Exploring the therapeutic potential of demethoxycurcumin in periodontitis

doi:10.21203/rs.3.rs-4881974/v1

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Research Article

Exploring the therapeutic potential of demethoxycurcumin in periodontitis

https://doi.org/10.21203/rs.3.rs-4881974/v1

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Objectives

This computational analysis investigated the potential benefits of Demethoxycurcumin (DMC) and studied the antimicrobial ligand binding sites of DMC specifically in the key endotoxin, Lipid A of P.gingivalis and host modulation with chemokine receptor of oral fibroblasts (CCR3/CCR4).

Materials and Methods

Protein structure preparation was performed using CHARMM force fields and protein-ligand docking was performed using Discovery Studio 2.0 software. DMC was docked with lipid A of P.gingivalis using the UCSF Chimaera program and the interactions in binding pockets of the resulting poses were analyzed using the VMD program.

Results

The results were promising, indicating a strong affinity between DMC and the active sites on the targeted proteins of P.gingivalis, suggesting a potential for DMC to interrupt the pathogenic mechanisms. The study identified several amino acid residues that are potentially capable of forming bonds with DMC, which may elucidate its mechanisms as an antimicrobial agent.

Conclusion

This study provides important data on the molecular efficacy of DMC, offering potential new approach for local drug delivery in combination with host modulation for management of periodontitis, which, if further developed and validated through clinical studies, could revolutionize periodontal therapy.

Clinical Relevance

Demethoxycurcumin is known for its anti-inflammatory and antimicrobial properties. Molecular docking showed that DMC can serve as a potential local drug delivery agent for periodontitis management. In addition to antimicrobial action against P.gingivalis, DMC also exhibits host modulating property on oral fibroblasts in molecular dynamic simulation.

Curcumin

Demethoxycurcumin

Lipid A

Molecular docking simulation

Periodontitis

Demethoxycurcumin (DMC) is a natural molecule derived from curcumin, the active component of turmeric spices. It is one of the three primary curcuminoids found in turmeric, in addition to curcumin and bisdemethoxycurcumin. DMC is structurally similar to curcumin, but it differs in terms of the placement of one methoxy group (-OCH3). Similar to curcumin, DMC exhibits various pharmacological properties and is considered a potential therapeutic agent. Its antioxidant, anti-inflammatory, anticancer, and neuroprotective effects have been studied. However, it is important to note that the research on DMC is still in its early stages, and further studies are needed to fully understand its potential health benefits and mechanisms of action. It is worth mentioning that while curcumin and its derivatives, including DMC, show promise in laboratory studies, their bioavailability and stability in the human body are limited. These compounds have relatively low solubility and are rapidly metabolized and eliminated from the body. Researchers are currently exploring different formulations and delivery methods to enhance their absorption and bioavailability. DMC has exhibits antibacterial properties against many bacterial species, including both gram-positive and gram-negative microorganisms. It has been reported that to inhibit the growth of pathogens such as Staphylococcus aureus, Escherichia coli, Salmonella typhimurium, and Helicobacter pylori. The exact mechanisms by which DMC exerts its antibacterial effects are not fully understood but may involve disruption of bacterial cell membranes and interference with bacterial enzyme activity. DMC has demonstrated antifungal activity against various fungal species, including Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes. DMC exerts its antifungal properties by perturbing fungal cell membranes, obstructing fungal cell division, and inhibiting fungal enzymes. Limited research has explored the antiviral capabilities of DMC. It has demonstrated inhibitory effects on specific viruses such as hepatitis B virus and herpes simplex virus type 1. DMC interferes with viral replication and inhibits viral enzymes, leading to reduced viral infectivity. However, further research is needed to fully understand the antiviral mechanisms and evaluate its effectiveness against a broader range of viruses.

The complex interplay between the oral microbiome and the host immune response is the cause of periodontitis, a prevalent inflammatory disease. The pursuit of targeted therapies with minimal side effects and enhanced efficacy remains an active area of research, despite the fact that current treatment modalities predominantly concentrate on mechanical debridement and antimicrobial agents. Demethoxycurcumin, a naturally occurring curcumin analogue, has attracted substantial attention due to its therapeutic potential in a variety of conditions. It is important to note that DMC possesses antimicrobial and anti-inflammatory properties, which may indicate a potential function in the prevention of periodontitis.

