The role of oxidative stress biomarkers in the development of peri-implant disease: A systematic review and meta-analysis.

OBJECTIVES: To analyze the role of oxidative stress (OS) biomarkers in peri­implant diseases using a systematic review and meta-analysis approach. DATE: The review incorporated cross-sectional studies, randomized controlled trials, and case-control trials to evaluate the differences in OS biomarkers of peri­implant disease. SOURCES: A comprehensive literature search was conducted in electronic databases such as PubMed, Scopus, Embase, Web of Science, and CNKI, and no restrictions were applied during the search process. STUDY SELECTION: A total of 452 studies were identified, of which 18 were eligible for inclusion. Risk of bias and sensitivity analysis were assessed using Egger's test and funnel plots. RESULTS: We found that the levels of glutathione peroxidase (GSH-Px) in the peri­implant sulcus fluid (PISF) of patients with peri­implant diseases were significantly reduced (SMD = -1.40; 95 % CI = 1.70, -1.11; p < 0.001), while the levels of total myeloperoxidase (MPO) and malondialdehyde (MDA) were significantly increased (SMD = 0.46; 95 % CI = 0.12, 0.80; p = 0.008; SMD = 0.28; 95 % CI = 0.01, 0.56; p = 0.043). However, there were no significant differences of MPO concentration (SMD = 0.38; 95 % CI = -0.39, 1.15; p = 0.331) and superoxide dismutase (SOD)(SMD = -0.43; 95 % CI = -1.94, 1.07; p = 0.572) in PISF between peri­implant disease group and control group. Similarly, salivary MPO did not show significant differences (SMD = 1.62; 95 % CI = -1.01, 4.24; p = 0.227). CONCLUSIONS: Our results supported that the level of local OS biomarkers was closely related to peri­implant diseases. GSH-Px, total MPO and MDA may be PISF biomarkers with good capability to monitor the development of peri­implant disease. CLINICAL SIGNIFICANCE: This study found significant differences in the levels of local OS biomarkers (GSH-Px, total MPO, and MDA) between patients with peri­implant diseases and healthy subjects, which may be ideal candidate biomarkers for predicting and diagnosing peri­implant diseases.

Interpenetrating nanofibrillar membrane of self-assembled collagen and antimicrobial peptides for enhanced bone regeneration.

Bone regeneration remains a major clinical challenge, especially when infection necessitates prolonged antibiotic treatment. This study presents a membrane composed of self-assembled and interpenetrating GL13K, an antimicrobial peptide (AMP) derived from a salivary protein, in a collagen membrane for antimicrobial activity and enhanced bone regeneration. Commercially available collagen membranes were immersed in GL13K solution, and self-assembly was initiated by raising the solution pH to synthesize the multifunctional membrane called COL-GL. COL-GL was composed of interpenetrating large collagen fibers and short GL13K nanofibrils, which increased hydrophobicity, reduced biodegradation from collagenase, and stiffened the matrix compared to control collagen membranes. Incorporation of GL13K led to antimicrobial and anti-fouling activity against early oral surface colonizer Streptococcus gordonii while not affecting fibroblast cytocompatibility or pre-osteoblast osteogenic differentiation. GL13K in solution also reduced macrophage inflammatory cytokine expression and increased pro-healing cytokine expression. Bone formation in a rat calvarial model was accelerated at eight weeks with COL-GL compared to the gold-standard collagen membrane based on microcomputed tomography and histology. Interpenetration of GL13K within collagen sidesteps challenges with antimicrobial coatings on bone regeneration scaffolds while increasing bone regeneration. This strength makes COL-GL a promising approach to reduce post-surgical infections and aid bone regeneration in dental and orthopedic applications. STATEMENT OF SIGNIFICANCE: The COL-GL membrane, incorporating the antimicrobial peptide GL13K within a collagen membrane, signifies a noteworthy breakthrough in bone regeneration strategies for dental and orthopedic applications. By integrating self-assembled GL13K nanofibers into the membrane, this study successfully addresses the challenges associated with antimicrobial coatings, exhibiting improved antimicrobial and anti-fouling activity while preserving compatibility with fibroblasts and pre-osteoblasts. The accelerated bone formation observed in a rat calvarial model emphasizes the potential of this innovative approach to minimize post-surgical infections and enhance bone regeneration outcomes. As a promising alternative for future therapeutic interventions, this material tackles the clinical challenges of extended antibiotic treatments and antibiotic resistance in bone regeneration scenarios.

