Special Issue "Biological Efficacy of Natural and Chemically Modified Products against Oral Inflammatory Lesions"

A special issue of Medicines (ISSN 2305-6320).

Deadline for manuscript submissions: closed (31 October 2018)

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A printed edition of this Special Issue is available here.

Special Issue Editor

Guest Editor
Prof. Dr. Hiroshi Sakagami

Meikai University Research Institute of Odontology (M-RIO), 1-1 Keyakidai, Sakado, Saitama 350-0283, Japan
Website | E-Mail
Phone: +81-49-279-2758
Interests: informatics; information network; pharmacy; biological pharmacy; basic medicine; general pharmacology; boundary medicine; laboratory medicine; dentistry

Special Issue Information

Dear Colleagues,

Oral inflammatory diseases including stomatitis (such as apthalae and glossitis), periodontitis, gingivititis and pulpitis are asociated with pain. The first line of therapy for relieaf from these deseases is the topical application of corticosteroids that reduce the inflammation and modulate the immune response. However, steroids have serious immunosuppressive action, and therefore cannot be recommended for infection-derived diseases. There are numerous natural products that show excellent anti-inflammatory, analgesic, anti-oxidative, antibacterial and antiviral actitivies. This Special Issue of Medicines focuses on the therapeutic potential of traditional herbal medicines and nutrients, plant extracts, purified and chemically modified compounds against oral inflammatory lesions; the elucidation of action mechanisms, and clinical application.

This issue invites original research contributions, as well as review articles, related to the search for anti-inflammatory, analgesic, antibacterial or antiviral substances; isolation and determination of the chemical structure of the active principle; the action mechanism in cell culture and animal experiments; clinical effects; food science.

We look forward to receiving your contributions to this Special Issue.

Prof. Dr. Hiroshi Sakagami
Guest Editor

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Keywords

  • natural and chemically modified products
  • oral inflammatory diseases
  • antioxidant
  • bacteria
  • virus
  • in vitro experiment
  • animal experiment
  • clinical data
  • food science

Published Papers (12 papers)

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Editorial

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Open AccessEditorial
Introduction to the Special Issue “Biological Efficacy of Natural and Chemically Modified Products against Oral Inflammatory Lesions”
Received: 23 April 2019 / Accepted: 25 April 2019 / Published: 28 April 2019
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Abstract
This editorial is a brief introduction to the Special Issue of “Biological Efficacy of Natural and Chemically Modified Products against Oral Inflammatory Lesions”. From the natural resources and chemical modifications of the backbone structures of natural products, various attractive substances with new biological [...] Read more.
This editorial is a brief introduction to the Special Issue of “Biological Efficacy of Natural and Chemically Modified Products against Oral Inflammatory Lesions”. From the natural resources and chemical modifications of the backbone structures of natural products, various attractive substances with new biological functions were excavated. Best fit combination of these materials may contribute in the treatment of oral diseases. Full article
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Research