This study employed computational molecular docking techniques to examine the potential of DMC for periodontitis treatment as a local drug delivery and host modulation. We concentrate on two primary targets: Lipid A, a potent immunostimulatory component of P.gingivalis lipopolysaccharide, and chemokine receptors CCR3/CCR4, which are expressed on oral fibroblasts and are involved in inflammatory responses. Our objective is to establish a molecular-level comprehension of the therapeutic effects of DMC and its potential in the context of periodontitis by elucidating the binding interactions between DMC and these targets.

This study aimed to evaluate the potential advantages of DMC as a local drug delivery for periodontitis treatment. The objectives were to identify the ligand binding site of DMC in microbial proteins (Lipid A of P.gingivalis) and chemokine receptor of oral fibroblast (CCR3 / CCR4). The study parameters were the prediction of binding affinity, docking score and H-bond distance.

Protein processing

The 3D crystallographic structures of lipid A from Porphyromonas gingivalis (P.g) and DMC were obtained from the RCSB PDB database (https://www.rcsb.org/pdb) for subsequent analysis. Protein structure modification involves tasks such as inserting missing atoms into incomplete residues, deleting alternate confirmations, modelling missing loop regions, protonating titrable residues, predicting pKs, standardizing atom names, removing water molecules or heteroatoms, and adding hydrogen atoms. Proteins were synthesized using the CHARMM force fields.

Protein-ligand docking

Discovery Studio 2.0 (Accelrys, USA) software was used to dock DMC into the active sites of Lipid A of P.gingivalis and CCR3/CCR4. Docking scores were calculated using the LibDock program which revealed the bioactive binding sites of the receptors. We also identified the amino acid residues protein sites that could potentially form hydrogen bonds with DMC. In LibDock, two polar and apolar protein sites were available as hotspots. Additionally, DMC is engaged with both the polar and apolar regions of receptors. A 2D depiction of the docking investigation was conducted to identify the individual interaction residues of the receptor with the bound ligand. The docking computation utilized the Gasteiger charges. DMC was docked with lipid A of P.gingivalis using molecular techniques. The UCSF Chimaera program version 1.15, was used to minimize the finest pose achieved. For the drug molecules and the protein minimalization, the GAFF force fields and Amber14SB force field were employed. The visual molecular dynamics (VMD) program was employed for both the visualization of the binding mode and its analysis. In addition, the VMD program was used to analyze the interactions of the obtained pose-binding pocket. Analyses and further interpretations were performed.

Methods for docking

The co-crystal structures were prepared using MOE v.2019.01, by setting the Merck Molecular Force Field 94X (MM94X) force field because of its ability to parametrize gas-phase small molecules with good accuracy among various organic and drug-like molecules. In addition, it uses the internal bond-charge-increment charge model which is highly compatible with the Born solvation model. The protein preparation parameters included utilizing the 3D protonation capability and enabling Asn, Gln, and His flips during protonation. Water molecules deletion at a distance higher than 4.5 Å from either the ligands or the receptors were applied. The complex was enhanced until it reached an RMS gradient value of 0.1 Kcal/mol/Å.

Molecular Dynamics Techniques

Molecular dynamics (MD) simulations were conducted using the GROMACS 2019 software suite. MD simulations were conducted for two protein-ligand complexes utilizing the CHARMM36 force field for protein topology and the official CHARMM General Force Field server (CGenFF) for ligand topology. The systems were solvated in a dodecahedron box using the SPC water model, and explicit-solvent periodic boundary conditions were applied. The solvated complexes were neutralized with sodium and chloride ions. Both systems were minimized using the steepest descent method for 5000 steps to address any steric conflicts or geometric irregularities. The system was equilibrated under a constant number of particles, Volume, and Temperature (NVT) ensemble for 100 ps using a Berendsen thermostat to guarantee a stable starting structure. The second equilibration cycle was conducted under constant pressure (NPT ensemble) with a Parrinello-Rahman barostat for an additional 100 ps. The position restrictions were removed, and the system was simulated in the production run using an NPT ensemble (Nose-Hoover thermostat and Parrinello-Rahman barostat) for 50 ns with a time step of 2 fs. The simulation data were analyzed using Visual Molecular Dynamics (VMD) software, version 1.9.3.

