氧化应激诱发糖尿病性牙周炎作用及机制

糖尿病和牙周炎有双向关系,二者间作用机制尚不清楚。糖尿病长期高糖状态可诱发氧化应激(oxidative stress,OS)反应,产生大量活性氧族(ROS),可通过改变信号传导通路等途径引起炎症因子基因和蛋白质表达异常,导致炎症反应增强,破坏牙周组织。该文从OS诱发糖尿病性牙周炎作用、OS诱发糖尿病性牙周炎机制、抗氧化物治疗及前景等方面进行研究,为糖尿病性牙周炎治疗和研究提供依据。     

破骨细胞与糖尿病相关慢性牙周炎关系的研究进展

糖尿病是慢性牙周炎（chronic periodontitis,CP）发生的危险因素,糖尿病患者长期高血糖会使机体产生大量高级糖基化终产物（advanced glycosylation end products,AGEs）,通过氧化应激、细胞信号传导等途径将机体固有免疫系统激活,进而增强牙周组织的炎症反应,导致糖尿病相关性CP发生。破骨细胞（osteoclasts,OC）主要参与骨改建及骨吸收过程,对于维持人体骨组织稳态具有重要作用。OC与CP患者牙槽骨吸收密切相关,但与糖尿病相关CP的关系尚不明确。本文基于糖尿病相关CP发病机制,从炎症反应、AGEs、活性氧（reactive oxygen species,ROS）三个方面阐述OC与糖尿病相关CP的潜在关系,并做一综述。     

高级氧化蛋白产物在糖尿病相关性牙周炎中的作用

高级氧化蛋白产物(AOPP)是在氧化应激过程中对机体产生的一系列病理生理性作用的一组蛋白质产物的总称,而其所介导的氧化应激作用是糖尿病相关性牙周炎加重的发病机制之一.本文就AOPP的结构及其理化特性,AOPP的合成和分离及鉴定,AOPP与糖尿病相关性牙周炎的关系,糖尿病相关性牙周炎的治疗等研究进展作一综述.     

糖尿病前期与牙周炎关系的研究进展

糖尿病前期(pre-diabetes mellitus, Pre-DM)是介于正常血糖稳态和2型糖尿病之间的中间高血糖状态, 我国一半以上的成年人处于Pre-DM。牙周炎主要是由菌斑微生物引起的慢性炎症性疾病, 与糖尿病等非传染性疾病的发生具有共同的危险因素, 且互相影响。Pre-DM可能增加罹患牙周炎的风险, 牙周炎也可能影响糖尿病的发生和发展。氧化应激、系统性炎症、肠道菌群是目前牙周炎与Pre-DM互相联系的主要机制。本文主要对Pre-DM与牙周炎的关系及潜在的相关机制进行综述, 为两者的防治提供新的依据。     

牙周炎与炎症性肠病的相关性研究进展

牙周炎（periodontitis，PD）和炎症性肠病（inflammatory bowel disease，IBD）都是由宿主免疫炎症反应与菌群之间复杂的相互作用所介导的慢性炎症性疾病。两者具有相似的致病途径，其中一种疾病可能由于其导致的菌群失调及系统性炎症反应而诱发另一种疾病的产生或加重其严重程度。文章就PD与IBD的相关性研究进展做一综述，旨在探究两者相互影响的可能机制，并为未来PD与IBD双向关联研究指出方向。     

牙周病与慢性肾病关系研究进展

慢性肾病是各种原因引起的肾脏结构或功能异常 ≥ 3个月,伴或不伴有肾小球滤过率下降,或不明原因的肾小球滤过率下降（< 60 mL/min/1.73 m2）超过3个月。牙周病是发生在牙齿支持组织的慢性炎症性疾病。许多研究发现,慢性肾病患者牙周病的发病率显著高于普通人群,牙周病亦可增加慢性肾病的发病率与严重程度,且与后者的不良预后密切相关。但目前关于牙周病诱发或加重慢性肾病的机制尚不明确,可能与牙周致病菌、炎症因子及氧化应激等途径有关。文章就近年关于牙周病与慢性肾脏病的关系、可能的关联机制以及牙周治疗对慢性肾病预后影响等方面的研究文献进行综述,以期为临床开展二者的联合防治提供借鉴。     