Regulatory role of PDK1 via integrated gene analysis of mitochondria-immune response in periodontitis.

AIMS: To investigate the association between mitochondrial events and immune response in periodontitis and related regulatory genes. MAIN METHODS: Gene expression profiles in gingival tissues were retrieved from the Gene Expression Omnibus. Mitochondria-immune response-related differentially expressed genes (MIR-DEGs) between the healthy and periodontitis samples were determined. WGCNA, GO, and KEGG were used to investigate the function and the enriched pathways of MIR-DEGs. The correlation between MIR-DEGs expression and clinical probing pocket depth was analyzed. The MIR-DEGs were further identified and verified in animal samples. A periodontitis model was established in C57BL/6 mice with silk ligation. Micro-computed tomography was used to assess alveolar bone loss. Western blot, quantitative real-time polymerase chain reaction, and immunohistochemical analyses further validated the differential expression of the MIR-DEGs. KEY FINDINGS: A total of ten MIR-DEGs (CYP24A1, PRDX4, GLDC, PDK1, BCL2A1, CBR3, ARMCX3, BNIP3, IFI27, and UNG) were identified, the expression of which could effectively distinguish patients with periodontitis from the healthy controls. Enhanced immune response was detected in the periodontitis group with that in the healthy controls, especially in B cells. PDK1 was a critical MIR-DEG correlated with B cell immune response and clinical periodontal probing pocket depth. Both animal and clinical periodontal samples presented higher gene and protein expression of PDK1 than the control samples. Additionally, PDK1 colocalized with B cells in both animal and clinical periodontal tissues. SIGNIFICANCE: Mitochondria participate in the regulation of the immune response in periodontitis. PDK1 may be the key mitochondria-related gene regulating B-cell immune response in periodontitis.

Design, Synthesis, and Biological Evaluation of ß-Trifluoroethoxydimethyl Selenides as Potent Antiosteoporosis Agents.

An efficient protocol for the synthesis of ß-trifluoroethoxydimethyl selenides was achieved under mild reaction conditions, and 39 compounds were prepared. All compounds were evaluated for their abilities to inhibit RANKL-induced osteoclastogenesis, compound 4aa exhibited the most potent activity. Further investigations revealed that 4aa could inhibit F-actin ring generation, bone resorption, and osteoclast-specific gene expression in vitro. Western blot analyses demonstrated that compound 4aa abrogated the RANKL-induced mitogen-activated protein kinase and NF-kB-signaling pathways. In addition, 4aa also displayed a notable impact on the osteoblastogenesis of MC3T3-E1 preosteoblasts. In vivo experiments revealed that compound 4aa significantly ameliorated bone loss in an ovariectomized (OVX) mice model. Furthermore, the surface plasmon resonance experiment results revealed that 4aa probably bound to RANKL. Collectively, the above-mentioned findings suggested that compound 4aa as a potential RANKL inhibitor averted OVX-triggered osteoporosis by regulating the inhibition of osteoclast differentiation and stimulation of osteoblast differentiation.

3-methyl-1H-indol-1-yl dimethylcarbamodithioate attenuates periodontitis through targeting MAPK signaling pathway-regulated mitochondrial function.

