Open access peer-reviewed chapter

Evaluation of Trans-Resveratrol as a Treatment for Periodontitis

Written By

Tracey Lynn Harney

Submitted: 21 October 2021 Reviewed: 02 November 2021 Published: 22 December 2021

DOI: 10.5772/intechopen.101477

From the Edited Volume

Oral Health Care - An Important Issue of the Modern Society

Edited by Lavinia Cosmina Ardelean and Laura Cristina Rusu

Chapter metrics overview

283 Chapter Downloads

View Full Metrics

Abstract

Periodontitis is a globally prevalent inflammation-mediated disease that can result in varying degrees of destruction to the tissues supporting the teeth. The microbial pathogenic dysbiosis, oxidative stress, and deregulated inflammation, found in patients with periodontitis, make it a multifaceted condition that is difficult to fully resolve. Further to this, periodontitis has been associated with other systemic inflammatory conditions. Trans-resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a plant-derived molecule present in many foods, which have been shown to exhibit antimicrobial, antioxidant, anti-inflammatory, and regenerative properties. However, trans-resveratrol has been reported to have physicochemical shortcomings, which make its clinical translation a challenge. This review outlines a critical analysis of identified samples from the scientific literature that was conducted to assess the potential of RES as a viable therapeutic for periodontitis. The potential for the improvement of the limiting pharmacological profile of trans-resveratrol via nanoformulation is also explored.

Keywords

  • periodontitis
  • trans-resveratrol
  • nanotechnology
  • pharmacognosy
  • pharmacology

1. Introduction

Periodontal disease (PD) is a chronic condition accompanied by a progressive pathogenic biofilm that continuously triggers inflammation, potentially resulting in the loss of both soft and bony periodontal tissues. Ultimately, in severe cases, edentulism may result (Figure 1) [1].

Figure 1.

An illustration of a healthy tooth and periodontal tissue (left side) compared to periodontal disease (right side).

Although aspects such as age, genetics, or sex can affect the chance of developing PD, there are also modifiable risk factors that have been identified. That is, smoking, nutrition (e.g., low vitamin D and calcium), and poorly managed diseases (e.g., diabetes, rheumatoid arthritis, and obesity) as well as stress, have also been found to play a significant role in susceptibility [2, 3, 4].

According to several epidemiological reports, the prevalence of PD is increasing over time. In fact, current publications indicate that approximately 10% of the global population presents with severe periodontitis, while almost half of the remaining 90% of all adults present with a less severe form of the disease. By and large, the most conservative estimate places the prevalence of PD at approximately 50% of the adult population worldwide [1, 5, 6, 7].

Since people suffering from PD may experience chronic pain and tissue destruction, which can lead to anxiety and depression, the overall loss of quality of life has become an additional area of epidemiological observation. In fact, the deleterious impact of PD on wellness has recently been quantified using the index for Oral Health-Related Quality of Life (OHRQoL) and it was reported that the quality of life significantly decreases proportionally to the severity of PD [8, 9].

Additionally, PD has been found to have a widespread detrimental economic impact. For example, a recent study using accumulated data from the USA and 32 European countries, reported the approximate expenditure due to PD to be $154.06B in the USA, and 158.64B Euros in Europe [10].

Overall, a body of epidemiological evidence has emerged, reporting the increasing prevalence, economic burden, and diminished quality-of-life for a large enough portion of the global population, that PD has gained attention as growing concern of global proportion.

Although compiled review reports pertaining to the epidemiology of PD have been used as a benchmark, the distinction between gingivitis, mild to moderate PD, and more severe disease forms, has been inconsistent, creating a lack of comparability between and within the various epidemiological demographics [11].

Despite these steps towards unified categorisation, the ability to compare studies may still be diminished by the variation in classification of PD between clinicians and investigators [11, 12, 13].

Advertisement

2. Other inflammation-mediated conditions associated with PD

The conflicting reports, regarding the extent and severity of PD in the epidemiological literature, do not change the legitimate growing concern around the prevalence of the disease, especially when one considers the many inflammation-mediated systemic diseases with which it has been associated. For example, several reports indicate that PD can potentially increase the chance of developing heart disease [14, 15, 16, 17, 18, 19, 20], neurodegenerative disease [21, 22, 23], and autoimmune disease [24, 25] (Figure 2).

Figure 2.

An overview of some of the diseases that have been associated with PD.

Further to this, chronic PD has been linked to a range of malignancies [26, 27, 28, 29, 30] and respiratory diseases [31, 32, 33, 34] (Figure 2). Accordingly, the necessity for more ways to effectively prevent, manage, and treat PD, remains paramount.

Advertisement

3. Healthy periodontium and the pathogenesis of periodontitis

The periodontium consists of the tooth’s surrounding anatomical structures, which include, from superficial to deep, the gingiva, gingival ligament, root cementum, and alveolar bone (Figure 3).

Figure 3.

An illustration of a healthy tooth and its surrounding structures (i.e., periodontium).

In a healthy periodontium, the supportive anatomical structures adhere to the tooth by way of connective and epithelial tissue types [35]. The epithelia exist as different subtypes around the erupted tooth and have been described as the first line of defence, protecting the underlying tissues of the periodontium from microbial infiltration from the oral cavity (Figure 4) [35]. The pathogenesis of PD first involves a shift in the oral milieu which optimizes the formation of a dysbiotic microbial biofilm, resulting gingival inflammation, which then progresses to the subgingival region (Figure 4) [36].

Figure 4.

An overview of the pathogenesis of PD starting with gingivitis progressing to severe PD.

Clinically, people suffering from PD present with bleeding gingiva upon probing and varying degrees of detachment (i.e., clinical attachment loss [CAL]) of the gingiva from the tooth as measured with a periodontal probe (ada.org) (Figure 5).

Figure 5.

Measuring of the depth of periodontal pockets with a probe is part of the diagnostic criteria predicting the severity of periodontal disease.

Advertisement

4. Porphyromonas gingivalis and its central role in the pathogenesis of PD

Understanding further details of the disease process of PD from the perspective of the oral microbiome can assist in the creation of novel preventative and treatment applications.

Overall, bacteria, fungi, viruses, and protozoa are among the estimated 1000 microbial species that make up the oral microbiome. However, more than 700 microbes are bacterial, giving investigators a rationale for focusing on the bacterial taxa of the oral cavity, when examining health status [36, 37, 38].

Keystone pathogen, P. gingivalis (Pg), is a Gram-negative, anaerobic, non-motile, a-saccharolytic bacteria, which is a part of the normal flora of the subgingival region of the oral cavity, becomes an opportunistic pathogen when the microenvironmental factors permit it to thrive [39].

Also of note, is lipopolysaccharide (LPS), a feature found in the cell walls of Gram-negative bacteria, which triggers an inflammatory response as a pathogen-associated molecular pattern (PAMP). inflammation [40].

Detection by the host complement system is avoided due to the capsule, which is seen in most strains of Pg [41]. Also, the bacterial virulence factors, FimA and Mfa, which are proteins that make up the bacterial appendages, fimbriae, and pili, allow Pg to adhere to the periodontal cells whilst encouraging agglutination between bacteria, thus promoting the formation of a pathogenic biofilm [39, 42, 43, 44] (Figure 6).

Figure 6.

A schematic of the major virulence factors of Porphyromonas gingivalis and a general overview of their involvement in pathogenicity.

Following adherence to the gingival epithelia, Pg can enter into its host cell with ease, due to the secretion of the serine phosphatase, SerB, which enters the host cell and triggers the de-polymerisation of cytoskeletal actin microfilaments [45] (Figure 6).

For increased success in gaining an intracellular foothold, Pg also employs a sophisticated secretory system (e.g., Type IX Secretory System [T9SS]), which spans the periplasmic space and allows for the passage of its secretory products from the cytoplasm into the extracellular environment [46, 47].

