Mechanisms by which smoking worsens periodontitis discovered

 

Smoking tobacco is known to worsen symptoms of periodontitis and reduce responsiveness to treatment. Using high-resolution spatial transcriptomics, researchers identified differences between smokers and non-smokers in the expression of genes that weaken gum epithelial integrity and cause bone damage through inflammation. They also identified CXCL12 secreted by endothelial cells in gums as a crucial mediator of immune-cell recruitment that drives excessive inflammation. CXCL12 is a possible target for new therapies against periodontitis aggravated by smoking.

Healthy gums, or periodontal tissue, are a key to good oral health. Gums provide crucial nutritional, immunological and mechanical support to the teeth and jaws. Unfortunately, millions of people suffer from severe chronic inflammation of the gums, a condition called periodontitis. Periodontitis occurs when the immune system responds abnormally to microbes entering the gum tissue. Over time, periodontitis causes gums to recede, bones surrounding the mouth to weaken, and may even lead to the loss of teeth.

Previous research has shown that tobacco smokers are not only more likely to develop periodontitis, but the disease also progresses faster, shows more severe symptoms, and responds poorly to treatment compared with non-smokers. These differences have been linked to smoking-related alterations in:

• the gum’s epithelial barrier,
• fibroblast function and epithelial–fibroblast communication, and
• immune and inflammatory responses within periodontal tissue.

Yet, the precise cellular mechanisms have remained unclear due to limitations in available research technologies.

A team of researchers from Sun Yat-sen University, China, led by Professor Chuanjiang Zhao, have used high resolution Visium HD single-cell spatial transcriptomics to analyze the different molecular pathways activated in smokers and non-smokers with periodontitis. Their findings have been published in Volume 17 of the International Journal of Oral Science on August 01, 2025.

“Understanding the complex cellular interactions that contribute to disease progression in smoking-associated periodontitis is important,” remarked Prof. Zhao regarding the importance of this study. He added, “By employing the Visium HD platform, we aimed to map the spatial distribution of different cell types within healthy and diseased periodontal tissues and identify smoking-induced changes in gene expression patterns across various cell populations.”

To explore how smoking affects epithelial cells, the team first examined cells exposed to bacterial lipopolysaccharide (LPS) alone versus LPS plus nicotine. The combination triggered larger changes in genes related to epithelial structure, barrier integrity, communication, and inflammation—suggesting that smoking weakens the epithelial barrier and heightens inflammatory susceptibility.

The researchers then compared gene expression across multiple cell types in tissue samples from healthy gums (HG), non-smokers with periodontitis (P), and smokers with periodontitis (SP).

Describing differences in fibroblasts, cells that maintain gum structure and integrity, Prof. Zhao says, “Our results revealed that individuals in the smoking group, as opposed to healthy controls, presented upregulated expression of genes linked to ageing, intrinsic apoptotic signalling, and mitotic processes.” SP fibroblasts also showed elevated expression of genes associated with inflammation and immune cell recruitment, helping explain the more pronounced tissue damage in smokers.

Spatial transcriptomic analysis further revealed that endothelial cells and macrophages were positioned in close proximity only in smoking-associated periodontitis, enabling stronger inflammatory interactions. SP tissues also contained a higher proportion of pro-inflammatory macrophages, which played a central role in driving periodontal destruction.

Interestingly, this recruitment and activation of macrophages seemed to depend on one molecule –C-X-C motif chemokine 12 or CXCL12. In the presence of CXCL12 secreted by endothelial cells, macrophages turned pro-inflammatory. Suppressing CXCL12 secretion made the macrophages anti-inflammatory. As further confirmation of these findings, the team found that CXCL12 suppression reduced inflammation and bone damage in mice with periodontitis aggravated by nicotine.

“Targeting CXCL12 shows promise in mitigating inflammation and bone resorption in individuals with smoking-induced periodontitis,” says Prof. Zhao, describing a potential new therapeutic approach.  He concludes, “Future research should investigate local delivery systems, like nanoparticles or liposomes, to reduce systemic side effects and improve treatment precision.”

