017. Sirt1 Inhibits 
Oxidative Stress in Vascular Endothelial Cells. Oxid Med Cell Longev. 2017: 
7543973.  
10 Frye RA. 2000. Phylogenetic classification of prokaryotic and eukaryotic Sir2-
like proteins. Biochem Biophys Res Commun. 273: 793-8. 
11 Lam YY, Peterson CM, Ravussin E. 2013. Resveratrol vs. calorie restriction: 
data from rodents to humans. Exp Gerontol.  48: 1018-24. 
12 Mansur AP, Roggerio A, Goes MFS, Avakian SD, Leal DP, Maranhão RC, 
Strunz CMC. 2017. Randomized study of 30 days of resveratrol and caloric 
restriction on serum levels of sirtuin1 in healthy subjects. Int J Cardiol. 227: 788-
94. 
13 Moschen AR, Wieser V, Gerner RR, Bichler A, Enrich B, Moser P, 
Ebenbichler CF, Kaser S, Tilg H. 2013. Adipose tissue and liver expression of 
SIRT1, 3, and 6 increase after extensive weight loss in morbid obesity. J 
Hepatol. 59: 1315-22.   
14 Osborn O, Olefsky JM. 2012. The cellular and signaling networks linking the 
immune system and metabolism in disease. Nat Med. 18: 363–74.   
15 Lee YM, Shin SI, Shin KS, Lee YR, Park BH, Kim EC. 2011. The role of 
sirtuin 1 in osteoblastic differentiation in human periodontal ligament cells. J 
Periodontal Res.  46:  712–21. 
16 Lang NP, Bartold PM. 2018. Periodontal health. J Clin Periodontol. 45: 9-16.  
17 Caton GJ, Armitage G, Berglundh T, Chapple ILC, Jepsen S, Kornman 
KS, et al. 2018. A new classification scheme for periodontal and peri-implant 
diseases and conditions - Introduction and key changes from the 1999 
classification. J Clin Periodontol. 45: 1-8.  
18 Lang NP, Bartold PM. Periodontal health. J Clin Periodontol. 2018; 45: 9-16.  
19 O`Leary TJ, Drake RB, Naylor JE. 1972. The plaque control record. J. 
Periodontol. 43:  38 

                                                                                                                                          
20 Lenox JA, Kopczyk RA. 1973. A clinical system for scoring a patient’s oral 
hygiene performance. J Am Dent Assoc. 86: 849-52. 
21 Evans JD. Straightforward statistics for the behavioral sciences. Pacific 
Grove, CA:  Brooks/Cole Publishing.1996. 
22 Mansur AP, Roggerio A, Goes MFS, Takada JY, Avakian SD, Strunz 
CMC. 2015. xRandomized study of 30 days of resveratrol and caloric restriction 
on serum levels of sirtuin1 in healthy subjects. Eur Heart J. 36: 1152-3. 
23 Apatzidou DA, Kinane DF. Nonsurgical mechanical treatment strategies for 
periodontal disease. Dent Clin North Am. 2010; 54: 1-12. 
24 Heitz-Mayfield LJ, Trombelli L, Heitz F, et al. A systematic review of the effect 
of surgical debridement vs non-surgical debridement for the treatment of 
chronic periodontitis. J Clin Periodontol 2002; 29: 92–102. 
25 Feres M, Soares GM, Mendes JA, Silva MP, Faveri M, Teles R, Socransky 
SS, Figueiredo LC. Metronidazole alone or with amoxicillin as adjuncts to non-
surgical treatment of chronic periodontitis:  a 1-year double-blinded, placebo-
controlled, randomized clinical trial. J Clin Periodontol. 2012; 39: 1149-58. 
26 Sgolastra F, Gatto R, Petrucci A, Monaco A. Effectiveness of systemic 
amoxicillin / metronidazole as adjunctive therapy to scaling and root planing in 
the treatment of chronic periodontitis:  a systematic review and meta-analysis. J 
Periodontol. 2012 Oct; 83(10): 1257-69 
27 Feres M, Retamal-Valdes B, Mestnik MJ, de Figueiredo LC, Faveri M, Duarte 
PM, Fritoli A, Faustino E, Souto MLS, de Franco Rodrigues M, Giudicissi 
M, Nogueira BCL, Saraiva L, Romito GA, Pannuti CM. The ideal time of 
systemic metronidazole and amoxicillin administration in the treatment of severe 
periodontitis: study protocol for a randomized controlled trial. Trials. 2018; 19: 
201. 
28 Maffei G, Brouwer N, Dolman KM, van der Velden, Roos D, Loos BG. Plasma 
levels of mannan-binding lectin in relation to periodontitis and smoking. J 
Periodontol.  2005; 76:  1881-9. 
29 Káplár M, Sweni S, Kulcsár J, Cogoi B, Esze R, Somodi S, Papp M, Oláh 
L, Magyar MT, Szabó K, Czuriga-Kovács KR, Hársfalvi J, Paragh G. Mannose-
Binding Lectin Levels and Carotid Intima-Media Thickness in Type 2 Diabetic 
Patients J Diabetes Res. 2016; 2016:  8132925 

