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Drug-induced gingival overgrowth (DIGO) is one of the side effects produced by therapeutic agents, most commonly phenytoin, nifedipine and cyclosporin A. However, the precise mechanism of DIGO is not entirely understood. A literature search of the MEDLINE/PubMed databases was conducted to identify the mechanisms involved in DIGO. The available information suggests that the pathogenesis of DIGO is multifactorial, but common pathogenic sequelae of events emerge, i.e., sodium and calcium channel antagonism or disturbed intracellular handling of calcium, which finally lead to reductions in intracellular folic acid levels. Disturbed cellular functions, mainly in keratinocytes and fibroblasts, result in increased collagen and glycosaminoglycans accumulation in the extracellular matrix. Dysregulation of collagenase activity, as well as integrins and membrane receptors, are key mechanisms of reduced degradation or excessive synthesis of connective tissue components. This manuscript describes the cellular and molecular factors involved in the epithelial–mesenchymal transition and extracellular matrix remodeling triggered by agents producing DIGO.

Periodontal diseases include periodontitis and gingival overgrowth. Periodontitis is a bacterial infectious disease, and its pathological cascade is regulated by many inflammatory cytokines secreted by immune or tissue cells, such as interleukin-6. In contrast, gingival overgrowth develops as a side effect of specific drugs, such as immunosuppressants, anticonvulsants, and calcium channel blockers. Human gingival fibroblasts (HGFs) are the most abundant cells in gingival connective tissue, and human periodontal ligament fibroblasts (HPLFs) are located between the teeth and alveolar bone. HGFs and HPLFs are both crucial for the remodeling and homeostasis of periodontal tissue, and their roles in the pathogenesis of periodontal diseases have been examined for 25 years. Various responses by HGFs or HPLFs contribute to the progression of periodontal diseases. This review summarizes the biological effects of HGFs and HPLFs on the pathogenesis of periodontal diseases.

Gingival overgrowth caused by cyclosporine A is due to increased fibroblast proliferation in gingival tissues. Cell cycle system balances proliferation and anti-proliferation of gingival fibroblasts and plays a role in the maintenance of its population in gingival tissues. When cells detect and respond to abnormalities (e.g. DNA damage), cell cycle progression is arrested in the G 1 phase until the completion of damage restoration. In this study, we investigated the effects of cyclosporine A on G 1 cell cycle arrest and on its regulators in gingival fibroblasts to clarify the mechanism of cyclosporine A-induced gingival overgrowth. Human gingival fibroblasts from healthy donors were cultured to semi-confluence and were then treated with or without 200 ng/mL (166 nM) cyclosporine A in D-MEM with 2% fetal bovine serum. Cell proliferation was assessed by counting total cell numbers. The distribution of cell cycle phases was assessed using flow cytometric analysis. The levels of mRNA and protein expression for cell cycle regulators were quantified using reverse transcription-quantitative PCR and western blot analysis, respectively. Treatment with cyclosporine A markedly increased cell proliferation, inhibited G 1 cell cycle arrest, significantly increased CDC25A and CYCLIN E1 mRNA expression levels, significantly decreased P21 , SMAD3 and SMAD4 mRNA expression levels, significantly upregulated the protein expression levels of CDC25A, CYCLIN E1, pCDK2 and pRB1 and significantly downregulated the protein expression levels of P21, SMAD3 and SMAD4. Treatment with cyclosporine A also increased MYC and ATM mRNA expression levels and decreased CDK2 , ATR , P27 , P53 and RB1 mRNA expression levels but not significantly. These results demonstrate that cyclosporine A causes gingival overgrowth due to the following mechanism in gingival fibroblasts: cyclosporine A increases levels of phospho-CDK2 and CYCLIN E1 by upregulating CDC25A and downregulating P21 with the downregulation of SMAD3 and SMAD4, which results in the inhibition of G 1 cell cycle arrest.