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Open AccessArticle
QSAR Prediction Model to Search for Compounds with Selective Cytotoxicity Against Oral Cell Cancer
Received: 28 February 2019 / Revised: 25 March 2019 / Accepted: 26 March 2019 / Published: 1 April 2019
Cited by 1 | PDF Full-text (1214 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Background: Anticancer drugs often have strong toxicity against tumours and normal cells. Some natural products demonstrate high tumour specificity. We have previously reported the cytotoxic activity and tumour specificity of various chemical compounds. In this study, we constructed a database of previously [...] Read more.
Background: Anticancer drugs often have strong toxicity against tumours and normal cells. Some natural products demonstrate high tumour specificity. We have previously reported the cytotoxic activity and tumour specificity of various chemical compounds. In this study, we constructed a database of previously reported compound data and predictive models to screen a new anticancer drug. Methods: We collected compound data from our previous studies and built a database for analysis. Using this database, we constructed models that could predict cytotoxicity and tumour specificity using random forest method. The prediction performance was evaluated using an external validation set. Results: A total of 494 compounds were collected, and these activities and chemical structure data were merged as database for analysis. The structure-toxicity relationship prediction model showed higher prediction accuracy than the tumour selectivity prediction model. Descriptors with high contribution differed for tumour and normal cells. Conclusions: Further study is required to construct a tumour selective toxicity prediction model with higher predictive accuracy. Such a model is expected to contribute to the screening of candidate compounds for new anticancer drugs. Full article
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Open AccessArticle
Antimicrobial Susceptibilities of Oral Isolates of Abiotrophia and Granulicatella According to the Consensus Guidelines for Fastidious Bacteria
Medicines 2018, 5(4), 129; https://doi.org/10.3390/medicines5040129
Received: 7 November 2018 / Revised: 29 November 2018 / Accepted: 29 November 2018 / Published: 3 December 2018
Cited by 1 | PDF Full-text (264 KB) | HTML Full-text | XML Full-text
Abstract
Background: The genera Abiotrophia and Granulicatella, previously known as nutritionally variant streptococci (NVS), are fastidious bacteria requiring vitamin B6 analogs for growth. They are members of human normal oral microbiota, and are supposed to be one of the important pathogens for [...] Read more.
Background: The genera Abiotrophia and Granulicatella, previously known as nutritionally variant streptococci (NVS), are fastidious bacteria requiring vitamin B6 analogs for growth. They are members of human normal oral microbiota, and are supposed to be one of the important pathogens for so-called “culture-negative” endocarditis. Methods: The type strains and oral isolates identified, by using both phenotypic profiles and the DNA–DNA hybridization method, were examined for susceptibilities to 15 antimicrobial agents including penicillin (benzylpenicillin, ampicillin, amoxicillin, and piperacillin), cephem (cefazolin, ceftazidime, ceftriaxone, and cefaclor), carbapenem (imipenem), aminoglycoside (gentamicin), macrolide (erythromycin), quinolone (ciprofloxacin), tetracycline (minocycline), glycopeptide (vancomycin), and trimethoprim-sulfamethoxazole complex. The minimum inhibitory concentration and susceptibility criterion were determined, according to the consensus guideline from the Clinical and Laboratory Standards Institute. Results: Isolates of Abiotrophia defectiva were susceptible to ampicillin, amoxicillin ceftriaxone, cefaclor, imipenem, ciprofloxacin, and vancomycin. Isolates of Granulicatella adiacens were mostly susceptible to benzylpenicillin, ampicillin, amoxicillin, cefazolin, ceftriaxone, imipenem, minocycline, and vancomycin. The susceptibility profile of Granulicatella elegans was similar to that of G. adiacens, and the susceptibility rate was higher than that of G. adiacens. Conclusions: Although Abiotrophia and Granulicatella strains are hardly distinguishable by their phenotypic characteristics, their susceptibility profiles to the antimicrobial agents were different among the species. Species-related differences in susceptibility of antibiotics should be considered in the clinical treatment for NVS related infections. Full article
Open AccessArticle
Quercetin Enhances the Thioredoxin Production of Nasal Epithelial Cells In Vitro and In Vivo