糖尿病前期和牙周炎的相互关系

糖尿病前期是从早期代谢异常到糖尿病的过渡期,牙周炎是发生在牙周组织的慢性感染性疾病.糖尿病前期和牙周炎之间存在着相关性,即糖尿病前期增加牙周炎的发病率及其严重程度,牙周炎亦加重糖尿病前期的严重程度,牙周炎治疗可以有效改善糖尿病前期患者的糖代谢.氧化应激和细胞因子,包括肿瘤坏死因子-α以及白细胞介素-1β和6,可能是影响这两种疾病发生发展的关键环节.肥胖和年龄是这两种疾病的共同危险因素,可促进这两种疾病同时发生发展.本文主要就糖尿病前期与牙周炎相关性及可能作用机制进行阐述.     

氧化应激和线粒体质量控制与牙周炎关系的研究进展

牙周炎主要是由菌斑微生物引起的牙周支持组织的慢性炎症性疾病.近年来,关于线粒体质量控制与牙周炎之间的关系受到学者们的广泛关注.线粒体质量控制包括线粒体的生物发生、动力学和自噬三部分,任何一个部分紊乱都会导致线粒体功能障碍,进而诱发相关疾病.氧化应激会导致线粒体质量控制失衡,可能在牙周炎发展中起关键作用.本文就氧化应激、...     

牙周炎与动脉粥样硬化相关性研究进展

牙周炎是菌斑微生物引起的慢性多因子炎症性疾病,其造成了局部和全身的炎症反应.动脉粥样硬化是心血管疾病的病理基础,其发生发展与氧化应激、炎症和血脂紊乱均密切相关.近年来大量研究在作用机制、动物实验和临床病例中阐释了二者的相关性,且牙周炎是动脉粥样硬化的独立危险因素.但因两种疾病的多方面和长期性使得很难建立明确的因果关系,...     

神经免疫：牙周病和阿尔茨海默病口-脑轴研究的新进展

阿尔茨海默病(Alzheimer’s disease, AD)是继癌症、心血管病、脑血管病之后威胁老年人健康的第四大原发病。AD的病因尚不清楚。牙周病是最常见的菌群失调引起的口腔慢性炎症性疾病,也是AD的重要危险因素。流行病学证据显示,牙周病患者AD的患病风险显著增加,但其具体机制仍未可知。慢性神经炎症与AD的病理生理学相关,全身炎症可诱发和加剧中枢神经系统免疫反应参与AD,牙周病同样可以引发机体慢性炎症。已经有研究表明,牙周病可能通过引发神经炎症参与AD发病。然而,目前仍缺乏关于牙周病通过神经免疫途径参与AD发病机制的系统评价。因此,本文总结了牙周病和AD之间已知的相互作用,并强调了对牙周病通过神经免疫和神经炎症途径参与AD发病机制的见解,以期为牙周病与AD的相关机制研究提供更多的思路。     

Reactive oxygen species: a potential role in the pathogenesis of periodontal diseases

The pathological events leading to the destruction of the periodontium during inflammatory periodontal diseases are likely to represent complex interactions involving an imbalance in enzymic and non-enzymic degradative mechanisms. This paper aims to review the increasing body of evidence implicating reactive oxygen species (ROS), derived from many metabolic sources, in the pathogenesis of periodontal tissue destruction. ROS are generated predominantly by polymorphonuclear leukocytes (PMN) during an inflammatory response and are regarded as being highly destructive in nature. The detection of ROS oxidation products, the elevation of iron and copper ions, which catalyse the production of the most reactive radical species, and the identification of an imbalance in the oxidant/antioxidant activity within periodontal pockets, suggests a significant role for ROS in periodontal tissue destruction. In vitro studies have shown that ROS are capable of degrading a number of extracellular matrix components including proteoglycans, resulting in the modification of amino acid functional groups, leading to fragmentation of the core protein, whilst the constituent glycosaminoglycan chains undergo limited depolymerisation. The identification and characterisation of connective tissue metabolites in gingival crevicular fluid (GCF) resulting from the degradation of periodontal tissues, notably alveolar bone, provides further evidence for a role for ROS in tissue destruction associated with inflammatory periodontal diseases.     