Further to this, gingipains are involved in the manipulation of the host immune system, making them key players in tissue destruction through chronic inflammation. For example, gingipains have been found to degrade many cytokines as well as the CD4 and CD8 integral membrane proteins of T lymphocytes, creating interference within the host’s adaptive immune system [46, 48, 49, 50].

Moreover, an autoimmune attack on host tissue is assisted by the effector protein, peptidylarginine deaminase (PAD), which post-translationally modifies host proteins through citrullination, setting them up as immune targets [46, 51, 52] (Figure 6).

Other significant virulence factors of Pg include outer membrane vesicles (OMVs), which are released from most Gram-negative bacteria and can infiltrate places that the bacteria cannot. However, those derived from Pg, are armed with an outer membrane layer, consisting of a capsule, LPS, and gingipains, enclosing an internal compartment loaded with effector proteins and other macromolecules such as nucleic acids. Indeed, OMVs are pro-inflammatory agents of cytotoxic destruction aiding in biofilm formation, as well as the manipulation and evasion of the host immune response [46, 53] (Figure 6).

Advertisement

5. Pg links to PD-related diseases

Common and frequent activities like mastication and oral care, have been found to release oral pathogens and their components into the lymphatic and cardiovascular systems of PD patients. Therefore, periodontal Pg infections likely act as pathogenic reservoirs, possibly promoting certain systemic diseases [52, 54].

5.1 Neurodegenerative disease

A 2021 study by Franciotii et al. hypothesised that there is a “bidirectional oral-brain” highway through which neurodegenerative processes are stimulated by pro-inflammatory oral processes and vice versa [55].

Most importantly, initiatives towards the innovation of preventative measures for PD have been recommended, especially since the global population is ageing [55].

5.2 Head and neck cancer

The reports regarding Pg infection as a risk factor for oral squamous cell and oesophageal carcinoma, align with the emerging perspective in the clinical arena linking chronic systemic inflammation to serious disease states [23, 56, 57, 58, 59].

5.3 Cardiovascular disease

Regarding PD as it relates to cardiovascular disease, decades of literature reflect a close association [15, 19, 60]. DNA (i.e., 16S rDNA) from Pg has been identified in atheroma isolated from patients with coronary heart disease through PCR analysis [61]. Interestingly, Pg may also encourage atherosclerosis by switching HDL properties from antiatherogenic to proatherogenic via the manipulation of monocytes [62].

Further to this, Pg has been shown to invade and multiply within coronary endothelia in vitro, whilst damaging the smooth muscle cells and possibly distorting the vasodilatory mechanism of the central arterial system [63, 64].

Overall, the literature encourages appreciation of the clinical significance of the assault on the coronary endothelia demonstrated by Pg, especially since the vasculature acts as a vital line of defence for the cardiovascular system [63, 65].

5.4 Respiratory disease

Mortality risks from aspiration pneumonia are high in geriatric populations [66]. Of note, in vitro studies have identified Pg as a potent pro-inflammatory agent in isolated respiratory epithelia cells [67]. Additional in vitro studies identified Pg-derived OMVs as significant bacterial virulence factors which connect PD to respiratory disease [68].

5.5 Liver disease

It is worth noting that a significant correlation (P < 0.05) between non-alcoholic steatohepatitis (NASH) and oral Pg, has been reported. Furthermore, following treatment for PD, an improvement of liver function, displayed by the normalisation of AST and ALT, has been demonstrated [54, 69].

5.6 Diabetes mellitus

The relationship between PD and diabetes mellitus (DM) has also been studied with respect to Pg. For example, gingipains carried by OMVs derived from oral Pg, decreased the insulin sensitivity of hepatocytes whilst hepatocytes invaded by Pg were also found to display a decrease in glycogen synthesis in vitro (human) and in vivo (mouse model) [70].

5.7 Rheumatoid arthritis

DNA sequences from Pg have been isolated from the synovial fluid and bloodstream of patients with rheumatoid arthritis (RA). Further to this, the consistently reported relationship between an oral Pg infection and RA has encouraged medical clinicians to place more emphasis on the oral health of their patients [71].

5.8 Adverse pregnancy outcomes

Pg DNA has also been detected in the amniotic fluid, umbilical cord, and placenta of women who encountered pregnancy complications such as preeclampsia and preterm birth [72]. Additionally, results from animal studies suggest that the mechanism involves the direct invasion and damage of the uterine and placental tissue [65].

The adage that correlation does not mean causation, should be considered, and although Pg cannot be the sole etiological agent of all the systemic diseases with which it is associated, there is accumulating evidence demonstrating its value as a modifiable risk factor for the prevention, management, and treatment of PD and other systemic diseases (Figure 7) [65].

Figure 7.

The virulence factors of Pg and the systemic illnesses with which they have been associated. (A) Alzheimer’s disease, Parkinson’s disease, depression, (B) head and neck cancers, (C) atherosclerosis, myocardial infarction, aortic aneurism (D) aspiration pneumonia, (E) non-alcoholic fatty liver disease (NASH) (F) diabetes mellitus (G) rheumatoid arthritis (H) adverse pregnancy outcomes.

Advertisement

6. Treatment of PD

Typically, treatment for periodontitis includes physical removal of the biofilm and calculus from under the gingiva by way of scaling and root planning (SRP) followed by comprehensive care (CC) (www.NHS.uk; www.ADA.org) (Figure 8). Whereas, in cases where more severe destruction has occurred, flap surgery is performed, which is often accompanied by expensive reconstructive treatments and/or procedures. In all cases of PD, patients are advised to adhere to lifelong CC to mitigate any further destruction [73, 74, 75, 76].

Figure 8.

Scaling and root planning with an open (left) and closed (right) curettage for the treatment of periodontitis.

Adjunct therapies are often combined to optimise results following SRP [76]. For example, one type of host modulation therapy (HMT) consisting of a sub-antimicrobial dose of doxycycline (SDD), is an internationally approved adjunct treatment for PD. SDD acts through the inhibition of the pathogenic collagenase activity in the host, thus decreasing inflammation and tissue destruction [77].

Interestingly, some naturally occurring phytonutrients also may work through the management of the host inflammatory response. For example, chemically modified curcumin has been shown to be safe and effective for the treatment of PD and other inflammation-mediated diseases in animal models [77, 78, 79]. Another bioactive phytonutrient of interest is trans-resveratrol, which in combination with curcumin, has been gaining attention as a supplement for the prevention and treatment of PD and other inflammation-mediated conditions [80].

Advertisement

7. Resveratrol: a bioactive polyphenol with attractive medicinal properties

Trans-resveratrol (trans-3,5,4′-trihydroxystilbene) (RES) is a polyphenol that can be sourced from various edible plants, which has demonstrated antioxidant, anti-inflammatory, antimicrobial, anticancer, and restorative properties [81, 82, 83, 84]. Therefore, RES is positioned in alignment with the treatment principles for PD and the diseases with which it has been associated (Figure 9).

Figure 9.

The molecular structures of trans-resveratrol (trans-3,5,4′-trihydroxystilbene) (RES) (see left), which is the more stable, and therefore bioactive form compared to its isomer, cis-resveratrol (see right) (Gambini et al. [85]).

Even though RES is found in a breadth of plant-based foods (e.g., red wine, berries, peanuts, and dark chocolate), the naturally occurring concentrations of RES are not substantial enough (e.g., 0.1–0.7 mg/L in red wine) to reasonably attain the therapeutic values reported in the scientific literature (e.g., an oral dose of approximately 10 mg/kg body) [86, 87, 88].

Consequently, the purified and optimised extracts of RES are often used in research and some products have been made commercially available as wellness supplements (https://megaresveratrol.net; https://biotivia.com/pages/transmax-tr-1).

However, RES is a hydrophobic molecule and therefore, like other promising phytotherapeutics such as curcumin, has poor water solubility (<0.05 mg/mL). RES has also been found to rapidly metabolise in vivo and revert to its less stable isomer when exposed to light, demonstrating its instability and photosensitivity, respectively [85].