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Reference

A new ally against tooth decay: Arginine offers sweet relief

Fermentation of sugars in our food by the numerous bacteria in our mouth produces acids that destroy our teeth to form caries cavities. These bacteria reside in plaque-like communities called “dental biofilms”. Arginine, an amino acid naturally found in our saliva, has been shown to be helpful in preventing tooth decay. A few beneficial bacteria have an arginine deiminase system (ADS) that helps break down arginine to form alkali that can neutralize the acids. Increased availability of arginine helps in the multiplication of these beneficial bacteria, while at the same time inhibiting the growth of acid-producing bacteria. Recently, studies conducted outside the human body also showed that arginine availability changes the composition of dental biofilms.

To further prove these findings in the human mouth, a team of dentists and researchers led by Post.doc. Yumi C. Del Rey and Professor Sebastian Schlafer from Aarhus University in Denmark have conducted a clinical trial and published their findings in the International Journal of Oral Science.

They recruited 12 participants with active caries and prepared specialized dentures that allow for the collection of intact biofilms, spanning both sides of the jaw. The participants were instructed to dip the dentures in a sugar solution for 5 minutes, immediately followed by distilled water (as placebo) or arginine for 30 minutes, one on each side. This was to be repeated three times a day, with arginine treatment done on the same side each time. “The aim was to investigate the impact of arginine treatment on the acidity, type of bacteria, and the carbohydrate matrix of biofilms from patients with active caries,” explains Sebastian Schlafer, professor at the Department of Dentistry and Oral Health. After 4 days, when the biofilm was developed, the dentures were removed for detailed analysis.

A special pH-sensitive dye called “C-SNARF-4” was used to analyze the acidity of the collected biofilms in different locations. Biofilms treated with arginine showed a significantly higher pH (lower acidity) at 10 and 35 minutes after a sugar challenge. “Our results revealed differences in acidity of the biofilms, with the ones treated with arginine being significantly more protected against acidification caused by sugar metabolism” says the first author, Yumi C. Del Rey.

Then, carbohydrate-binding proteins called lectins, tagged with a fluorescent dye, were used to stain two common carbohydrate components of the biofilms: fucose and galactose. These components make up a large portion of dental biofilms and may contribute to the creation of “acidic pockets” inside them. With arginine treatment, an overall reduction was seen in the amount of fucose-based carbohydrates, possibly making the biofilm less harmful. In addition, there was a change in the structure of the biofilm, with galactose-containing carbohydrates decreasing at the bottom and increasing at the top.

Further, to determine which bacteria were present in the biofilm, they sequenced all bacterial genomes using a technique called “16S rRNA gene sequencing”. Though biofilms treated with arginine and placebo were predominantly dominated by Streptococcus and Veillonella species, arginine significantly reduced the mitis/oralis group of streptococci, which produce acid but are not strong producers of alkali, and slightly increased streptococci with considerable arginine metabolism, thereby improving the pH. Overall, arginine made the biofilms less harmful by reducing their acidity, altering their carbohydrate structure, and reshaping the microbiome within them.

Dental caries, being prevalent across all ages and regions, could be combated using strategies such as supplementation of arginine in toothpastes or oral rinses for people who are more susceptible to them. Arginine, being an amino acid naturally produced in our body and present in dietary proteins, is harmless and could find application even in children. 

Study links low lycopene intake to higher risk of severe gum disease in older adults

 

 — A new study has found that insufficient dietary lycopene intake is associated with a significantly higher risk of severe periodontitis among U.S. adults ages 65 to 79, with differences in risk patterns observed across race and sex. The research was published in The Journal of Nutrition, Health and Aging.

The research team included lead author Katherine Kwong of the Department of Human Development at Connecticut College in New London, Connecticut, along with collaborators from Tulane University, the University of California San Diego, Yunnan University, Southern Illinois University and Louisiana State University Health Sciences Center.

The study analyzed data from 1,227 participants in the National Health and Nutrition Examination Survey (2009–2014). Nearly half (48.7%) of older adults in the study had some level of periodontitis, and 77.9% consumed insufficient dietary lycopene — a carotenoid commonly found in tomatoes and other red fruits.

After adjusting for age, sex, race, smoking status and education, the study found that older adults with sufficient lycopene intake had about one-third the odds of severe periodontitis compared with those with insufficient intake.