Medicines 2018, 5(4), 124; https://doi.org/10.3390/medicines5040124
Received: 17 October 2018 / Revised: 18 November 2018 / Accepted: 18 November 2018 / Published: 21 November 2018
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Abstract
Background: Thioredoxin (TRX) acts as both a scavenger of reactive oxygen species (ROS) and an immuno-modulator. Although quercetin has been shown to favorably modify allergic rhinitis (AR) symptoms, its influence on TRX production is not well defined. The present study was designed [...] Read more.
Background: Thioredoxin (TRX) acts as both a scavenger of reactive oxygen species (ROS) and an immuno-modulator. Although quercetin has been shown to favorably modify allergic rhinitis (AR) symptoms, its influence on TRX production is not well defined. The present study was designed to examine whether quercetin could favorably modify AR symptoms via the TRX production of nasal epithelial cells in vitro and in vivo. Methods: Human nasal epithelial cells (HNEpCs) were stimulated with H2O2 in the presence of quercetin. TRX levels in 24-h culture supernatants were examined with ELISA. BALB/c male mice were intraperitoneally sensitized to ovalbumin (OVA) and intranasally challenged with OVA every other day, beginning seven days after the final sensitization. The mice were orally administered quercetin once a day for five consecutive days, beginning seven days after the final sensitization. Nasal symptoms were assessed by counting the number of sneezes and nasal rubbing behaviors during a 10-min period immediately after the challenge. TRX levels in nasal lavage fluids obtained 6 h after the challenge were examined by ELISA. Results: Treatment with 1.0 nM quercetin increased H2O2-induced TRX levels. The oral administration of 20.0 mg/kg of quercetin significantly inhibited nasal symptoms after the challenge. The same dose of quercetin significantly increased TRX levels in nasal lavage fluids. Conclusions: Quercetin’s ability to increase TRX production may account, at least in part, for its clinical efficacy toward AR. Full article
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Open AccessArticle
Changes in Metabolic Profiles of Human Oral Cells by Benzylidene Ascorbates and Eugenol
Medicines 2018, 5(4), 116; https://doi.org/10.3390/medicines5040116
Received: 21 September 2018 / Revised: 23 October 2018 / Accepted: 24 October 2018 / Published: 31 October 2018
Cited by 1 | PDF Full-text (5274 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Background: Sodium-5,6-benzylidene-L-ascorbate (SBA), and its component units, benzaldehyde (BA) and sodium ascorbate (SA), are known to exert antitumor activity, while eugenol exerts anti-inflammatory activity. To narrow down their intracellular targets, metabolomic analysis was performed. Methods: Viable cell number was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium [...] Read more.
Background: Sodium-5,6-benzylidene-L-ascorbate (SBA), and its component units, benzaldehyde (BA) and sodium ascorbate (SA), are known to exert antitumor activity, while eugenol exerts anti-inflammatory activity. To narrow down their intracellular targets, metabolomic analysis was performed. Methods: Viable cell number was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Fine cell structures were observed under transmission electron microscope. Cellular metabolites were extracted with methanol and subjected to capillary electrophoresis-mass spectrometry (CE-MS) for quantification of intracellular metabolites. Results: SBA was cleaved into BA and SA under acidic condition. Among these three compounds, BA showed the highest-tumor specificity in vitro against human oral squamous cell carcinoma (OSCC) cell line. BA did not induce the vacuolization in HSC-2 OSCC cells, and its cytotoxicity was not inhibited by catalase, in contrast to SBA and SA. Only BA suppressed the tricarboxylic acid (TCA) cycle at early stage of cytotoxicity induction. Eugenol more rapidly induced the vacuolization and suppressed the TCA cycle in three human normal oral cells (gingival fibroblast, periodontal ligament fibroblast, pulp cell). Neither BA nor eugenol affected the ATP utilization, further supporting that they do not induce apoptosis. Conclusions: The present study demonstrated for the first time that both BA and eugenol suppressed the TCA cycle in tumor cells and normal cells, respectively. It is crucial to design methodology that enhances the antitumor potential of BA and reduces the cytotoxicity of eugenol to allow for safe clinical application. Full article
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Review

