Publications by authors named "Hsi-Ming Lee"

44 Publications

A Novel Modified-Curcumin Promotes Resolvin-Like Activity and Reduces Bone Loss in Diabetes-Induced Experimental Periodontitis.

J Inflamm Res 2021 16;14:5337-5347. Epub 2021 Oct 16.

Department of General Dentistry, School of Dental Medicine, Stony Brook University, Stony Brook, NY, 11794, USA.

Purpose: Clinically, it is challenging to manage diabetic patients with periodontitis. Biochemically, both involve a wide range of inflammatory/collagenolytic conditions which exacerbate each other in a "bi-directional manner." However, standard treatments for this type of periodontitis rely on reducing the bacterial burden and less on controlling hyper-inflammation/excessive-collagenolysis. Thus, there is a crucial need for new therapeutic strategies to modulate this excessive host response and to promote enhanced resolution of inflammation. The aim of the current study is to evaluate the impact of a novel chemically-modified curcumin 2.24 (CMC2.24) on host inflammatory response in diabetic rats.

Methods: Type I diabetes was induced by streptozotocin injection; periodontal breakdown then results as a complication of uncontrolled hyperglycemia. Non-diabetic rats served as controls. CMC2.24, or the vehicle-alone, was administered by oral gavage daily for 3 weeks to the diabetics. Micro-CT was used to analyze morphometric changes and quantify bone loss. MMPs were analyzed by gelatin zymography. Cell function was examined by cell migration assay, and cytokines and resolvins were measured by ELISA.

Results: In this severe inflammatory disease model, administration of the pleiotropic CMC2.24 was found to normalize the excessive accumulation and impaired chemotactic activity of macrophages in peritoneal exudates, significantly decrease MMP-9 and pro-inflammatory cytokines to near normal levels, and markedly increase resolvin D (RvD) levels in the thioglycolate-elicited peritoneal exudates (tPE). Similar effects on MMPs and RvD were observed in the non-elicited resident peritoneal washes (rPW). Regarding clinical relevance, CMC2.24 significantly inhibited the loss of alveolar bone height, volume and mineral density (ie, diabetes-induced periodontitis and osteoporosis).

Conclusion: In conclusion, treating hyperglycemic diabetic rats with CMC2.24 (a tri-ketonic phenylaminocarbonyl curcumin) promotes the resolution of local and systemic inflammation, reduces bone loss, in addition to suppressing collagenolytic MMPs and pro-inflammatory cytokines, suggesting a novel therapeutic strategy for treating periodontitis complicated by other chronic diseases.
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http://dx.doi.org/10.2147/JIR.S330157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528548PMC
October 2021

Therapeutic potential of a novel semi-synthetic-sulfated-polysaccharide to suppress inflammatory mediators in P. gingivalis LPS stimulated human monocytes/macrophages.

J Inflamm (Lond) 2021 Sep 4;18(1):26. Epub 2021 Sep 4.

Colgate Palmolive Company, Piscataway, NJ, 08854, USA.

Background: Chronic periodontitis is associated with an increased risk for systemic conditions such as cardiovascular disease, diabetes, and osteoporosis. During chronic periodontitis, endotoxin (lipopolysaccharide, LPS) produced by P. gingivalis provokes monocyte accumulation and differentiation into macrophages and increased secretion of pro-inflammatory cytokines and matrix metalloproteases (MMPs). While normal levels of MMPs are important in cellular function, increased levels of cytokines and MMPs can cause connective tissue destruction.

Results: In the current study, we investigated the therapeutic capability of a novel semi-synthetic sulfated polysaccharide (SAGE) on the production of cytokines and MMPs by cultured human mononuclear cells and macrophages stimulated with endotoxin LPS produced by P. gingivalis, a periodontally-relevant cell culture model. Our research demonstrated SAGE inhibited the LPS induced synthesis of inflammatory mediators including TNF-α, IL-1β, PGE, and MMP-9 in this periodontal-relevant cell culture model. In addition, TLR-2 and TLR-4 levels were also reduced with the SAGE treatment.

Conclusions: The therapeutic potential of this novel semi-synthetic sulfated polysaccharide compound may help to prevent tissue damage and bone loss in patients with periodontal disease or other inflammatory diseases.
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http://dx.doi.org/10.1186/s12950-021-00292-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418013PMC
September 2021

Active matrix metalloproteinase-8 (aMMP-8) point-of-care test (POCT) in the COVID-19 pandemic.

Expert Rev Proteomics 2021 08 11;18(8):707-717. Epub 2021 Sep 11.

Unit of Pedodontics and Preventive Dentistry, Oral Health Sciences Centre, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India.

Introduction: Active matrix metalloproteinase (aMMP)-8 utilized in point-of-care testing (POCT) is regarded as a potential biomarker for periodontal and peri-implant diseases. Various host and microbial factors eventually influence the expression, degranulation, levels and activation of aMMP-8. The type of oral fluids (saliva, mouthrinse, gingival crevicular, and peri-implant sulcular fluids [GCF/PISF], respectively) affect the analysis.

Areas Covered: With this background, we aimed to review here the recent studies on practical, inexpensive, noninvasive and quantitative mouthrinse and GCF/PISF chair-side POCT lateral flow aMMP-8 immunoassays (PerioSafe and ImplantSafe/ORALyzer) and how they help to detect, predict, monitor the course, treatment and prevention of periodontitis and peri-implantitis. The correlations of aMMP-8 POCT to other independent and catalytic activity assays of MMP-8 are also addressed.

Expert Opinion: The mouthrinse aMMP-8 POCT can also detect prediabetes/diabetes and tissue destructive oral side-effects due to the head and neck cancers' radiotherapy. Chlorhexidine and doxycycline can inhibit collagenolytic human neutrophil and GCF aMMP-8. Furthermore, by a set of case-series we demonstrate the potential of mouthrinse aMMP-8 POCT to real-time/online detect periodontitis as a potential risk disease for coronavirus disease 2019 (COVID-19). The clinical interdisciplinary utilization of aMMP-8 POCT requires additional oral, medical, and interdisciplinary studies.
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http://dx.doi.org/10.1080/14789450.2021.1976151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442753PMC
August 2021

Chemically-Modified Curcumin 2.24: A Novel Systemic Therapy for Natural Periodontitis in Dogs.

J Exp Pharmacol 2020 10;12:47-60. Epub 2020 Feb 10.

Department of General Dentistry, School of Dental Medicine, Stony Brook University, Stony Brook, NY 11794, USA.

Purpose: To determine the effect of a pleiotropic MMP-inhibitor, a novel chemically-modified curcumin 2.24 (CMC2.24), on the clinical and biological measures of naturally-occurring periodontitis in the beagle dog.

Methods: Eight adult female dogs with generalized periodontitis were distributed into two groups: Placebo and Treatment (n=4/group). After a 1-hr full-mouth scaling and root planing (SRP) at time 0, placebo or CMC2.24 (10mg/kg) capsules were orally administered once/day for 3 months. Various clinical periodontal parameters (e.g., pocket depth, gingival index) were measured at different time periods (0, 1, 2 and 3 months), and gingival crevicular fluid (GCF) samples and gingival tissue biopsies (3-month) were analyzed for cytokines, MMPs and cell-signaling molecules. Standardized radiographs were taken at 0 and 3-month; in addition, peripheral blood monocytes/macrophages from these dogs at 3-month were cultured and analyzed for the pro-, activated-, and total-forms of both MMP-2 and MMP-9.