The study also found disparities in disease risk. Severe periodontitis was more common among men and non-Hispanic Black adults.

Key findings include:

• Adequate lycopene intake was associated with a reduced likelihood of severe periodontitis (odds ratio 0.33; 95% CI 0.17–0.65).
• Non-Hispanic Black adults had higher odds of severe periodontitis than non-Hispanic White adults (odds ratio 2.82; 95% CI 1.46–5.45).
• Women were less likely than men to experience severe periodontitis (odds ratio 0.27; 95% CI 0.14–0.55).
• Among non-Hispanic White adults, both female sex and sufficient lycopene intake were associated with lower risk.
• Among non-Hispanic Black adults, the same lycopene association was not observed, suggesting differences in risk patterns.

The authors write that the findings suggest dietary lycopene may be an important modifiable factor for preventing severe gum disease among older adults. However, because the study was cross-sectional, causality cannot be determined.

The study also highlights racial and sex disparities in periodontal disease, with non-Hispanic Black adults and men experiencing a higher prevalence of severe disease. The authors recommend that future prevention strategies consider race- and sex-specific dietary interventions, and call for longitudinal or randomized controlled trials to examine whether increasing lycopene intake reduces disease risk or progression.

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Artificial saliva containing sugarcane protein helps protect the teeth of patients with head and neck cancer

 

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An artificial saliva in the form of a mouthwash, produced with the CANECPI-5 protein extracted from sugarcane and modified in a laboratory, can aid in treating teeth in patients with head and neck cancer. In these cases, radiotherapy very close to the mouth can destroy salivary glands and compromise saliva production, which is essential for controlling bacteria and disease.

According to research conducted at the Bauru School of Dentistry at the University of São Paulo (FOB-USP) in Brazil, CANECPI-5 forms a protective “shield” for the teeth, guarding the enamel against weakening acids found in juices, alcoholic beverages, and even stomach acids. The results were published in the Journal of Dentistry. 

The study was conducted during Natara Dias Gomes da Silva’s doctoral studies at FOB-USP. She collaborated with researchers from the Federal University of São Carlos (UFSCar), also in Brazil; the University of California in San Francisco, in the United States; and Yonsei University College of Dentistry, in South Korea.
    
The work is part of the Thematic Project “Modulation of acquired pellicle to control dental mineral loss: unveiling mechanisms to make therapies possible”, which is coordinated by Professor Marília Afonso Rabelo Buzalaf from FOB-USP. 

“We tested the mouthwash developed with CANECPI-5 by applying this solution to small pieces of animal teeth once a day for one minute. Based on these results, we’ll conduct further research so that we can think about applications of this product,” adds Silva, the first author of the article.

“This is the first product that uses the concept of acquired pellicle [a thin protective layer that quickly forms on the tooth surface] to treat xerostomia, which is the sensation of a dry mouth caused by a lack of saliva. We use substances that will reformulate the composition of the proteins that bind to the teeth,” explains Buzalaf.

“We’ve developed a process in which CANECPI-5 binds directly to tooth enamel, helping to make teeth more resistant to the action of acids produced by bacteria,” Silva points out.

The data published in the article showed that the CANECPI-5 protein is most effective when combined with fluoride and xylitol. In these tests, the artificial saliva spray significantly reduced bacterial activity and tooth demineralization – the process by which teeth lose calcium and phosphate, making them more susceptible to cavities. 

This discovery is significant because patients undergoing treatment for head and neck cancer do not yet have access to a specific product on the market that can help combat and treat the most aggressive cavities that develop after radiation therapy.

“Artificial saliva improves the sensation of dry mouth and sores. This helps with discomfort and also combats bacteria. In some cases, the use of this type of product is only for a short time. In others, it’s permanent, because many individuals lose the ability to produce saliva,” adds Buzalaf.

The patent for the CANECPI-5 protein was filed a few years ago. According to the researchers, the challenge now is to scale up in partnership with companies interested in the technology so that the artificial saliva can be produced.

“We’ve already tested the solution as a mouthwash, gel, and orodispersible film, which is a type of plastic that’s placed on the tongue and dissolves, releasing the protein. We’ve tested it in several vehicles and found that CANECPI-5 works very well in all of them. We’ll continue testing other technologies within the Thematic Project to use not only this protein, but others as well,” says Buzalaf.