Several attempts have been made to elucidate the pathogenesis of drug-induced gingival overgrowth (DIGO), which is triggered by the chronic use of certain drugs that fall into three main categories: anticonvulsants, immunosuppressants, and calcium channel blockers. Previous research suggests that cytokines and impaired cellular functions play a role in DIGO. Of particular interest are macrophages, immune cells that can switch between M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes in response to exogenous signals and stimuli. An imbalance between M1 and M2 macrophage populations may underlie DIGO. M1 may contribute to the initial tissue damage in DIGO, while M2 may then attempt to repair the damage with anti-inflammatory mechanisms. To test the hypothesis that drugs associated with DIGO could influence macrophage polarization, human monocytes (precursors of macrophages) were induced to differentiate into M0-naïve macrophages and then exposed to drugs: diphenylhydantoin, gabapentin, mycophenolate, and amlodipine. Quantitative real-time PCR amplification was used to measure the expression of specific genes associated with macrophage polarization. All of the drugs tested induced M0 macrophages to overexpress genes typical of the M1 phenotype, such as CCL5, CXCL10, and IDO1. This investigation provides the first evidence of a link between drugs that cause DIGO and M1 pro-inflammatory macrophage polarization. The knowledge gained from this research could be valuable for future DIGO treatment strategies.

Elemental diets have been employed for the management of various diseases for over 50 years, with several mechanisms mediating their beneficial effects. Yet, they are underutilized due to poor palatability, access, cost, and lack of awareness regarding their clinical efficacy. Therefore, in this review, we aimed to systematically search and review the literature to summarize the formulation variability, mechanisms of action, clinical applications, and tolerability of the elemental diets in gastrointestinal diseases. While large prospective trials are lacking, elemental diets appear to exhibit objective and subjective clinical benefit in several diseases, including eosinophilic esophagitis, eosinophilic gastroenteritis, inflammatory bowel diseases, small intestinal bacterial overgrowth, intestinal methanogen overgrowth, chemoradiotherapy-associated mucositis, and celiac disease. Although some data support the long-term use of elemental diets as an add-on supplement for chronic pancreatitis and Crohn’s disease, most of the literature on exclusive elemental diets focuses on inducing remission. Therefore, subsequent treatment strategies for maintaining remission need to be adopted in chronic/relapsing diseases. Several mechanistic pathways were identified to mediate the effects of elemental diets, including food additive and allergen-free content, high passive absorption rate, and anti-inflammatory properties. High rates of intolerance up to 40% are seen in the trials where exclusive elemental diets were administered orally due to poor organoleptic acceptability; however, when tolerated, adverse events were rare. Other limitations of elemental diets are cost, access, and lifestyle/social restrictions. Moreover, judicious use is advised in presence of a concomitant restrictive food intake disorders. Elemental diets offer a potentially highly efficacious dietary intervention with minor side effects. Palatability, cost, access, and social restrictions are common barriers of use. Prospective clinical trials are needed to elucidate the role of elemental formulas in the management of individual diseases.

Background Patients with aplastic anemia are at increased risk of bleeding, which often limits conventional periodontal treatment. Although drug-induced gingival overgrowth is well-documented, its management in this high-risk population has not been thoroughly studied. Case presentation We respectively reviewed the cases of seven aplastic anemia patients (4 males, 3 females; aged 33–57) with cyclosporine-associated drug-induced gingival overgrowth who were treated with initial periodontal therapy (IPT) under hematologist supervision from May 2018 to October 2024. Within 1–6 months follow-up visit, 6 of 7 patients achieved complete resolution of gingival overgrowth. One patient with severe overgrowth and concurrent felodipine use required 15 months for full resolution. Two cases of postoperative bleeding were controlled by removing chronic inflammatory tissue. One patient experienced recurrence after discontinuing follow-up for 2 years. No infections occurred during treatment. Conclusions IPT can safely and effectively treat severe drug-induced gingival overgrowth in patients with aplastic anemia. A maintenance therapy frequency of no less than once every three months is crucial to prevent recurrence in these patients.