Recombinant bone morphogenetic protein-2 induces up-regulation of vascular endothelial growth factor and interleukin 6 in human pre-osteoblasts: role of reactive oxygen species

ObjectiveBone morphogenetic proteins (BMPs) and vascular endothelial growth factor (VEGF) have been reported in many studies to play a major role in the communication between endothelial cells and osteoblasts. The inflammatory reaction and relative hypoxia at the site of bone injury are the first stages of the fracture repair. rhBMP-2 has been used extensively in spinal fusion and reconstruction of maxillofacial bone defects with main complication is the formation of seroma. The aim of this study was to test whether rhBMP-2 regulates the expression of the angiogenic and inflammatory mediators in pre-osteoblasts via generating reactive oxygen species (ROS).MethodsrhBMP-2 effect on angiogenesis and inflammatory genes was assessed using normal human osteoblasts (NHOst). Angiogenesis genes were measured using angiogenic PCR array. VEGF and IL6 production were analysed using ELISA kit and real-time PCR. ROS production was assessed using dihydroethidine and dichlorofluorescein staining and lipid peroxidation. HIF-1α immunoreactivity was performed using immunofluorescence staining.ResultsThere was an increase in the pro-angiogenic and -inflammatory genes as well as VEGF and IL6 protein expression in NHOst by rhBMP-2. This increase in VEGF and IL6 was blocked by the ROS scavenger N-acetyl cysteine (NAC).ConclusionThe regulatory effect of rhBMP-2 on angiogenesis and inflammation is mediated through a ROS-dependent mechanism, which involves upregulation of crucial angiogenic and inflammatory mediators such as VEGF and IL6. These findings highlight the need for future studies to identify new therapeutic targets downstream from rhBMP-2 to potentiate its beneficial effect or limit its complications such as seroma formation.     

Anti-inflammatory effects of zinc in PMA-treated human gingival fibroblast cells

Objectives: Abnormal cellular immune response has been considered to be responsible for oral lesions in recurrent aphthous stomatitis. Zinc has been known to be an essential nutrient metal that is necessary for a broad range of biological activities including antioxidant, immune mediator, and anti-inflammatory drugs in oral mucosal disease. The objective of this study was to investigate the effects of zinc in a phorbol-12-myristate-13-acetate (PMA)-treated inflammatory model on human gingival fibroblast cells (hGFs). Study Design: Cells were pre-treated with zinc chloride, followed by PMA in hGFs. The effects were assessed on cell viability, cyclooxygenease-1,2(COX-1/2) protein expression, PGE2 release, ROS production and cytokine release, Results: The effects were assessed on cell viability, COX1/2 protein expression, PGE2 release, ROS production, cytokine release. The results showed that, in the presence of PMA, zinc treatment leads to reduce the production of ROS, which results in decrease of COX-2 expression and PGE2 release. Conclusions: Thus, we suggest that zinc treatment leads to the mitigation of oral inflammation and may prove to be an alternative treatment for recurrent aphthous stomatitis. Key words:Zinc, inflammatory response, cytokines, phorbol-12-myristate-13-acetate, gingival fibroblasts cells.     

The anti-inflammatory effects of human recombinant copper-zinc superoxide dismutase on pulp inflammation

Inflammation in the dental pulp is accompanied by release of a wide variety of highly oxidative molecules known as reactive oxygen species (ROS). ROS concentrations are controlled in vivo by an antioxidant enzyme scavenger system that may be overwhelmed by the increases in ROS production seen during inflammation. Supplementation of the antioxidant defense system, therefore, may limit the severity of the inflammatory response to injury due to this component. To test this hypothesis, this study examined the effects of superoxide radical scavenging on pulpal inflammation induced in rat molars by standardized cavity preparation. The extent of pulp inflammation was compared histomorphometrically between animals treated with exogenous administration of a human recombinant antioxidant enzyme, copper-zinc superoxide dismutase, conjugated to polyethylene glycol (hr-CuZn-SOD), versus saline-vehicle controls. There was a statistically significant reduction in area of inflammation involvement in those animals treated with hrCuZn-SOD, compared with controls. Although hrCuZn-SOD administration did not completely eliminate inflammation in all animals treated, there was a statistically significant lessening of the severity of the inflammatory response, as well as a greater degree of reparative dentin observed in the hrCuZn-SOD-treated animals.     