Regarding the discovery of CANECPI-5

According to Flávio Henrique Silva, a professor in the Department of Genetics and Evolution at UFSCar, who worked on developing the CANECPI-5 protein, the work with cystatins (a family of proteins involved in various biological processes) is linked to research carried out under the Sugarcane Genome Project (SUCEST, FAPESP). His laboratory is part of that project.

“At that time, our group identified and produced, in a recombinant form in bacteria, the first cystatin from sugarcane. We named it CANECPI-1. We then identified and produced five other cane cystatins, including CANECPI-5, which had potent inhibitory activities against cysteine peptidases, which are its target enzymes. Throughout our work, we noticed that this protein bound strongly to smooth surfaces, such as the quartz cuvettes used in activity measurements. This led us to conduct tests in partnership with Professor Marília Buzalaf on the binding of the protein to tooth enamel.”

According to the researchers, the discovery that CANECPI-5 protects tooth enamel while also regulating the oral microbiota makes it a highly promising molecule for dentistry research.

“CANECPI-5 has also been used in the work of other colleagues in the field of dentistry, particularly involving periodontitis. We also have a collaborative project with a colleague from the Federal University of Uberlândia, using subcutaneous sponge implants in mice, which has shown that it’s capable of reducing inflammation and promoting angiogenesis [the formation of new blood vessels] and fibrinogenesis [the formation of fibrin, a protein essential for blood clotting], important processes in tissue repair, making it a candidate molecule for use in wound healing,” Silva points out.

Next steps 

Within the Thematic Project, the researchers will continue trying to understand how CANECPI-5 interacts with other substances. 

According to Buzalaf, one possible avenue is to study CANECPI-5 fused with a peptide derived from statherin, a protein found in saliva, to see if the new hybrid protein is more effective against the acids that weaken teeth when they come from the stomach. Another possible avenue is to try to understand how to combat periodontal disease.

“Another aspect of the Thematic Project is to associate CANECPI-5 with vitamin E because this vitamin acts as a carrier, bringing the protein into contact with the tooth. We imagine that this could facilitate the application of the product directly by the patient at home,” says the researcher.

A

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Journal

Journal of Dentistry

DOI

10.1016/j.jdent.2025.106176 

The oral-systemic relationship: lessons learned and the road ahead

  The International Association for Dental, Oral, and Craniofacial Research (IADR) and the American Association for Dental, Oral, and Craniofacial Research (AADOCR) have announced the publication of a special issue of Journal of Dental Research that highlights the experimental studies, advances in data architecture, and population-based investigations that seek to provide a more comprehensive understanding of the relationship between oral health and systemic health.

The relationship between oral and systemic disease has evolved from early speculation to systematic investigation. A century after William Hunter’s focal infection theory placed the mouth at the center of myriad illnesses, the field now interrogates that premise with contemporary tools—causal frameworks, large registries, rigorous trials, and integrated clinical data, as well as experimental studies that allow approaches to isolate variables and to perform cause-and-effect experiments to investigate the mechanisms underlying oral and systemic disease connections.

The goal of this Special Issue is not to deliver a final verdict on whether “oral health affects systemic health,” but to refine the question to one that is clinically actionable: for which people, through which pathways, and at what points in the life course does oral health alter systemic risk, and how should health systems respond? By combining methodological rigor, mechanistic insight, population-scale data, and interprofessional practice, as well as experimental studies to test in a straightforward and precise way hypotheses generated by human-derived data, the studies in this issue bring that question within reach. The charge now is rapid, responsible, and equitable translation to interventions that promote both oral and systemic health and enable more effective prevention or management of chronic diseases, and healthy aging across diverse communities.

New composite hydrogel shows promise for treating dental pulp infection

 

The injectable bioceramics-containing composite hydrogel could enable pulp-dentin complex repair by facilitating innervation and odontogenic differentiation.

