Publications by authors named "Lorne M Golub"

57 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

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

Periodontal disease in acute coronary syndrome patients.

Am J Dent 2021 Apr;34(2):97-100

Colgate Palmolive Company, Piscataway, New Jersey, USA.

Purpose: This pilot study assessed the periodontal status and biomarkers of systemic inflammation in acute coronary syndrome (ACS) patients.

Methods: 15 ACS patients on statin (anti-cholesterol) therapy, were recruited into the study an average of 9 months after discharge from university hospital. Blood and mouthrinse samples were collected for analysis of inflammatory biomarkers including high sensitivity C-reactive protein (hsCRP), IL-6, IL-1β, TNF-α, and MMP-9. Full-mouth periodontal examination, including pocket depth (PD), clinical attachment levels (CAL), bleeding on probing (BOP), and tooth mobility, was performed.

Results: When their periodontal status was assessed by CAL, 100% of these statin-treated ACS patients exhibited moderate (66.7%) to severe (33.3%) periodontal disease, which appears to be higher than the rate described for the general adult population (i.e., 47% for periodontitis). In addition, (1) their blood hsCRP levels ranged from 0.94 to 12.6 mg/L with a mean of 3.41 mg/L, which is considered high risk for cardiovascular disease (CVD) in spite of their statin therapy, and (2) the data demonstrated a positive correlation between severe periodontitis and elevated blood hsCRP levels (P< 0.05), consistent with systemic inflammation.

Clinical Significance: This pilot study provides preliminary data for future large-scale studies to define the relationship between ACS and chronic periodontitis, the underlying mechanisms, and the potential therapeutic efficacy of appropriate periodontal management to reduce the risk for cardiovascular disease.
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April 2021

An Unexplored Pharmacologic/Diagnostic Strategy for Peri-Implantitis: A Protocol Proposal.

Diagnostics (Basel) 2020 Dec 5;10(12). Epub 2020 Dec 5.

National University Centre for Oral Health, Faculty of Dentistry, National University of Singapore, Singapore 119077, Singapore.

Dental implants are widely utilized for the replacement of missing teeth and are increasingly being placed in patients with systemic diseases, as well as in those who are medically healthy. Furthermore, it is recognized that peri-implant mucositis and peri-implantitis are highly prevalent, affecting large numbers of patients with implants, and it is pertinent to consider whether there may be any systemic impact of these conditions, given that there are known links between periodontitis and a number of chronic inflammatory diseases. In this article, we propose that the potential systemic complications of peri-implant diseases should be investigated in future clinical research, together with studies to identify whether systemically-administered host modulation therapies (HMTs) may be of benefit in the treatment of peri-implant diseases. These "HMTs" may prove a useful adjunct to routinely employed debridement and disinfection protocols, as well as potentially being of benefit in reducing risks of systemic complications. We also consider the use of chair-side diagnostic tests for active matrix metalloproteinase-8 (aMMP-8) in the detection of peri-implant disease given the ability of such tests to detect active tissue breakdown associated with peri-implantitis and periodontitis before conventional clinical and radiographic measurements indicate pathologic changes. These novel diagnostic and therapeutic strategies are relevant to consider as they may improve the management of peri-implant disease (beyond local debridement procedures), especially in those patients in whom systemic inflammation might be of concern.
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http://dx.doi.org/10.3390/diagnostics10121050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762163PMC
December 2020

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

Dose-response assessment of chemically modified curcumin in experimental periodontitis.

J Periodontol 2019 05 20;90(5):535-545. Epub 2018 Dec 20.

Department of Diagnosis and Surgery, School of Dentistry at Araraquara, UNESP, Araraquara, Brazil.

Background: CMC2.24, a novel tri-ketonic chemically modified compound based on natural di-ketonic curcumin, has been shown to reduce bone loss and inflammatory mediators in experimental periodontitis, however, a potential dose-response relationship was not determined. The purpose of this study was to assess the effects of different doses of CMC2.24 on inflammation and bone resorption in vivo and also to describe on the effects of CMC2.24 on macrophage response.

