心血管领域复方创新药的范例：缬沙坦沙库比曲片 与依那普利叶酸片 ——给我国新药创制带来的启示

缬沙坦沙库比曲片与依那普利叶酸片均属于复方创新药,即其中单药在组成复方后的疗效或适应证发生新的变化。针对临床需求、 疗效以及循证依据,详细剖析这两种复方创新药的组方特点,重点探讨复方创新药与一般复方药的区别,为以临床价值为导向和基于患者 人群特点的重大新药创制提供借鉴。     

Influence of connection type on the biomechanical behavior of distal extension mandibular removable partial dentures supported by implants and natural teeth

Few studies are performed to evaluate the influence of connection type on the stress distribution of distal extension mandibular removable partial dentures (RPDs) supported by both implants and natural teeth. In this study, five three-dimensional finite element models were prepared to simulate mandibular bilateral partially edentulous arches. Four were RPDs supported by both implants and natural teeth, and the other one was RPDs supported only by natural teeth. The maximum equivalent (EQV) stress values of bone around implants, the abutments, and the mucosa displacements of the related supporting structures were measured. It was found that a non-rigid telescopic coping was more favorable to protect the implant than a rigid telescopic coping. Compared with other connection types, the easy resilient attachment (ERA) system seemed to be effective to associate implant without complications. However, the results obtained in the present study should be cautiously interpreted in the clinic.     

Mechanical response comparison in an implant overdenture retained by ball attachments on conventional regular and mini dental implants: a finite element analysis

This study investigates the bone/implant mechanical responses in an implant overdenture retained by ball attachments on two conventional regular dental implants (RDI) and four mini dental implants (MDI) using finite element (FE) analysis. Two FE models of overdentures retained by RDIs and MDIs for a mandibular edentulous patient with validation within 6% variation errors were constructed by integrating CT images and CAD system. Bone grafting resulted in 2 mm thickness at the buccal side constructed for the RDIs-supported model to mimic the bone augmentation condition for the atrophic alveolar ridge. Nonlinear hyperelastic material and frictional contact element were used to simulate characteristic of the ball attachment-retained overdentures. The results showed that a denture supported by MDIs presented higher surrounding bone strains than those supported by RDIs under different load conditions. Maximum bone micro strains were up to 6437/2987 and 13323/5856 for MDIs/RDIs under single centric and lateral contacts, respectively. Corresponding values were 4429/2579 and 9557/5774 under multi- centric and lateral contacts, respectively. Bone micro strains increased 2.06 and 1.96-folds under single contact, 2.16 and 2.24-folds under multiple contacts for MDIs and RDIs when lateral to axial loads were compared. The maximum RDIs and MDIs implant stresses in all simulated cases were found by far lower than their yield strength. Overdentures retained using ball attachments on MDIs in poor edentulous bone structure increase the surrounding bone strain over the critical value, thereby damaging the bone when compared to the RDIs. Eliminating the occlusal single contact and oblique load of an implant-retained overdenture reduces the risk for failure.     

Novel CaO/polylactic acid nanoscaffold as dental resin nanocomposites and the investigation of physicochemical properties

In this study, for the first time, calcium oxide (CaO)/polylactic acid nanoscaffolds were synthesized by co‐precipitation assistant reverse micelles method. The physical and chemical (physicochemical) properties of the structures as dental resin composites were also studied. Nanocomposite materials as primary and basic dental compounds can be conveniently applied as dental filling materials with a high esthetic quality. In this research nanoscaffolds act as a bed for nanoparticles and improve the mechanical and chemical (mechanochemical) properties, CaO nanoparticles were loading in polylactic acid nanoscaffold as a bioactivity polymer for usage in the dental resin composites. Mechanical properties of the dental resin composite containing CaO/polylactic acid nanoscaffold were calculated: the flexural strength (137.2 MPa), modulus (12.9GPa) and compressive strength (344.2 MPa). Potential of the basic nanoparticle and the products were characterized by X‐ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), dynamic light scattering (DLS), ultraviolet‐visible spectroscopy (UV‐visible) and atomic force microscopy (AFM) showed the size of the optimized nanostructures was about 85 to 120 nm. According to TGA results of polylactic acid nanofibers with thermal stability below 300°C these high thermal stability materials can be used as dental resin composites.     