Results: CMC2.24 treatment significantly reduced gingival inflammation (gingival index, GCF flow), pocket depth (PD), and the numbers of pockets (PD≥4mm), compared to placebo. CMC2.24 also significantly reduced MMP-9 and MMP-2 (primarily in the activated-form) in gingival tissue, alveolar bone loss, and reduced GCF IL-1β. Cell-signaling molecules, TLR-2 (but not TLR-4) and p38 MAPK, responded to CMC2.24 in a pattern consistent with reductions in inflammation and collagenolysis. In culture, CMC2.24 had no effect on pro-MMP-9 but essentially completely blocked the conversion of pro- to activated-MMP-9 in systemic blood-derived monocytes/macrophages from these dogs.

Conclusion: In the beagle dog model of natural periodontitis, orally administered CMC2.24 (a novel triketonic phenylaminocarbonyl-curcumin) significantly decreased clinical measures of periodontitis as well as pro-inflammatory cytokines, MMPs, and cell-signaling molecules. These and previous studies, using other in vitro and in vivo models, support the clinical potential of CMC2.24 as a novel adjunct to SRP in the treatment of chronic periodontitis.
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http://dx.doi.org/10.2147/JEP.S236792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020920PMC
February 2020

Periodontal therapeutics: Current host-modulation agents and future directions.

Periodontol 2000 2020 02;82(1):186-204

Department of Oral Biology & Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, New York, USA.

With the recognition in the 1960s and 1970s of the periodontopathic importance of the microbial biofilm and its specific anaerobic microorganisms, periodontitis was treated as an infectious disease (more recently, as a dysbiosis). Subsequently, in the 1980s, host-response mechanisms were identified as the mediators of the destruction of the collagen-rich periodontal tissues (gingiva, periodontal ligament, alveolar bone), and the periodontopathogens were now regarded as the "trigger" of the inflammatory/collagenolytic response that characterizes actively destructive periodontitis. Also at this time a new pharmacologic strategy emerged, entitled "host-modulation therapy", based on 2 major findings: (1) that the ability of tetracycline antibiotics to inhibit periodontal breakdown was due (in large part) to their previously unrecognized ability to inhibit the host-derived matrix metalloproteinases (notably, the collagenases, gelatinases, macrophage metalloelastase), and by mechanisms unrelated to the antimicrobial properties of these medications; and (2) that nonsteroidal anti-inflammatory drugs, such as flurbiprofen, again by nonantimicrobial mechanisms, could reduce the severity of periodontitis (however, the adverse effects of long-term therapy precluded their development as safe and effective host-modulatory agents). Additional mechanistic studies resulted in the development of novel nonantimicrobial formulations (Periostat® [now generic] and Oracea®) and compositions of tetracyclines (notably chemically modified tetracycline-3) as host-modulator drugs for periodontitis, arthritis, cardiovascular and pulmonary diseases, cancer, and, more recently, for local and systemic bone loss in postmenopausal women. Identification of the cation-binding active site in the tetraphenolic chemically modified tetracycline molecules drove the development of a new category of matrix metalloproteinase-inhibitor compounds, with a similar active site, the biphenolic chemically modified curcumins. A lead compound, chemically modified curcumin 2.24, has demonstrated safety and efficacy in vitro, in cell culture, and in vivo in mouse, rat, rabbit, and dog models of disease. In conclusion, novel host-modulation compounds have shown significant promise as adjuncts to traditional local therapy in the clinical management of periodontal disease; appear to reduce systemic complications of this all-too-common "inflammatory/collagenolytic" disease; and Oracea® is now commonly prescribed for inflammatory dermatologic diseases.
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http://dx.doi.org/10.1111/prd.12315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973248PMC
February 2020

Osteoimmunology of Oral and Maxillofacial Diseases: Translational Applications Based on Biological Mechanisms.

Front Immunol 2019 18;10:1664. Epub 2019 Jul 18.

Forsyth Institute, Cambridge, MA, United States.

The maxillofacial skeleton is highly dynamic and requires a constant equilibrium between the bone resorption and bone formation. The field of osteoimmunology explores the interactions between bone metabolism and the immune response, providing a context to study the complex cellular and molecular networks involved in oro-maxillofacial osteolytic diseases. In this review, we present a framework for understanding the potential mechanisms underlying the immuno-pathobiology in etiologically-diverse diseases that affect the oral and maxillofacial region and share bone destruction as their common clinical outcome. These otherwise different pathologies share similar inflammatory pathways mediated by central cellular players, such as macrophages, T and B cells, that promote the differentiation and activation of osteoclasts, ineffective or insufficient bone apposition by osteoblasts, and the continuous production of osteoclastogenic signals by immune and local stromal cells. We also present the potential translational applications of this knowledge based on the biological mechanisms involved in the inflammation-induced bone destruction. Such applications can be the development of immune-based therapies that promote bone healing/regeneration, the identification of host-derived inflammatory/collagenolytic biomarkers as diagnostics tools, the assessment of links between oral and systemic diseases; and the characterization of genetic polymorphisms in immune or bone-related genes that will help diagnosis of susceptible individuals.
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http://dx.doi.org/10.3389/fimmu.2019.01664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657671PMC
October 2020

Loss of alveolar bone density in postmenopausal, osteopenic women is associated with circulating levels of gelatinases.

J Periodontal Res 2019 Oct 29;54(5):525-532. Epub 2019 Apr 29.

Department of Surgical Specialties, University of Nebraska Medical Center College of Dentistry, Lincoln, Nebraska.

Objective: To determine whether circulating levels of two matrix metalloproteinases, MMP-2 and MMP-9, are associated with loss of alveolar bone density (ABD) or height (ABH), or with progression of periodontitis (relative clinical attachment level [RCAL]), among postmenopausal women with local and systemic bone loss.

Background: This study was planned as part of a 2-year randomized, double-blind, placebo-controlled, clinical trial examining efficacy/safety of subantimicrobial dose doxycycline (20 mg bid) in postmenopausal osteopenic women. This study examines whether serum levels of gelatinases are associated with local changes in the periodontium.

Methods: A sample of 113 women received periodontal maintenance for moderate to advanced chronic periodontitis and consented to analysis of stored serum biomarkers. Posterior vertical bitewings were taken, and serum collected, at baseline, one, and 2 years. ABD was determined by computer-assisted densitometric image analysis (CADIA), ABH by the Hausmann et al (1992, J Periodontol 63, 657) method, and RCAL by Florida Probe (every 6 months). MMPs were measured densitometrically on gelatin zymograms using denatured type I collagen as substrate and purified MMP-2 (72 kDa) and MMP-9 (92 kDa) as standards. Evidence of worsening in the periodontium at a tooth site was defined as a change from baseline of, for ABD, at least 14 densitometric units (for subcrestal locations) or 17 units (for crestal locations); of at least 0.4 mm for ABH; and of at least 1.5 mm for RCAL. Logistic regression models, while accounting for clustering, compared the odds of worsening in ABD, ABH, or RCAL, after 2 years of observation, between groups defined by baseline and concurrent levels of serum gelatinases.

Results: Changes in ABH and RCAL were not associated with circulating levels of MMP-2 or MMP-9. However, elevated odds of ABD loss over 24 months were associated, among smokers, with both baseline and concurrent levels of MMP-9 in the middle and highest tertile, and with concurrent levels of MMP-2 in the middle (but not the highest) tertile. Elevated odds of ABD loss were also associated, among women within 5 years of menopause, with baseline levels of MMP-2 in the highest tertile.