                                                                                                                                          
30 Albert RK, Connett J, Curtis JL, Martinez FJ, Han MK, Lazarus SC, et al. 
Mannose-binding lectin deficiency and acute exacerbations of chronic 
obstructive. Int J Copd. 2012; 7: 767–77. 
31 Eagan TM, Aukrust P, Bakke PS, Damås JK, Skorge TD, Hardie JA, et al. 
Systemic mannose-binding lectin is not associated with chronic obstructive 
pulmonary disease. Respir Med. 2010; 104: 283–90.  
32 Neth O, Jack DL, Dodds AW, Holzel HJ, Klein MH, Turner MW. Mannose-
binding lectin binds to a range of clinically relevant microorganisms and 
promotes complement deposition. Infect Immun. 2000; 68: 688–93. 
33 Goeldner I, Skare TL, Utiyama SR, Nisihara RM, Van Tong H, Messias-
Reason IJT. Mannose binding lectin and susceptibility to rheumatoid arthritis in 
Brazilian patients and their relatives. PLoS One. 2014; 9: e95519. 
34 Louropoulou A, van der Velden U, Schoenmaker T, Catsburg A, Savelkoul 
PH, Loos BG. Mannose-binding lectin gene polymorphisms in relation to 
periodontitis. J Clin Periodontol. 2008; 35:  923-30. 
35 Ezekowitz RA, Day LE, Herman GA. A human mannose-binding protein is an 
acute-phase reactant that shares sequence homology with other vertebrate 
lectins. J Exp Med. 1988; 167: 1034-46. 
36 Thiel S, Holmskov U, Hviid L, Laursen SB, Jensenius JC. The concentration 
of the C-type lectin, mannan-binding protein, in human plasma increases during 
an acute phase response. Clin Exp Immunol. 1992; 90:  31-5. 
37  Aittoniemi J, Rintala E, Miettinen A, Soppi E. Serum mannan-binding lectin 
(MBL) in patients with infection:  clinical and laboratory correlates: 
APMIS. 1997; 105:  617-22. 
38 Stein S, Lohmann C, Schafer N, Hofmann J, Rohrer L, Besler C and 
Rothgiesser KM, et al. SIRT1 decreases Lox-1-mediated foam cell formation in 
atherogenesis. Eur Heart J. 2010, 31: 2301-09. 
39 Mattagajasingh I, Kim CS, Naqvi A, Yamamori T, Hoffman TA, Jung SB, 
DeRicco J, Kasuno K, Irani K. SIRT1 promotes endothelium-dependent 
vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl 
Acad Sci USA. 2007; 104: 14855-60. 

                                                                                                                                          
40 Allard JS, Heilbronn LK, Smith C, Hunt ND, Ingram DK, Ravussin E; Team 
PC, de Cabo R. In vitro cellular adaptations of indicators of longevity in 
response 
to 
treatment 
with 
serum 
collected 
from 
humans 
on calorie restricted diets. PLoS One. 2008; 3: e3211. 
41 Tomofuji T, Yamamoto T, Tamaki N, Ekuni D, Azuma T, Sanbe T, Irie K, 
Kasuyama K, Umakoshi M, Murakami J, Kokeguchi S, Morita M. Effects of 
obesity on gingival oxidative stress in a rat model. J Periodontol. 2009; 80: 
1324-9. 
42 Yang Z, Meng Q, Zhao Y, Han R, Huang S, Li M, Wu X, Cai W, Wang H. 
Resveratrol Promoted Interferon-α-Induced Growth Inhibition and Apoptosis of 
SMMC7721 Cells by Activating the SIRT/STAT1. J Interferon Cytokine Res. 
2018; 38: 261-71. 
43 Casati MZ, Algayer C, Cardoso da Cruz, Ribeiro FV, Casarin RC, Pimentel 
SP, Cirano FR. 
 Resveratrol decreases periodontal breakdown and modulates local levels of 
cytokines during periodontitis in rats. J Periodontol. 2013; 84: 58–64. 
44 Corrêa MG, Pires PR, Ribeiro FV, Pimentel SZ, Cirano FR, Napimoga MH, 
Casati MZ, Casarin RCV. Systemic treatment with resveratrol and/or curcumin 
reduces the progression of experimental periodontitis in rats. PLoS One. 2018; 
13: e0204414.  
45 Park YD, Kim YS, Jung YM, Lee SI, Lee YM, Bang JB, Kim EC. 
Porphyromonas gingivalis lipopolysaccharide regulates interleukin (IL)-17 and 
IL-23 expression via SIRT1 modulation in human periodontal ligament cells. 
Cytokine. 2012; 60: 284-93. 
46 Qu L, Yu Y, Qiu L, Yang D, Yan L, Guo J, Jahan R. Sirtuin 1 regulates matrix 
metalloproteinase-13 expression induced by Porphyromonas endodontalis 
lipopolysaccharide via targeting nuclear factor-κB in osteoblasts. J Oral 
Microbiol. 2017; 9: 1317578. 
47 Machida T, Tomofuji T, Ekuni D, Yamane M, Yoneda T, Kawabata K, 
Kataoka K, Tamaki N, Morita M. Longitudinal relationship between plasma 
reactive 
oxygen 
metabolites 
and 
periodontal 
condition 
in 
the 
maintenance phase of periodontal treatment. Dis Markers. 2014; 2014: 489292.