Periodontitis, the second most common oral disease, is primarily initiated by inflammatory responses and osteoclast differentiation, in which the MAPK signaling pathway and mitochondrial function play important roles. 3-methyl-1H-indol-1-yl dimethylcarbamodithioate (3o), a hybrid of indole and dithiocarbamate, was first synthesized by our group. It has shown anti-inflammatory activity against lipopolysaccharide-induced acute lung injury. However, it is not known if 3o can exert effects in periodontitis. In vitro study: LPS-induced macrophage inflammation initiation and a receptor activator of nuclear factor κB ligand-stimulated osteoclast differentiation model were established. Cell viability, inflammatory cytokines, osteoclast differentiation, the MAPK signaling pathway, and mitochondrial function before and after treatment with 3o were investigated. In vivo study: Alveolar bone resorption, inflammatory cytokine expression, osteoclast differentiation, and the underlying mechanisms were assessed in mice with periodontitis. Inflammatory cytokine expression and osteoclast differentiation appeared downregulated after 3o treatment. 3o inhibited the MAPK signaling pathway and restored mitochondrial function, including mitochondrial reactive oxygen species, mitochondrial membrane potential, and ATP production. Meanwhile, 3o reduced inflammation activation and bone resorption in mice with periodontitis, reflected by the decreased expression of inflammatory cytokines and osteoclasts, implying that 3o inhibited the MAPK signaling pathway and the mitochondrial oxidative DNA damage marker 8-OHdG. These results highlight the protective role of 3o in periodontitis in mice and reveal an important strategy for preventing periodontitis.

Melatonin protects TEGDMA-induced preodontoblast mitochondrial apoptosis via the JNK/MAPK signaling pathway.

Resin monomer-induced dental pulp injury presents a pathology related to mitochondrial dysfunction. Melatonin has been regarded as a strong mitochondrial protective bioactive compound from the pineal gland. However, it remains unknown whether melatonin can prevent dental pulp from resin monomer-induced injury. The aim of this study is to investigate the effects of melatonin on apoptosis of mouse preodontoblast cells (mDPC6T) induced by triethylene glycol dimethacrylate (TEGDMA), a major component in dental resin, and to determine whether the JNK/MAPK signaling pathway mediates the protective effect of melatonin. A well-established TEGDMA-induced mDPC6T apoptosis model is adopted to investigate the preventive function of melatonin by detecting cell viability, apoptosis rate, expressions of apoptosis-related proteins, mitochondrial ROS (mtROS) production, mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) level. Inhibitors of MAPKs are used to explore which pathway is involved in TEGDMA-induced apoptosis. Finally, the role of the JNK/MAPK pathway is verified using JNK agonists and antagonists. Our results show that melatonin attenuates TEGDMA-induced mDPC6T apoptosis by reducing mtROS production and rescuing MMP and ATP levels. Furthermore, mitochondrial dysfunction and apoptosis are alleviated only by the JNK/MAPK inhibitor SP600125 but not by other MAPK inhibitors. Additionally, melatonin downregulates the expression of phosphorylated JNK and counteractes the activating effects of anisomycin on the JNK/MAPK pathway, mimicking the effects of SP600125. Our findings demonstrate that melatonin protects mDPC6T cells against TEGDMA-induced apoptosis partly through JNK/MAPK and the maintenance of mitochondrial function, offering a novel therapeutic strategy for the prevention of resin monomer-induced dental pulp injury.

Biodegradable Zn-5Dy Alloy with Enhanced Osteo/Angio-Genic Activity and Osteointegration Effect via Regulation of SIRT4-Dependent Mitochondrial Function.

Zinc (Zn)-dysprosium (Dy) binary alloys are promising biodegradable bone fracture fixation implants owing to their attractive biodegradability and mechanical properties. However, their clinical application is a challenge for bone fracture healing, due to the lack of Zn-Dy alloys with tailored proper bio-mechanical and osteointegration properties for bone regeneration. A Zn-5Dy alloy with high strength and ductility and a degradation rate aligned with the bone remodeling cycle is developed. Here, mechanical stability is further confirmed, proving that Zn-5Dy alloy can resist aging in the degradation process, thus meeting the mechanical requirements of fracture fixation. In vitro cellular experiments reveal that the Zn-5Dy alloy enhances osteogenesis and angiogenesis by elevating SIRT4-mediated mitochondrial function. In vivo Micro-CT, SEM-EDS, and immunohistochemistry analyses further indicate good biosafety, suitable biodegradation rate, and great osteointegration of Zn-5Dy alloy during bone healing, which also depends on the upregulation of SIRT4-mediated mitochondrial events. Overall, the study is the first to report a Zn-5Dy alloy that exerts remarkable osteointegration properties and has a strong potential to promote bone healing. Furthermore, the results highlight the importance of mitochondrial modulation and shall guide the future development of mitochondria-targeting materials in enhancing bone fracture healing.