Molecular docking can assist in identifying the optimal intermolecular interactions between macromolecules and medicinal compounds. In this study, docking was conducted using lipid A of P.gingivalis and DMC. Supplementary Table 1 shows the binding energies acquired from molecular docking for the most favorable docked conformations. The docking scores for DMC with Lipid A of P.gingivalis and CCR3/CCR4 were 98.7 and 88.8, respectively. These scores suggest that DMC has a high affinity for the active sites of these proteins, with an extremely high affinity for P.g. We identified several amino acid residues that could potentially form hydrogen bonds with DMC. These residues include H-Ala263, O-Gln227, O-Tyr270, O-Asn211, and C-Tyr199 in Lipid A of P.gingivalis and O-Tyr121, O-His113, and H-Asp97 in CCR3/CCR4. Identifying the ideal intermolecular interactions between the test compounds and macromolecules may be aided by molecular docking. Furthermore, molecular docking was carried out with two distinct macromolecules: Lipid A of P.gingivalis and chemokine receptor (CCR3/CCR4), employing DMC. In the molecular docking studies, DMC showed significant docking scores, as shown in Supplementary Table 1, with essential binding interactions with the active binding pockets of the target macromolecules (Figs. 1–2). The hydroxy group attached to the 4th position in the DMC showed hydrogen bond interactions with the Asn211 and Ala263 amino acid residues. The oxygen group at the 3,5-dione position forms hydrogen bond interactions with the Gln227 and Tyr270 amino acid residues at the active sites of the Lipid A of P.g. Several hydrophobic bond interactions, such as Pi-sigma, Pi-Pi-T-shaped, and Pi-Alkyl bonds, are also engaged in the binding interactions, as illustrated in Fig. 1.

Molecular docking analysis between DMC and the chemokine receptor (CCR3/CCR4) also showed significant binding interactions, including hydrogen bonds and hydrophobic bonds. Similarly, the same 4-hydroxyl group of the DMC showed hydrogen bond interactions with the Tyr121 and Asp97 amino acid residues of the CCR3 active binding sites. The oxygen group attached to the 3rd position of the diene chain also showed hydrogen-bond interactions with the Tyr121 amino acid residue of the chemokine receptor. DMC exhibited hydrophobic interactions, such as pi-sigma, pi-pi stacking, alkyl, and pi-alkyl bonds interactions with the Arg188, Val112, Trp94, and Trp102 amino acid residues located in the CCR3 active binding sites, as illustrated in Fig. 2.

The protein root mean square deviation (RMSD) over the 50 ns simulation indicates the stability of the protein upon ligand binding. Greater stability was achieved with fewer fluctuations. The CCR4 protein starts to reach a stable state in less than 10 ns, which reflects its high stability, where very small oscillations are observed from 10 to 50 ns. The lipid A protein demonstrated high stability is observed from the beginning of the simulation, where the oscillation range was less than 0.05 nm which is a very good range (Fig. 3). Ligand root mean square deviation (RMSD throught the 50 ns simulation represents the stability of the ligand itself upon binding to the target protein. The lower the fluctuation, the more stable and tight the binding. A very small fluctuation was observed throughout the first 25 ns confirming the high binding affinity and stability of the CCR4 ligand towards its target. A small jump is observed at nanosecond 25, then it returns quickly to its stable state which indicates its stable binding. A very high stability was observed from the beginning of the simulation, where the oscillation range was less than 0.05 nm which is a very good range for Lipid A (Fig. 4).

The radius of gyration (Rg) represents the distribution of atoms in a protein along its axis. Rg denotes the distance between the point of rotation and the point at which energy transfer has the greatest impact. The Rg value of a protein is an indicator of its degree of compactness. Proteins with stable folding were expected to exhibit a consistent Rg values. Rg for CCR4 validates the RMSD of the protein, at which point it begins to fold compatibly after approximately 10–15 ns. A small jump is observed at 40 ns, but it was still within the accepted range. This means that the ligand binding may have an effect on the protein folding at the beginning of the simulation, but rapidly it reached a stable folding while maintaining a relatively steady value of Rg. For Lipid A, Rg was stable from the beginning to the end of the simulation, with very minor oscillation. This confirmed the high stability of the complex without affecting the protein folding (Fig. 5. For CCR4, SASA was stable throughout the simulation, showing the high stability of the protein-ligand complex, and for Lipid A is stable throughout the simulation, showing the high stability of the protein-ligand complex (Fig. 6).