Additionally, the low oral bioavailability of RES has been considered a significant obstacle to its clinical translation, resulting in the development of drug carrier models. In fact, there is ample evidence indicating that nano-formulation may be a successful strategy to improve the pharmacological indices of RES under physiological conditions [89, 90, 91].

Interestingly, the design of functional foods also includes the application of nanotechnology, via the incorporation of liposomal nanocarriers or other nano-encapsulated systems. In this way, the therapeutic potential of customised, effective, and stable fortified foods with specific pharmacokinetic parameters, such as steady time-release, can be investigated [92].

Indeed, both oral and buccal delivery systems, such as those possible via functional food design, have plausible applications regarding PD therapeutics, especially since the primary target area for treatment is in the oral cavity. In fact, many nano-formulations also aim to enhance the delivery and efficacy of targeted therapeutics by engineering combinations of selected bioactive molecules that offer specific properties that promise to optimise the probability of the desired treatment outcome [93].

Advertisement

8. The attenuation of inflammatory processes by RES in vitro

The modulation of deregulated inflammation, which has been consistently reported for RES in the in vitro reports within the literature, is a central treatment principle for a viable therapeutic for PD. Additionally, in vitro studies allow for a breadth of experiment parameter manipulation not afforded by in vivo studies. So, although such studies cannot probe disease development and treatment, they can support the elucidation of mechanisms of action, thus identifying potential molecular targets for therapeutic applications.

For example, studies that used LPS-stimulated human gingival fibroblasts (HGFs), found through ELISA, and MTT assays, that RES significantly decreased IL-6 and IL-8, but did not increase cell viability. Interestingly, once RES was combined with the polyphenol silymarin (SIL), the viability increased in combination with the decrease in IL-6, IL-8 as well as TNF-α, suggesting that RES- ± SIL have a more widespread modulatory effect on LPS-induced inflammation [94, 95].

Additionally, in 2014, Fordham et al. examined the effect of RES (plus antioxidants, phloretin, silymarin, hesperetin) on LPS-stimulated peripheral blood mononuclear cells (PBMCs) obtained from healthy human donors. ELISA showed that RES decreased the secretion of IL-1β, IL-6, and IFN-ɣ in the LPS-induced PBMCs. Further to this, TNF-α was attenuated at the level of mRNA, as determined by RT-PCR. The researchers concluded that hesperetin and RES significantly inhibited (p < 0.05) the inflammatory response in LPS-stimulated PBMCs [96].

Advertisement

9. The influence of RES on regenerative processes in periodontal cells

RES has also shown promise regarding the restoration of periodontal tissue, which is a crucial part of the complete treatment of PD. For example, in a complex human in vitro and in situ study, Wang and colleagues reported that RES preserved cell aggregation and osteo-differentiation of normal human periodontal ligamental stem cells (HPLSCs) treated with TNF-α. In this study, histological analysis confirmed that RES treatment (even pre-implantation) improved regeneration in tissue originating from both healthy and pro-inflammatory microenvironments [97].

In accordance, Yuan and colleagues also found through histochemical analysis, RT-PCR, Western blot, and ELISA, that RES attenuated TNF-α – induced osteogenic suppression in HPLSCs in vitro [98].

Advertisement

10. RES as an attenuator of risk factors and conditions associated with PD

It has been well-established that PD is associated, to varying degrees, with a collection of modifiable risk factors as well as a myriad of systemic inflammation-mediated diseases [24, 99]. Hence, studies examining the effect of RES on PD in combination with purported comorbidity, and/or risk factor, could contribute to the argument regarding the breadth of its benefits.

Studies employing the integration of RA, DM, cigarette smoking, or osteoporosis (OP) into the induced-PD model have demonstrated that RES may assist in the mitigation of the periodontal damage contributed by associated risk factors and concomitant conditions. For example, with cigarette smoking added to the animal model, it was found that RES decreased both alveolar bone loss and oxidative stress [100, 101]. Additionally, using a ligature-induced PD model, RES was found to reduce alveolar bone loss and attenuate hyperglycemia in diabetic mice [102, 103].

Another study, which employed an induced-PD and RA animal model, determined immunoenzymatically, that both Ibuprofen and RES reduced the tissue levels of anti-cyclic citrullinated peptide antibody (ACCPA) by 99 and 72%, respectively (p < 0.05), and RES alone, was reported to reduce serum rheumatoid factor (RF) (p < 0.05) [101].

Interestingly, the results of a study that used an induced-PD model which concurrently induced osteoporosis (OP) by ovariectomising the rats, suggested that RES may reduce alveolar bone loss in oestrogen-deficient rats via the attenuation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, making NADPH oxidase a potential drug target for RES [104].

Also of note, an extensive in vitro study showed the potential for RES to address Pg-related disease, with a particular focus on the prevention of Alzheimer’s disease. Using a human in vitro model for neuroinflammation, Bahar and Singarao demonstrated that RES successfully modulated the ROS and deregulated inflammation. A total of 96 genes were analysed in Pg LPS-induced human neuroblastoma cells via qPCR followed by pathway analysis. In this way, RES was found to diminish NF-κB, neuroinflammatory acute phase pathways [105].

11. Animal studies: the amelioration of ligature-induced PD by RES

Although microbial dysbiosis is a necessary early occurrence in the pathogenesis of PD, the resulting chronic inflammation is the causal factor regarding its progression and continuous tissue destruction [106, 107]. Therefore, an effective therapeutic approach for the mitigation of PD would be to address the pathogenetically deregulated inflammatory pathways, mediators, and markers, encouraging the system to return to balance without deleterious side effects.

In a commonly used animal model, PD is induced by fitting a ligature around the neck of pre-selected molar teeth. Typically, PD that is induced in this way predictably presents with significant alveolar bone loss, accompanied by the increased expression of pro-inflammatory genes such as those for IL-1β, IL-6, and TNF-α. Notably, increased mRNA expression of genes coding for osteoclastogenic proteins and receptor activator of nuclear factor-k B ligand (RANKL) has also been reported when applying this model [108].

Morphometric analysis [27, 100, 101, 103, 109, 110, 111] and/or Micro-CT [104, 112, 113, 114] has been employed to demonstrate that RES reduced the alveolar bone loss from experimentally induced PD. The micro-CT analyses also reported improved bone density, suggesting that at the very least, RES has therapeutic potential as an adjunct to traditional SRP. This of course is caveated by emphasising the dependence of this data on the relevance of the PD animal model, and the need for validation with human studies.

12. Low bioavailability and stability: an obstacle to the clinical translation of RES

The poor water solubility of RES is well established. However, RES is highly stable in aqueous solutions of acidic pH. Moreover, researchers must consider that RES degrades rapidly in buffers of 7.4 pH or higher [115]. For example, RES incorporated into buffered cell medium was found to degrade to 50% of its original concentration within 24 h of incubation at 37°C [115]. Hence, many of the in vitro studies, which assume that the pre-determined RES concentration is consistent for the study duration, are likely to produce misleading results regarding therapeutic dose.

Research has emerged employing novel RES formulations to overcome the pharmacological limitations and optimise therapeutic potential, ultimately improving its clinical translation [116, 117, 118, 119].

13. Overcoming therapeutic limitations of RES by the application of nanotechnology

RES has been reported as having notably poor water solubility as well as high sensitivity to heat and pH [115]. Also, since RES is unstable under physiological pH and temperature, in vivo assays are challenging to design and in vitro assays are likely to have low translatability [92, 120, 121].

Additionally, oral administration of RES has demonstrated unfavourable pharmacokinetics due to its extensive first pass, resulting in the accumulation of potentially recycled conjugates, RES-glucuronides, and RES-sulphates; although these metabolites have also been found to possess biological activity, it may not match that of the parental compound [85].

