Genipin Regulates Mitochondrial Dysfunction Through Nrf2 To Relieve Oxidative Stress Damage In Periodontitis

Background:Periodontitis is an inflammatory disease caused by local microbial community imbalance,which is characterized by an imbalance in the relative abundance of microbial species.After colonization of the "critical" pathogen,the composition and total number of the microbiome changes,increasing the pathogenicity of the entire community.As a result,the immune response is overactivated,leading to immune cell infiltration,activation of osteoclast activity,and destruction of soft and hard tissues.Recent estimates suggest that more than 10 percent of the world’s adults may be affected by severe periodontitis.Excessive accumulation of reactive oxygen species(ROS)causes the body to be in a state of peroxide called oxidative stress.Either increased production of ROS or depletion of the antioxidant enzyme system can lead to the development of disease.Many facts have proven that oxidative stress is associated with periodontal tissue damage,but the specific mechanism is still unclear.Clinical studies have shown that the occurrence of periodontitis is associated with elevated levels of lipid peroxides in saliva and gingival sulcus fluid.Oxidative stress can also induce mitochondrial dysfunction and the opening of essential mitochondrial channels and trigger the onset of endogenous apoptotic pathways.Therefore,an indepth investigation into the pathogenesis of periodontitis and the search for a drug with protective properties of mitochondrial function could help to slow down the development of periodontitis.Genipin(GP),a glycoside ligand derived from iridoid glycosides,is widely distributed in plants.GP is the main metabolite of geniposide in humans or animals and is the main active form with a pharmacokinetic function.GP has antioxidant and anti-inflammatory properties.GP reduces acute lung damage by regulating mitochondria-dependent apoptosis and endoplasmic reticulum stress,and its pharmacological effects are mediated through the regulation of nuclear factor erythroid 2-related factor 2(Nrf2).During oxidative stress Nrf2 is allowed to translocate to the nucleus to function as a transcription factor,activating stress response pathways to reshape metabolism and gene expression to protect cells in response to cellular stress.The heme oxygenase-1(HO-1),is thought to be an important mediator in promoting the antioxidant and anti-inflammatory properties of Nrf2.It is an inducible protective protein that catalyzes the reaction of the heme moiety with biliverdin,which is reduced to the strong antioxidant bilirubin.However,it is unclear whether GP can influence periodontitis development by regulating Nrf2 and its downstream antioxidant enzyme HO-1.Therefore,in this study,we investigated whether GP alleviates ROS production and mitochondrial dysfunction through the regulation of Nrf2,the damage of periodontal tissue in rats was reduced,aims to provide a new strategy for the management of periodontitis.Methods:1.In vitro experiments: the human periodontal membrane cells treated with hydrogen peroxide were restored by GP,and the cell vitality,apoptosis,mitochondrial function and the levels of Nrf2,HO-1 and other oxidative stress-related factors were detected by CCK-8,Western Blot and fluorescence staining.2.In vivo experiments: by successfully constructing a rat periodontitis model and giving GP intervention,HE staining,Western Blot,immunohistochemistry and fluorescent staining techniques were used to detect periodontal tissue damage,mitochondrial function and the expression of oxidative stress-related factors such as Nrf2 and HO-1.Results:1.In vitro experiments: CCK-8 results showed that GP significantly restored cell viability.Western Blot and fluorescence staining showed that GP significantly reduced cell apoptosis,alleviated mitochondrial dysfunction,reduced oxidative stress response,and increased the expression of Nrf2 and HO-1.2.In vivo experiments: GP can relieve the inflammation degree of periodontal tissue,reduce alveolar bone resorption,reduce the apoptosis level of periodontal tissue,relieve mitochondrial dysfunction,and improve the antioxidant capacity of the body.Conclusions:1.Mitochondrial dysfunction plays an important role in the occurrence and development of periodontitis.2.Genipin improves periodontitis injury in rats by alleviating mitochondrial dysfunction and apoptosis.3.Genipin alleviates mitochondrial dysfunction and improves periodontitis injury in rats by up-regulating Nrf2.