The roles of NADPH oxidase in modulating neutrophil effector responses

Neutrophils are phagocytic innate immune cells essential for killing bacteria via activation of a wide variety of effector responses and generation of large amounts of reactive oxygen species (ROS). Majority of the ROS in neutrophils is generated by activation of the superoxide‐generating enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Independent of their anti‐microbial function, NADPH oxidase‐derived ROS have emerged as key regulators of host immune responses and neutrophilic inflammation. Data from patients with inherited defects in the NADPH oxidase subunit alleles that ablate its enzyme function as well as mouse models demonstrate profound dysregulation of host inflammatory responses, neutrophil hyper‐activation and tissue damage in response to microbial ligands or tissue trauma. A large body of literature now demonstrates how oxidants function as essential signaling molecules that are essential for the regulation of neutrophil responses during priming, degranulation, neutrophil extracellular trap formation, and apoptosis, independent of their role in microbial killing. In this review we summarize how NADPH oxidase‐derived oxidants modulate neutrophil function in a cell intrinsic manner and regulate host inflammatory responses. In addition, we summarize studies that have elucidated possible roles of oxidants in neutrophilic responses within the oral mucosa and periodontal disease.     

Reactive oxygen species removal activity of davallialactone reduces lipopolysaccharide-induced pulpal inflammation through inhibition of the extracellular signal-regulated kinase 1/2 and nuclear factor kappa b pathway

Introduction

Davallialactone, hispidin analogues derived from the mushroom Inonotus xeranticus, has antioxidant properties. This study examined whether the reactive oxygen species (ROS) removal activity of davallialactone affects the lipopolysaccharide (LPS)-induced anti-inflammatory activity in human dental pulp cells.

Methods

The LPS-induced formation of ROS was analyzed by using dichlorofluorescein diacetate with fluorescence-activated cell sorter, and the expression of inflammatory molecules in primary cultured human dental pulp cells was determined by immunoblotting. The inflammatory mechanism of the davallialactone-involved signal pathway was examined by immunoblotting.

Results

Davallialactone acted as an antioxidant to confirm the elimination of ROS formation and elevation of Cu/Zn superoxide dismutase and Mn superoxide dismutase expression in LPS-induced pulp cells. The antioxidant activity of davallialactone leads to inhibition of LPS-induced inflammation by blocking the extracellular signal-regulated kinase (ERK1/2) and nuclear factor kappa B (NF-κB) pathway, which decreases the expression of inflammatory molecules such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, matrix metalloproteinase-2, matrix metalloproteinase-9, inducible nitric oxide synthase, and cyclooxygenase-2. The character of davallialactone was more effective in comparison with N-acetylcysteine as the control antioxidant in this study.

Conclusions

Davallialactone has antioxidant activity and anti-inflammatory effects in LPS-induced human dental pulp cells through the suppression of ERK1/2 activation followed by blockage of NF-κB translocation from cytosol into nuclear. Therefore, the good anti-inflammatory capacity of davallialactone might be used for oral diseases such as pulpitis and periodontitis.     

Anti-inflammatory mechanism of PPARγ on LPS-induced pulp cells: role of the ROS removal activity