Previous reports highlighting the physicochemical limitations of RES indicate that meticulous consideration of aqueous solubility, pH, temperature, and light, during the experimental design phase is crucial for the optimisation of clinical translation [122].

Consequently, the search for effective strategies for the improvement of the limited oral bioavailability and stability, is a complex, yet necessary, undertaking for the successful development of RES as a therapeutic.

Regarding RES, improvement of one or more physicochemical and/or pharmacological parameters has been reported when in a nano form, indicating the potential of nanotechnological formulation as a viable strategy for improving its physicochemical stability and pharmacological profile.

Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are commonly employed to improve the therapeutic potential of hydrophobic drugs such as RES. Furthermore, findings that assessed the pharmacological potential of RES-loaded SLNs and NLCs, indicated their higher stability and sustained release compared to RES in its bulk form [123, 124, 125, 126, 127, 128].

Further to this, studies seeking out to fortify and/or functionalise foods with RES, reported that nanoencapsulation substantially increased thermostability and photostability whilst retaining or optimising the desired biological activity. For example, an in vitro investigation examining the nano-encapsulation of RES in starch, conducted at pH 7.4 at 37° C, was reported to demonstrate an almost ten-fold increase in drug retention following a food extrusion process, as well as higher anti-diabetic, anti-obesity, and antioxidant effects, compared to bulk RES [129].

Similarly, the sustained release of RES from ZEIN-encapsulated nanoparticles (NPs) under physiological conditions (pH 7.4, 37°C) was reported [130] and casein-encapsulated RES NPs, designed by Penlava et al., were found to be stable through a continuous pH range mimicking those of the gastrointestinal compartments (i.e., pH 1.2 for 2 h and pH 6.8 for 2–24 h). Interestingly, the latter study also demonstrated in vivo (using rats), a ten-fold increase in oral availability of casein-nano-encapsulated RES compared to the bulk form as determined by blood plasma assays over a 24 h period following a single oral dose of 15 mg/kg of RES (in ddH2O and PEG) or casein-encapsulated RES NPs [131].

These studies and others bring to light the prospect of the customisation of functional foods, to serve as both local and systemic delivery system for the effective prevention, management, and treatment of PD.

14. Restoration of tissue damage from PD: potential of current Nano RES formulations

Nano-RES formulations intended specifically for the treatment of PD, are only beginning to emerge. For example, Berta et al., reported a nano-formulated RES-cyclodextrin mouthwash that was found to reduce plaque and bleeding gums in children [132]. Nonetheless, there are several nano RES formulations, intended to treat other conditions, which could, in theory, be studied as potential formulations for PD, with little divergence from the original formula.

For example, in a 2021 study, Li and colleagues produced nano-hydroxyapatite-RES-chitosan (CS) microspheres for bone generation, which could potentially be used to restore bone loss due to PD [133].

Also, electrospun 3-D nano-scaffolds loaded with RES, consisting of a biodegradable polymer (PLA)-biopolymer-gelatin (GEL) nano-scaffold was found to repair cartilage defects in the rat model [134].

Notably, monodispersed, spherical chitosan-zinc oxide-RES (CS-ZnO-RES) nanoparticles (NP) (38 nm) engineered by Du et al., were reported to attenuate gestational DM (GDM) [135].

Moreover, the successful application of nano-RES as a potential treatment for AD has been reported by Sun et al., who designed a RES-loaded mesoporous selenium-Fc-β-cyclodextrin-Borneol nanoparticle that crossed a blood-brain barrier model [136].

15. RES has evolved to be a viable agent for the treatment of PD

RES has been shown to execute biological action that alleviates deregulated inflammation, and restores both soft and bony tissues, in vitro, and in vivo, via modulation on the genetic, protein, and cellular level, thus strengthening the case for RES as a therapeutic for PD. Further to this, improvement of the pharmacokinetic and physicochemical limitations of RES has been demonstrated via nanoformulation. There is now much work to be done in identifying and optimising the ideal nanoformulation and administration route to achieve optimal benefit from the activities RES has demonstrated.