Lipopolysaccharide upregulates the proliferation,migration, and odontoblastic differentiation of NG2+ cells from human dental pulp in vitro

NG2⁺ cells have been proven to differentiate into odontoblasts in vivo, and their contribution to odontoblasts is significantly increased, especially after tooth injury. However, their characteristics in vitro, especially under an inflammatory environment, are still not fully understood. Therefore, this study aimed to explore their proliferation, migration, and odontoblastic differentiation ability after treatment with lipopolysaccharide (LPS) in vitro. In our study, NG2 ⁺ cells were isolated from the human dental pulp by magnetic‐activated cell sorting, and these isolated cells were proven to be NG2 ⁺ by immunostaining. When compared with human dental pulp cells (hDPCs), the NG2 ⁺ cells showed no significant differences in cell migration with or without LPS incubation, but their proliferative ability was weaker. When treated with LPS, NG2 ⁺ cells expressed elevated levels of pro‐inflammatory cytokines including interleukin‐1β (IL‐1β), IL‐6, IL‐8, and tumor necrosis factor‐α, and among these, the expression of IL‐1β and IL‐6 were higher than that of hDPCs. Their multipotent differentiation potential was confirmed by the induction of odontoblastic and adipogenic differentiation, and LPS increased their odontoblastic differentiation capacity. In the odontoblastic differentiation process, Wnt5a, BMP2, and BMP7 mRNA were increased, while the canonical Wnt‐related genes were decreased. In conclusion, the LPS stimulation promotes the migration, proliferative, and odontoblastic differentiation ability of NG2 ⁺ cells from the human dental pulp in vitro, and bone morphogenetic protein and the noncanonical Wnt pathway may be involved in their odontoblastic differentiation. These results indicated their special roles in tooth injury repair and potential application in pulp regeneration.     

燃煤污染型氟中毒患者氟暴露、骨相损伤程度与骨形成标志物的关系

慢性氟暴露是世界范围内的公共卫生问题之一.为研究燃煤污染型氟中毒患者中氟暴露、骨相损伤程度与骨形成标志物血清碱性磷酸酶(ALP)、骨钙素(BGP)之间的相关关系,以贵州省织金县荷花村(燃煤污染型地方性氟中毒病区)和安顺市张官村(非氟暴露村)为调查点,采集环境样品,采用氟离子选择电极法测定环境介质及食物中的氟含量.在知情同意的原则下,对295例氟暴露和85例非氟暴露调查对象进行氟斑牙、氟骨症诊断;收集其尿液及外周血,测定尿氟(UF)浓度、ALP活性和BGP含量.结果表明: 病区环境中大米、辣椒、玉米、饮水、黏土、菜土、煤以及室内外空气氟含量均明显高于对照区,但较以往报道数据降低;随着尿氟浓度的升高,ALP活性、BGP含量显著升高,氟骨症病情差异有统计学意义,氟斑牙病情差异无统计学意义;氟骨症病情与ALP活性、BGP含量呈正相关.表明燃煤污染型低氟暴露可引起人群的骨相损害,且ALP、BGP可用于评估氟骨症患者骨转换情况,在氟骨症的辅助诊断、疗效评估中有着一定的应用价值.     

