Newly discovered clouting interplay between matrix metalloproteinases structures and novel quaternary Ammonium K21: computational and in-vivo testing.

AIMS AND OBJECTIVES: To analyze anti-MMP mode of action of Quaternary Ammonium Silane (QAS, codenamed as k21) by binding onto specific MMP site using computational molecular simulation and Anti-Sortase A (SrtA) mode of action by binding onto specific site using computational molecular simulation. MATERIALS AND METHODS: In silico Molecular Dynamics (MD) was used to determine the interactions of K21 inside the pocket of the targeted protein (crystal structure of fibroblast collagenase-1 complexed to a diphenyl-ether sulphone based hydroxamic acid; PDB ID: 966C; Crystal structure of MMP-2 active site mutant in complex with APP-derived decapeptide inhibitor. MD simulations were accomplished with the Desmond package in Schrödinger Drug Discovery Suite. Blood samples (~ 0.5 mL) collected into K2EDTA were immediately transferred for further processing using the Litron MicroFlow® PLUS micronucleus analysis kit for mouse blood according to the manufacturer's instructions. Bacterial Reverse Mutation Test of K21 Molecule was performed to evaluate K21 and any possible metabolites for their potential to induce point mutations in amino acid-requiring strains of Escherichia coli (E. coli) (WP2 uvrA (tryptophan-deficient)). RESULTS: Molecular Simulation depicted that K21 has a specific pocket binding on various MMPs and SrtA surfaces producing a classical clouting effect. K21 did not induce micronuclei, which are the result of chromosomal damage or damage to the mitotic apparatus, in the peripheral blood reticulocytes of male and female CD-1 mice when administered by oral gavage up to the maximum recommended dose of 2000 mg/kg. The test item, K21, was not mutagenic to Salmonella typhimurium (S. typhimurium) strains TA98, TA100, TA1535 and TA1537 and E. coli strain WP2 uvrA in the absence and presence of metabolic activation when tested up to the limit of cytotoxicity or solubility under the conditions of the test. CONCLUSION: K21 could serve as a potent protease inhibitor maintaining the physical and biochemical properties of dental structures.

Clinical and microbiologic effect of local application of curcumin as an adjunct to scaling and root planing in periodontitis: Systematic review.

BACKGROUND: The main aim of periodontal therapy is to halt the progression of periodontitis. Curcumin, one of the main components of Curcumin longa, has been well known to possess antimicrobial, anti-inflammatory, and even anticarcinogenic properties. This systematic review assessed the impact of local application of curcumin in the pocket on the clinical and microbiologic parameters as an adjunct to scaling and root planing in periodontitis patients. METHODS: The electronic literature search retrieved 61 studies from PubMed, MEDLINE, and ScienceDirect. After screening titles, abstracts, and keywords and reading through these articles, we identified 9 articles meeting all inclusion criteria, which were included for systematic review. RESULTS: There was a significant difference in both clinical parameters in a short duration of a month after curcumin chips were placed as an adjunct to scaling and root planing as compared to the control. Local application of curcumin also results in slight to significant reduction in the red complex microorganisms. CONCLUSION: This review suggested that local application of curcumin can be considered as a viable adjunct to mechanical debridement in periodontitis. However, further studies need to be conducted to establish its optimum dose, delivery method, and frequency in achieving the best clinical outcomes.

Current appraises of therapeutic applications of nanocurcumin: A novel drug delivery approach for biomaterials in dentistry.