References

  1. 1. Genco R, Sanz M. Clinical and public health implications of periodontal and systemic diseases: An overview. Periodontology 2000. 2020;83(1):7-13. DOI: 10.1111/prd.12344
  2. 2. Genco R, Borgnakke W. Risk factors for periodontal disease. Periodontology 2000. 2013;62(1):59-94. DOI: 10.1111/j.1600-0757.2012.00457.x
  3. 3. Peruzzo D, Benatti B, Ambrosano G, Nogueira-Filho G, et al. A systematic review of stress and psychological factors as possible risk factors for periodontal disease. Journal of Periodontology. 2007;78(8):1491-1504
  4. 4. Reynolds M. Modifiable risk factors in periodontitis: At the intersection of aging and disease. Periodontology 2000. 2013;64(1):7-19
  5. 5. Bernabe E, Marcenes W, Hernandez C, Bailey J, et al. Global, regional, and national levels and trends in burden of oral conditions from 1990 to 2017: A systematic analysis for the global burden of disease 2017 Study. Journal of Dental Research. 2020;99(4):362-373. DOI: 10.1177/0022034520908533
  6. 6. Frencken J, Sharma P, Stenhouse L, Green D, et al. Global epidemiology of dental caries and severe periodontitis – A comprehensive review. Journal of Clinical Periodontology. 2017;44:94-105. DOI: 10.3390/ma13112631
  7. 7. Tonetti M, Jepsen S, Jin L, Otomo-Corgel J. Impact of the global burden of periodontal diseases on health, nutrition and wellbeing of mankind: A call for global action. Journal of Clinical Periodontology. 2017;44(5):456-462
  8. 8. Buset S, Walter C, Friedmann A, Weiger R, et al. Are periodontal diseases really silent? A systematic review of their effect on quality of life. Journal of Clinical Periodontology. 2016;43(4):333-344. DOI: 10.1111/jcpe.12517
  9. 9. Duane B, Reynolds I. Periodontal disease has an impact on patients’ quality of life. Evidence-Based Dentistry. 2018;19(1):14-15
  10. 10. Botelho J, Machado V, Leira Y, Proença L, et al. Economic burden of periodontitis in the United States and Europe – An updated estimation. Journal of Periodontology. 2021. DOI: 10.1101/2021.01.19.21250090
  11. 11. Papapanou P, Susin C. Periodontitis epidemiology: Is periodontitis under-recognized, over-diagnosed, or both? Periodontology 2000. 2017;75(1):45-51
  12. 12. Baelum V, Lopez R. Epidemiology of periodontal diseases. In: Peres MA, Antunes JLF, Watt RG, editors. A Textbook on Oral Health Conditions, Research Topics and Methods. Cham: Springer; 2021. pp. 55-57
  13. 13. Papapanou P. The prevalence of periodontitis in the us. Journal of Dental Research. 2012;91(10):907-908
  14. 14. Agarwal S. Impact of periodontitis on cardiovascular diseases. European Journal of Dental and Oral Health. 2021;2(2):1-8. DOI: 10.24018/EJDENT.2021.2.2.48
  15. 15. Bengtsson V, Persson G, Berglund J, Renvert S. Periodontitis related to cardiovascular events and mortality: A long-time longitudinal study. Clinical Oral Investigations. 2021;25(6):4085-4095. DOI: 10.1007/s00784-020-03739-x
  16. 16. Bodanese L, Louzeiro G, Magnus G, Baptista Â, et al. Association between periodontitis and myocardial infarction: Systematic review and meta-analysis. International Journal of Cardiovascular Sciences. 2021;34(5Supl.1):121-127
  17. 17. Sia S, Jan M, Wang Y, Huang Y, Wei J. Periodontitis is associated with incidental valvular heart disease: A nationwide population-based cohort study. Journal of Clinical Periodontology. 2021;48(8):1085-1092
  18. 18. Surma S, Romańczyk M, Witalińska-Łabuzek J, Czerniuk M, et al. Periodontitis, blood pressure, and the risk and control of arterial hypertension: Epidemiological, clinical, and pathophysiological aspects – Review of the literature and clinical trials. Current Hypertension Reports. 2021;23(5). DOI: 10.1007/s11906-021-01140-x
  19. 19. Tiensripojamarn N, Lertpimonchai A, Tavedhikul K, Udomsak A, et al. Periodontitis is associated with cardiovascular diseases: A 13-year study. Journal of Clinical Periodontology. 2021;48(3):348-356
  20. 20. Trindade F, Perpétuo L, Ferreira R, Leite-Moreira A, et al. Automatic text-mining as an unbiased approach to uncover molecular associations between periodontitis and coronary artery disease. Biomarkers. 2021;26(5):385-394
  21. 21. Abbayya K, Chidambar Y, Naduwinmani S, Puthanakar N. Association between periodontitis and alzheimer’s disease. North American Journal of Medical Sciences. 2015;7(6):241. DOI: 10.4103/1947-2714.159325
  22. 22. Cerajewska T, Davies M, West N. Periodontitis: A potential risk factor for Alzheimer’s disease. British Dental Journal. 2015;218(1):29-34. DOI: 10.1038/sj.bdj.2014.1137
  23. 23. Olsen I, Yilmaz Ö. Possible role of porphyromonas gingivalis in oro-digestive cancers. Journal of Oral Microbiology. 2019;11(1):1563410. DOI: 10.1080/20002297.2018.1563410
  24. 24. Bae S, Lee Y. Causal association between periodontitis and risk of rheumatoid arthritis and systemic lupus erythematosus: A Mendelian randomization. Zeitschrift für Rheumatologie. 2020;79(9):929-936. DOI: 10.1007/s00393-019-00742-w
  25. 25. Bolstad A, Sehjpal P, Lie S, Fevang B. Periodontitis in patients with systemic lupus erythematosus: A nation-wide study of 1990 patients. Journal of Periodontology. 2021:1-8. DOI: 10.1002/JPER.21-0181
  26. 26. Krishnasree R, Jayanthi P, Karthika P, Nandhakumar K, Rathy R. Association of chronic periodontitis and oral cancer: A review on pathogenetic mechanism and clinical implication. Journal of Dr NTR University of Health Sciences. 2020;9:209-212
  27. 27. Chen P, Chen Y, Lin C, Yeh Y, et al. Effect of periodontitis and scaling and root planing on risk of pharyngeal cancer: A nested case-control study. International Journal of Environmental Research and Public Health. 2020;18(1):8. DOI: 10.3390/ijerph18010008
  28. 28. Ma H, Zheng J, Li X. Potential risk of certain cancers among patients with periodontitis: A supplementary meta-analysis of a large-scale population. International Journal of Medical Sciences. 2020;17(16):2531-2543
  29. 29. Vedamanickam S. Microbiological assessment in plaque samples of patients with oral cancer with or without smoking. Annals of the Romanian Society for Cell Biology. 2021;25(1):5294-5301
  30. 30. Zhang Y, He J, He B, Huang R, Li M. Effect of tobacco on periodontal disease and oral cancer. Tobacco Induced Diseases. 2019;17(May):1-15. DOI: 10.18332/tid/106187
  31. 31. Candeo L, Rigonato-Oliveira N, Brito A, Marcos R, et al. Effects of periodontitis on the development of asthma: The role of photodynamic therapy. PLoS One. 2017;12(11):187945. DOI: 10.1371/journal.pone.0187945
  32. 32. Gomes-Filho I, Cruz S, Trindade S, Passos-Soares J, et al. Periodontitis and respiratory diseases: A systematic review with meta-analysis. Oral Diseases. 2019;26(2):439-446. DOI: 10.1111/odi.13228
  33. 33. Marouf N, Cai W, Said K, Daas H, et al. Association between periodontitis and severity of COVID-19 infection: A case-control study. Journal of Clinical Periodontology. 2021;48(4):483-491
  34. 34. Soledade-Marques K, Gomes-Filho I, da Cruz S, Passos-Soares J, et al. Association between periodontitis and severe asthma in adults: A case-control study. Oral Diseases. 2017;24(3):442-448
  35. 35. Harris S, Rakian A, Foster B, Chun Y, Rakian R. The periodontium. Principles of Bone Biology. 2020:1061-1082. DOI: 10.1016/B978-0-12-814841-9.00043-9
  36. 36. Berger D, Rakhamimova A, Pollack A, Loewy Z, et al. Oral biofilms: Development, control, and analysis. High-Throughput. 2018;7(3):24. DOI: 10.3390/ht7030024
  37. 37. Deo P, Deshmukh R. Oral microbiome: Unveiling the fundamentals. Journal of Oral and Maxillofacial Pathology. 2019;23(1):122-128. DOI: 10.4103/jomfp.JOMFP_304_18