Detection of dental plaque and its potential pathogenicity using quantitative light‐induced fluorescence

Quantitative light‐induced fluorescence (QLF) technology can detect some dental plaque as red fluorescence. This in vivo study aimed to identify the microbial characteristics of red fluorescent (RF) dental plaque using 16S rRNA gene sequencing and evaluate the correlations between RF plaque and the clinical symptoms of dental diseases. Paired supragingival plaque samples collected from each 10 subjects and consisted of RF and non‐RF dental plaques as observed by QLF technology using a 405 nm blue light source for excitation. The characteristics of the bacterial communities in the RF and non‐RF plaque samples were compared by sequencing analysis. An increase in microbial diversity was observed in RF plaque compared with the non‐RF plaque. There were significant differences in the community compositions between the 2 types of dental plaque. Periodontopathic bacteria were significantly more abundant in the RF plaque than non‐RF plaque. The fluorescence intensity of RF plaque was significantly related to the proportion of the periodontopathic bacterial community and the presence of gingival inflammation. In conclusion, the plaque red fluorescence is associated with changes in the microbial composition and enrichment of periodontopathic pathogens, which suggests that RF plaque detected by QLF technology could be used as a risk indicator for gingival inflammation.      

Antimicrobial Peptides and their Potential as Oral Therapeutic Agents

Dental caries (tooth decay) and periodontal diseases are the most prevalent bacterial infectious diseases of mankind, together affecting almost the entire population of the world. Both diseases are caused by oral bacteria that exist as components of a polymicrobial biofilm, known as dental plaque, on the tooth surface. The control of specific types of bacteria and/or total numbers of bacteria in dental plaque could lead to prevention or resolution of disease. Antimicrobial peptides isolated from a wide range of natural sources have been known for over 30 years yet little progress had been made in the therapeutic application of these peptides. This is due in part to the characteristics, including susceptibility to proteolysis, of the cationic amphipathic antimicrobial peptides that form the majority of peptides discovered to date. Bovine milk is a readily available source of a range of bioactive peptides. We have isolated and characterized a novel anionic antimicrobial peptide, Kappacin, from bovine milk. Antibacterial activity of the peptide is increased when it is complexed with zinc ions. We have demonstrated that a Kappacin:Zn²⁺ preparation is able to suppress the growth of oral cariogenic bacteria in a biofilm. The Kappacin:Zn²⁺ antibacterial complex may have potential as an additive to oral care products and other delivery vehicles for the control of oral disease.     

Aggregation of human dental pulp cells into 3D spheroids enhances their migration ability after reseeding

Multicellular three-dimensional (3D) spheroids allow intimate cell–cell communication and cell–extracellular matrix interaction. Thus, 3D cell spheroids better mimic microenvironment in vivo than two-dimensional (2D) monolayer cultures. The purpose of this study was to evaluate the behaviors of human dental pulp cells (DPCs) cultured on chitosan and polyvinyl alcohol (PVA) membranes. The protein expression of hypoxia-inducible factor 1-α (HIF-1α) and vascular endothelial growth factor (VEGF), and the migration ability of the DPCs from 2D versus 3D environments were investigated. The results showed that both chitosan and PVA membranes support DPCs aggregation to form multicellular spheroids. In comparison to 2D cultures on tissue culture polystyrene, DPC spheroids exhibited higher protein expression of HIF-1α and VEGF. The treatment with YC-1 (inhibitor to HIF-1α) blocked the upregulation of VEGF, indicating a downstream event to HIF-1α expression. When DPC spheroids were collected and subjected to the transwell assay, the cells growing outward from 3D spheroids showed greater migration ability than those from 2D cultures. Moreover, DPCs aggregation and spheroid formation on chitosan membrane were abolished by Y-27632 (inhibitor to Rho-associated kinases), whereas the inhibitory effect did not exist on PVA membrane. This suggests that the mechanism regulating DPCs aggregation and spheroid formation on chitosan membrane is involved with the Rho-associated kinase signaling pathway. In summary, the multicellular spheroid structure was beneficial to the protein expression of HIF-1α and VEGF in DPCs and enhanced the migration ability of the cells climbing from spheroids. This study showed a new perspective in exploring novel strategies for DPC-based research and application.