Curcumin is a natural herb and polyphenol that is obtained from the medicinal plant Curcuma longa. It's anti-bacterial, anti-inflammatory, anti-cancer, anti-mutagenic, antioxidant and antifungal properties can be leveraged to treat a myriad of oral and systemic diseases. However, natural curcumin has weak solubility, limited bioavailability and undergoes rapid degradation, which severely limits its therapeutic potential. To overcome these drawbacks, nanocurcumin (nCur) formulations have been developed for improved biomaterial delivery and enhanced treatment outcomes. This novel biomaterial holds tremendous promise for the treatment of various oral diseases, the majority of which are caused by dental biofilm. These include dental caries, periodontal disease, root canal infection and peri-implant diseases, as well as other non-biofilm mediated oral diseases such as oral cancer and oral lichen planus. A number of in-vitro studies have demonstrated the antibacterial efficacy of nCur in various formulations against common oral pathogens such as S. mutans, P. gingivalis and E. faecalis, which are strongly associated with dental caries, periodontitis and root canal infection, respectively. In addition, some clinical studies were suggestive of the notion that nCur can indeed enhance the clinical outcomes of oral diseases such as periodontitis and oral lichen planus, but the level of evidence was very low due to the small number of studies and the methodological limitations of the available studies. The versatility of nCur to treat a diverse range of oral diseases augurs well for its future in dentistry, as reflected by rapid pace in which studies pertaining to this topic are published in the scientific literature. In order to keep abreast of the latest development of nCur in dentistry, this narrative review was undertaken. The aim of this narrative review is to provide a contemporaneous update of the chemistry, properties, mechanism of action, and scientific evidence behind the usage of nCur in dentistry.

Antimicrobial FiteBac® K21 promotes antimicrobial Potency and wound healing.

Objectives: Successful root canal therapy is dependent on the efficacy of complete instrumentation and adequate use of chemical irrigant to eliminate the biofilm from dentin surface. The aim of the study was to examine antibiofilm and antimicrobial effectiveness of newly formulated Quaternary ammonium silane (QAS/also codenamed K21; against Fusobacterium nucleatum (F. nucleatum) and Enterococcus faecalis (E. faecalis) biofilm on radicular dentin with evaluation of the anti-inflammatory consequence in vivo. Methods: Fourier Transform Infrared Spectroscopy (FTIR) was performed after complete hydrolysis of K21 solution. Human teeth were inoculated with biofilms for 7-days followed by treatment with various irrigants. The irrigant groups were Sodium hypochlorite [NaOCl (6%)], Chlorhexidine [CHX (2%)], K21 (0.5%), K21 (1%) and Saline. Scanning electron microscopy (SEM) was performed for biofilm and resin-dentin penetration. Transmission Electron Microscopy (TEM) of biofilms was done to evaluate application of K21. For in vivo evaluation, Albino wistar rats were injected subcutaneously and sections were stained with haematoxylin/eosin. Macrophage, M1/M2 expression were evaluated along with molecular simulation. Raman measurements were done on dried biofilms. Results: FTIR K21 specimens demonstrated presence of ethanol/silanol groups. Raman band at 1359 cm-1 resemble to -CH2- wagging displaying 29Si atoms in Nuclear Magnetic Resonance (NMR). 0.5%K21 showed cells exhibiting folded membranes. SEM showed staggering amount of resin tags with 0.5% K21 group. TEM showed membrane disruption in K21-groups. K21 groups were initially irritant, which subsided completely afterwards showing increased CD68. K21 and MMP/collagen complex was thermodynamically favourable. Conclusion: K21 root canal irrigant was able to penetrate bacterial wall and can serve as a potential irrigant for therapeutic benefits. Expression of M2 polarized subsets showed K21 can serve in resolving inflammation and potentiate tissue repair.

Recent Update on Applications of Quaternary Ammonium Silane as an Antibacterial Biomaterial: A Novel Drug Delivery Approach in Dentistry.

Quaternary ammonium silane [(QAS), codename - k21] is a novel biomaterial developed by sol-gel process having broad spectrum antimicrobial activities with low cytotoxicity. It has been used in various concentrations with maximum antimicrobial efficacy and biocompatibility. The antimicrobial mechanism is displayed via contact killing, causing conformational changes within the bacterial cell membrane, inhibiting Sortase-A enzyme, and causing cell disturbances due to osmotic changes. The compound can attach to S1' pockets on matrix metalloproteinases (MMPs), leading to massive MMP enzyme inhibition, making it one of the most potent protease inhibitors. Quaternary ammonium silane has been synthesized and used in dentistry to eliminate the biofilm from dental tissues. QAS has been tested for its antibacterial activity as a cavity disinfectant, endodontic irrigant, restorative and root canal medication, and a nanocarrier for drug delivery approaches. The review is first of its kind that aims to discuss applications of QAS as a novel antibacterial biomaterial for dental applications along with discussions on its cytotoxic effects and future prospects in dentistry.