OTUD6A in tubular epithelial cells mediates angiotensin II-induced kidney injury by targeting STAT3.

Kidney fibrosis is a prominent pathological feature of hypertensive kidney diseases (HKD). Recent studies have highlighted the role of ubiquitinating/deubiquitinating protein modification in kidney pathophysiology. Ovarian tumor domain-containing protein 6 A (OTUD6A) is a deubiquitinating enzyme involved in tumor progression. However, its role in kidney pathophysiology remains elusive. We aimed to investigate the role and underlying mechanism of OTUD6A during kidney fibrosis in HKD. The results revealed higher OTUD6A expression in kidney tissues of nephropathy patients and mice with chronic angiotensin II (Ang II) administration than that from the control ones. OTUD6A was mainly located in tubular epithelial cells. Moreover, OTUD6A deficiency significantly protected mice against Ang II-induced kidney dysfunction and fibrosis. Also, knocking OTUD6A down suppressed Ang II-induced fibrosis in cultured tubular epithelial cells, whereas overexpression of OTUD6A enhanced fibrogenic responses. Mechanistically, OTUD6A bounded to signal transducer and activator of transcription 3 (STAT3) and removed K63-linked-ubiquitin chains to promote STAT3 phosphorylation at tyrosine 705 position and nuclear translocation, which then induced profibrotic gene transcription in epithelial cells. These studies identified STAT3 as a direct substrate of OTUD6A and highlighted the pivotal role of OTUD6A in Ang II-induced kidney injury, indicating OTUD6A as a potential therapeutic target for HKD.NEW & NOTEWORTHY Ovarian tumor domain-containing protein 6 A (OTUD6A) knockout mice are protected against angiotensin II-induced kidney dysfunction and fibrosis. OTUD6A promotes pathological kidney remodeling and dysfunction by deubiquitinating signal transducer and activator of transcription 3 (STAT3). OTUD6A binds to and removes K63-linked-ubiquitin chains of STAT3 to promote its phosphorylation and activation, and subsequently enhances kidney fibrosis.

The effect of periapical bone defects on stress distribution in teeth with periapical periodontitis: a finite element analysis.

BACKGROUND: Apical periodontitis directly affects the stress state of the affected tooth owing to the destruction of the periapical bone. Understanding the mechanical of periapical bone defects/tooth is clinically meaningful. In this study, we evaluate the effect of periapical bone defects on the stress distribution in teeth with periapical periodontitis using finite element analysis. METHODS: Finite element models of normal mandibular second premolars and those with periapical bone defects (spherical defects with diameters of 5, 10, 15, and 20 mm) were created using a digital model design software. The edges of the mandible were fixed and the masticatory cycle was simplified as oblique loading (a 400 N force loaded obliquely at 45° to the long axis of the tooth body) to simulate the tooth stress state in occlusion and analyze the von Mises stress distribution and tooth displacement distribution in each model. RESULTS: Overall analysis of the models: Compared to that in the normal model, the maximum von Mises stresses in all the different periapical bone defect size models were slightly lower. In contrast, the maximum tooth displacement in the periapical bone defect model increased as the size of the periapical bone defect increased (2.11-120.1% of increase). Internal analysis of tooth: As the size of the periapical bone defect increased, the maximum von Mises stress in the coronal cervix of the tooth gradually increased (2.23-37.22% of increase). while the von Mises stress in the root apical region of the tooth showed a decreasing trend (41.48-99.70% of decrease). The maximum tooth displacement in all parts of the tooth showed an increasing trend as the size of the periapical bone defect increased. CONCLUSIONS: The presence of periapical bone defects was found to significantly affect the biomechanical response of the tooth, the effects of which became more pronounced as the size of the bone defect increased.