  38. 38. Radaic A, Kapila Y. The oralome and its dysbiosis: New insights into oral microbiome-host interactions. Computational and Structural Biotechnology Journal. 2021;19:1335-1360
  39. 39. Nagano K, Hasegawa Y, Iijima Y, Kikuchi T, Mitani A. Distribution of porphyromonas gingivalis fimA and mfa1fimbrial genotypes in subgingival plaques. PeerJ. 2018;6:5581. DOI: 10.7717/peerj.5581
  40. 40. Matsuura M. Structural modifications of bacterial lipopolysaccharide that facilitate gram-negative bacteria evasion of host innate immunity. Frontiers in Immunology. 2013;4:1-9. DOI: 10.3389/fimmu.2013.00109
  41. 41. Singh A, Wyant T, Anaya-Bergman C, Aduse-Opoku J, et al. The capsule of porphyromonas gingivalis leads to a reduction in the host inflammatory response, evasion of phagocytosis, and increase in virulence. Infection and Immunity. 2011;79(11):4533-4542
  42. 42. Gully N, Bright R, Marino V, Marchant C, et al. Porphyromonas gingivalis peptidylarginine deiminase, a key contributor in the pathogenesis of experimental periodontal disease and experimental arthritis. PLoS One. 2014;9(6):100838. DOI: 10.1371/journal.pone.0100838
  43. 43. Kuboniwa M, Amano A, Hashino E, Yamamoto Y, et al. Distinct roles of long/short fimbriae and gingipains in homotypic biofilm development by porphyromonas gingivalis. BMC Microbiology. 2009;9(1):105
  44. 44. Ikai R, Hasegawa Y, Izumigawa M, Nagano K, et al. Mfa4, an accessory protein of mfa1 fimbriae, modulates fimbrial biogenesis, cell auto-aggregation, and biofilm formation in porphyromonas gingivalis. PLoS One. 2015;10(10):0139454
  45. 45. Hajishengallis G, Lamont R. Breaking bad: Manipulation of the host response byPorphyromonas gingivalis. European Journal of Immunology. 2014;44(2):328-338
  46. 46. Lunar Silva I, Cascales E. Molecular Strategies Underlying Porphyromonas gingivalis Virulence. Journal of Molecular Biology. 2021;433(7):166836
  47. 47. Vincent M, Canestrari M, Leone P, Stathopulos J, et al. Characterization of the porphyromonas gingivalis type IX secretion Trans-envelope por KLMNP core complex. Journal of Biological Chemistry. 2017;292(8):3252-3261
  48. 48. Dahlen G, Basic A, Bylund J. Importance of virulence factors for the persistence of oral bacteria in the inflamed gingival crevice and in the pathogenesis of periodontal disease. Journal of Clinical Medicine. 2019;8(9):1339. DOI: 10.3390/jcm8091339
  49. 49. de Diego I, Veillard F, Sztukowska M, Guevara T, et al. Structure and mechanism of cysteine peptidase gingipain K (Kgp): A major virulence factor of porphyromonas gingivalis in periodontitis. Journal of Biological Chemistry. 2014;289(46):32291-32302. DOI: 10.1074%2Fjbc.M114.602052
  50. 50. Jia L, Han N, Du J, Guo L, et al. Pathogenesis of important virulence factors of porphyromonas gingivalis via toll-like receptors. Frontiers in Cellular and Infection Microbiology. 2019;9:1-14. DOI: 10.3389/fcimb.2019.00262
  51. 51. Aliko A, Kamińska M, Bergum B, Gawron K, et al. Impact of porphyromonas gingivalis peptidylarginine deiminase on bacterial biofilm formation, epithelial cell invasion, and epithelial cell transcriptional landscape. Scientific Reports. 2018;8(1):1-9. DOI: 10.1038/s41598-018-32603-y
  52. 52. Mulhall H, Huck O, Amar S. Porphyromonas gingivalis, a long-range pathogen: Systemic impact and therapeutic implications. Microorganisms. 2020;8(6):869. DOI: 10.3390/microorganisms8060869
  53. 53. De Andrade K, Almeida-da-Silva C, Coutinho-Silva R. Immunological pathways triggered by porphyromonas gingivalis and fusobacterium nucleatum: Therapeutic possibilities? Mediators of Inflammation. 2019:1-20. DOI: 10.1155/2019/7241312
  54. 54. Zhang Z, Liu D, Liu S, Zhang S, Pan Y. The role of porphyromonas gingivalis outer membrane vesicles in periodontal disease and related systemic diseases. Frontiers in Cellular and Infection Microbiology. 2021;10:1-12. DOI: 10.3389/fcimb.2020.585917
  55. 55. Franciotti R, Pignatelli P, Carrarini C, Romei F, et al. Exploring the connection between porphyromonas gingivalis and neurodegenerative diseases: A pilot quantitative study on the bacterium abundance in oral cavity and the amount of antibodies in serum. Biomolecules. 2021;11(6):845. DOI: 10.3390/biom11060845
  56. 56. Gopinath D, Menon R, K Veettil S, Botelho M, et al. Periodontal diseases as putative risk factors for head and neck cancer: Systematic review and meta-analysis. Cancers. 2020;12(7):1893. DOI: 10.3390/cancers12071893
  57. 57. Kong L, Qi X, Huang S, Chen S, et al. Theaflavins inhibit pathogenic properties of P. gingivalis and MMPs production in P. gingivalis-stimulated human gingival fibroblasts. Archives of Oral Biology. 2015;60(1):12-22
  58. 58. Liu X, Gao Z, Sun C, Wen H, et al. The potential role of P. gingivalis in gastrointestinal cancer: A mini review. Infectious Agents and Cancer. 2019;14(1). DOI: 10.1186/s13027-019-0239-4
  59. 59. Ibáñez L, de Mendoza I, Maritxalar Mendia X, García de la Fuente A, Quindós Andrés G, Aguirre Urizar J. Role of porphyromonas gingivalis in oral squamous cell carcinoma development: A systematic review. Journal of Periodontal Research. 2019;55(1):13-22
  60. 60. Dorn B, Dunn W, Progulske-Fox A. Porphyromonas gingivalis traffics to autophagosomes in human coronary artery endothelial cells. Infection and Immunity. 2001;69(9):5698-5708. DOI: 10.1128/IAI.69.9.5698-5708.2001
  61. 61. Rao A, D’Souza C, Subramanyam K, Rai P, Thomas B, Gopalakrishnan M, et al. Molecular analysis shows the presence of periodontal bacterial DNA in atherosclerotic plaques from patients with coronary artery disease. Indian Heart Journal. 2021;73(2):218-220
  62. 62. Kim H, Cha G, Kim H, Kwon E, et al. Porphyromonas gingivalis accelerates atherosclerosis through oxidation of high-density lipoprotein. Journal of Periodontal & Implant Science. 2018;48(1):60
  63. 63. Fiorillo L, Cervino G, Laino L, D’Amico C, et al. Porphyromonas gingivalis, periodontal and systemic implications: A systematic review. Dentistry Journal. 2019;7(4):114. DOI: 10.3390/dj7040114
  64. 64. Sun W, Wu J, Lin L, Huang Y, et al. Porphyromonas gingivalis stimulates the release of nitric oxide by inducing expression of inducible nitric oxide synthases and inhibiting endothelial nitric oxide synthases. Journal of Periodontal Research. 2010;45(3):381-388
  65. 65. Mei F, Xie M, Huang X, Long Y, et al. Porphyromonas gingivalis and its systemic impact: Current status. Pathogens. 2020;9(11):944. DOI: 10.3390/pathogens9110944
  66. 66. Pace C, McCullough G. The association between oral microorgansims and aspiration pneumonia in the institutionalized elderly: Review and recommendations. Dysphagia. 2010;25(4):307-322. DOI: 10.1007/s00455-010-9298-9
  67. 67. Takahashi T, Muro S, Tanabe N, Terada K, et al. Relationship between periodontitis-related antibody and frequent exacerbations in chronic obstructive pulmonary disease. PLoS One. 2012;7(7):40570. DOI: 10.1371/journal.pone.0040570
  68. 68. He Y, Shiotsu N, Uchida-Fukuhara Y, Guo J, et al. Outer membrane vesicles derived from porphyromonas gingivalis induced cell death with disruption of tight junctions in human lung epithelial cells. Archives of Oral Biology. 2020;118:104841. DOI: 10.1016/j.archoralbio.2020.104841
  69. 69. Yoneda M, Naka S, Nakano K, Wada K, et al. Involvement of a periodontal pathogen, porphyromonas gingivalis on the pathogenesis of non-alcoholic fatty liver disease. BMC Gastroenterology. 2012;12(1). DOI: 10.1186/1471-230X-12-16
  70. 70. Seyama M, Yoshida K, Yoshida K, Fujiwara N, et al. Outer membrane vesicles of porphyromonas gingivalis attenuate insulin sensitivity by delivering gingipains to the liver. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease. 2020;1866(6):165731. DOI: 10.1016/j.bbadis.2020.165731