Peer-Reviewed Publication

Editorial Office of West China School of Stomatology, Sichuan University

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image: 

Traditional treatment strategies involved in pulp-dentin complex repair do not promote innervation or odontogenesis. A newly developed injectable composite hydrogel now shows promising results on this front, promoting neural differentiation and odontogenesis, and paving the way for a new treatment strategy.

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Credit: UN Women Asia & the Pacific from openverse Image Source Link: https://openverse.org/image/df79ffba-d6fc-466a-9631-e57f722f6896?q=dentist+chamber&p=19

The dental pulp is a soft tissue of the teeth involved in sensory information transmission, immunoprotection, and dentin formation. Odontoblast cells in the pulp differentiate and lead to the formation of dentin that helps in maintaining the structure and function of the teeth. The pulp-dentin complex is also densely innervated by a variety of nerve fibers that are crucial for tooth sensation and pain perception.

The dental pulp is sensitive and susceptible to microbial infection that can damage not only the pulp but also the dentin-oral complex structure. Moreover, the process of odontogenesis (tooth development) and nerve differentiation in the pulp-dentin complex are affected by the defects caused by microbial infection. Unfortunately, traditional treatment strategies, including root canal therapy and vital pulp therapy, which target the pulp instead of the complex do not promote neural regeneration, and thus cannot completely repair this damage.

Modern treatment plans, involving biomaterials such as hydrogels, aim to overcome these limitations. Biomaterials find applications in drug delivery, remineralization, and tissue regeneration. Silicate-based bioceramics are often used in oral therapies owing to their biocompatibility and biodegradable properties. Involvement of lithium (Li) ions, known for neuroprotective properties, and calcium (Ca) ions, which is primarily involved in dentin formation, can further improve the effectiveness of the biomaterials.

A team of researchers from China, led by Professor Chengtie Wu from Shanghai Institute of Ceramics, Chinese Academy of Sciences, set out to explore the efficiency of Li-Ca-Si (LCS) bioceramics in promoting innervated pulp-dentin complex regeneration. “Most biomaterials that are currently used are focused on antibacterial properties, immune regulation, and mineral deposition. As nerves play a very important role in the dentin-pulp complex, the re-innervation property of the biomaterial used in the treatment is equally important,” explains Prof. Chengtie Wu, speaking about the motivation underlying the study, which was published in International Journal of Oral science on October 01, 2025.

The researchers developed a composite hydrogel composed of LCS bioceramics particles and gelatin methacryloyl (GelMA) matrix for the treatment of pulp-dentin complex defects. Both in vivo and in vitro experiments were conducted to check the innervation properties of the hydrogel.

Property analysis of the LCS bioceramics hydrogel showed good injectability, shape fidelity, and photo-crosslinking ability, along with enhanced mechanical strength and mineralization ability. This resulted in convenient dental filling along with a rapid curing as observed by the team. “The composite hydrogel maintained stable structure once filled in even under the erosion of flush water and maintained its stability when immersed in a simulated oral fluid,” highlights Prof. Zhiguang Huan, the Co-corresponding author of the study.

Schwann cells (SCs), which form a prominent glial network in the dentin-pulp complex, play a crucial role in nerve and dental tissue repair and regeneration. The hydrogel promoted SC regeneration and migration. Moreover, the hydrogel showed cytocompalitibility for both SC cells and dental pulp stem cells (DPSCs), along with promoting the proliferation, migration, and odontogenic differentiation of DPSCs.

“DPSC differentiation is usually regulated by the nerve cells in the dentin-pulp complex. We also wanted to see if the odontogenic differentiation of DPSCs was modulated by neural cells under the treatment of bioceramics-containing composite hydrogels,” explains Ms. Xingyu Tao, the first author of this study. The team’s findings suggested that the composite hydrogel helped create a suitable neuro-modulatory microenvironment for odontogenesis, facilitating an integrated dentin-pulp repair via the coupling of neuro-odontogenesis.

Studies in rat model also showed promising results. There was an increase in bone volume and bone mineral density following a hydrogel-based treatment. Innervation and pulp-dentin regeneration was achieved in the in vivo model and pulp tissue morphology also indicated the repairing property of the hydrogel.

Further research on these composite hydrogels could aid our understanding of the biological mechanism of innervation and regeneration process influenced by the treatment. “While the immunomodulatory and antibacterial properties of the hydrogel remain to be fully understood, our study offers a promising approach for functional pulp-dentin integrated repair,” concludes Prof. Chengtie Wu.