Curcumin, a polyphenolic compound derived from the spice turmeric, has attracted substantial attention due to its potential therapeutic applications in periodontitis. Its capacity to regulate glucose metabolism, mitigate oxidative stress, and induce anti-inflammatory effects has been demonstrated in a multitude of in vitro studies. Additionally, curcumin has been demonstrated to possess potent antimicrobial and anti-inflammatory properties, both of which are essential for the treatment of periodontitis [1]. Curcumin may exert its beneficial effects in the treatment of periodontitis through the following mechanisms: i) Downregulation of inflammatory mediators, such as tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), which are essential in the pathogenesis of the disease; ii) Inhibition of matrix metalloproteinases (MMPs) and iii) Modulation of the host immune response, thereby restoring the equilibrium between pro- and anti-inflammatory cytokines [2]. In the field of pharmacology, DMC has gained interest due to its potential antimicrobial and anti-inflammatory properties [3]. Periodontal disease is a sustainable inflammatory condition that impacts the tissues supporting the teeth, mostly due to pathogenic microbes in plaque biofilm [4]. The potential therapeutic applications and effects of DMC on periodontal pathogens have been the subject of a limited number of studies. It has been observed that it can inhibit the growth and reduce the viability of bacteria frequently linked to periodontal disease, such as P.gingivalis, Prevotella intermedia, Aggregatibacter actinomycetemcomitans, and Fusobacterium nucleatum [5]. These bacteria are proven to be essential in the advancement and progression of periodontal disease. Evidence indicates that it may inhibit the generation of inflammatory cytokines, such interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), which play a role in the development of periodontitis [6]. Dental plaque biofilms are complex microbial communities that contribute to periodontal disease. DMC has demonstrated the ability to disrupt and inhibit the formation of biofilms by periodontal pathogens [7]. By inhibiting biofilm formation, DMC may help prevent the establishment and persistence of pathogenic bacteria in the oral cavity. The majority of studies on the role of DMC in periodontal microbiology have been conducted in vitro, employing cell cultures or laboratory models [8].

Multiple clinical trials have examined the effectiveness of curcumin in treating periodontitis, either alone or in conjunction with conventional treatment methods such scaling and root planing (SRP). Curcumin has shown encouraging outcomes by significantly reducing clinical measures, including as probing depth, gingival index, and plaque index, when compared to placebo or conventional treatments [9–11].

In a clinicomicrobiologic randomized trial involving 30 patients, local application of curcumin led to improvement of periodontal parameters within one month [12]. Curcumin inhibited the LPS-induced decrease in OPG/sRANKL ratio and NF-κB activation, and attenuated the production of IL-1β and TNF-α in rat gingival fibroblasts stimulated by Lipopolysaccharide (LPS). In vivo, curcumin substantially reduced gingival inflammation and modulated collagen fibre and alveolar bone loss. Curcumin inhibits NF-κB activation and reduces the OPG/sRANKL ratio induced by LPS, thereby modulating inflammatory activity in rat periodontitis [13]. The injection of curcumin-loaded nanoparticles in Wistar rat models led to a complete inhibition of inflammatory bone resorption, a significant reduction in both osteoclast counts and the inflammatory infiltrate, and a significant attenuation of p38 MAPK and NF-kB activation [14]. A 2% turmeric gel as local delivery agent as an adjunct to SRP was found to be effective in pocket reduction [15]. This 2% formulation was more effective than 1% chlorhexidine gel [16]. A controlled release form of curcumin produced similar clinicomicrobiological results to chlorhexidine [17]. Similar results were obtained in various studies [18–21].

In a systematic review which evaluated different formulations of curcumin showed that in nine studies there was a statistically significant difference in the pocket reduction when curcumin topical gel was used as compared with the control [22]. In contrast, in a meta-analysis, the use of curcumin/turmeric along with SRP showed a statistically significant difference compared to SRP alone. However, this change was deemed clinically insignificant [23].

Although these findings offer useful insights, additional studies are required to assess the effectiveness and safety of DMC in clinical settings and its potential as an adjunct therapy for periodontal disease. Additionally, it is worth considering that DMC bioavailability and stability in the oral cavity need to be carefully addressed to ensure effective delivery and penetration into periodontal tissues [24]. Clinical studies are required to determine optimal dosages, formulations, and modes of administration for DMC in the context of periodontal microbiology. DMC has been studied for its potential effects against P.gingivalis, a bacterium commonly associated with periodontal diseases such as gingivitis and periodontitis [25]. It has been shown to inhibit the growth and viability of this bacterium in laboratory studies. The exact mechanisms of its antibacterial effects are not fully understood, but they are believed to involve the disruption of bacterial cell membranes and interference with bacterial enzyme activity. P.gingivalis produces various virulence factors that contribute to its ability to colonize and penetrate the gingival epithelium. DMC has been shown to hinder the synthesis and function of various virulence factors, such as proteases and fimbriae [26]. By inhibiting these factors, DMC may help attenuate the pathogenicity of P.gingivalis and reduce its ability to cause tissue damage. It demonstrates anti-inflammatory effects by decreasing the production of pro-inflammatory cytokines including interleukin-1 beta (IL-1β) and interleukin-6 (IL-6), that have a role in the inflammatory process linked to P.g-induced periodontal destruction [27].