  71. 71. Kriauciunas A, Gleiznys A, Gleiznys D, Janužis G. The influence of porphyromonas gingivalis bacterium causing periodontal disease on the pathogenesis of rheumatoid arthritis: Systematic review of literature. Cureus. 2019;11(5):e4775. DOI: 10.7759/cureus.4775
  72. 72. Chopra A, Radhakrishnan R, Sharma M. Porphyromonas gingivalisand adverse pregnancy outcomes: A review on its intricate pathogenic mechanisms. Critical Reviews in Microbiology. 2020;46(2):213-236. DOI: 10.1080/1040841X.2020.1747392
  73. 73. Ramanauskaite E, Machiulskiene V. Antiseptics as adjuncts to scaling and root planing in the treatment of periodontitis: a systematic literature review. BMC Oral Health. 2020;20:143. DOI: 10.1186/s12903-020-01127-1
  74. 74. Sanz-Martín I, Cha J, Yoon S, Sanz-Sánchez I, Jung U. Long-term assessment of periodontal disease progression after surgical or non-surgical treatment: A systematic review. Journal of Periodontal and Implant Science. 2019;49(2):60
  75. 75. Suvan J, Leira Y, Moreno Sancho F, Graziani F, et al. Subgingival instrumentation for treatment of periodontitis. A systematic review. Journal of Clinical Periodontology. 2020;47(S22):155-175
  76. 76. Tan O, Safii S, Razali M. Commercial local pharmacotherapeutics and adjunctive agents for nonsurgical treatment of periodontitis: A contemporary review of clinical efficacies and challenges. Antibiotics. 2019;9(1):1. DOI: 10.3390/antibiotics9010011
  77. 77. Golub L, Lee H. Periodontal therapeutics: Current host-modulation agents and future directions. Periodontology 2000. 2019;82(1):186-204. DOI: 10.1111/prd.12315
  78. 78. Curylofo-Zotti F, Elburki M, Oliveira P, Cerri P, et al. Differential effects of natural curcumin and chemically modified curcumin on inflammation and bone resorption in model of experimental periodontitis. Archives of Oral Biology. 2018;91:42-50
  79. 79. Deng J, Golub L, Lee H, Lin M, et al. Chemically modified curcumin: A novel systemic therapy for natural periodontitis in dogs. Journal of Experimental Pharmacology. 2020;12:47-60. DOI: 10.2147%2FJEP.S236792
  80. 80. Bisht K, Wagner K, Bulmer A. Curcumin, resveratrol and flavonoids as anti-inflammatory, cyto- and DNA-protective dietary compounds. Toxicology. 2010;278(1):88-100. DOI: 10.1016/j.tox.2009.11.008
  81. 81. Gorbunov N, Petrovski G, Gurusamy N, Ray D, et al. Regeneration of infarcted myocardium with resveratrol-modified cardiac stem cells. Journal of Cellular and Molecular Medicine. 2011;16(1):174-184
  82. 82. Meng T, Xiao D, Muhammed A, Deng J, et al. Anti-inflammatory action and mechanisms of resveratrol. Molecules. 2021;26(1):229. DOI: 10.3390/molecules26010229
  83. 83. Murgia D, Mauceri R, Campisi G, De Caro V. Advance on resveratrol application in bone regeneration: Progress and perspectives for use in oral and maxillofacial surgery. Biomolecules. 2019;9(3):94. DOI: 10.3390/biom9030094
  84. 84. Perrone D, Fuggetta M, Ardito F, Cottarelli A, et al. Resveratrol (3,5,4′-trihydroxystilbene) and its properties in oral diseases. Experimental and Therapeutic Medicine. 2017;14(1):3-9
  85. 85. Gambini J, Inglés M, Olaso G, Lopez-Grueso R, et al. Properties of resveratrol: In vitro and in vivo studies about metabolism, bioavailability, and biological effects in animal models and humans. Oxidative Medicine and Cellular Longevity. 2015:1-13. DOI: 10.1155/2015/837042
  86. 86. Giovinazzo G, Grieco F. Functional properties of grape and wine polyphenols. Plant Foods for Human Nutrition. 2015;70(4):454-462. DOI: 10.1007/s11130-015-0518-1
  87. 87. Salehi B, Mishra A, Nigam M, Sener B, et al. Resveratrol: A double-edged sword in health benefits. Biomedicine. 2018;6(3):91. DOI: 10.3390/biomedicines6030091
  88. 88. Weiskirchen S, Weiskirchen R. Resveratrol: How much wine do you have to drink to stay healthy? Advances in Nutrition: An International Review Journal. 2016;7(4):706-718
  89. 89. Jose S, Anju S, Cinu T, Aleykutty N, et al. In vivo pharmacokinetics and biodistribution of resveratrol-loaded solid lipid nanoparticles for brain delivery. International Journal of Pharmaceutics. 2014;474(1-2):6-13
  90. 90. Pandita D, Kumar S, Poonia N, Lather V. Solid lipid nanoparticles enhance oral bioavailability of resveratrol, a natural polyphenol. Food Research International. 2014;62:1165-1174
  91. 91. Summerlin N, Soo E, Thakur S, Qu Z, et al. Resveratrol nanoformulations: Challenges and opportunities. International Journal of Pharmaceutics. 2015;479(2):282-290
  92. 92. Singh A, Ahmad I, Ahmad S, Iqbal Z, Ahmad F. A novel monolithic controlled delivery system of resveratrol for enhanced hepatoprotection: Nanoformulation development, pharmacokinetics, and pharmacodynamics. Drug Development and Industrial Pharmacy. 2016;42(9):1524-1536
  93. 93. Jeong H, Samdani K, Yoo D, Lee D, et al. Resveratrol cross-linked chitosan loaded with phospholipid for controlled release and antioxidant activity. International Journal of Biological Macromolecules. 2016;93:757-766
  94. 94. Farzanegan A, Shokuhian M, Jafari S, Shirazi F, Shahidi M. Anti-histaminic effects of resveratrol and silymarin on human gingival fibroblasts. Inflammation. 2019;42(5):1622-1629. DOI: 10.1007/s10753-019-01023-z
  95. 95. Shahidi M, Vaziri F, Haerian A, Farzanegan A, et al. Proliferative and anti-inflammatory effects of resveratrol and silymarin on human gingival fibroblasts: A view to the future. Journal of dentistry (Tehran, Iran). 2017;14(4):203-211
  96. 96. Fordham J, Raza Naqvi A, Nares S. Leukocyte production of inflammatory mediators is inhibited by the antioxidants phloretin, silymarin, hesperetin, and resveratrol. Mediators of Inflammation. 2014:1-11. DOI: 10.1155/2014/938712
  97. 97. Wang Y, Zhao P, Sui B, Liu N, et al. Resveratrol enhances the functionality and improves the regeneration of mesenchymal stem cell aggregates. Experimental and Molecular Medicine. 2018;50(6):1-15
  98. 98. Yuan J, Wang X, Ma D, Gao H, et al. Resveratrol rescues TNF α induced inhibition of osteogenesis in human periodontal ligament stem cells via the ERK1/2 pathway. Molecular Medicine Reports. 2020;21:2085-2094. DOI: 10.3892/mmr.2020.11021
  99. 99. Hajishengallis G, Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nature Reviews Immunology. 2021;21:426-440. DOI: 10.1038/s41577-020-00488-6
  100. 100. Ribeiro F, Pino D, Franck F, Benatti B, et al. Resveratrol inhibits periodontitis-related bone loss in rats subjected to cigarette smoke inhalation. Journal of Periodontology. 2017;88(8):788-798
  101. 101. Corrêa M, Pires P, Ribeiro F, Pimentel S, et al. Systemic treatment with resveratrol reduces the progression of experimental periodontitis and arthritis in rats. PLoS One. 2018;13(10):204414. DOI: 10.1371/journal.pone.0204414
  102. 102. Ashour A, Xue M, Al-Motawa M, Thornalley P, Rabbani N. Glycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducer. BMJ Open Diabetes Research and Care. 2020;8(2):1458. DOI: 10.1136/bmjdrc-2020-001458
  103. 103. Zhen L, Fan D, Zhang Y, Cao X, Wang L. Resveratrol ameliorates experimental periodontitis in diabetic mice through negative regulation of TLR4 signaling. Acta Pharmacologica Sinica. 2014;36(2):221-228
  104. 104. Molez A, Nascimento E, Haiter Neto F, Cirano F, et al. Effect of resveratrol on the progression of experimental periodontitis in an ovariectomized rat model of osteoporosis: Morphometric, immune-enzymatic, and gene expression analysis. Journal of Periodontal Research. 2020;55(6):840-849