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Open AccessReview
Kampo Therapies and the Use of Herbal Medicines in the Dentistry in Japan
Received: 13 February 2019 / Revised: 22 February 2019 / Accepted: 25 February 2019 / Published: 28 February 2019
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Abstract
Dental caries and periodontal disease are two major diseases in the dentistry. As the society is aging, their pathological meaning has been changing. An increasing number of patients are displaying symptoms of systemic disease and so we need to pay more attention to [...] Read more.
Dental caries and periodontal disease are two major diseases in the dentistry. As the society is aging, their pathological meaning has been changing. An increasing number of patients are displaying symptoms of systemic disease and so we need to pay more attention to immunologic aggression in our medical treatment. For this reason, we focused on natural products. Kampo consists of natural herbs—roots and barks—and has more than 3000 years of history. It was originated in China as traditional medicine and introduced to Japan. Over the years, Kampo medicine in Japan has been formulated in a way to suit Japan’s natural features and ethnic characteristics. Based on this traditional Japanese Kampo medicine, we have manufactured a Kampo gargle and Mastic Gel dentifrice. In order to practically utilize the effectiveness of mastic, we have developed a dentifrice (product name: IMPLA CARE) and treated implant periodontitis and severe periodontitis. Full article
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Open AccessReview
Search for Drugs Used in Hospitals to Treat Stomatitis
Received: 4 January 2019 / Revised: 22 January 2019 / Accepted: 26 January 2019 / Published: 29 January 2019
Cited by 1 | PDF Full-text (1813 KB) | HTML Full-text | XML Full-text
Abstract
Stomatitis is an inflammatory disease of the oral mucosa, often accompanied by pain. Usually it is represented by aphthous stomatitis, for which treatment steroid ointment is commonly used. However, in the cases of refractory or recurrent stomatitis, traditional herbal medicines have been used [...] Read more.
Stomatitis is an inflammatory disease of the oral mucosa, often accompanied by pain. Usually it is represented by aphthous stomatitis, for which treatment steroid ointment is commonly used. However, in the cases of refractory or recurrent stomatitis, traditional herbal medicines have been used with favorable therapeutic effects. Chemotherapy, especially in the head and neck region, induces stomatitis at higher frequency, which directly affects the patient’s quality of life and treatment schedule. However, effective treatment for stomatitis has yet to be established. This article presents the clinical report of Kampo medicines on the stomatitis patients in the Nihon university, and then reviews the literature of traditional medicines for the treatment of stomatitis. Among eighteen Kampo medicines, Hangeshashinto has been the most popular for the treatment of stomatitis, due to its prominent anti-inflammatory activity. It was unexpected that clinical data of Hangeshashinto on stomatitis from Chinese hospital are not available. Kampo medicines have been most exclusively administered to elder person, as compared to pediatric population. Supplementation of alkaline plant extracts rich in lignin-carbohydrate complex may further extend the applicability of Kampo medicines to viral diseases. Full article
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Open AccessReview
Recent Progress of Basic Studies of Natural Products and Their Dental Application
Received: 14 November 2018 / Revised: 10 December 2018 / Accepted: 19 December 2018 / Published: 25 December 2018
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Abstract
The present article reviews the research progress of three major polyphenols (tannins, flavonoids and lignin carbohydrate complexes), chromone (backbone structure of flavonoids) and herbal extracts. Chemical modified chromone derivatives showed highly specific toxicity against human oral squamous cell carcinoma cell lines, with much [...] Read more.