The effect of root canal treatment and post-crown restorations on stress distribution in teeth with periapical periodontitis: a finite element analysis.

AIM: To evaluate the effects of root canal treatment (RCT) and post-crown restoration on stress distribution in teeth with periapical bone defects using finite element analysis. METHODOLOGY: Finite element models of mandibular second premolars and those with periapical bone defects (spherical defects with diameters of 5, 10, 15, and 20 mm) were created using digital model design software. The corresponding RCT and post-crown restoration models were constructed based on the different sizes of periapical bone defect models. The von Mises stress and tooth displacement distributions were comprehensively analyzed in each model. RESULTS: Overall analysis of the models: RCT significantly increased the maximum von Mises stresses in teeth with periapical bone defects, while post-crown restoration greatly reduced the maximum von Mises stresses. RCT and post-crown restoration slightly reduced tooth displacement in the affected tooth. Internal analysis of tooth: RCT dramatically increased the maximum von Mises stress in all regions of the tooth, with the most pronounced increase in the coronal surface region. The post-crown restoration balances the internal stresses of the tooth and is most effective in periapical bone defect - 20-mm model. RCT and post-crown restoration slightly reduced the tooth displacement in all regions of the affected tooth. CONCLUSIONS: Root canal treatment seemed not to improve the biomechanical state of teeth with periapical bone defects. In contrast, post-crown restoration might effectively balance the stress concentrations caused by periapical bone defects, particularly extensive ones.

Biomechanical evaluation of a novel anterior transpedicular screw-plate system for anterior cervical corpectomy and fusion (ACCF): a finite element analysis.

Background and objective: Cervical fusion with vertebral body screw (VBS)-plate systems frequently results in limited biomechanical stability. To address this issue, anterior transpedicular screw (ATPS) fixation has been developed and applied preliminarily to multilevel spinal fusion, osteoporosis, and three-column injury of the cervical spine. This study aimed to compare the biomechanical differences between unilateral ATPS (UATPS), bilateral ATPS (BATPS), and VBS fixation using finite element analysis. Materials and methods: A C6 corpectomy model was performed and a titanium mesh cage (TMC) and bone were implanted, followed by implantation of a novel ATPS-plate system into C5 and C7 to simulate internal fixation with UATPS, BATPS, and VBS. Internal fixation with UATPS comprises ipsilateral transpedicular screw-contralateral vertebral body screw (ITPS-CVBS) and cross transpedicular screw-vertebral body screw (CTPS-VBS) fixations. Mobility, the maximal von Mises stress on TMC, the stress distribution and maximal von Mises stress on the screws, and the maximum displacement of the screw were compared between the four groups. Results: Compared with the original model, each group had a reduced range of motion (ROM) under six loads. After ACCF, the stress was predominantly concentrated at two-thirds of the length from the tail of the screw, and it was higher on ATPS than on VBS. The stress of the ATPS from the cranial part was higher than that of the caudal part. The similar effect happened on VBS. The screw stress cloud maps did not show any red areas reflective of a concentration of the stress on VBS. Compared with VBS, ATPS can bear a greater stress from cervical spine movements, thus reducing the stress on TMC. The maximal von Mises stress was the lowest with bilateral transpedicular TMC and increased with cross ATPS and with ipsilateral ATPS. ITPS-CVBS, CTPS-VBS, and BATPS exhibited a reduction of 2.3%-22.1%, 11.9%-2.7%, and 37.9%-64.1% in the maximum displacement of screws, respectively, compared with that of VBS. Conclusion: In FEA, the comprehensive stability ranked highest for BATPS, followed by CTPS-VBS and ITPS-CVBS, with VBS demonstrating the lowest stability. Notably, utilizing ATPS for fixation has the potential to reduce the occurrence of internal fixation device loosening after ACCF when compared to VBS.