Review on synthesis, properties and multifarious therapeutic applications of nanostructured zirconia in dentistry.

Amongst dental ceramics, nano zirconia (ZrNp) has shown exceptional developments in the field of dentistry in recent years. Zirconia is an oxide that possess superior optical, mechanical, and biological properties. As a novel nanoparticle, it has been widely used in various fields of dentistry due to its improved mechanical properties, biocompatibility, and stable structure. Provision of metal free solutions is one of the prime requirements in dental materials. Many metal alloys used extensively possess unaesthetic colors and display chemical interactions in the oral cavity encouraging use of zirconia for dental use. Use of ZrNp based ceramics has increased due to its resistance to corrosion, superior color matching that enhances esthetics and improved strength compared to conventional biomaterials. This review discusses the recent scientific literature on the synthesis, properties and types, applications, and toxicity of ZrNp in the field of dentistry.

Biochemical changes and macrophage polarization of a silane-based endodontic irrigant in an animal model.

Silane-based/fully hydrolyzed, endodontic irrigant exhibiting antimicrobial properties, is prepared, and is hypothesized to control macrophage polarization for tissue repair. Albino wistar rats were injected with 0.1 ml root canal irrigant, and bone marrow cells procured. Cellular mitochondria were stained with MitoTracker green along with Transmission Electron Microscopy (TEM) performed for macrophage extracellular vesicle. Bone marrow stromal cells (BMSCs) were induced for M1 and M2 polarization and Raman spectroscopy with scratch assay performed. Cell counting was used to measure cytotoxicity, and fluorescence microscopy performed for CD163. Scanning Electron Microscopy (SEM) was used to investigate interaction of irrigants with Enterococcus faecalis. K21 specimens exhibited reduction in epithelium thickness and more mitochondrial mass. EVs showed differences between all groups with decrease and increase in IL-6 and IL-10 respectively. 0.5%k21 enhanced wound healing with more fibroblastic growth inside scratch analysis along with increased inflammation-related genes (ICAM-1, CXCL10, CXCL11, VCAM-1, CCL2, and CXCL8; tissue remodelling-related genes, collagen 1, EGFR and TIMP-2 in q-PCR analysis. Sharp bands at 1643 cm-1 existed in all with variable intensities. 0.5%k21 had a survival rate of BMSCs comparable to control group. Bacteria treated with 0.5%k21/1%k21, displayed damage. Antimicrobial and reparative efficacy of k21 disinfectant is a proof of concept for enhanced killing of bacteria across root dentin acquiring functional type M2 polarization for ethnopharmacological effects.

Synthesis and Incorporation of Quaternary Ammonium Silane Antimicrobial into Self-Crosslinked Type I Collagen Scaffold: A Hybrid Formulation for 3D Printing.

Novel 3D-biomaterial scaffold is constructed having a combination of a new quaternary ammonium silane (k21) antimicrobial impregnated in 3D collagen printed scaffolds cross linked with Riboflavin in presence of d-alpha-tocopheryl poly(ethyleneglycol)-1000-succinate. Groups of "0.1% and 0.2% k21", and "0.1% and 0.2% Chlorhexidine (CHX)" are prepared. k21/CHX with neutralized collagen is printed with BioX. Riboflavin is photo-activated and examined using epifluorescence for Aggregatibacter actinomycetemcomitans (7-days). Collagen is examined using TEM and measured for porosity, and shape-fitting. Raman and tandem mass/solid-state are performed with molecular-docking and circular-dichroism. X-ray diffractions, rheological tests, contact angle, and ninhydrin assay are conducted. k21 samples demonstrated collagen aggregates while 0.1% CHX and 0.2% CHX showed irregularities. Porosity of control and "0.1% and 0.2% k21" scaffolds show no differences. Low contact angle, improved elastic-modulus, rigidity, and smaller strain in k21 groups are seen. Bacteria are reduced and strong organic intensities are seen in k21 scaffolds. Simulation shows hydrophobicity/electrostatic interaction. Crosslinking is observed in 0.2% CHX/79% and 0.2% k21/80%. Circular dichroism for k21 are suggestive of triple helix. XRD patterns appear at d = 5.97, 3.03, 2.78, 2.1, and 2.90 A°. 3D-printing of collagen impregnated with quaternary ammonium silane produces a promising scaffold with antimicrobial potency and structural stability.