The present article reviews the research progress of three major polyphenols (tannins, flavonoids and lignin carbohydrate complexes), chromone (backbone structure of flavonoids) and herbal extracts. Chemical modified chromone derivatives showed highly specific toxicity against human oral squamous cell carcinoma cell lines, with much lower toxicity against human oral keratinocytes, as compared with various anticancer drugs. QSAR analysis suggests the possible correlation between their tumor-specificity and three-dimensional molecular shape. Condensed tannins in the tea extracts inactivated the glucosyltransferase enzymes, involved in the biofilm formation. Lignin-carbohydrate complexes (prepared by alkaline extraction and acid-precipitation) and crude alkaline extract of the leaves of Sasa species (SE, available as an over-the-counter drug) showed much higher anti-HIV activity, than tannins, flavonoids and Japanese traditional medicine (Kampo). Long-term treatment with SE and several Kampo medicines showed an anti-inflammatory and anti-oxidant effects in small size of clinical trials. Although the anti-periodontitis activity of synthetic angiotensin II blockers has been suggested in many papers, natural angiotensin II blockers has not yet been tested for their possible anti-periodontitis activity. There should be still many unknown substances that are useful for treating the oral diseases in the natural kingdom. Full article
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Open AccessReview
Kampo (Traditional Japanese Herbal) Formulae for Treatment of Stomatitis and Oral Mucositis
Medicines 2018, 5(4), 130; https://doi.org/10.3390/medicines5040130
Received: 10 November 2018 / Revised: 27 November 2018 / Accepted: 29 November 2018 / Published: 10 December 2018
Cited by 4 | PDF Full-text (713 KB) | HTML Full-text | XML Full-text
Abstract
Stomatitis is occasionally multiple, recurrent, and refractory. Currently, mucositis induced by chemotherapy and radiation therapy in patients with cancer has become a significant clinical problem. Effective treatments have not been established and the treatment of numerous cases remains a challenge for physicians. Traditional [...] Read more.
Stomatitis is occasionally multiple, recurrent, and refractory. Currently, mucositis induced by chemotherapy and radiation therapy in patients with cancer has become a significant clinical problem. Effective treatments have not been established and the treatment of numerous cases remains a challenge for physicians. Traditional Japanese herbal medicines termed Kampo formulae (i.e., Hangeshashinto, Orengedokuto, Inchinkoto, Orento, Byakkokaninjinto, Juzentaihoto, Hochuekkito, and Shosaikoto) are used for treating various types of stomatitis and mucositis. Its use has been based on the Kampo medical theories—empirical rules established over thousands of years. However, recently, clinical and basic research studies investigating these formulae have been conducted to obtain scientific evidence. Clinical studies investigating efficacies of Shosaikoto and Orento for the treatment of cryptogenic stomatitis and acute aphthous stomatitis and those investigating the effects of Hangeshashinto, Orengedokuto, and Juzentaihoto on chemotherapy- or radiotherapy-induced mucositis have been conducted. The Kampo formulae comprise several crude drugs, whose mechanisms of action are gradually being clarified. Most of these drugs that are used for the treatment of stomatitis possess anti-inflammatory, analgesic, and antioxidative properties. In this review, we introduce the clinical applications and summarize the available evidence on the Kampo formulae for the treatment of stomatitis and oral mucositis. Full article
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Open AccessFeature PaperReview
The Biological Efficacy of Natural Products against Acute and Chronic Inflammatory Diseases in the Oral Region
Medicines 2018, 5(4), 122; https://doi.org/10.3390/medicines5040122
Received: 26 October 2018 / Revised: 8 November 2018 / Accepted: 8 November 2018 / Published: 13 November 2018
Cited by 1 | PDF Full-text (642 KB) | HTML Full-text | XML Full-text
Abstract
The oral inflammatory diseases are divided into two types: acute and chronic inflammatory diseases. In this review, we summarize the biological efficacy of herbal medicine, natural products, and their active ingredients against acute and chronic inflammatory diseases in the oral region, especially stomatitis [...] Read more.
The oral inflammatory diseases are divided into two types: acute and chronic inflammatory diseases. In this review, we summarize the biological efficacy of herbal medicine, natural products, and their active ingredients against acute and chronic inflammatory diseases in the oral region, especially stomatitis and periodontitis. We review the effects of herbal medicines and a biscoclaurin alkaloid preparation, cepharamthin, as a therapy against stomatitis, an acute inflammatory disease. We also summarize the effects of herbal medicines and natural products against periodontitis, a chronic inflammatory disease, and one of its clinical conditions, alveolar bone resorption. Recent studies show that several herbal medicines such as kakkonto and ninjinto reduce LPS-induced PGE 2 production by human gingival fibroblasts. Among herbs constituting these herbal medicines, shokyo (Zingiberis Rhizoma) and kankyo (Zingiberis Processum Rhizoma) strongly reduce PGE 2 production. Moreover, anti-osteoclast activity has been observed in some natural products with anti-inflammatory effects used against rheumatoid arthritis such as carotenoids, flavonoids, limonoids, and polyphenols. These herbal medicines and natural products could be useful for treating oral inflammatory diseases. Full article