Further research, including well-designed clinical trials, is needed to validate these findings and determine the optimal dosage, formulation, and mode of administration for DMC in the context of P.gingivalis-associated periodontal destruction. DMC has demonstrated potential as a local drug delivery agent for the treatment of periodontitis, a persistent immuno-inflammatory condition. Local drug delivery involves the delivery of therapeutic agents directly to the site of infection or inflammation to enhance their effectiveness. DMC demonstrates anti-inflammatory properties that can help in controlling the inflammation linked to periodontitis [28]. By delivering DMC directly to the affected periodontal tissues, it may help reduce inflammation and prevent further tissue damage. DMC has been shown to possess antibacterial properties against periodontal pathogens, including P.gingivalis, which is a key bacterium associated with periodontitis. The local drug delivery of DMC may help inhibit the growth and activity of these pathogenic bacteria, aiding in the control of the infection [29]. Periodontitis involves an immune response that can contribute to tissue destruction. DMC modifies the host immune response by diminishing the generation of pro-inflammatory cytokines while promoting anti-inflammatory responses. Local delivery of DMC may help regulate the immune response in the periodontal tissues, promoting healing and reducing tissue damage [30]. Utilizing DMC as a local drug delivery agent allows for controlled release of the compound at the site of infection or inflammation. This sustained release can help maintain the therapeutic levels of DMC over an extended period, maximizing its effectiveness in treating periodontitis [31]. The administration technique for DMC in periodontal therapy can vary depending on the chosen formulation. For example, if a gel formulation is used, it may be applied topically to the affected periodontal tissues using a syringe or an applicator. The dental professional will provide specific instructions on the proper administration technique to ensure the optimal delivery and distribution of DMC. The treatment duration and frequency of DMC usage should be determined by the dental professional based on the individual's condition and response to treatment [32]. The optimal usage of DMC in periodontal therapy also relies on patient compliance [33]. Patients should follow the instructions provided by the dental professional, including proper application techniques, adherence to the recommended treatment schedule, and maintenance of good oral hygiene practices. It is important to note that the specific recommendations for DMC usage in periodontal therapy may vary based on the latest research findings and individual patient needs. Therefore, it is crucial to consult with a dental professional for personalized advice and guidance.

It is important to note that while DMC shows promise as an antimicrobial agent in laboratory studies, its efficacy and safety in clinical settings are still being investigated [34]. Further research, including in vivo and clinical trials, is necessary to determine its potential therapeutic applications against microbial infections. Additionally, the formulation, concentration, and delivery methods of DMC need to be optimized to enhance its antimicrobial activity and bioavailability [35]. It is important to note that while DMC shows promise as a local drug delivery drug in periodontitis, further research is needed to establish its efficacy, safety, and optimal delivery methods [36]. Clinical studies are necessary to evaluate the appropriate dosages, formulations, and techniques for local administration of DMC in periodontal therapy [37]. DMC can be formulated into various delivery systems, including gels, nanoparticles, liposomes, or microspheres. The choice of formulation depends on factors such as the desired release profile, ease of application, and stability of DMC [38]. The selection of an appropriate delivery system should be based on scientific evidence and expertise of the dental professional [39]. In conclusion, the current body of evidence indicates that curcumin has the potential to be a promising adjunctive therapy for the treatment of diabetes-associated periodontitis. Curcumin is an attractive candidate for the treatment of this severely debilitating condition due to its antioxidant, antimicrobial, and anti-inflammatory properties, as well as its capacity to regulate the host immune response. In order to optimize the delivery and administration of curcumin in the clinical setting and to elucidate the precise mechanisms of action, additional research is necessary. This study hypothesized that DMC could be an effective local drug delivery method specifically for periodontitis through its action against P.gingivalis and by modulating inflammatory responses in oral fibroblasts. Nevertheless, while this study focuses on molecular docking, it is important to acknowledge the limits in the in-vivo environment that impact the drug circulation, sustainability, release kinetics and elimination. These limitations can be better understood through conducting appropriate animal trials.