Methods: CMC2.24 was administered daily to animals for 28 days by oral gavage, at the following doses: 0 (control), 1, 3, 10, and 30 mg/kg of body weight. Experimental periodontitis was induced by injections of lipopolysaccharide (LPS) into the gingival tissues. Outcomes assessed were bone resorption, detection of tartrate-resistant acid phosphatase, and determination of gene expression. In vitro, macrophages (RAW264.7) were treated with different concentrations of CMC2.24: 1, 3, 10, and 30 μM and then subjected to different activation stimuli. Gene expression, phagocytic activity, production of reactive oxygen species (ROS) and cytokine production were evaluated.

Results: CMC2.24 inhibited bone resorption, osteoclastogenesis, and tumor necrosis factor (TNF)-α expression in vivo. These beneficial responses reached maximum levels at a dose of 1 mg/kg, i.e. no dose-dependent effect. In vitro, CMC2.24 reduced the production of TNF-α and interleukin-10, inhibited phagocytic activity and stimulated production of ROS. A dose-dependent effect was observed only for ROS production.

Conclusion: Low doses of CMC2.24 (1 mg/kg/day) administered orally were sufficient to significantly inhibit alveolar bone resorption associated with the experimental periodontal disease; whereas in vitro macrophage inflammatory gene expression and phagocytosis were reduced, whereas production of ROS was stimulated.
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http://dx.doi.org/10.1002/JPER.18-0392DOI Listing
May 2019

A novel tricarbonylmethane agent (CMC2.24) reduces human pancreatic tumor growth in mice by targeting Ras.

Mol Carcinog 2018 09 8;57(9):1130-1143. Epub 2018 May 8.

Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, New York.

Pancreatic Cancer (PC) is a deadly disease in need of new therapeutic options. We recently developed a novel tricarbonylmethane agent (CMC2.24) as a therapeutic agent for PC, and evaluated its efficacy in preclinical models of PC. CMC2.24 inhibited the growth of various human PC cell lines in a concentration and time-dependent manner. Normal human pancreatic epithelial cells were resistant to CMC2.24, indicating selectivity. CMC2.24 reduced the growth of subcutaneous and orthotopic PC xenografts in mice by up to 65% (P < 0.02), and the growth of a human patient-derived tumor xenograft by 47.5% (P < 0.03 vs vehicle control). Mechanistically, CMC2.24 inhibited the Ras-RAF-MEK-ERK pathway. Based on Ras Pull-Down Assays, CMC2.24 inhibited Ras-GTP, the active form of Ras, in MIA PaCa-2 cells and in pancreatic acinar explants isolated from Kras mutant mice, by 90.3% and 89.1%, respectively (P < 0.01, for both). The inhibition of active Ras led to an inhibition of c-RAF, MEK, and ERK phosphorylation by 93%, 91%, and 87%, respectively (P < 0.02, for all) in PC xenografts. Furthermore, c-RAF overexpression partially rescued MIA PaCa-2 cells from the cell growth inhibition by CMC2.24. In addition, downstream of ERK, CMC2.24 inhibited STAT3 phosphorylation levels at the serine 727 residue, enhanced the levels of superoxide anion in mitochondria, and induced intrinsic apoptosis as shown by the release of cytochrome c from the mitochondria to the cytosol and the further cleavage of caspase 9 in PC cells. In conclusion, CMC2.24, a potential Ras inhibitor, is an efficacious agent for PC treatment in preclinical models, deserving further evaluation.
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http://dx.doi.org/10.1002/mc.22830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461215PMC
September 2018

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

Non-antibacterial tetracycline formulations: host-modulators in the treatment of periodontitis and relevant systemic diseases.

Int Dent J 2016 Jun 23;66(3):127-35. Epub 2016 Mar 23.