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Open AccessFeature PaperReview
Pathogenic Viruses Commonly Present in the Oral Cavity and Relevant Antiviral Compounds Derived from Natural Products
Medicines 2018, 5(4), 120; https://doi.org/10.3390/medicines5040120
Received: 24 October 2018 / Revised: 5 November 2018 / Accepted: 7 November 2018 / Published: 12 November 2018
Cited by 1 | PDF Full-text (2515 KB) | HTML Full-text | XML Full-text
Abstract
Many viruses, such as human herpesviruses, may be present in the human oral cavity, but most are usually asymptomatic. However, if individuals become immunocompromised by age, illness, or as a side effect of therapy, these dormant viruses can be activated and produce a [...] Read more.
Many viruses, such as human herpesviruses, may be present in the human oral cavity, but most are usually asymptomatic. However, if individuals become immunocompromised by age, illness, or as a side effect of therapy, these dormant viruses can be activated and produce a variety of pathological changes in the oral mucosa. Unfortunately, available treatments for viral infectious diseases are limited, because (1) there are diseases for which no treatment is available; (2) drug-resistant strains of virus may appear; (3) incomplete eradication of virus may lead to recurrence. Rational design strategies are widely used to optimize the potency and selectivity of drug candidates, but discovery of leads for new antiviral agents, especially leads with novel structures, still relies mostly on large-scale screening programs, and many hits are found among natural products, such as extracts of marine sponges, sea algae, plants, and arthropods. Here, we review representative viruses found in the human oral cavity and their effects, together with relevant antiviral compounds derived from natural products. We also highlight some recent emerging pharmaceutical technologies with potential to deliver antivirals more effectively for disease prevention and therapy. Full article
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Open AccessReview
New Functions of Classical Compounds against Orofacial Inflammatory Lesions
Medicines 2018, 5(4), 118; https://doi.org/10.3390/medicines5040118
Received: 13 September 2018 / Revised: 11 October 2018 / Accepted: 13 October 2018 / Published: 1 November 2018
Cited by 2 | PDF Full-text (5839 KB) | HTML Full-text | XML Full-text
Abstract
Anti-inflammatory agents have been widely used to ameliorate severe inflammatory symptoms of a number of diseases, and such therapeutics are particularly useful for diseases with intolerable pain without significant mortality. A typical example of this is a disease known as stomatitis; although stomatitis [...] Read more.
Anti-inflammatory agents have been widely used to ameliorate severe inflammatory symptoms of a number of diseases, and such therapeutics are particularly useful for diseases with intolerable pain without significant mortality. A typical example of this is a disease known as stomatitis; although stomatitis itself is not a life-threatening disease, it severely impairs the individual’s quality of life, and thus a standard therapeutic strategy for it has already been established. The topical application of a bioactive agent is quite easy, and a strong anti-inflammatory agent can be used without significant adverse effects. In contrast, natural products with relatively mild bioactivity are used for systemic intervention. However, new aspects of classical drugs used in these established therapeutic methods have recently been discovered, which is expanding the utility of these compounds to other oral diseases such as osteoarthritis of temporomandibular joints (TMJ-OA). In this review article, after summarizing the general concept and pathobiology of stomatitis, its established therapeutics are explained. Thereafter, recent advances in the research into related compounds, which is uncovering new biological functions of the agents used therein, are introduced. Indeed, regenerative therapeutics for TMJ-OA may be developed with the classical compounds currently being used. Full article
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