Serum antibody response against periodontal bacteria and coronary heart disease: Systematic review and meta-analysis.

AIM: The present systematic review and meta-analysis assessed the strength of a reported association between elevated serum anti-periodontal bacterial antibody responses and coronary heart disease (CHD). MATERIALS AND METHODS: Twenty original studies were identified after systematically searching five databases. The majority (n = 11) compared serum anti-Porphyromonas gingivalis (Pg) and/or anti-Aggregatibacter actinomycetemcomitans (Aa) IgG antibody responses between CHD patients and control participants. The strength of the association between serum anti-Pg antibodies and CHD (n = 10) and serum anti-Aa antibodies and CHD (n = 6) was investigated using a meta-analysis approach separately. RESULTS: Most studies (61%) reported that the serum IgG antibody responses were elevated in CHD patients than in controls. The meta-analyses showed a significant association between elevated serum IgG antibody responses (anti-Pg and anti-Aa) and CHD, with pooled odds ratios of 1.23 [95% confidence interval (CI): 1.09-1.38, p = .001] and 1.25 (95% CI: 1.04-1.47, p = .0004), respectively. CONCLUSIONS: A modest increase of CHD events in individuals with higher serum anti-Pg and anti-Aa IgG antibody responses may support their use as potential biomarkers to detect and monitor at-risk populations. However, the observed inconsistencies with the design and interpretation of immunoassays warrant standardization of the immunoassays assessing antibody responses against periodontal bacteria.

Antibacterial and antibiofilm efficacy of k21-E in root canal disinfection.

OBJECTIVES: The aim of the current project was to study the antimicrobial efficacy of a newly developed irrigant, k21/E against E. faecalis biofilm. METHODS: Root canals were instrumented and randomly divided into the following groups: irrigation with saline, 6% NaOCl (sodium hypochlorite), 6% NaOCl+2% CHX (Chlorhexidine), 2% CHX, 0.5% k21/E (k21 - quaternary ammonium silane) and 1% k21/E. E. faecalis were grown (3-days) (1×107CFU mL-1), treated, and further cultured for 11-days. Specimens were subjected to SEM, confocal and Raman analysis and macrophage vesicles characterized along with effect of lipopolysaccharide treatment. 3T3 mouse-fibroblasts were cultured for alizarin-red with Sortase-A active sites and Schrödinger docking was performed. TEM analysis of root dentin substrate with matrix metalloproteinases profilometry was also included. A cytotoxic test analysis for cell viability was measured by absorbance of human dental pulp cells after exposure to different irrigant solutions for 24h. The test percentages have been highlighted in Table 1. RESULTS: Among experimental groups, irrigation with 0.5% k21/E showed phase separation revealing significant bacterial reduction and lower phenylalanine 1003cm-1 and Amide III 1245cm-1 intensities. Damage was observed on bacterial cell membrane after use of k21/E. No difference in exosomes distribution between control and 0.5%k21/E was observed with less TNFα (*p<0.05) and preferential binding of SrtA. TEM images demonstrated integrated collagen fibers in control and 0.5%k21/E specimens and inner bacterial membrane damage after k21/E treatment. The k21 groups appeared to be biocompatible to the dental pulpal cells grown for 24h. SIGNIFICANCE: Current investigations highlight potential advantages of 0.5% k21/E as irrigation solution for root canal disinfection.

Idiopathic Desquamative Gingivitis.

Desquamative gingivitis is described as an erythematous, desquamated gingival lesion. There are many etiologic factors for the appearance of such lesions. The aim of this case report is to diagnose the cause of the lesion by analyzing the complete medical, dental, and personal histories. An elaborated differential diagnosis is done, and the lesion is successfully treated accordingly. The gold standard treatment is usually provided by systemic or topical corticosteroids. Another treatment option is antioxidant therapy which provides rapid healing of the tissue.

Recent update on potential cytotoxicity, biocompatibility and preventive measures of biomaterials used in dentistry.

