Flavonoids - Clinical effects and applications in dentistry: A review.

Flavonoids include a huge group of naturally occurring organic compounds. It is found in a large variety of plants including fruits, seeds, grains, tea vegetables, nuts, and wine. Many studies have shown that there is a strong association between flavonoid intake and the long-term effects on mortality. It is widely used in dentistry and it has many clinical effects. This article summarizes the effects of flavonoids to humankind and its clinical applications in dentistry.

Flavonoids are a group of natural substances with variable phenolic structures. They are found primarily in fruit, grains, bark, vegetables, roots, flowers, tea, wine, and stems.[1] It is predicted that in the Western diet, mixed flavonoids are consumed for approximately 1 g, on a daily basis. On the basis of the number of experimental animal studies, numerous health-promoting properties are being attributed to flavonoids. The major effects include antiinflammatory, antiviral antiallergic, and anticancer.[2] Above 4000 varieties of flavonoids have been recognized. Some flavonoids also possess antioxidant and vitamin C sparing activity.[3]

In a research carried out in flavonoids and the added inclination with the discovery of the French paradox, low cardiovascular mortality was seen in the Mediterranean populations, in association with high saturated fat intake and red wine consumption.[4] It is estimated that there is a significant decrease in the mortality of cardiovascular diseases and the intake of flavonoids.

Clinical Effects

Antiatherosclerotic effects

Flavonoids have major influence on the vascular system due to their antioxidant properties. Lower density lipoproteins are oxidized by oxygen radicals and causes endothelial injury. As a consequence of endothelial injury, it can promote atherosclerotic changes.[5] Oxidative stress and vascular damage are ascribed as the major key role in dementia. Moreover, it is reported that dementia can be prevented by the intake of red wine, which contains flavonoids. Hence flavonoids when consumed regularly might reduce the risk death from coronary heart diseases.[6]

Antiosteoporotic effects

In a study, the mineral density of bone was compared between older women who consumed tea and those who did not consume the tea. In this study, it was concluded that women who drank tea had higher mineral density of bone that the women who did not drink tea. The flavonoids which is present in tea might be accountable for the prevention of osteoporosis.[7]

Anti-inflammatory effects

The general inflammatory response involves the release of arachidonic acid by the lipoxygenase and cyclooxygenase, which are the major inflammatory mediators. Neutrophils contains lipoxygenase generate chemo tactic compounds from arachidonic acid. Release of cytokines is also provoked by neutrophils. Preferred phenol compounds were shown to inhibit both the cyclooxygenase and 5-lipoxygenase pathways. This inhibition of these pathways reduces the release of arachidonic acid. The accurate mechanism by which flavonoids inhibit these enzymes is not understood. Quercetin, a type of flavonoids, which inhibits both cyclooxygenase and lipoxygenase pathways, thus withdrawing the formation of these inflammatory metabolites.

An important anti-inflammatory feature of flavonoids is the capability to inhibit eicosanoids biosynthesis. Prostaglandins, which are eicosanoids, are involved in number of immunologic responses, as well as are the final products of the cyclooxygenase and lipoxygenase pathways. Flavonoids also inhibit the action of cytosolic and membrane tyrosine kinase. Tyrosine 3-monooxygenase kinases, which are the integral membrane proteins, are involved in a variety of functions. These are mainly transport across membranes, enzyme catalysis, transduction of signals and energy transfer in adenosine triphosphate synthesis.[8] If these proteins are inhibited, it results in inhibition of uncontrolled cell growth and proliferation.[9] Tyrosine kinase substrates appear to play important roles in the signal transduction pathway and regulate cell proliferation. Inhibition of neutrophil degranulation is another important property of flavonoids. This is important way to withdraw the release of arachidonic acid by immune cells and neutrophils.[10]

Anti-thrombogenic effects

Platelet aggregation contributes to formation of atherosclerosis and acute platelet thrombus formation. This is the leads to the embolization of stenosed arteries.

The platelets adhering to vascular endothelium is activated and generates lipid peroxides and oxygen free radicals. The generated radicals inhibit the endothelial formation and nitrous oxide. In 1960s, it was shown that tea pigment can significantly reduce, increase fibrinolysis, blood coagulability, and inhibit platelet adhesion and aggregations.[11]

Preferred flavonoids, such as kempferol, quercetin, and myricetin were shown to be successful inhibitors of platelet aggregation in monkeys and dogs. Flavonoids are predominantly antithrombotic since they directly diminish free radicals; by this means, it maintains appropriate concentrations of endothelial prostacyclin and nitric oxide.[12] Many studies have shown that flavonoids are potent antithrombotic agents in vitro and in vivo since, they have the action of inhibition of the cyclooxygenase and lipoxygenase pathways.[12] It is recognized that arachidonic acid, which is release during the inflammatory conditions, is metabolized by platelets to form endoperoxides, prostaglandin, and thromboxane A2, which leads primarily to platelet activation and aggregation. The most important anti-aggregatory effect of flavonoids is considered to be by inhibition of thromboxane A2 formation. Flavonoids influence arachidonic acid metabolism in diverse ways.[13]

Antitumor effects

Antioxidant systems are habitually inadequate, and damage caused by the reactive oxygen species is anticipated to be involved in carcinogenesis.[14] Reactive oxygen species can cause damage to DNA, and division of cells. The damage can be unrepaired or misrepaired, which leads to mutations. If this damage occurs in significant genes, such as tumor suppressor genes or oncogenes, initiation or progression may result. Reactive oxygen species can obstruct directly with cell signaling and growth. The cellular damage, which is caused by reactive oxygen species, can induce mitosis, which leads in increasing the risk that damaged DNA, which subsequently lead to mutations, and can amplify the exposure of DNA to mutagens.