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

Traditionally, the dental profession has primarily treated periodontitis using a mechanical/surgical, rather than a pharmaceutical, approach. However, based on experiments several decades ago which demonstrated that tetracyclines, unexpectedly, inhibit collagen- and bone-destructive mammalian-derived enzymes (e.g. the collagenases), and through non-antibiotic mechanisms, the concept of host-modulation therapy (HMT) was developed. Accordingly, two drug-development strategies evolved: (i) the development of non-antimicrobial formulations of doxycycline; and (ii) the chemical modification of tetracyclines to eliminate their antibiotic activity but retain (or even enhance) their anti-collagenase properties. Regarding the latter, these chemically modified tetracyclines (CMTs) showed efficacy in vitro, in animal models of periodontal (and relevant systemic) disease, and in preliminary clinical trials on patients with Kaposi's sarcoma (however, at the high doses used, photosensitivity was a significant side-effect). In the first strategy, subantimicrobial-dose doxycycline (SDD) demonstrated safety and efficacy in human clinical trials and was approved by the U S Food and Drug Administration (U S FDA) and in other countries for the treatment of periodontitis (20 mg, twice daily, i.e. once every 12 hours) adjunctive to scaling and root planing, and for chronic inflammatory skin diseases (40-mg sustained-release 'beads'). SDD also showed efficacy in patients with systemic diseases relevant to periodontitis, including diabetes mellitus and arthritis, and in postmenopausal women with local and systemic bone loss. Importantly, long-term administration of SDD, of up to 2 years, in clinical trials did not produce antibiotic side-effects. SDD (and in the future, new HMTs, such as low-dose CMT-3, resolvins and chemically modified curcumins) may shift the paradigm of periodontal therapy from a predominantly surgical approach to the greater use of medicinal/pharmacologic strategies, ultimately to benefit larger numbers of patients.
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http://dx.doi.org/10.1111/idj.12221DOI Listing
June 2016

DIFFERENTIAL SUSCEPTIBILITY OF HUMAN SP-B GENETIC VARIANTS ON LUNG INJURY CAUSED BY BACTERIAL PNEUMONIA AND THE EFFECT OF A CHEMICALLY MODIFIED CURCUMIN.

Shock 2016 Apr;45(4):375-84

*Department of Surgery, SUNY Upstate Medical University, Syracuse, New York †Department of Emergency Medicine, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People's Republic of China ‡Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, People's Republic of China §Department of Pharmacological Sciences ||Department of Oral Biology and Pathology, State University of New York at Stony Brook, Stony Brook, New York.

Staphylococcus aureus is a common cause of nosocomial pneumonia frequently resulting in acute respiratory distress syndrome (ARDS). Surfactant protein B (SP-B) gene expresses two proteins involved in lowering surface tension and host defense. Genotyping studies demonstrate a significant association between human SP-B genetic variants and ARDS. Curcumins have been shown to attenuate host inflammation in many sepsis models. Our hypothesis is that functional differences of SP-B variants and treatment with curcumin (CMC2.24) modulate lung injury in bacterial pneumonia. Humanized transgenic mice, expressing either SP-B T or C allele without mouse SP-B gene, were used. Bioluminescent labeled S. aureus Xen 36 (50 μL) was injected intratracheally to cause pneumonia. Infected mice received daily CMC2.24 (40 mg/kg) or vehicle alone by oral gavage. Dynamic changes of bacteria were monitored using in vivo imaging system. Histological, cellular, and molecular indices of lung injury were studied in infected mice 48 h after infection. In vivo imaging analysis revealed total flux (bacterial number) was higher in the lung of infected SP-B-C mice compared with infected SP-B-T mice (P < 0.05). Infected SP-B-C mice demonstrated increased mortality, lung injury, apoptosis, and NF-κB expression compared with infected SP-B-T mice. Compared with controls, CMC2.24 treatment significantly reduced the following: mortality, total bacterial flux and lung tissue apoptosis, inflammatory cells, NF-κB expression (P < 0.05), and MMPs-2, -9, -12 activities (P < 0.05). We conclude that mice with SP-B-C allele are more susceptible to S. aureus pneumonia than mice with SP-B-T allele, and that CMC2.24 attenuates lung injury thus reducing mortality.
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http://dx.doi.org/10.1097/SHK.0000000000000535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792714PMC
April 2016

The Use of Doxycycline and Tetracycline in Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae Colonization.

Clin Infect Dis 2015 Sep 18;61(6):1031. Epub 2015 Jul 18.

Department of Oral and Maxillofacial Diseases, Helsinki University and University Hospital, Finland Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.

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http://dx.doi.org/10.1093/cid/civ502DOI Listing
September 2015

The Link Between Periodontitis and Rheumatoid Arthritis: A Periodontist's Perspective.

Curr Oral Health Rep 2015;2:20-29

Omaha Veterans Affairs Medical Center (VAMC) and Nebraska Arthritis Outcomes Research Center, Division of Rheumatology, Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, 983025 Nebraska Medical Center, Omaha, NE 68198-3025 USA.