ObjectivesPPARγ has an anti-inflammatory effect on LPS-induced pulpal inflammation by decreasing the expression of MMPs, ICAM-1 and VCAM-1. However, the anti-inflammatory mechanism of PPARγ on the cell adhesion molecules and their upper signal pathways has not been clarified in pulp cells. The aim of this study is to investigate the anti-inflammatory mechanism of PPARγ in pulpal inflammation.MethodsHuman dental pulp cells (HDPCs) were isolated from freshly extracted third molar and cultured. The over-expression of PPARγ was used by adenoviral PPARγ (Ad/PPARγ). The formation of ROS was analysed using DCFH-DA with FACS, and NO was analysed using colorimetric bioassay. The expression of inflammatory molecules and inflammatory mechanism of PPARγ involved signal pathway were determined by immunoblotting.ResultsLPS-induced HDPC decreased PPARγ expression gradually and strongly activated the ERK1/2 signals amongst the MAPK, and induced NF-κB translocation from the cytosol to the nucleus. On the other hand, the cells to restore PPARγ with Ad/PPARγ were inhibited ERK1/2 despite being stimulated with LPS. In addition, the cells treated with rosiglitazone (PPARγ agonist) also were inhibited ERK1/2 activation, and the expression of ICAM-1, VCAM-1 and NF-κB translocation under LPS stimulation. The GW9667 (PPARγ antagonist)-treated HDPC did not affect the adhesion molecules and signal activation. LPS-induced HDPC produced significant NO and ROS levels, but their production was attenuated in the PPARγ over-expressed cells. Overall, the PPARγ effect under LPS stimulation is due to the removal activity of cellular NO and ROS formation.ConclusionThese results suggest that anti-inflammatory mechanism of PPARγ is due to the removal activity of NO and ROS, and its removal effect suppressed ERK1/2 signal activation and NF-κB translocation. Therefore, the NO and ROS removal activity of PPARγ suggests major anti-inflammatory mechanism in HDPC, and it might offer us a possible molecule for various types of inflammatory inhibition.     

缺血再灌注对大鼠颌下腺分泌功能的影响

目的 探讨单纯缺血再灌注引起的大鼠颌下腺损伤-应激反应及其对颌下腺分泌功能的影响。方法 建立大鼠颌下腺原位缺血再灌注模型,以对侧腺体作为对照组,实验侧颌下腺经历90 min缺血,分别再灌注1、12、24、72 h后,检测各组腺体的分泌量,组织学变化,活性氧水平及细胞凋亡情况。结果大鼠颌下腺经历缺血再灌注后1 h和12 h,腺体分泌量显著降低,至再灌注72 h腺体的分泌量逐渐恢复正常。组织学观察发现,经历缺血再灌注后,腺体组织开始出现水肿及炎症细胞浸润,至再灌注12 h最为严重,其后逐渐恢复至正常。腺体组织活性氧水平及细胞凋亡也表现出相同的变化趋势,经历再灌注1 h和12 h后,腺体组织内活性氧信号增多,细胞凋亡水平显著增高。结论缺血再灌注损伤是移植腺体早期分泌功能低下的重要原因之一。     

Effect of priming in subpopulations of peripheral neutrophils from patients with chronic periodontitis

Background: Patients with periodontal disease are reported to generate more reactive oxygen species (ROS) than matched controls, suggesting increased inflammatory defense activity. The purpose of this study is to determine whether there are subpopulations of peripheral neutrophils in patients with chronic periodontitis (CP) that generate different levels of intracellular ROS when primed with tumor necrosis factor‐α (TNF‐α) or the chemokine interleukin‐8 (IL‐8, CXCL8) compared to controls. Methods: Venous blood was collected from 13 patients with CP despite careful maintenance over 2 to 8 years and from 13 healthy age‐ and sex‐matched controls. Neutrophils were separated from whole blood over a Percoll gradient and then activated via the Fcγ receptor with opsonized Staphylococcus aureus after priming with TNF‐α or IL‐8. The samples were analyzed by flow cytometry using the fluorescent probe dihydrorhodamine 123. Generation of ROS was measured as the intensity of fluorescence (IFL). Results: Two subpopulations were found in both patients and controls: one with low and one with high generation of IFL. The subpopulation with high generation of IFL in patients with CP was more responsive to IL‐8 (P <0.05) than the same subpopulation in healthy controls. No other differences in generation of ROS or priming effects were found between patients with CP and controls. Generation of ROS was dependent on nicotinamide adenine dinucleotide phosphate oxidase, and the intracellular ROS was primarily the oxygen anion. Conclusion: Patients with CP had a subpopulation of peripheral neutrophils that were more responsive to IL‐8 priming than controls.