Dental treatment is provided for a wide variety of oral health problems like dental caries, periodontal diseases, periapical infections, replacement of missing teeth and orthodontic problems. Various biomaterials, like composite resins, amalgam, glass ionomer cement, acrylic resins, metal alloys, impression materials, bone grafts, membranes, local anaesthetics, etc., are used for dental applications. The physical and chemical characteristics of these materials influence the outcome of dental treatment. It also impacts on the biological, allergic and toxic potential of biomaterials. With innovations in science and their positive results, there is also a need for awareness about the biological risks of these biomaterials. The aim of dental treatment is to have effective, yet safe, and long-lasting results for the benefit of patients. For this, it is important to have a thorough understanding of biomaterials and their effects on local and systemic health. Materials used in dentistry undergo a series of analyses before their oral applications. To the best of our knowledge, this is the first and original review that discusses the reasons for and studies on the toxicity of commonly used biomaterials for applications in dentistry. It will help clinicians to formulate a methodical approach for the selection of dental biomaterials, thus providing an awareness for forecasting their risk of toxic reactions.

Evaluation of anatomic variations of mandibular lingual concavities from cone beam computed tomography scans in a Malaysian population.

STATEMENT OF PROBLEM: Lingual plate perforation can be life-threatening when vital structures are damaged during implant placement. Knowledge of the anatomy of lingual concavities is imperative for safe implant surgery. PURPOSE: The purpose of this clinical study was to determine the prevalence of type of posterior mandibular ridge morphology in a Malaysian population and to evaluate the buccolingual width of the alveolar ridge (Wb and Wc); alveolar ridge height (Vcb); and concavity angle, length, and depth for both left and right first and second molars in different age groups and sexes by using cone beam computed tomography (CBCT). MATERIAL AND METHODS: Bilateral posterior mandibular lingual concavities at the first and second molars were retrospectively studied in cross-sectional views of 150 CBCT scans (n=600 sites evaluated). The sample size was calculated at a power of 80%, confidence interval of 95%, and margin of error of .05. The buccolingual width from the base and crest of the ridge and the ridge height were measured to determine the type of ridge. For the U-shaped ridge, the concavity angle, length, and depth were assessed. The independent t test was used to compare mean values of CBCT measurements between sexes and tooth type, while the ANOVA and Pearson chi-squared test were used to determine the correlations with age groups and types of ridge morphology, respectively. To compare the left and right readings for first and second molars in the same patient, the paired t test was performed (α=.05 for all tests). RESULTS: The Pearson correlation showed a strong agreement between the 2 examiners with an interobserver reliability of 87.3%. Significant difference was noted in all dimensional measurements when comparing right and left first and second molars (P<.001). The degree of concavity was significantly different (P<.05), except for the depth of the concavity at the left molars (P=.075). The type C ridge (51.7%) was the most prevalent ridge among a Malaysian population. Only dimensional measurements were significantly different when compared among age groups (P<.05). Ridge width and height were significantly greater in men (P<.05). Men exhibited greater concavity depth than women in the left second molar region (P=.03). CONCLUSIONS: Lingual concavity was found in the mandible in 32.8% of a Malaysian population. Significant differences were found in dimensional measurements and degree of concavity between left and right first and second molars, with deeper concavity depth found in second molars. Significant age and sex-related variations were found in the dimensional measurements of the mandible between left and right sides with no significant difference in degree of concavity.

Oral peptide delivery: challenges and the way ahead.

Peptides and proteins have emerged as potential therapeutic agents and, in the search for the best treatment regimen, the oral route has been extensively evaluated because of its non-invasive and safe nature. The physicochemical properties of peptides and proteins along with the hurdles in the gastrointestinal tract (GIT), such as degrading enzymes and permeation barriers, are challenges to their delivery. To address these challenges, several conventional and novel approaches, such as nanocarriers, site-specific and stimuli specific delivery, are being used. In this review, we discuss the challenges to the oral delivery of peptides and the approaches used to tackle these challenges.

Detection of periodontal microorganisms in coronary atheromatous plaque specimens of myocardial infarction patients: A systematic review and meta-analysis.