Conclusion: Among postmenopausal osteopenic women, loss of ABD was associated, in smokers, with elevated circulating levels of MMP-9 and MMP-2. In those within 5 years of menopause, ABD loss was associated with elevated circulating levels of MMP-2.
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http://dx.doi.org/10.1111/jre.12656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776678PMC
October 2019

Enhanced efficacy of chemically modified curcumin in experimental periodontitis: systemic implications.

J Exp Pharmacol 2019 23;11:1-14. Epub 2019 Jan 23.

Department of General Dentistry, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA,

Introduction: Dental microbial biofilm initiates gingival inflammation, and its suppression is the current dominant strategy for treating periodontitis. However, the host response to the biofilm is largely responsible for the connective tissue breakdown including alveolar bone loss, which is mediated by proinflammatory cytokines and matrix metalloproteinases (MMPs).

Methods: The current study compared the efficacy of a novel host-modulation compound, a chemically modified curcumin (CMC 2.24), to that of its parent compound (natural curcumin), in both lipopolysaccharide (LPS) (a bacterial endotoxin)-induced cell culture and in vivo models of periodontitis.

Results: In cell culture, both CMC 2.24 and curcumin appeared similarly effective in suppressing LPS-induced cytokine (IL-1β and TNF-α) secretion by mononuclear inflammatory cells; however, CMC 2.24 significantly reduced MMP-9 secretion by 78% (<0.05) whereas curcumin was ineffective. In vivo, CMC 2.24 administration was more effective than curcumin in suppressing (a) IL-1β in gingival tissue and (b) MMP-9 in both gingiva and plasma, the latter indicating a reduced severity of systemic inflammation. The difference in primary clinical outcome between the two treatments was that CMC 2.24 reduced the pathologically excessive alveolar bone loss, assessed morphometrically at multiple sites, by 80%-90% (<0.01), whereas curcumin, surprisingly, either increased (<0.05) or had no effect on alveolar bone loss at these sites.

Conclusion: These data, plus that from previous studies, support the therapeutic potential of CMC 2.24 in the management of inflammatory periodontal disease and its ability to reduce the risk of associated systemic diseases. The current study also indicates that the MMP-9 inhibitor efficacy is associated with the ability of CMC 2.24 (but not curcumin) to inhibit alveolar bone loss in this rat model of periodontitis.
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http://dx.doi.org/10.2147/JEP.S171119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350653PMC
January 2019

Differential effects of natural Curcumin and chemically modified curcumin on inflammation and bone resorption in model of experimental periodontitis.

Arch Oral Biol 2018 Jul 10;91:42-50. Epub 2018 Apr 10.

Department of Restorative Dentistry School of Dentistry of Riberão Preto University of São Paulo Riberão Preto SP Brazil. Electronic address:

Objective: The purpose of this study was to compare the effects of the oral administration of natural curcumin and a chemically modified curcumin (CMC2.24) on osteoclast-mediated bone resorption, apoptosis, and inflammation in a murine model of experimental periodontal disease.

Design: Fifty male rats were distributed among the following treatment groups: (i) 2% carboxymethylcellulose, (ii) CMC2.24 30 mg/kg body weight, (iii) Curcumin 100 mg/kg body weight and (iv) no treatment. Compounds were administered daily by oral intubation over a 15-day period of time. Periodontal disease was induced by injections of LPS (lipopolysaccharide) into the gingival tissues three times per week. Contralateral sides were injected with the same volume of PBS (phosphate buffered saline) vehicle. After 15 days, hemimaxillae and gingival tissues were harvested. Bone resorption was assessed by μCT (microcomputer tomography). Formalin-fixed, paraffin embedded histological sections were stained with haematoxylin/eosin (H/E) for the assessment of cellular infiltrate or subjected to immunohistochemistry for detecting TRAP (tartrate-resistant acid phosphatase)-positive cells and caspase-3. Apoptosis was assessed in the gingival tissues by DNA fragmentation.

Results: CMC2.24 and curcumin caused a significant reduction of the inflammatory cell infiltrate, however μCT analysis showed that only CMC2.24 reduced bone resorption and the number of TRAP-positive multinucleated cells (osteoclasts). Curcumin, but not CMC2.24, significantly reduced the number of apoptotic cells in the gingival tissues and of osteocytes in the alveolar bone crest.

Conclusions: The results suggest that CMC2.24 and curcumin inhibit inflammation by different mechanisms, but only CMC2.24 was capable of reducing alveolar bone resorption in the LPS-induced model of periodontitis.
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http://dx.doi.org/10.1016/j.archoralbio.2018.04.007DOI Listing
July 2018

A Chemically Modified Curcumin (CMC 2.24) Inhibits Nuclear Factor κB Activation and Inflammatory Bone Loss in Murine Models of LPS-Induced Experimental Periodontitis and Diabetes-Associated Natural Periodontitis.

Inflammation 2017 Aug;40(4):1436-1449

Department of Oral Biology and Pathology, School of Dental Medicine, SUNY at Stony Brook, Stony Brook, NY, USA.

The purpose of this study was to assess the effect of a novel chemically modified curcumin (CMC 2.24) on NF-κB and MAPK signaling and inflammatory cytokine production in two experimental models of periodontal disease in rats. Experimental model I: Periodontitis was induced by repeated injections of LPS into the gingiva (3×/week, 3 weeks); control rats received vehicle injections. CMC 2.24, or the vehicle, was administered by daily oral gavage for 4 weeks. Experimental model II: Diabetes was induced in adult male rats by streptozotocin injection; periodontal breakdown then results as a complication of uncontrolled hyperglycemia. Non-diabetic rats served as controls. CMC 2.24, or the vehicle, was administered by oral gavage daily for 3 weeks to the diabetics. Hemimaxillae and gingival tissues were harvested, and bone loss was assessed radiographically. Gingival tissues were pooled according to the experimental conditions and processed for the analysis of matrix metalloproteinases (MMPs) and bone-resorptive cytokines. Activation of p38 MAPK and NF-κB signaling pathways was assessed by western blot. Both LPS and diabetes induced an inflammatory process in the gingival tissues associated with excessive alveolar bone resorption and increased activation of p65 (NF-κB) and p38 MAPK. In both models, the administration of CMC 2.24 produced a marked reduction of inflammatory cytokines and MMPs in the gingival tissues, decreased bone loss, and decreased activation of p65 (NF-κB) and p38 MAPK. Inhibition of these cell signaling pathways by this novel tri-ketonic curcuminoid (natural curcumin is di-ketonic) may play a role in its therapeutic efficacy in locally and systemically associated periodontitis.
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http://dx.doi.org/10.1007/s10753-017-0587-4DOI Listing
August 2017

A Novel Chemically Modified Curcumin "Normalizes" Wound-Healing in Rats with Experimentally Induced Type I Diabetes: Initial Studies.

J Diabetes Res 2016 13;2016:5782904. Epub 2016 Apr 13.

Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY 11794, USA.