In this review, we critically evaluate the case-control studies examining the relationship between rheumatoid arthritis (RA) and periodontitis, two common chronic inflammatory diseases with a similar host-mediated pathogenesis. We review the "two-hit" periodontitis model that our group previously proposed, in which we elucidate how a systemic disease such as RA can potentially exacerbate or initiate periodontitis. Furthermore, we discuss adjunctive host modulation therapy, originally developed for periodontitis (i.e., subantimicrobial-dose doxycycline alone or in combination with an anti-inflammatory agent), to simultaneously mitigate RA and periodontitis. Finally, we review studies describing periodontal treatment effects on both RA disease activity measures and systemic inflammation. Current evidence suggests that an association exists between periodontitis and RA. Well-designed multicenter longitudinal clinical trials and studies with sufficient sample sizes are needed to ascertain the temporal relationship between these two diseases and whether periodontal treatment can reduce the severity of RA or prevent its onset.
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http://dx.doi.org/10.1007/s40496-014-0040-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312393PMC
January 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

Inhibition of anthrax lethal factor by curcumin and chemically modified curcumin derivatives.

J Enzyme Inhib Med Chem 2014 Oct 9;29(5):663-9. Epub 2013 Oct 9.

Department of Pathology .

Curcumin (diferuloylmethane), the active ingredient in the eastern spice turmeric (Curcuma longa), has been shown to inhibit the activities of numerous enzymes and signaling molecules involved in cancer, bacterial and viral infections and inflammatory diseases. We have investigated the inhibitory activities of curcumin and chemically modified curcumin (CMC) derivatives toward lethal factor (LF), the proteolytic component of anthrax toxin produced by the bacterium Bacillus anthracis. Curcumin (Compound 1) appears to inhibit the catalytic activity of LF through a mixture of inhibitory mechanisms, without significant compromise to the binding of oligopeptide substrates, and one CMC derivative in particular, Compound 3 (4-phenylaminocarbonylbis-demethoxycurcumin), is capable of inhibiting LF with potency comparable with the parent compound, while also showing improved solubility and stability. The quantitative reduction in catalytic activity achieved by the different CMC derivatives appears to be a function of the proportion of the multiple mechanisms through which they inhibit the enzyme.
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http://dx.doi.org/10.3109/14756366.2013.837901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196590PMC
October 2014

Prostate cancer stem cell-targeted efficacy of a new-generation taxoid, SBT-1214 and novel polyenolic zinc-binding curcuminoid, CMC2.24.

PLoS One 2013 24;8(9):e69884. Epub 2013 Sep 24.

Department of Pathology, Stony Brook University Medical Center, Stony Brook, New York, United States of America ; Institute of Chemical Biology & Drug Development, Stony Brook University, Stony Brook, New York, United States of America.

Background: Prostate cancer is the second leading cause of cancer death among men. Multiple evidence suggests that a population of tumor-initiating, or cancer stem cells (CSCs) is responsible for cancer development and exceptional drug resistance, representing a highly important therapeutic target. The present study evaluated CSC-specific alterations induced by new-generation taxoid SBT-1214 and a novel polyenolic zinc-binding curcuminoid, CMC2.24, in prostate CSCs.

Principal Findings: The CD133(high)/CD44(high) phenotype was isolated from spontaneously immortalized patient-derived PPT2 cells and highly metastatic PC3MM2 cells. Weekly treatment of the NOD/SCID mice bearing PPT2- and PC3MM3-induced tumors with the SBT-1214 led to dramatic suppression of tumor growth. Four of six PPT2 and 3 of 6 PC3MM2 tumors have shown the absence of viable cells in residual tumors. In vitro, SBT-1214 (100 nM-1 µM; for 72 hr) induced about 60% cell death in CD133(high)/CD44(+/high) cells cultured on collagen I in stem cell medium (in contrast, the same doses of paclitaxel increased proliferation of these cells). The cytotoxic effects were increased when SBT-1214 was combined with the CMC2.24. A stem cell-specific PCR array assay revealed that this drug combination mediated massive inhibition of multiple constitutively up-regulated stem cell-related genes, including key pluripotency transcription factors. Importantly, this drug combination induced expression of p21 and p53, which were absent in CD133(high)/CD44(high) cells. Viable cells that survived this treatment regimen were no longer able to induce secondary spheroids, exhibited significant morphological abnormalities and died in 2-5 days.

