Funding informationSelf-funded project Cyclosporine induces overgrowth of human gingiva. Previously we have shown (i) cyclosporine-inducing ER stress in human gingival fibroblasts (HGF), (ii) increased matrix protein expression, and (iii) interference with mitochondrial pro-and anti-apoptotic factors.This study was undertaken to assess the effects of melatonin (an antioxidant), 4PBA (an ER stress inhibitor), and simvastatin on the expression of ER Stress markers as well as on matrix and mitochondrial markers. HGF incubated with cyclosporine, or without melatonin/4PBA/ statin. After 24 hr of incubation, mRNA expression of ER stress markers (GRP78, CHOP, XBP1, and XBPs) and matrix protein markers (like α-SMA, VEGF, TGF-β, CTGF), and mitochondrial apoptosis markers estimated and compared with housekeeping gene GAPDH.Compared to the control cyclosporine significantly augmented ER Stress and matrix proteins, which decreased significantly with the use of melatonin, 4PBA, and simvastatin. The mitochondrial proapoptotic molecule cyclophilin D, as well as Bcl2 expression also decreased after PBA treatment, paralleling an increase in cytochrome c expression. The effect of 4PBA was much more pronounced than the influence of other two. In conclusion, 4PBA could be a viable therapeutic option for drug-induced gingival overgrowth. K E Y W O R D Scyclosporine, ER stress, gingiva, 4PBA | INTRODUCTIONCyclosporine has increased the survival rate of patients who have undergone transplantations, but the same cannot be said about improving the quality of life of those patients. Through its calcineurin blocking property, cyclosporine induces significant immunosuppression property. However, akin to other immune suppressants cyclosporine also induces toxicity and one common side effect of cyclosporine is gingival overgrowth (cyclosporine induced gingival overgrowth (Boltchi, Rees, & Iacopino, 1999) which compromises aesthetics and masticatory function. The overgrowth according to some authors is vascular (Kataoka, Kido, Shinohara, & Nagata, 2005).Though many researchers have observed fibrosis markers like α smooth muscle actin (αSMA), (Chen, Yang, Yu, Yu, & Gong, 2016) transforming growth factor β (TGFβ) and connective tissue growth factor (CTGF) (Yang, Deng, Hsieh, Wu, & Kuo, 2015), etc. At the cellular level, cyclosporine is notoriously anti-apoptotic in gingival fibroblast (Jung, Jeong, Jeong, Chung, & Kim, 2008). Many theories have proposed for the overgrowth and the most acceptable by many researchers is the concept of fibroblast heterogeneity (Tipton, Stricklin, & Dabbous, 1991). Apart from cyclosporine, phenytoin, and nifedipine also induce gingival overgrowth, but histopathological they are quite a fibrosis.In addition to gingiva, cyclosporine induces many systemic side effects, the most common being renal fibrosis. One of the significant observation in cyclosporine triggered renal fibrosis is the generation of oxidative stress (O'Connell, Tuite, Slattery, Ryan, & McMorrow, 2012), and the drug demonstrated a tendency to indu...

Drug induced gingival overgrowth is one of the side effects affecting the gingiva due to administration of certain systemic drugs. Cyclosporine A is one such drug which is commonly used in organ transplant conditions. The resultant overgrowth is fibrotic and extensive in nature which could impair patient esthetics and masticatory function. Endoplasmic reticulum stress is a recently identified phenomenon implicated in other fibrotic pathologies such as lung and renal fibrosis. In fact, endoplasmic reticulum stress has been known to play an important role in cyclosporine A induced renal fibrosis. Thus in this study, we sought to identify it's role in drug induced gingival overgrowth.

Introduction: It is well known that the SARS-CoV-2 virus that causes COVID-19 could enter the human host through the oral cavity. In patients with periodontal disease, there is an increase of Furin, Cathepsin, and CD14+ CD16+ monocytes. The hypothesis stated here sheds light on the regular need of periodontal management to reduce inflammation and the levels of deleterious host enzymes and cytokines, which could pave the way for deadly viral diseases such as COVID-19. The Hypothesis: Patients with periodontal disease are at increased risk of SARS-CoV-2 infection due to elevated levels of Furin and Cathepsin in oral cavity and COVID-19 complications like cytokine storm could occur with increased frequency in patients with periodontal disease due to the significant increase of CD14+ CD16+ monocytes in blood. Evaluation of the Hypothesis: Oral and periodontal examination of patients with mild, moderate, and severe SARS-CoV-2 infection could shed light on the significant role played by periodontal disease in making an individual more prone to get SARS-CoV-2 infection by elevation of Furin and Cathepsin and the elevation of CD14+CD16+ monocytes and proinflammatory cytokines in the blood that could consequently worsen COVID-19 complications like cytokine storm. The blood counts of CD14+CD16+ monocytes need to be assayed in SARS-CoV-2 patients with and without periodontal disease to observe if periodontal disease as a coexisting condition elevates the proportion of CD14 CD16+ monocytes in SARS-CoV-2 patients. In fact, assessment of monocyte subsets in peripheral blood could be used as an immunosurveillance marker in SARS-CoV-2 patients. Hence, SARS-CoV-2 positive patients with chronic periodontal disease should be closely monitored for potential signs of a cytokine storm and its related complications.

Background:To evaluate the effect of Cyclosporin A (CsA) and angiotensin II (Ang II) on cytosolic calcium levels in cultured human gingival fibroblasts (HGFs).Materials and Methods:Healthy gingival samples from six volunteers were obtained, and primary HGFs were cultured. Cell viability and proliferation assay were performed to identify the ideal concentrations of CsA and Ang II. Cytosolic calcium levels in cultured gingival fibroblasts treated with CsA and Ang II were studied using colorimetric assay, confocal and fluorescence imaging. Statistical analyses were done using SPSS software and GraphPad Prism.Results:Higher levels of cytosolic levels were evident in cells treated with CsA and Ang II when compared to control group and was statistically significant (P < 0.05) in both colorimetric assay and confocal imaging. Fluorescent images of the cultured HGFs revealed the same.Conclusion:Thus calcium being a key player in major cellular functions, plays a major role in the pathogenesis of drug-induced gingival overgrowth.