4PBA strongly attenuates endoplasmic reticulum stress, fibrosis, and mitochondrial apoptosis markers in cyclosporine treated human gingival fibroblasts.
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.
Faculty of Dental Sciences, Department of Periodontology and Implantology, Sri Ramachandra University, Porur, Chennai, India.
Suresh
S
Ranga Rao
Centre for Regenerative Medicine and Stem Cell Research, Central Research Facility, Sri Ramachandra University, Porur, Chennai, India.
Rajasekaran
R
Subbarayan
Faculty of Dental Sciences, Department of Periodontology and Implantology, Sri Ramachandra University, Porur, Chennai, India.
Supraja
S
Ajitkumar
Centre for Indian Systems of Medicine Quality Assurance and Standardization, Sri Ramachandra University, Chennai, India.
Dinesh
D
Murugan Girija
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000633:toxicity*; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005881:Gingiva / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019214:Gingival Overgrowth / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008550:Melatonin / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010654:Phenylbutyrates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; D016572:Cyclosporine; D019821:Simvastatin; D008550:Melatonin
4PBA; ER stress; cyclosporine; gingiva