Additionally, it is worth mentioning that DMC should not be considered as a standalone treatment for P.gingivalis infections or periodontal diseases. It should be used in conjunction with conventional dental care, including professional cleanings, proper oral hygiene practices, and guidance from dental professionals. Consulting with a dental healthcare provider is essential for a comprehensive evaluation and personalized treatment planning. DMC should be considered as a complementary therapy rather than a standalone treatment for periodontal disease. It can be utilized in conjunction with traditional periodontal therapies, including scaling and root planing, to improve the overall effectiveness of the treatment. The results of this study indicate that DMC is a potential candidate for the development of a new local medication delivery agent. DMC has a high affinity for the active sites of P.gingivalis and oral fibroblast, and it could potentially form hydrogen bonds with several amino acid residues. These interactions may help restrict the replication of P.gingivalis and modulate the oral fibroblasts, perhaps acting as a local agent to regulate periodontal inflammation. Additional research is required to verify the effectiveness of DMC and to explore its possible negative effects.

The present molecular docking study provides insightful evidence into the affinity and potential binding mechanisms of DMC as a local therapeutic agent for periodontitis. Through the employment of advanced computational tools, it was demonstrated that DMC exhibits a strong affinity for the lipid A structure of P.gingivalis and the chemokine receptors of oral fibroblasts, which are vital players in the pathogenesis of periodontal disease. The discovery of key amino acid residues that might form hydrogen bonds with DMC offers a molecular basis for its antimicrobial and anti-inflammatory properties. Our findings pave the way for considering DMC as a promising candidate for localized drug delivery in the treatment of periodontitis. Its high binding affinity to target proteins essential in disease progression indicates that DMC could interfere effectively with the pathogenic pathways of periodontitis. Furthermore, the high specificity of DMC for P.gingivalis suggests that it could be developed into a targeted intervention, minimizing potential side effects and resistance issues associated with broad-spectrum antimicrobial treatments. While these results are preliminary and derived from computational analysis, they suggest a strong potential for DMC in periodontal therapy. Future research, including in vitro and in vivo experiments, will be essential to validate and exploit the therapeutic potential of DMC. If clinical studies corroborate these findings, DMC could be a valuable addition to the armamentarium against periodontitis, offering a novel mode of addressing this widespread and impactful oral health concern.

Author Contribution Statement

Saravanan Sampoornam Pape Reddy – Conceptualization, Methodology, Data collection Writing original draft

Delfin Lovelina Francis & Harshini Thirumoorthi – Methodology, Data collection, Reviewing final draft

Devendra Srivastava – Data Analysis

Neelima Katti – Data interpretation, final reviewing

Sukhbir Singh Chopra – Project administration, final manuscript reviewing

Acknowledgements

Nil

Conflicts of interest – Nil

Compliance with Ethical Standards

Disclosure of potential conflicts of interest – All authors declare that they do not have any potential or actual conflicts of interest.

Research involving Human Participants and/or Animals – This research does not involve human participants or animals