  105. 105. Bahar B, Singhrao S. An evaluation of the molecular mode of action of trans-resveratrol in the porphyromonas gingivalis lipopolysaccharide challenged neuronal cell model. Molecular Biology Reports. 2020;48(1):147-156. DOI: 10.1007%2Fs11033-020-06024-y
  106. 106. Delima A, Karatzas S, Amar S, Graves D. Inflammation and tissue loss caused by periodontal pathogens is reduced by interleukin-1 antagonists. The Journal of Infectious Diseases. 2002;186(4):511-516. DOI: 10.1086/341778
  107. 107. Könönen E, Gursoy M, Gursoy U. Periodontitis: A multifaceted disease of tooth-supporting tissues. Journal of Clinical Medicine. 2019;8(8):1135. DOI: 10.3390/jcm8081135
  108. 108. De Molon R, Park C, Jin Q, Sugai J, Cirelli J. Characterization of ligature-induced experimental periodontitis. Microscopy Research and Technique. 2018;81(12):1412-1421. DOI: 10.1002/jemt.23101
  109. 109. Casati M, Algayer C, Cardoso da Cruz G, Ribeiro F, et al. Resveratrol decreases periodontal breakdown and modulates local levels of cytokines during periodontitis in rats. Journal of Periodontology. 2013;84(10):58-64. DOI: 10.1902/jop.2013.120746
  110. 110. Corrêa M, Pires P, Ribeiro F, Pimentel S, et al. Systemic treatment with resveratrol and/or curcumin reduces the progression of experimental periodontitis in rats. Journal of Periodontal Research. 2016;52(2):201-209. DOI: 10.1111/jre.12382
  111. 111. Corrêa M, Absy S, Tenenbaum H, Ribeiro F, et al. Resveratrol attenuates oxidative stress during experimental periodontitis in rats exposed to cigarette smoke inhalation. Journal of Periodontal Research. 2019;54(3):225-232. DOI: 10.1111/jre.12622
  112. 112. Adhikari N, Prasad Aryal Y, Jung J, Ha J, et al. Resveratrol enhances bone formation by modulating inflammation in the mouse periodontitis model. Journal of Periodontal Research. 2021;56(4):735-745. DOI: 10.1111/jre.12870
  113. 113. Bhattarai G, Poudel S, Kook S, Lee J. Resveratrol prevents alveolar bone loss in an experimental rat model of periodontitis. Acta Biomaterialia. 2016;29:398-408. DOI: 10.1016/j.actbio.2015.10.031
  114. 114. Tamaki N, Cristina Orihuela-Campos R, Inagaki Y, Fukui M, et al. Resveratrol improves oxidative stress and prevents the progression of periodontitis via the activation of the Sirt1/AMPK and the Nrf2/antioxidant defense pathways in a rat periodontitis model. Free Radical Biology and Medicine. 2014;75:22-229. DOI: 10.1016/j.freeradbiomed.2014.07.034
  115. 115. Zupančič Š, Lavrič Z, Kristl J. Stability and solubility of trans-resveratrol are strongly influenced by pH and temperature. European Journal of Pharmaceutics and Biopharmaceutics. 2015;93:196-204
  116. 116. Ahmadi Z, Mohammadinejad R, Ashrafizadeh M. Drug delivery systems for resveratrol, a non-flavonoid polyphenol: Emerging evidence in last decades. Journal of Drug Delivery Science and Technology. 2019;51:591-604. DOI: 10.1016/j.jddst.2019.03.017
  117. 117. Augustin M, Sanguansri L, Lockett T. Nano- and micro-encapsulated systems for enhancing the delivery of resveratrol. Annals of the New York Academy of Sciences. 2013;1290(1):107-112. DOI: 10.1111/nyas.12130
  118. 118. Aras A, Khokhar A, Qureshi M, Silva M, et al. Targeting cancer with nano-bullets: Curcumin, EGCG, resveratrol and quercetin on flying carpets. Asian Pacific Journal of Cancer Prevention. 2014;15(9):3865-3871. DOI: 10.7314/APJCP.2014.15.9.3865
  119. 119. Soo E, Thakur S, Qu Z, Jambhrunkar S, et al. Enhancing delivery and cytotoxicity of resveratrol through a dual nanoencapsulation approach. Journal of Colloid and Interface Science. 2016;462:368-374
  120. 120. Smoliga J, Vang O, Baur J. Challenges of translating basic research into therapeutics: Resveratrol as an example. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2011;67A(2):158-167
  121. 121. Subramanian L, Youssef S, Bhattacharya S, Kenealey J, et al. Resveratrol: Challenges in translation to the clinic – A critical discussion. Clinical Cancer Research. 2010;16(24):5942-5948
  122. 122. Delmas D, Aires V, Limagne E, Dutartre P, et al. Transport, stability, and biological activity of resveratrol. Annals of the New York Academy of Sciences. 2011;1215(1):48-59. DOI: 10.1111/j.1749-6632.2010.05871.x
  123. 123. Midha K, Nagpal N, Polonini HC, et al. Nano delivery systems of resveratrol to enhance its oral bioavailability. American Journal of Pharmacy and Health Research. 2015;3(7):72-81
  124. 124. Naseri N, Valizadeh H, Zakeri-Milani P. Solid lipid nanoparticles and nanostructured lipid carriers: Structure, preparation and application. Advanced Pharmaceutical Bulletin. 2015;5(3):305-313. DOI: 10.15171/apb.2015.043
  125. 125. Poonia N, Kaur Narang J, Lather V, Beg S, Sharma T, Singh B, et al. Resveratrol loaded functionalized nanostructured lipid carriers for breast cancer targeting: Systematic development, characterization and pharmacokinetic evaluation. Colloids and Surfaces B: Biointerfaces. 2019;181:756-766. DOI: 10.1016/j.colsurfb.2019.06.004
  126. 126. Qin L, Lu T, Qin Y, He Y, Cui N, et al. In vivo effect of resveratrol-loaded solid lipid nanoparticles to relieve physical fatigue for sports nutrition supplements. Molecules. 2020;25(22):5302. DOI: 10.3390/molecules25225302
  127. 127. Soeratri W, Hidayah R, Rosita N. Effect of combination soy bean oil and oleic acid to characteristic, penetration, physical stability of nanostructure lipid carrier resveratrol. Folia Medica Indonesiana. 2019;55(3):213
  128. 128. Zu Y, Overby H, Ren G, Fan Z, et al. Resveratrol liposomes and lipid nanocarriers: Comparison of characteristics and inducing browning of white adipocytes. Colloids and Surfaces B: Biointerfaces. 2018;164:414-423
  129. 129. Ahmad M, Gani A. Development of novel functional snacks containing nano-encapsulated resveratrol with anti-diabetic, anti-obesity and antioxidant properties. Food Chemistry. 2021;352:129-323. DOI: 10.1016/j.foodchem.2021.129323
  130. 130. Jayan H, Maria Leena M, Sivakama Sundari S, et al. Improvement of bioavailability for resveratrol through encapsulation in zein using electrospraying technique. Journal of Functional Foods. 2019;57:417-424
  131. 131. Peñalva R, Morales J, González-Navarro C, Larrañeta E, et al. Increased oral bioavailability of resveratrol by its encapsulation in casein nanoparticles. International Journal of Molecular Sciences. 2018;19(9):2816
  132. 132. Berta G, Romano F, Vallone R, Abbadessa G, et al. An innovative strategy for oral biofilm control in early childhood based on a resveratrol-cyclodextrin nanotechnology approach. Materials. 2021;14(14):3801. DOI: 10.3390/ma14143801
  133. 133. Li L, Yu M, Li Y, Li Q, et al. Synergistic anti-inflammatory and osteogenic n-HA/resveratrol/chitosan composite microspheres for osteoporotic bone regeneration. Bioactive Materials. 2021;6(5):1255-1266
  134. 134. Ming L, Zhipeng Y, Fei Y, Feng R, et al. Microfluidic-based screening of resveratrol and drug-loading PLA/Gelatine nano-scaffold for the repair of cartilage defect. Artificial Cells, Nanomedicine, and Biotechnology. 2018;46(1):336-346
  135. 135. Du S, Lv Y, Li N, Huang X, et al. Biological investigations on therapeutic effect of chitosan encapsulated nano resveratrol against gestational diabetes mellitus rats induced by streptozotocin. Drug Delivery. 2020;27(1):953-963. DOI: 10.1080/10717544.2020.1775722
  136. 136. Sun J, Wei C, Liu Y, Xie W, Xu M, et al. Progressive release of mesoporous nano-selenium delivery system for the multi-channel synergistic treatment of Alzheimer’s disease. Biomaterials. 2019;197:417-431

Written By

Tracey Lynn Harney

Submitted: 21 October 2021 Reviewed: 02 November 2021 Published: 22 December 2021