 

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Reference
DOI: https://doi.org/10.1038/s41368-025-00398-0

 

Gum disease may be linked to plaque buildup in arteries, higher risk of major CVD events

 There is increasing evidence that gum disease is associated with increased risk of cardiovascular events, including heart attack, stroke, atrial fibrillation, heart failure and cardiometabolic health conditions. Effective prevention and treatment of gum disease, also called periodontal disease, could potentially decrease the burden of cardiovascular disease, according to a new scientific statement published today in the American Heart Association’s flagship journal Circulation.

The new American Heart Association scientific statement, “Periodontal Disease and Atherosclerotic Cardiovascular Disease,” features new data supporting an association between periodontal disease and atherosclerotic cardiovascular disease (ASCVD) and updates the Association’s 2012 scientific statement. ACSVD, the leading cause of death globally, is caused by buildup of arterial plaque (fatty deposits in the arteries) and refers to conditions that include coronary heart disease, stroke, peripheral artery disease and aortic aneurysms.

“Your mouth and your heart are connected,” said Chair of the scientific statement writing group Andrew H. Tran, M.D., M.P.H., M.S., FAHA, a pediatric cardiologist and the director of the preventive cardiology program at Nationwide Children's Hospital in Columbus, Ohio. “Gum disease and poor oral hygiene can allow bacteria to enter the bloodstream, causing inflammation that may damage blood vessels and increase the risk of heart disease. Brushing, flossing and regular dental checkups aren’t just about a healthy smile—they’re an important part of protecting your heart.”

Highlights of the statement include:

• Periodontal disease is a chronic inflammatory condition affecting over 40% of U.S. adults over age 30. The earliest stage is gingivitis (inflammation of the gums due to buildup of oral plaque). If left untreated, gingivitis may progress to periodontitis, where the gums begin to pull away from the teeth, forming small pockets that can trap bacteria and lead to infection. The most advanced stage, severe periodontitis, involves extensive damage to the bones supporting the teeth; teeth may become loose and fall out. This stage often requires surgical intervention. 

• Periodontal disease is more common in individuals with poor oral hygiene and other cardiovascular disease risk factors, such as high blood pressure, overweight or obesity, diabetes and smoking. The prevalence of periodontal disease is also higher among men, older adults, individuals with low physical activity and people affected by adverse social determinants of health, such as lower socioeconomic status, food insecurity and/or lack of access to health care including dental care.

• Although periodontal disease and ASCVD share common risk factors, emerging data indicates there is an independent association between the two conditions. Potential biological mechanisms linking periodontal disease with poor cardiovascular outcomes include direct pathways such as bacteria in the blood and vascular infections, as well as indirect pathways such as chronic systemic inflammation.

• Numerous studies have found that periodontal disease is associated with an increased risk of heart attack, stroke, atrial fibrillation, heart failure, peripheral artery disease, chronic kidney disease and cardiac death. Although periodontal disease clearly contributes to chronic inflammation that is associated with ASCVD, a cause-and-effect relationship has not been confirmed.

• There is also no direct evidence that periodontal treatment will help prevent cardiovascular disease. However, treatments that reduce the lifetime exposure to inflammation appear to be beneficial to reducing the risk of developing ASCVD. The treatment and control of periodontal disease and associated inflammation may contribute to the prevention and improved management of ASCVD.

• People with one or more cardiovascular disease risk factors are considered to be at higher risk and may benefit from regular dental screenings and targeted periodontal care to address chronic inflammation. Previous studies have found that more frequent tooth brushing is associated with lower 10-year ASCVD risk (13.7% for once-daily or less brushing vs. 7.35% for brushing three or more times per day) and reduced inflammatory markers.

• More research, including long-term studies and randomized controlled trials, is needed to determine whether periodontal treatment can impact ASCVD progression and outcomes.

• In addition, the role of socioeconomic status, access to dental care and other social factors that adversely affect health should be explored to develop targeted prevention and treatment strategies that can help reduce the prevalence and adverse outcomes of periodontal disease and ASCVD.