Introduction. Impaired wound-healing in diabetics can lead to life-threatening complications, such as limb amputation, associated in part with excessive matrix metalloproteinase- (MMP-) mediated degradation of collagen and other matrix constituents. In the current study, a novel triketonic chemically modified curcumin, CMC2.24, was tested for efficacy in healing of standardized skin wounds in streptozotocin-induced diabetic rats. Initially, CMC2.24 was daily applied topically at 1% or 3% concentrations or administered systemically (oral intubation; 30 mg/kg); controls received vehicle treatment only. Over 7 days, the diabetics exhibited impaired wound closure, assessed by gross and histologic measurements, compared to the nondiabetic controls. All drug treatments significantly improved wound closure with efficacy ratings as follows: 1% 2.24 > systemic 2.24 > 3% 2.24 with no effect on the severe hyperglycemia. In subsequent experiments, 1% CMC2.24 "normalized" wound-healing in the diabetics, whereas 1% curcumin was no more effective than 0.25% CMC2.24, and the latter remained 34% worse than normal. MMP-8 was increased 10-fold in the diabetic wounds and topically applied 1% (but not 0.25%) CMC2.24 significantly reduced this excessive collagenase-2; MMP-13/collagenase-3 did not show significant changes. Additional studies indicated efficacy of 1% CMC2.24 over more prolonged periods of time up to 30 days.
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http://dx.doi.org/10.1155/2016/5782904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846750PMC
June 2017

Impact of chemically-modified tetracycline 3 on intertwined physiological, biochemical, and inflammatory networks in porcine sepsis/ARDS.

Int J Burns Trauma 2015 20;5(1):22-35. Epub 2015 Mar 20.

Department of Surgery, University of Pittsburgh Pittsburgh, PA, USA ; Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh Pittsburgh, PA, USA.

Sepsis can lead to multiple organ dysfunction, including the Acute Respiratory Distress Syndrome (ARDS), due to intertwined, dynamic changes in inflammation and organ physiology. We have demonstrated the efficacy of Chemically-Modified Tetracycline 3 (CMT-3) at reducing inflammation and ameliorating pathophysiology in the setting of a clinically realistic porcine model of ARDS. Here, we sought to gain insights into the derangements that characterize sepsis/ARDS and the possible impact of CMT-3 thereon, by combined experimental and computational studies. Two groups of anesthetized, ventilated pigs were subjected to experimental sepsis via placement of a peritoneal fecal clot and intestinal ischemia/reperfusion by clamping the superior mesenteric artery for 30 min. The treatment group (n = 3) received CMT-3 at 1 hour after injury (T1), while the control group (n = 3) received a placebo. Multiple inflammatory mediators, along with clinically relevant physiologic and blood chemistry variables, were measured serially until death of the animal or T48. Principal Component Analysis (PCA) and Dynamic Bayesian Network (DBN) inference were used to relate these variables. PCA revealed a separation of cardiac and pulmonary physiologic variables by principal component, and a decreased rank of oxygen index and arterial PO2/FiO2 ratio in the treatment group compared to control. DBN suggested a conserved network structure in both control and CMT-3 animals: a response driven by positive feedback between interleukin-6 and lung dysfunction. Resulting networks further suggested that in control animals, acute kidney injury, acidosis, and respiratory failure play an increased role in the response to insult compared to CMT-3 animals. These combined in vivo and in silico studies in a high fidelity, clinically applicable animal model suggest a dynamic interplay between inflammatory, physiologic, and blood chemistry variables in the setting of sepsis and ARDS that may be dramatically altered by pleiotropic interruption of inflammation by CMT-3.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448085PMC
June 2015

A novel chemically modified curcumin reduces severity of experimental periodontal disease in rats: initial observations.

Mediators Inflamm 2014 29;2014:959471. Epub 2014 Jun 29.

Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY 11794, USA.

Tetracycline-based matrix metalloproteinase- (MMP-) inhibitors are currently approved for two inflammatory diseases, periodontitis and rosacea. The current study addresses the therapeutic potential of a novel pleiotropic MMP-inhibitor not based on an antibiotic. To induce experimental periodontitis, endotoxin (LPS) was repeatedly injected into the gingiva of rats on one side of the maxilla; the contralateral (control) side received saline injections. Two groups of rats were treated by daily oral intubation with a chemically modified curcumin, CMC 2.24, for two weeks; the control groups received vehicle alone. After sacrifice, gingiva, blood, and maxilla were collected, the jaws were defleshed, and periodontal (alveolar) bone loss was quantified morphometrically and by μ-CT scan. The gingivae were pooled per experimental group, extracted, and analyzed for MMPs (gelatin zymography; western blot) and for cytokines (e.g., IL-1β; ELISA); serum and plasma samples were analyzed for cytokines and MMP-8. The LPS-induced pathologically excessive bone loss was reduced to normal levels based on either morphometric (P = 0.003) or μ-CT (P = 0.008) analysis. A similar response was seen for MMPs and cytokines in the gingiva and blood. This initial study, on a novel triketonic zinc-binding CMC, indicates potential efficacy on inflammatory mediators and alveolar bone loss in experimental periodontitis and warrants future therapeutic and pharmacokinetic investigations.
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http://dx.doi.org/10.1155/2014/959471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101223PMC
April 2015

4-methoxycarbonyl curcumin: a unique inhibitor of both inflammatory mediators and periodontal inflammation.

Mediators Inflamm 2013 24;2013:329740. Epub 2013 Dec 24.

Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY 11794, USA.

Chronic inflammatory diseases such as periodontitis have been associated with increased risk for various medical conditions including diabetes and cardiovascular disease. Endotoxin (lipopolysaccharide, LPS), derived from gram-negative periodonto-pathogens, can induce the local accumulation of mononuclear cells in the inflammatory lesion, increasing proinflammatory cytokines and matrix metalloproteinases (MMPs). This ultimately results in the destruction of periodontal connective tissues including alveolar bone. Curcumin is the principal dyestuff in the popular Indian spice turmeric and has significant regulatory effects on inflammatory mediators but is characterized by poor solubility and low bioactivity. Recently, we developed a series of chemically modified curcumins (CMCs) with increased solubility and zinc-binding activity, while retaining, or further enhancing, their therapeutic effects. In the current study, we demonstrate that a novel CMC (CMC 2.5: 4-methoxycarbonyl curcumin) has significant inhibitory effects, better than the parent compound curcumin, on proinflammatory cytokines and MMPs in in vitro, in cell culture, and in an animal model of periodontal inflammation. The therapeutic potential of CMC 2.5 and its congeners may help to prevent tissue damage during various chronic inflammatory diseases including periodontitis and may reduce the risks of systemic diseases associated with this local disorder.
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http://dx.doi.org/10.1155/2013/329740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3886587PMC
October 2014

Subantimicrobial-dose doxycycline treatment increases serum cholesterol efflux capacity from macrophages.

Inflamm Res 2013 Jul 7;62(7):711-20. Epub 2013 May 7.

Institute of Dentistry, University of Helsinki, P.O. Box 63, 00014 Helsinki, Finland.

Objective: Subantimicrobial-dose doxycycline (SDD) treatment has been reported to reduce the severity of chronic inflammation and to increase serum high-density lipoprotein cholesterol. In a double-blind, placebo-controlled clinical trial, we determined whether SDD affects the ability of serum to facilitate cholesterol removal from macrophages.

Methods: Forty-five postmenopausal osteopenic women with periodontitis were randomly assigned to take placebo (n = 26) or doxycycline hyclate (20 mg, n = 19) tablets twice daily for 2 years. Serum samples were collected at baseline, 1-, and 2-year appointments. The cholesterol efflux capacity of serum from cultured human macrophages (THP-1) was measured.

Results: SDD subjects demonstrated a significant increase in serum-mediated cholesterol efflux from macrophages at both time points compared to baseline (p < 0.04 for each). Mean cholesterol efflux levels over the first year of follow-up were 3.0 percentage points (unit change) higher among SDD subjects compared to placebo subjects (p = 0.010), while there was no significant difference in 2-year changes. There were no significant differences in the changes of apolipoprotein A-I, apolipoprotein A-II, or serum amyloid A levels between the groups.