The aim of this study was to evaluate the antiproliferative properties of low-level laser therapy (LLLT) on gingival fibroblasts obtained from calcium channel blocker-induced gingival overgrowth (GO). Gingival fibroblasts of patients with GO were compared to healthy gingival fibroblasts (H). Both cells were exposed to LLLT (685 nm wavelength, 25mW power, diode laser) and compared to those not treated with LLLT. Cell proliferation and viability were measured with MTT assay at baseline and after 24 and 72 h. TGF-β1, CTGF, and collagen Type 1 levels were evaluated with Enzyme-Linked Immunosorbent Assay (ELISA). LLLT significantly decreased the proliferation of GO fibroblasts (p < 0.05) while leading to a significantly higher proliferation in H fibroblasts compared to the untreated cells (p < 0.05). GO cells showed significantly higher CTGF, TGF-β, and collagen Type 1 expression than the H cells (p < 0.05). LLLT significantly reduced CTGF levels in GO cells compared to the control group (p < 0.05). In H cells, CTGF and TGF-β levels were also significantly decreased in response to LLLT compared to the control group (p < 0.05). While LLLT significantly reduced collagen expression in the H group (p < 0.05), it did not significantly impact the GO cells. LLLT significantly reduced the synthesis of the growth factors and collagen in both groups with an antiproliferative effect on the gingival fibroblasts from calcium channel blocker-induced GO, suggesting that it can offer a therapeutic approach in the clinical management of drug-induced GO, reversing the fibrotic changes.

BackgroundMethanogens are associated with gut dysmotility in animal models but have not been robustly studied in humans. The WMC assesses regional transit time (TT) and pH in the GI tract.AimsTo study the segmental TT and pH among patients with SIBO or IMO utilizing WMC.MethodsWe conducted a retrospective study of 207 patients who underwent a glucose or lactulose breath test (BT) and WMC from 2010 to 2022. Diagnosis of SIBO and IMO were based on the 2017 North American consensus criteria. TT and pH were extracted from WMC recordings. We tested for differences in means of continuous variables and frequencies of categorical variables using two-sample t tests, Wilcoxon Rank Sum test, Chi-square, and Fisher exact tests. We used R version 3.3.1 (2016-06-21) for all statistical analyses.ResultsA total of 196 patients met criteria, mean age 47.4 years and 155 (79.1%) females. Of the 86 (43.9%) patients with a positive BT, 42 (58.3%) had IMO only (meeting only CH4 criteria) and 30 (34.9%) met both H2 and CH4 criteria. Colonic TT was longer in patients with a positive BT compared to negative patients (40 h:29 min vs 28 h:51 min, p = 0.028). Small bowel TT and colonic TT were longer in patients with IMO compared to negative patients (SBTT: 5 h:15 min vs 4 h:32 min, p = 0.021; CTT: 44 h:23 min vs 28 h:51 min, p = 0.030). There were no significant differences in segmental pH compared to negative patients.ConclusionTo our knowledge, this is the largest study of patients who have undergone both BT and WMC. A positive BT was associated with delayed CTT, while having IMO only was associated with both delayed CTT and SBTT, but neither with pH. Future investigation is needed to elucidate whether changes in intestinal microbiota affect gut transit.

We reviewed the literature on the prevalence of small intestinal bacterial overgrowth (SIBO) after Roux-en-Y gastric bypass (RYGB). Eight studies examining 893 patients were included. The mean age of the patients was 48.11 ± 4.89 years. The mean BMI before surgery and at the time of SIBO diagnosis was 44.57 ± 2.89 kg/m 2 and 31.53 ± 2.29 kg/m 2 , respectively. Moreover, the results showed a 29% and 53% prevalence of SIBO at < 3-year and > 3-year follow-up after RYGB, respectively. Symptoms included abdominal pain, diarrhea, bloating, nausea, vomiting, constipation, soft stool, frequent defecation, flatulence, rumpling, dumping syndrome, and irritable bowel syndrome. SIBO is prevalent after RYGB; digestive symptoms should prompt the consideration of SIBO as a potential etiology. Antibiotic therapy has proven to be therapeutic.