BACKGROUND: Microbial translocation from inflamed periodontal pockets into coronary atheroma via systemic circulation is one of the proposed pathways that links periodontitis and myocardial infarction (MI). The purpose of this systematic review is to determine the reported prevalence of periodontal microorganisms in coronary atheroma and/or aspirated clot samples collected from MI patients with periodontal disease. METHODOLOGY: The "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) guidelines were followed. Six databases were systematically searched using Medical Subject Headings/Index and Entree terms. After a thorough screening, fourteen publications spanning over ten years (2007-2017) were eligible for this systematic review and meta-analysis. RESULTS: Out of 14 included studies, 12 reported presence of periodontal bacterial DNA in coronary atherosclerotic plaque specimens. Overall, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans were the most frequently detected periodontal bacterial species. Meta-analysis revealed that the prevalence of P. gingivalis was significantly higher than A. actinomycetemcomitans in coronary atheromatous plaque samples. Apart from periodontal microbes, DNA from a variety of other microbes e.g. Pseudomonas fluorescens, Streptococcus species, Chlamydia pneumoniae were also recovered from the collected samples. CONCLUSION: Consistent detection of periodontal bacterial DNA in coronary atheroma suggests their systemic dissemination from periodontal sites. It should further be investigated whether they are merely bystanders or induce any structural changes within coronary arterial walls.

Recent advances and prospects in gemcitabine drug delivery systems.

Cancer is a community health hazard which progress at a fatal rate in various countries across the globe. An agent used for chemotherapy should exhibit ideal properties to be an effective anticancer medicine. The chemotherapeutic medicines used for treatment of various cancers are, gemcitabine, paclitaxel, etoposide, methotrexate, cisplatin, doxorubicin and 5-fluorouracil. However, many of these agents present nonspecific systemic toxicity that prevents their treatment efficiency. Of all, gemcitabine has shown to be an active agent against colon, pancreatic, colon, ovarian, breast, head and neck and lung cancers in amalgamation with various anticancer agents. Gemcitabine is considered a gold-standard and the first FDA approved agent used as a monotherapy in management of advanced pancreatic cancers. However due to its poor pharmacokinetics, there is need of newer drug delivery system for efficient action. Nanotechnology has shown to be an emerging trend in field of medicine in providing novel modalities for cancer treatment. Various nanocarriers have the potential to deliver the drug at the desired site to obtain information about diagnosis and treatment of cancer. This review highlights on various nanocarriers like polymeric nanoparticles, solid lipid nanoparticles, mesoporous silica nanoparticles, magnetic nanoparticles, micelles, liposomes, dendrimers, gold nanoparticles and combination approaches for delivery of gemcitabine for cancer therapy. The co-encapsulation and concurrent delivery of Gem with other anticancer agents can enhance drug action at the cancer site with reduced side effects.

Recent advances of gold nanoparticles as biomaterial in dentistry.

Major goal of dental treatment is to eradicate the existing diseases of the oral cavity and implement preventive measures to control the spread of the diseases. Various interventions are being used to cure the dental diseases. Due to the nanostructures, high surface volume and biocompatibility, Gold nanoparticles (GNPs) have been experimented in the treatment of gum diseases, dental caries, tissue engineering, dental implantology and diagnosis of cancers. GNPs possess antifungal and antibacterial activity, hence are incorporated in various biomaterials to potentiate the effect. They also enhance the mechanical properties of materials leading to improved outcomes. They are available in different sizes and concentrations to exhibits its beneficial outcomes. These properties of GNPs make these materials as choice of fillers in biomaterials. This review aims to discuss the effect of incorporation of GNPs in several biomaterials used for dental and medical applications.

The potential of dendrimer in delivery of therapeutics for dentistry.

Dendrimers are hyperbranched nanoparticle structures along with its surface modifications can to be used in dental biomaterials for biomimetic remineralisation of enamel and dentin. The review highlights the therapeutic applications of dendrimers in the field of dentistry. It addresses the possible mechanisms of enhancement of mechanical properties of adhesives and resins structure. Dendrimers due to its unique construction of possessing inner hydrophobic and outer hydrophilic structure can act as drug carrier for delivery of antimicrobial drugs for treatment of periodontal diseases and at peripheral dental implant areas. Dendrimers due to its hyperbranched structures can provides a unique drug delivery vehicle for delivery of a drug at specific site for sustained release for therapeutic effects. Thus, dendrimers can be one of the most important constituents which can be incorporated in dental biomaterials for better outcomes in dentistry.