Informed consent – Not applicable

Pandey P, Ali B, Mishra A (2022), July 1 Curcumin: A pharmacologically functional active ingredient from nature., 4(3), 06–11. https://doi.org/10.33545/27068919.2022.v4.i3a.810
Hussain Y, Khan H, Alotaibi G, Khan F, Alam W, Aschner M, Jeandet P, Saso L (2022) June 24). How Curcumin Targets Inflammatory Mediators in Diabetes: Therapeutic Insights and Possible Solutions. Multidisciplinary Digit Publishing Inst 27(13):4058–4058. https://doi.org/10.3390/molecules27134058
Alici H, Tahtaci H, Demir K (2022) Design and various in silico studies of the novel curcumin derivatives as potential candidates against COVID-19 -associated main enzymes. Comput Biol Chem 98:107657. 10.1016/j.compbiolchem.2022.107657
Jakubovics NS, Goodman SD, Mashburn-Warren L, Stafford GP, Cieplik F (2021) The dental plaque biofilm matrix. Periodontol 2000 86(1):32–56. 10.1111/prd.12361
Borisy GG, Valm AM (2021) Spatial scale in analysis of the dental plaque microbiome. Periodontol 2000 86(1):97–112. 10.1111/prd.12364
Kinane DF, Stathopoulou PG, Papapanou PN (2017) Periodontal diseases. Nat Rev Dis Primers 3:17038. 10.1038/nrdp.2017.38
Kotha RR, Luthria DL (2019) Curcumin. Biological, Pharmaceutical, Nutraceutical, and Analytical Aspects. Molecules 24(16):2930. 10.3390/molecules24162930
Hatamipour M, Ramezani M, Tabassi SAS, Johnston TP, Ramezani M, Sahebkar A, Demethoxycurcumin (2018) A naturally occurring curcumin analogue with antitumor properties. J Cell Physiol 233(12):9247–9260. 10.1002/jcp.27029
Yeung AWK, Horbańczuk M, Tzvetkov N, Mocan A, Carradori S, Maggi F, Marchewka J, Sut S, Dall’Acqua S, Gan R, Tancheva L, Polgár T, Berindan-Neagoe I, Pirgozliev V, Šmejkal K, Atanasov AG (2019) Curcumin: Total-Scale Analysis of the Scientific Literature. Multidisciplinary Digit Publishing Inst April 9(7):1393–1393. https://doi.org/10.3390/molecules24071393
Sivani BM, Azzeh M, Patnaik R, Stoian AP, Rizzo M, Banerjee Y (2022) July 12). Reconnoitering the Therapeutic Role of Curcumin in Disease Prevention and Treatment: Lessons Learnt and Future Directions. Multidisciplinary Digit Publishing Inst 12(7):639–639. https://doi.org/10.3390/metabo12070639
Ng MY, Lin TH, Chao S, Chu PY, Yu C (2022) June 22). Potential Therapeutic Applications of Natural Compounds in Diabetes-Associated Periodontitis. Multidisciplinary Digit Publishing Inst 11(13):3614–3614. https://doi.org/10.3390/jcm11133614
Nagasri M, Madhulatha M, Musalaiah SV, Kumar PA, Krishna CH, Kumar PM (2015) Efficacy of curcumin as an adjunct to scaling and root planning in chronic periodontitis patients: A clinical and microbiological study. J Pharm Bioallied Sci 7(Suppl 2):S554–S558. 10.4103/0975-7406.163537
Xiao CJ, Yu XJ, Xie JL, Liu S, Li S (2018) Protective effect and related mechanisms of curcumin in rat experimental periodontitis. Head Face Med. ;14(1):12. Published 2018 Aug 16. 10.1186/s13005-018-0169-1
Zambrano LMG, Brandao DA, Rocha FRG et al (2018) Local administration of curcumin-loaded nanoparticles effectively inhibits inflammation and bone resorption associated with experimental periodontal disease. Sci Rep. ;8(1):6652. Published 2018 Apr 27. 10.1038/s41598-018-24866-2
Behal R, Mali AM, Gilda SS, Paradkar AR (2011) Evaluation of local drug-delivery system containing 2% whole turmeric gel used as an adjunct to scaling and root planing in chronic periodontitis: A clinical and microbiological study. J Indian Soc Periodontol 15(1):35–38. 10.4103/0972-124X.82264
Jaswal R, Dhawan S, Grover V, Malhotra R (2014) Comparative evaluation of single application of 2% whole turmeric gel versus 1% chlorhexidine gel in chronic periodontitis patients: A pilot study. J Indian Soc Periodontol 18(5):575–580. 10.4103/0972-124X.142445
Gottumukkala SN, Sudarshan S, Mantena SR (2014) Comparative evaluation of the efficacy of two controlled release devices: Chlorhexidine chips and indigenous curcumin-based collagen as local drug delivery systems. Contemp Clin Dent 5(2):175–181. 10.4103/0976-237X.132310
Hugar SS, Patil S, Metgud R, Nanjwade B, Hugar SM (2016) Influence of application of chlorhexidine gel and curcumin gel as an adjunct to scaling and root planing: A interventional study. J Nat Sci Biol Med 7(2):149–154. 10.4103/0976-9668.184701
Anitha V, Rajesh P, Shanmugam M, Priya BM, Prabhu S, Shivakumar V (2015) Comparative evaluation of natural curcumin and synthetic chlorhexidine in the management of chronic periodontitis as a local drug delivery: A clinical and microbiological study. Indian J Dent Res 26(1):53–56. 10.4103/0970-9290.156806