Conclusions: We report here that the SBT-1214 alone, or in combination with CMC2.24, possesses significant activity against prostate CD133(high)/CD44(+/high) tumor-initiating cells. This drug combination efficiently inhibits expression of the majority of stem cell-related genes and pluripotency transcription factors. In addition, it induces a previously absent expression of p21 and p53 ("gene wake-up"), which can potentially reverse drug resistance by increasing sensitivity to anti-cancer drugs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069884PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782470PMC
July 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

The association between clinical and radiographic periodontitis measurements during periodontal maintenance.

J Periodontol 2013 Oct 3;84(10):1382-90. Epub 2012 Dec 3.

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

Background: The purpose of the present study is to examine the association between clinical and radiographic periodontitis measurements during 2 years of periodontal maintenance.

Methods: Secondary analyses were performed from a 2-year, double-masked, placebo-controlled, randomized clinical trial evaluating the efficacy and safety of subantimicrobial dose doxycycline (SDD) in 128 postmenopausal osteopenic females with moderate-to-severe chronic periodontitis. Relative clinical attachment level (relative CAL) and probing depth (PD) measurements were made. Posterior vertical bitewings were taken for alveolar bone density (ABD) and alveolar bone height (ABH) measurements. Generalized estimating equations were used to model associations.

Results: One-year ABD changes and 1-year relative CAL/PD changes did not predict 2-year ABH changes and ABH/ABD changes, respectively. Baseline relative CAL and PD were positively associated with baseline ABH loss (P <0.0001), and baseline PDs were associated with subsequent ABD and ABH loss (P <0.05 for each). Among placebo (but not SDD) participants, relative CAL changes were associated with concurrent ABD loss (P = 0.027) when considering 1- and 2-year changes combined. The odds of ABH loss were higher among sites with concurrent 1-year ABD loss versus no change (odds ratio [OR] = 3.15, P <0.0001) or concurrent PD increases versus no change (OR = 1.88, P = 0.0025) when considering 1- and 2-year changes combined.

Conclusions: In postmenopausal osteopenic females undergoing periodontal maintenance, baseline PD was associated with subsequent ABD and ABH loss. Although no longitudinal change preceded another measurement change, changes in PDs and relative CALs appeared to reflect changes in the underlying alveolar bone over time.
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http://dx.doi.org/10.1902/jop.2012.120484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612134PMC
October 2013

Non-antibacterial tetracycline formulations: clinical applications in dentistry and medicine.

J Oral Microbiol 2012 12;4. Epub 2012 Oct 12.

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

In 1983, it was first reported that tetracyclines (TCs) can modulate the host response, including (but not limited to) inhibition of pathologic matrix metalloproteinase (MMP) activity, and by mechanisms unrelated to the antibacterial properties of these drugs. Soon thereafter, strategies were developed to generate non-antibacterial formulations (subantimicrobial-dose doxycycline; SDD) and compositions (chemically modified tetracyclines; CMTs) of TCs as host-modulating drugs to treat periodontal and other inflammatory diseases. This review focuses on the history and rationale for the development of: (a) SDD which led to two government-approved medications, one for periodontitis and the other for acne/rosacea and (b) CMTs, which led to the identification of the active site of the drugs responsible for MMP inhibition and to studies demonstrating evidence of efficacy of the most potent of these, CMT-3, as an anti-angiogenesis agent in patients with the cancer, Kaposi's sarcoma, and as a potential treatment for a fatal lung disease (acute respiratory distress syndrome; ARDS). In addition, this review discusses a number of clinical studies, some up to 2 years' duration, demonstrating evidence of safety and efficacy of SDD formulations in humans with oral inflammatory diseases (periodontitis, pemphigoid) as well as medical diseases, including rheumatoid arthritis, post-menopausal osteopenia, type II diabetes, cardiovascular diseases, and a rare and fatal lung disease, lymphangioleiomyomatosis.
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http://dx.doi.org/10.3402/jom.v4i0.19227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471324PMC
October 2012

pKa, zinc- and serum albumin-binding of curcumin and two novel biologically-active chemically-modified curcumins.