Conclusions: Our results suggest that SDD treatment may reduce the risk of cardiovascular disease in this patient group by increasing the cholesterol efflux capacity of serum.
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http://dx.doi.org/10.1007/s00011-013-0626-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700361PMC
July 2013

Design, synthesis and biological activity of new polyenolic inhibitors of matrix metalloproteinases: a focus on chemically-modified curcumins.

Curr Med Chem 2012 ;19(25):4348-58

Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.

Matrix metalloproteinases (MMPs) are essential for the degradation and turnover of components of the extracellular matrix (ECM) and, when pathologically elevated, mediate connective tissue loss (including bone destruction) in various inflammatory and other diseases. Tetracyclines (TCs) are known inhibitors of mammalian-derived MMPs, and non-antibiotic formulations of Doxycycline are FDA-approved to treat periodontitis and the chronic inflammatory skin disease, rosacea. Because the C-11/ C-12 diketonic moiety of the tetracyclines is primarily responsible, through zinc-binding, for MMP inhibition, we have uniquely modified curcumin as a "core" molecule, since it contains a similar enolic system and is known to have beneficial effects in diseases where connective-tissue loss occurs. Specifically we have developed new congeners which exhibit improved zinc-binding and solubility, and potent reduction of excessive MMP levels and activity. We now describe a series of curcuminoid bi- and tri-carbonylmethanes in which all of these properties are substantially improved. An N-phenylaminocarbonyl derivative of bis-demethoxycurcumin (CMC2.24) was selected as the "lead" substance because it showed superior potency in vitro (i.e., the lowest IC(50)) against a series of neutral proteases (MMPs) associated with tissue erosion. Moreover, CMC2.24 administered to diabetic rats orally (30mg/kg), reduced the secretion of pathologically-excessive levels of MMP-9 to normal in cultured peritoneal macrophages with no evidence of toxicity. Thus, this (and other similar novel) compound(s) may be useful in various diseases of connective-tissue loss.
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http://dx.doi.org/10.2174/092986712802884295DOI Listing
April 2013

Chemically modified tetracycline 3 prevents acute respiratory distress syndrome in a porcine model of sepsis + ischemia/reperfusion-induced lung injury.

Shock 2012 Apr;37(4):424-32

Department of Surgery, Upstate Medical University, Syracuse, New York, USA.

Experimental pharmacotherapies for the acute respiratory distress syndrome (ARDS) have not met with success in the clinical realm. We hypothesized that chemically modified tetracycline 3 (CMT-3), an anti-inflammatory agent that blocks multiple proteases and cytokines, would prevent ARDS and injury in other organs in a clinically applicable, porcine model of inflammation-induced lung injury. Pigs (n = 15) were anesthetized and instrumented for monitoring. A "2-hit" injury was induced: (a) peritoneal sepsis-by placement of a fecal clot in the peritoneum, and (b) ischemia/reperfusion-by clamping the superior mesenteric artery for 30 min. Animals were randomized into two groups: CMT-3 group (n = 7) received CMT-3 (200 mg/kg); placebo group (n = 9) received the same dose of a CMT-3 vehicle (carboxymethylcellulose). Experiment duration was 48 h or until early mortality. Animals in both groups developed polymicrobial bacteremia. Chemically modified tetracycline 3 treatment prevented ARDS as indicated by PaO(2)/FIO(2) ratio, static compliance, and plateau airway pressure (P < 0.05 vs. placebo). It improved all histological lesions of ARDS (P < 0.05 vs. placebo). The placebo group developed severe ARDS, coagulopathy, and histological injury to the bowel. Chemically modified tetracycline 3 treatment prevented coagulopathy and protected against bowel injury. It significantly lowered plasma concentrations of interleukin 1β (IL-1β), tumor necrosis factor α, IL-6, IL-8, and IL-10. This study presents a clinically relevant model of lung injury in which CMT-3 treatment prevented the development of ARDS due in part to reduction of multiple plasma cytokines. Treatment of sepsis patients with CMT-3 could significantly reduce progression from sepsis into ARDS.
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http://dx.doi.org/10.1097/SHK.0b013e318245f2f9DOI Listing
April 2012

Non-antibacterial tetracyclines modulate mediators of periodontitis and atherosclerotic cardiovascular disease: a mechanistic link between local and systemic inflammation.

Pharmacol Res 2011 Dec 13;64(6):573-9. Epub 2011 Jul 13.

Department of General Dentistry, School of Dental Medicine, Stony Brook University, Stony Brook, NY 11794, United States.

Periodontitis, one of the most common chronic inflammatory diseases afflicting man, is increasingly being recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD). Non-antimicrobial tetracyclines are known to have inhibitory effects on inflammatory mediators and effector molecules, including cytokines and matrix metalloproteinases (MMPs), associated with both diseases. In this paper, we discuss the evidence that doxycycline and related non-antibiotic chemically modified tetracyclines (e.g., CMT-3) can effectively reduce cytokine (TNF-α, IL-6, and MCP-1) production by human mononuclear inflammatory cells when stimulated either by endotoxin (LPS) or by a complex of C-reactive protein/oxidized LDL cholesterol relevant to the pathogenesis of periodontal disease and ASCVD, respectively. This inhibition by tetracycline compounds appears to be mediated at least in part by a suppression of the phosphorylation/activation of the NFκB cell signaling pathway. We are currently conducting clinical trials on patients who exhibit both diseases, and our preliminary data suggest that virtually all acute coronary syndrome (ACS) patients exhibit moderate-to-severe periodontitis, a higher incidence of this oral inflammatory disease than that seen in the population at large. In other studies, a non-antimicrobial formulation of doxycycline (SDD) has been found to dramatically reduce hsCRP, IL-6 and MMP-9 levels in plasma of ACS patients, and SDD has also been found to significantly increase serum levels of both cardio-protective HDL cholesterol and its core molecule apolipoprotein A-I in ASCVD-vulnerable patients with periodontitis. Our current research suggests that one mechanism involved may be the ability of SDD to inhibit MMP-mediated HDL loss by protecting apolipoprotein A-I from proteinase attack. These pleiotropic mechanisms of non-antimicrobial tetracyclines provide significant therapeutic potential to treat chronic inflammatory diseases including both periodontitis and ASCVD.
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http://dx.doi.org/10.1016/j.phrs.2011.06.023DOI Listing
December 2011

Chemically modified tetracycline-3 (CMT-3): a novel inhibitor of the serine proteinase, elastase.

Pharmacol Res 2011 Dec 31;64(6):595-601. Epub 2011 May 31.

Department of General Dentistry, School of Dental Medicine, Stony Brook University, Stony Brook, NY 11794-8706, United States.

Two classes of enzymes play an important role in connective tissue breakdown during various inflammatory diseases: serine proteinases and matrix metalloproteinases (MMPs). Tetracyclines (TCs) exhibit important anti-inflammatory and MMP-inhibitory properties that are unrelated to their antibacterial activities. Of the various TCs and their chemically modified NON-antibiotic analogs (CMTs) tested in vitro and in vivo, CMT-3 (6-demethyl-6-deoxy 4 de-dimethylamino tetracycline) has repeatedly been shown to be the most potent inhibitor of MMP activity and cytokine production. In addition to its anti-MMP function, we have shown that among all CMTs, CMT-3 is the only CMT that can also directly inhibit both the amidolytic activity of human leukocyte elastase (HLE, a serine proteinase) and the extracellular matrix degradation mediated by HLE. In addition, CMT-3 has been found to reduce leukocyte elastase activity in vivo in gingival extracts of rats with experimental periodontal disease. Thus, CMT-3 can inhibit pathologic connective tissue breakdown by (at least) two mechanisms: direct inhibition of neutral proteinases (elastase and MMPs); and protecting their endogenous inhibitors, α(1)-PI and TIMPs, from being digested and inactivated by MMPs and HLE, respectively. The pleiotropic properties of CMT-3 including (but not limited to) inhibition of serine proteinases, MMPs, and cytokines provide impressive therapeutic potential to reduce excessive connective tissue breakdown during various pathologic processes including inflammatory diseases, cancer metastasis and metabolic bone diseases.
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http://dx.doi.org/10.1016/j.phrs.2011.05.011DOI Listing
December 2011

The effect of subantimicrobial-dose-doxycycline periodontal therapy on serum biomarkers of systemic inflammation: a randomized, double-masked, placebo-controlled clinical trial.