As antioxidants, flavonoids can inhibit carcinogenesis. A number of flavonoids – such as apigenin, and fisetin, luteolin – are stated to be effective inhibitors of cell proliferation.[15] A number of clinical study was conducted, suggested the occurrence of an inverse involvement between flavonoid intake and the subsequent incidence of lung cancer. Many studies have shown the invasive and metastatic growth of melanoma is inhibited by Quercetin and apigenin in mice.[16] This finding may suggest new insights about potential therapies for metastatic disease. In addition, it is being proposed that flavonoids can inhibit angiogenesis. Angiogenesis is in general a strictly controlled process in the human body. This process of angiogenesis is synchronized by a range of endogenous antigenic and antistatic factors. This process angiogenesis can be seen in wound healing. But the unregulated angiogenesis occurs in cancer.[17] Inhibitors of angiogenesis can interfere with a number of steps in angiogenesis, such as the proliferation of endothelial cells and migration of endothelial cells and finally lumen formation. Flavonoids seem to play an important role in angiogenesis inhibitors. Conversely, the mechanism of the antiangiogenetic effect of flavonoids not understood.

Quercetin in Oral Squamous Cell Carcinoma

In a study done by MaricelaHaghiac and Thomas Walle have shown that Quercetin Induces Necrosis and Apoptosis in oral cancer. Quercetin is the most abundant molecule in the broad class of polyphenolic flavonoids, universally found in plants and as often in consumed foods, such as apples, tea, onions, berries, and many others. Quercetin originally induces a stress response, which results in necrosis of the oral epithelial cells. Prolonged exposure to quercetin to the epithelial cells will cause apoptosis of the remaining cells.[18]

Antiviral effects

Wang et al. studied the antiviral effects of flavonoids.[19] Quantities of the viruses suspected to be affected by flavonoids are respiratory syncytial virus, herpes simplex virus, parainfluenza virus, and adenovirus. Quercetin potent flavonoids was reported to show signs of both anti-infective and antireplicative abilities. For instance some flavonoids occupy on the intracellular replication of viruses, while others hinder the infectious properties of viruses. By far, most studies of the effects on viruses were carried out in vitro and little studies were carried out to know about the antiviral effect of flavonoids in vivo. There is evidence stating that flavonoids in their glycine form appear to be more inhibitory on virus especially rotavirus, than are flavonoids which are in their a glycine form.[20]

From 1980, as there is worldwide spread of HIV, many investigations of the antiviral activity of flavonoids have mainly turned on HIV. Numerous natural products can inhibit varied stages of the replication cycle of the virus. The development of flavonoids as an anti-HIV agents have been expanded in the past two decades. Flavonoids have also studied in vitro experiments, but there is no clear contribution to the treatment of HIV – infected patients.[21]

Applications of Flavonoids in Dentistry

Propolis, flavonoids has been known as natural source of medicine in ancient times. It is used widely as locally or systemically in the treatment of diseases and in inflammatory conditions.

Propolis is often called the “Russian Penicillin.” It prevents and inhibits bacterial cell division and help to break down the bacterial cell wall and cytoplasm. Propolis is more prounced to Gram-positive bacteria than Gram-negative bacteria.[22]

Antibacterial effect

In many clinical study, propolis was demonstrated an in vitro antibacterial effect on the isolated oral streptococci and salivary bacterial counts. It was stated that the action of flavonoids have controlled dental caries.[23]

Plaque

According to a study conducted by Ammar et al., flavonoids, quercetrin and naringenin, were added into two pharmaceutical preparations in the form of toothpaste. It was found that the flavonoids inhibit plaque formation. It showed the significant decrease in the levels of Gram-positive streptococci by the usage of the toothpaste.[24]

Treatment in surgical wounds

It was found that propolis which was found in aqueous solution mouth rinses helps in the repair of intrabuccal surgical wounds and exerted mild anti-inflammatory and analgesic effects.[25]

Repair of dental sockets and skin wounds

Numerous studies have pointed out that topical application of 10% hydroalcohal solution of propolis in cutaneous wound healing and socket wound after the extraction of tooth in rats, promoted oral epithelial repair but had no effect on wound healing of the socket.

Outcome on Dentinal Hypersensitivity

Propolis had an undetermined effect in the control of dentinal hypersensitivity. Many studies have shown that propolis occluded dentinal tubules, periodontally involved.[26]

Act as a storage medium for avulsed teeth

Propolis is found to be a potent transport medium when compared with milk. It maintains the periodontal viability of the avulsed tooth and acts as a potent storage medium.[27]

Conclusion

Nowadays, there is a trend in using natural materials as cure for variety of diseases. Alternative medicine has made a lot of effect and contribution to modern medical practice. Flavonoids are one of the natural sources of medicine, and said to be antibacterial and anti-inflammatory, antioxidant properties, and stimulate immune system. They bound and seal viruses stimulating white blood cells and lymphocytes and produces interferon therefore stimulating immune system. There is a need for the future humankind and animal trial of this natural remedy in curing these diseases. To conclude, flavonoids is a natural medication with a promising future but further studies should be emphasized and conducted to explore its merit and demerits in clinical dentistry.