Curr Med Chem 2012 ;19(25):4367-75

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

The pH equilibria and the zinc ion and bovine serum albumin (BSA) binding behavior of curcumin and two chemically modified curcumins (CMCs), namely 4-methoxycarbonylcurcumin (CMC 2.5) and 4-phenylaminocarbonyl bis-demethoxy curcumin (CMC 2.24), were studied, in order to understand the basis of their differential effects on the zinc-enzyme matrix metalloproteinases (MMPs) as well as the effect of charge state on their behavior in vivo. Moreover, all three compounds transform rapidly in the pH range 5-10, CMC 2.5 largely in one step, and CMC 2.24 and curcumin first in a rapid process to an intermediate form that still displays an enolic and two phenolic hydrogen-ion equilibria, and then more slowly to forms absorbing primarily in the lower UV and lacking the strong absorbance in the visible characteristic of the enol-centered chromophore. The binding of these compounds in one of the hydrophobic pockets of the major transport protein, serum albumin, was therefore studied. CMC 2.24 binds more strongly to BSA than curcumin, with a dissociation constant of 0.56±0.08 μM compared to 1.32±0.17 μM. Binding to BSA shifts the decomposition half-lives from tens of seconds to tens of hours. The zero-time acid dissociation constants (pK(a)) for species H(3)D, H(2)D(-), and HD(2-) are 8.41, 9.94 and 11.2; 6.98, 8.40 and 9.8; and 6.50 and 8.82 ; for curcumin, CMC 2.24, and CMC 2.5 respectively (there is no distinguishable pK(a3) for CMC 2.5). Zn(2+) binds most strongly to CMC 2.24 compared to CMC 2.5 and curcumin, with dissociation constants of 0.77±0.02, 1.88±0.07, and 1.39±0.09 mM. The increased acidity and Zn(2+) and BSA affinities of CMC 2.24 correlate with its greater biological activity.
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http://dx.doi.org/10.2174/092986712802884240DOI Listing
April 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

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

Jack of all trades: pleiotropy and the application of chemically modified tetracycline-3 in sepsis and the acute respiratory distress syndrome (ARDS).

Pharmacol Res 2011 Dec 21;64(6):580-9. Epub 2011 Jun 21.

Department of Surgery, Upstate University Hospital, 750 East Adams Street, Syracuse, NY 13210, USA.

Sepsis is a disease process that has humbled the medical profession for centuries with its resistance to therapy, relentless mortality, and pathophysiologic complexity. Despite 30 years of aggressive, concerted, well-resourced efforts the biomedical community has been unable to reduce the mortality of sepsis from 30%, nor the mortality of septic shock from greater than 50%. In the last decade only one new drug for sepsis has been brought to the market, drotrecogin alfa-activated (Xigris™), and the success of this drug has been limited by patient safety issues. Clearly a new agent is desperately needed. The advent of recombinant human immune modulators held promise but the outcomes of clinical trials using biologics that target single immune mediators have been disappointing. The complex pathophysiology of the systemic inflammatory response syndrome (SIRS) is self-amplifying and redundant at multiple levels. In this review we argue that perhaps pharmacologic therapy for sepsis will only be successful if it addresses this pathophysiologic complexity; the drug would have to be pleiotropic, working on many components of the inflammatory cascade at once. In this context, therapy that targets any single inflammatory mediator will not adequately address the complexity of SIRS. We propose that chemically modified tetracycline-3, CMT-3 (or COL-3), a non-antimicrobial modified tetracycline with pleiotropic anti-inflammatory properties, is an excellent agent for the management of sepsis and its associated complication of the acute respiratory distress syndrome (ARDS). The purpose of this review is threefold: (1) to examine the shortcomings of current approaches to treatment of sepsis and ARDS in light of their pathophysiology, (2) to explore the application of COL-3 in ARDS and sepsis, and finally (3) to elucidate the mechanisms of COL-3 that may have potential therapeutic benefit in ARDS and sepsis.
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http://dx.doi.org/10.1016/j.phrs.2011.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195907PMC
December 2011

Clinical applications of non-antibacterial tetracyclines. Part II.

Pharmacol Res 2011 Dec 13;64(6):549-50. Epub 2011 Jun 13.

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http://dx.doi.org/10.1016/j.phrs.2011.06.004DOI Listing
December 2011
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