J Am Dent Assoc 2011 Mar;142(3):262-73

Department of Surgical Specialties, College of Dentistry, University of Nebraska Medical Center, Lincoln, Neb. 68583-0740, USA.

Background: Periodontitis has been reported to be associated with coronary artery disease (CAD). Research is needed to determine if therapies that improve periodontal health also reduce systemic measures of inflammation associated with both diseases.

Methods: The study registrar randomly assigned 128 eligible postmenopausal women with chronic periodontitis to a twice-daily regimen of subantimicrobial-dose-doxycycline (SDD) or placebo tablets for two years as an adjunct to periodontal maintenance therapy. Through a supplement to the main trial, in which they investigated alveolar bone and clinical attachment level changes, the authors assayed inflammatory mediators and lipid profiles in baseline, one-year and two-year serum samples. The authors analyzed the data by using generalized estimating equations.

Results: In the intent-to-treat analysis across two years, SDD treatment reduced median high-sensitivity C-reactive protein (hs-CRP) by 18 percent (primary outcome; P = .02) and reduced serum matrix metalloproteinase (MMP)-9 (92 kilodalton gelatinase; difference in mean scanning units, -28.44; P < .001), with no significant effect on serum lipids. However, in women more than five years postmenopausal, SDD elevated the level of high-density lipoprotein (HDL) cholesterol (difference in means [milligrams per deciliter], 5.99; P = .01).

Conclusion: A two-year SDD regimen in postmenopausal women significantly reduced the serum inflammatory biomarkers hs-CRP and MMP-9 and, among women more than five years postmenopausal, increased the HDL cholesterol level.

Clinical Implications: SDD significantly reduced the systemic inflammatory biomarkers hs-CRP and MMP-9. More research is needed to determine whether SDD has a role in managing the care of patients at risk of developing CAD.
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http://dx.doi.org/10.14219/jada.archive.2011.0165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077029PMC
March 2011

A tetracycline analog improves acute respiratory distress syndrome survival in an ovine model.

Ann Thorac Surg 2010 Aug;90(2):419-26

Department of Surgery, University of Kentucky College of Medicine, Lexington, KY, USA.

Background: Acute respiratory distress syndrome (ARDS) mortality remains high with no effective pharmacotherapy available. A chemically modified tetracycline (COL-3) is a potent inhibitor of matrix metalloproteinases. Prophylactic COL-3 administration has been shown to be effective in ARDS treatment. In the present study, the therapeutic effect of COL-3, given shortly after injury, was investigated in an ovine ARDS model.

Methods: The ovine ARDS model was induced by combined 40% body area third-degree burn, smoke inhalation, and barotrauma injuries. The sheep were randomly assigned into two groups: control (10% Solutol, n = 5) or COL-3 (200 mg/m(2), n = 5). Intravenous administration of COL-3 or vehicle was performed 1 hour after the smoke and burn injury. When ARDS criteria were met (arterial partial pressure of oxygen to fraction of inspired oxygen ratio < 200) or no later than 24 hours after injury (if criteria not met), animals underwent the ARDS Network ventilation protocol. At 96 hours after injury or at animal death, lung pathologic processes were assessed.

Results: Administration of COL-3 improved hemodynamics and reduced carbon dioxide levels. Administration of COL-3 also significantly delayed ARDS development and prolonged survival time compared with the control group (20.4 + or - 3.8 hours versus 12.9 + or - 3.3 hours; 94.2 + or - 4.0 hours versus 58.6 + or - 26.4 hours; p < 0.05, respectively). Survival analysis showed a higher 96-hour survival from ARDS with COL-3 administration as compared with control (80% versus 20%; p < 0.05). Lung pathologic processes were also improved by COL-3. Plasma matrix metalloproteinase-2 level increased in control but not in COL-3-treated animals.

Conclusions: Our present study suggests that COL-3 may be an effective pharmacotherapy for ARDS treatment.
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http://dx.doi.org/10.1016/j.athoracsur.2010.04.052DOI Listing
August 2010

Association of gingival crevicular fluid biomarkers during periodontal maintenance with subsequent progressive periodontitis.

J Periodontol 2010 Feb;81(2):251-9

Department of Surgical Specialties, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68583-0740, USA.

Background: The analysis of biomarkers in gingival crevicular fluid (GCF) may be helpful in forecasting patient vulnerability to future attachment loss. The purpose of this study is to correlate GCF biomarkers of inflammation and bone resorption with subsequent periodontal attachment and bone loss in a longitudinal trial of a matrix metalloproteinase (MMP) inhibitor.

Methods: GCF was collected from two periodontal pockets (mean +/- SD: 5.1 +/- 1.0 mm) at baseline and annually in postmenopausal females with moderate to advanced periodontitis undergoing periodontal maintenance every 3 to 4 months during a 2-year double-masked, placebo-controlled, randomized clinical trial of subantimicrobial dose doxycycline (SDD; 20 mg two times a day). Subjects were randomized to SDD (n = 64) or a placebo (n = 64). GCF was analyzed for the inflammation markers interleukin (IL)-1beta (using enzyme-linked immunosorbent assay), total collagenase activity (using hydrolysis of a synthetic octapeptide), and MMP-8 (using a Western blot) and the bone-resorption marker carboxyterminal telopeptide cross-link fragment of type I collagen (ICTP) (using a radioimmunoassay). Generalized estimating equations were used to associate these biomarkers, categorized into tertiles, with subsequent clinical attachment (using an automated disk probe) or interproximal bone loss (using radiography). Odds ratio (OR) values compared highest to lowest tertile groups.

Results: Increases in GCF IL-1beta and MMP-8 during the first year of periodontal maintenance were associated with increased odds of subsequent (year 2) periodontal attachment loss (OR = 1.67; P = 0.01 and OR = 1.50; P = 0.02, respectively) driven by the placebo group. Elevated baseline ICTP was also associated with increased odds of 1- and 2-year loss of alveolar bone density (OR = 1.98; P = 0.0001) in the placebo group, not the SDD group, and a loss of bone height (OR = 1.38; P = 0.06), again driven by the placebo group.

Conclusion: These data support the hypothesis that elevated GCF biomarkers of inflammation and bone resorption from a small number of moderate/deep sites have the potential to identify patients who are vulnerable to progressive periodontitis, and SDD may modify that risk.
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http://dx.doi.org/10.1902/jop.2009.090374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822998PMC
February 2010

Suppressive effects of formoterol and salmeterol on eotaxin-1 in bronchial epithelial cells.

Pediatr Allergy Immunol 2010 Mar 7;21(2 Pt 1):345-52. Epub 2009 Dec 7.

Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Eotaxin-1 (CCL11), an eosinophil-specific C-C chemokine, is a potent chemoattractant for mobilization of eosinophils into airways after allergic stimulation. Eotaxin-1 recruits eosinophils into inflammatory sites, and may play a role in the pathogenesis of asthma. Formoterol and salmeterol are two inhaled long acting beta(2) adrenoceptor agonists (LABAs), widely used for the local treatment of asthma. However, little is known about their effects on the eotaxin-1 expression of bronchial epithelial cells. BEAS-2B cells were stimulated by adding IL-4 with or without 2 h pre-treatment of formoterol or salmeterol. The protein and mRNA expression of eotaxin-1 were measured by ELISA assay and real-time PCR, respectively. Effects of formoterol and salmeterol on nuclear and cytosolic pSTAT-6 expression were evaluated by Western blot and immunofluorescence study. Formoterol and salmeterol (10(-7)-10(-10) m) significantly down-regulated IL-4- induced eotaxin-1 expression in BEAS-2B cells. A specific beta(2) adrenoceptor antagonist (ICI 118,551) reversed their suppression of eotaxin-1 production. Forskolin, an cAMP activator, could also suppress the expression of eotaxin-1 by IL-4 in a dose dependent manner (10(-7)-10(-10 )m). The western blot and immunofluorescence studies demonstrated that formoterol 10(-7 )m suppressed the nuclear expression of pSTAT-6. Formoterol and salmeterol, two inhaled long-acting beta(2) agonists, down-regulated IL-4- induced eotaxin-1 expression in BEAS-2B cells. The effect was mediated via the beta(2) adrenoceptor, and cAMP. Formoterol significantly down-regulated pSTAT6 at higher concentration, and further turned off the IL-4 signaling pathway.
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http://dx.doi.org/10.1111/j.1399-3038.2009.00906.xDOI Listing
March 2010

Doxycycline [corrected] inhibits mononuclear cell-mediated connective tissue breakdown.

FEMS Immunol Med Microbiol 2010 Mar 10;58(2):218-25. Epub 2009 Nov 10.

Department of General Dentistry, Stony Brook University, Stony Brook, NY, USA.

Chronic periodontitis is the most common chronic inflammatory disease and has been associated with an increased risk for serious medical conditions including cardiovascular disease (CVD). Endotoxin (lipopolysaccharide), derived from periodontopathogens, can induce the local accumulation of mononuclear cells in the inflammatory lesion, increasing proinflammatory cytokines and matrix metalloproteinases (MMPs), resulting in the destruction of periodontal connective tissues including bone. In this study, we show that doxycycline, originally developed as a broad-spectrum tetracycline antibiotic (and, more recently, as a nonantimicrobial therapy for chronic inflammatory periodontal and skin diseases), can inhibit extracellular matrix degradation in cell culture mediated by human peripheral blood-derived monocytes/macrophages. The mechanisms include downregulation of cytokines and MMP-9 protein levels and the inhibition of the activities of both collagenase and MMP-9. These pleiotropic, but nonantibiotic, effects of doxycycline explain, at least in part, its therapeutic potential for various chronic inflammatory diseases including periodontitis, and may reduce the risks of systemic diseases (e.g. CVDs, less manageable diabetes) associated with this and other local diseases.
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http://dx.doi.org/10.1111/j.1574-695X.2009.00625.xDOI Listing
March 2010

Subantimicrobial-dose doxycycline modulates gingival crevicular fluid biomarkers of periodontitis in postmenopausal osteopenic women.

J Periodontol 2008 Aug;79(8):1409-18

Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY 11794, USA.

Background: We recently demonstrated that a 2-year subantimicrobial-dose doxycycline (SDD) regimen (double-masked, placebo-controlled clinical trial) in postmenopausal (PM) women exhibiting mild systemic bone loss (osteopenia) and local bone loss (periodontitis) reduced the progression of periodontal attachment loss (intent-to-treat analysis) and the severity of gingival inflammation and alveolar bone loss (subgroups) without producing antibiotic side effects. We now describe SDD effects on biomarkers of collagen degradation and bone resorption in the gingival crevicular fluid (GCF) of the same vulnerable subjects.

Methods: GCF was collected from SDD- and placebo-treated PM subjects (n=64 each) at the baseline and 1- and 2-year appointments; the volume was determined; and the samples were analyzed for collagenase activity (using a synthetic peptide as substrate), relative levels of three genetically distinct collagenases (Western blot), a type-1 collagen breakdown product/bone resorption marker (a carboxyterminal telopeptide cross-link fragment of type I collagen [ICTP]; radioimmunoassay), and interleukin-1beta (enzyme-linked immunosorbent assay). Statistical analyses were performed using generalized estimating equations; primary analyses were intent-to-treat.

Results: Collagenase activity was significantly reduced by SDD treatment relative to placebo based on intent-to-treat (P=0.01). ICTP showed a similar pattern of change during SDD treatment, and GCF collagenase activity and ICTP were positively correlated at all time periods (P<0.001). Matrix metalloproteinase (MMP)-8 accounted for approximately 80% of total collagenase in GCF, with much less MMP-1 and -13, and SDD reduced the odds of elevated MMP-8 by 60% compared to placebo (P=0.006).

Conclusion: These observations support the therapeutic potential of long-term SDD therapy to reduce periodontal collagen breakdown and alveolar bone resorption in PM women; effects on serum biomarkers of systemic bone loss in these subjects are being analyzed.
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http://dx.doi.org/10.1902/jop.2008.070623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2553351PMC
August 2008

Characteristics of collagenase-2 from gingival crevicular fluid and peri-implant sulcular fluid in periodontitis and peri-implantitis patients: pilot study.

Acta Odontol Scand 2008 Aug;66(4):219-24

Department of General Dentistry, School of Dental Medicine, Stony Brook University, New York, Stony Brook, USA.

Objective: To compare collagenase activity and collagenolytic matrix metalloproteinase (MMP) levels in gingival crevicular fluid (GCF) and in peri-implant sulcular fluid (PISF) in gingivitis (G), chronic periodontitis (CP), and peri-implantitis (PI) human subjects.

Material And Methods: GCF and PISF were collected on filter paper strips, volume was determined, and samples were extracted in buffer containing general proteinase but not MMP inhibitors. Collagenase activity was measured using a DNP-synthetic octapeptide, and molecular and activation forms of collagenase-2 by Western immunoblotting.

Results: GCF from CP and G sites exhibited elevated collagenase activity and flow, but collagenase concentrations expressed per microl were not significantly different between the healthy and G sites. Minimal fluid was obtained from healthy PISF, and collagenase concentration was the same or lower than in healthy GCF. Although PISF flow was 34% lower than GCF flow in CP subjects, collagenase concentration in CP and in PI sites was 78% and 971% greater, respectively, than in the appropriate healthy sites. Western immunoblot revealed MMP-8 in both PISF and GCF; fibroblast-type MMP-8 was not detected in healthy GCF and PISF. Immunoreactivity level and inactive and activated forms of PMN-type MMP-8 in GCF and PISF increased with the severity of periodontitis and peri-implantitis. Enhanced levels of fibroblast-type MMP-8 in active form were detected only in severe CP GCF and PI PISF.

Conclusions: Peri-implantitis PISF contained higher collagenase-2 levels and activity than GCF from similar deep CP sites. GCF and PISF from severe CP and PI exhibited the highest activation of MMP-8 isoenzymes species (PMN and fibroblast-type).
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http://dx.doi.org/10.1080/00016350802183393DOI Listing
August 2008

Inflammatory mediator release following bone grafting in humans: a pilot study.