Ravishankar PL, Kumar YP, Anila EN, Chakraborty P, Malakar M, Mahalakshmi R (2017) Effect of local application of curcumin and ornidazole gel in chronic periodontitis patients. Int J Pharm Investig 7(4):188–192. 10.4103/jphi.JPHI_82_17
Elavarasu S, Suthanthiran T, Thangavelu A, Alex S, Palanisamy VK, Kumar TS (2016) Evaluation of superoxide dismutase levels in local drug delivery system containing 0.2% curcumin strip as an adjunct to scaling and root planing in chronic periodontitis: A clinical and biochemical study. J Pharm Bioallied Sci 8(Suppl 1):S48–S52. 10.4103/0975-7406.191967
Terby S, Shereef M, Ramanarayanan V, Balakrishnan B (2021) The effect of curcumin as an adjunct in the treatment of chronic periodontitis: A systematic review and meta-analysis. Saudi Dent J 33(7):375–385. 10.1016/j.sdentj.2021.07.008
Wendorff-Tobolla LM, Wolgin M, Wagner G, Klerings I, Dvornyk A, Kielbassa AM (2023) A Systematic Review and Meta-Analysis on the Efficacy of Locally Delivered Adjunctive Curcumin (Curcuma longa L.) in the Treatment of Periodontitis. Biomedicines 11(2):481 Published 2023 Feb 7. 10.3390/biomedicines11020481
Ramkumar M, Rajasankar S, Swaminathan Johnson WM, Prabu K, Venkatesh Gobi V (2019) Demethoxycurcumin ameliorates rotenone-induced toxicity in rats. Front Biosci 11(1):1–11. 10.2741/E841
Verma A, Azhar G, Zhang X, Patyal P, Kc G, Sharma S, Che Y, Wei JY (2023) P. gingivalis-LPS Induces Mitochondrial Dysfunction Mediated by Neuroinflammation through Oxidative Stress. Int J Mol Sci 24(2):950. 10.3390/ijms24020950
Zheng S, Yu S, Fan X, Zhang Y, Sun Y, Lin L, Wang H, Pan Y, Li C (2021) Porphyromonas gingivalis survival skills: Immune evasion. J Periodontal Res 56(6):1007–1018. 10.1111/jre.12915
Ramkumar M, Rajasankar S, Gobi VV, Janakiraman U, Manivasagam T, Thenmozhi AJ et al (2018) Demethoxycurcumin, a natural derivative of curcumin abrogates rotenone-induced dopamine depletion and motor deficits by its antioxidative and anti-inflammatory properties in parkinsonian rats. Pharmacogn Mag 14(53):9–16. 10.4103/pm.pm_113_17
Lu B, Chen X, Chen H, Li Q, Li H, Xu Y, Li Y, Shen X, Jiang R (2022) Demethoxycurcumin mitigates inflammatory responses in lumbar disc herniation via MAPK and NF-κB pathways in vivo and in vitro. Int Immunopharmacol 108:108914. 10.1016/j.intimp.2022.108914
Lee GJ, Lim H, Seo JY, Kang KR, Kim DK, You JS, Oh JS, Seo YS, Kim JS (2022) Demethoxycurcumin induces apoptosis via inhibition of NF-κB pathway in FaDu human head and neck squamous cell carcinoma. Transl Cancer Res 11(5):1064–1075. 10.21037/tcr-21-2410
Chainani-Wu N (2003) Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J Altern Complement Med 9(1):161–168. 10.1089/107555303321223035
Tran PHL, Tran TTD (2020) Dosage form designs for the controlled drug release of solid dispersions. Int J Pharm 15:581:119274. 10.1016/j.ijpharm.2020.119274
Di Colo G (1992) Controlled drug release from implantable matrices based on hydrophobic polymers. Biomaterials 13(12):850–856. 10.1016/0142-9612(92)90178-q
Wen H, Jung H, Li X (2015) Drug Delivery Approaches in Addressing Clinical Pharmacology-Related Issues: Opportunities and Challenges. AAPS J 17(6):1327–1340. 10.1208/s12248-015-9814-9
Aggarwal BB, Sundaram C, Malani N, Ichikawa H (2007) Curcumin: the Indian solid gold. Adv Exp Med Biol 595:1–75. 10.1007/978-0-387-46401-5_1
Jagetia GC, Aggarwal BB (2007) Spicing up of the immune system by curcumin. J Clin Immunol 27(1):19–35. 10.1007/s10875-006-9066-7
Kudva P, Tabasum ST, Gupta S (2012) Comparative evaluation of the efficacy of turmeric and curcumin as a local drug delivery system: A clinicomicrobiological study. Gen Dent 60(5):e283–e287
Anitha V, Rajesh P, Shanmugam M, Priya BM, Prabhu S, Shivakumar V (2015) Comparative evaluation of natural curcumin and synthetic chlorhexidine in the management of chronic periodontitis as a local drug delivery: a clinical and microbiological study. Indian J Dent Res 26(1):53–56. 10.4103/0970-9290.156806
Gottumukkala SN, Sudarshan S, Mantena SR (2014) Comparative evaluation of the efficacy of two controlled release devices: Chlorhexidine chips and indigenous curcumin-based collagen as local drug delivery systems. Contemp Clin Dent 5(2):175–181. 10.4103/0976-237X.132310
Hanes PJ, Purvis JP (2003) Local anti-infective therapy: pharmacological agents. A systematic review. Ann Periodontol 8(1):79–98. 10.1902/annals.2003.8.1.79

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Exploring the therapeutic potential of demethoxycurcumin in periodontitis

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