J Clin Periodontol 2007 Sep;34(9):797-804

Department of Surgical Specialties, University of Nebraska Medical Center, College of Dentistry, Lincoln, NE 68583-0740, USA.

Aim: The aim of this pilot study was to track markers of periodontal inflammation and bone resorption associated with decalcified freeze-dried bone allografts.

Material And Methods: Eleven subjects completed standardized treatment of intrabony defects > or =3 mm with allografts. Gingival crevicular fluid was collected from the defect site and an adjacent interproximal site within the surgical field at baseline, 2, 4, and 8 weeks post-operatively, and analysed for biochemical markers of inflammation/bone resorption. Probing depth, recession, bleeding on probing, plaque, and 6-month radiographic bone height change were measured.

Results: Both prostaglandin E(2) (p=0.007) and bone-specific type 1 collagen (p=0.01) increased in crevicular fluid after 2 weeks in the bone graft sites. Matrix metalloproteinase-9 levels remained constant over time. There were positive correlations between prostaglandin levels during the first 8 weeks and bone height change over 6 months.

Conclusions: Periodontal bone grafts stimulate an inflammatory response during the first 2 weeks post-operatively, and the potential negative effects of inhibiting prostaglandins post-operatively should be investigated further.
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http://dx.doi.org/10.1111/j.1600-051X.2007.01117.xDOI Listing
September 2007

Subantimicrobial dose doxycycline effects on alveolar bone loss in post-menopausal women.

J Clin Periodontol 2007 Sep;34(9):776-87

Department of Surgical Specialties, University of Nebraska Medical Center College of Dentistry, Lincoln, NE 68583-0740, USA.

Aim: Determine the efficacy of 2-year continuous subantimicrobial dose doxycycline (SDD; 20 mg bid) on alveolar bone in post-menopausal osteopenic, oestrogen-deficient women undergoing periodontal maintenance in a 2-year double-blind, placebo-controlled, randomized clinical trial.

Material And Methods: One-hundred and twenty-eight subjects randomized to SDD or placebo (n=64 each). Posterior vertical bite wings taken at baseline, 1 and 2 years for alveolar bone density (ABD), using radiographic absorptiometry (RA) and computer-assisted densitometric image analysis (CADIA), and alveolar bone height (ABH). Statistical analyses utilized generalized estimating equations; primary analyses were intent to treat (ITT). Results are presented as SDD versus placebo.

Results: Under ITT, there was no statistically significant effect of SDD on ABD loss (RA: p=0.8; CADIA: p=0.2) or ABH loss (p=0.2). Most sites (81-95%) were inactive. For subgroup analyses, mean CADIA was higher with SDD for non-smokers (p=0.05) and baseline probing depths > or =5 mm (p=0.003). SDD was associated with 29% lower odds of more progressive ABH loss in women >5 years post-menopausal (p=0.05) and 36% lower among protocol-adherent subjects (p=0.03).

Conclusions: In post-menopausal osteopenic women with periodontitis, SDD did not differ overall from placebo. Based on exploratory subgroup analyses, additional research is needed to determine the usefulness of SDD in non-smokers, subjects >5 years post-menopausal and in deeper pockets. Protocol registered at (ClinicalTrials.gov). Identifier: NCT00066027.
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http://dx.doi.org/10.1111/j.1600-051X.2007.01115.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2174266PMC
September 2007

Efficacy of sub-antimicrobial dose doxycycline in post-menopausal women: clinical outcomes.

J Clin Periodontol 2007 Sep;34(9):768-75

Department of Surgical Specialties, University of Nebraska Medical Center College of Dentistry, Lincoln, NE 68583-0740, USA.

Aims: To determine the clinical efficacy of a 2-year continuous sub-antimicrobial dose doxycycline (SDD; 20 mg bid) in post-menopausal, osteopenic, oestrogen-deficient women on periodontal maintenance.

Materials And Methods: One-hundred and twenty-eight subjects were randomized to SDD (n=64) or placebo (n=64). Clinical measurements were performed at posterior interproximal sites at baseline and every 6 months during this 2-year randomized, double-blind, placebo-controlled clinical trial with adjunctive, no-cost 3-4-month periodontal maintenance. Statistical analyses of secondary outcomes from this clinical trial used Generalized Estimating Equations in primarily intent-to-treat analyses.

Results: For the placebo group, 3.4% of the sites showed improvement in clinical attachment levels (CAL) and 2.7% had progressive loss in CAL; for the SDD group, 5.0% of the sites showed an improvement in CAL and 2.2% had progressive loss in CAL. This difference (2.1% of sites) was more favourable in the SDD group than in the placebo [odds ratio (OR)=0.81 [corrected] 95% confidence interval (CI): 0.67-0.97, p=0.03] in these well-maintained patients, whereas probing depths, bleeding on probing and supragingival plaque did not differ significantly between groups (p>0.2). However, in exploratory subgroup analysis of non-smokers, SDD showed reduced bleeding versus placebo (27%versus 33%; p=0.05). In protocol-adherent subjects, the odds of bleeding were 34% lower for SDD (p=0.05).

Conclusions: Analyses of secondary outcomes of this clinical trial indicated that SDD may be of benefit in reducing progressive attachment loss in post-menopausal females; additional research is needed to confirm these findings. Protocol registered at (ClinicalTrials.gov). Identifier:NCT00066027.
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http://dx.doi.org/10.1111/j.1600-051X.2007.01114.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2157554PMC
September 2007

Subantimicrobial dose doxycycline effects on osteopenic bone loss: microbiologic results.

J Periodontol 2007 Aug;78(8):1590-601

Department of Oral Biology, University of Florida, Gainesville, FL 32610-0424, USA.

Background: Based on microbiologic concerns, the safety of a 24-month regimen of subantimicrobial dose doxycycline (SDD; 20 mg twice a day) was evaluated in postmenopausal osteopenic women with periodontitis in a double-blind, placebo-controlled, randomized clinical trial.

Methods: Subgingival samples were collected from two sites (probing depth > or = 5 mm) in each of 128 subjects at baseline, with the same sites resampled at the conclusion of the 2-year period. The samples were enumerated on selective and non-selective media and on doxycycline (4 microg/ml) medium. Up to five different colonial morphologies were subcultured from the doxycycline medium, identified to species, and susceptibilities determined to doxycycline and five other antibiotics. Data were analyzed for microbial differences in total colony forming units (CFU), periodontal and opportunistic pathogens, and changes in species and in susceptibilities of isolates recovered on doxycycline medium.

Results: There was no significant evidence that changes in total anaerobic counts over the treatment period (P = 0.96) differed between treatment groups. Likewise, periodontal pathogens, opportunistic pathogens, or normal flora did not differ descriptively between groups. Although there was a significant increase (P <0.001) in the total CFU recovered from the 4 microg/ml doxycycline plates at 24 months for SDD versus placebo, the percentage that was clinically resistant to doxycycline (minimal inhibitory concentration [MIC] > or = 16 microg/ml) decreased over the 24-month period in both groups and did not differ between the treatment groups (SDD: 79% to 76%; placebo: 83% to 70%; P = 0.2). There were no significant differences (P >0.28 for each) in the change in cross-resistance between the groups for doxycycline and the other five antibiotics.

Conclusions: No antimicrobial effect on the subgingival flora was detected following treatment with SDD for 24 months, relative to baseline or to placebo. The increase in initial resistance (at 4 microg/ml) did not translate into a significant increase in the percent resistant to doxycycline (MIC > or = 16 microg/ml) for patients in the SDD group.
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http://dx.doi.org/10.1902/jop.2007.070015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2041927PMC
August 2007
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