Mechanical properties, corrosion and degradation behaviors, and in vitro cytocompatibility of a biodegradable Zn-5La alloy for bone-implant applications.

Zinc (Zn) and its alloys are used in bone-fixation devices as biodegradable bone-implant materials due to their good biosafety, biological function, biodegradability, and formability. Unfortunately, the clinical application of pure Zn is hindered by its insufficient mechanical properties and slow degradation rate. In this study, a Zn-5 wt.% lanthanum (Zn-5La) alloy with enhanced mechanical properties, suitable degradation rate, and cytocompatibility was developed through La alloying and hot extrusion. The hot-extruded (HE) Zn-5La alloy showed ultimate tensile strength of 286.3 MPa, tensile yield strength of 139.7 MPa, elongation of 35.7%, compressive yield strength of 262.7 MPa, and microhardness of 109.7 HV. The corrosion resistance of the HE Zn-5La in Hanks' and Dulbecco's modified Eagle medium (DMEM) solutions gradually increased with prolonged immersion time. Further, the HE Zn-5La exhibited an electrochemical corrosion rate of 36.7 µm/y in Hanks' solution and 11.4 µm/y in DMEM solution, and a degradation rate of 49.5 µm/y in Hanks' solution and 30.3 µm/y in DMEM solution, after 30 d of immersion. The corrosion resistance of both HE Zn and Zn-5La in DMEM solution was higher than in Hanks' solution. The 25% concentration extract of the HE Zn-5La showed a cell viability of 106.5%, indicating no cytotoxicity toward MG-63 cells. We recommend the HE Zn-5La alloy as a promising candidate material for biodegradable bone-implant applications. STATEMENT OF SIGNIFICANCE: This work reports the mechanical properties, corrosion and degradation behaviors, in vitro cytocompatibility and antibacterial ability of biodegradable Zn-5La alloy for bone-implant applications. Our findings demonstrate that the hot-extruded (HE) Zn-5La alloy showed an ultimate tensile strength of 286.3 MPa, a yield strength of 139.7 MPa, an elongation of 35.7%, compressive yield strength of 262.7 MPa, and microhardness of 109.7 HV. HE Zn-5La exhibited appropriate degradation rates in Hanks' and DMEM solutions. Furthermore, the HE Zn-5La alloy showed good cytocompatibility toward MG-63 and MC3T3-E1 cells and greater antibacterial ability against S. aureus.

The role of mitochondrial dysfunction in periodontitis: From mechanisms to therapeutic strategy.

Periodontitis is an inflammatory and destructive disease of tooth-supporting tissue and has become the leading cause of adult tooth loss. The most central pathological features of periodontitis are tissue damage and inflammatory reaction. As the energy metabolism center of eukaryotic cells, mitochondrion plays a notable role in various processes, such as cell function and inflammatory response. When the intracellular homeostasis of mitochondrion is disrupted, it can lead to mitochondrial dysfunction and inability to generate adequate energy to maintain basic cellular biochemical reactions. Recent studies have revealed that mitochondrial dysfunction is closely related to the initiation and development of periodontitis. The excessive production of mitochondrial reactive oxygen species, imbalance of mitochondrial biogenesis and dynamics, mitophagy and mitochondrial DNA damage can all affect the development and progression of periodontitis. Thus, targeted mitochondrial therapy is potentially promising in periodontitis treatment. In this review, we summarize the above mitochondrial mechanism in the pathogenesis of periodontitis and discuss some potential approaches that can exert therapeutic effects on periodontitis by modulating mitochondrial activity. The understanding and summary of mitochondrial dysfunction in periodontitis might provide new research directions for pathological intervention or treatment of periodontitis.

Activation of PGC-1α-dependent mitochondrial biogenesis supports therapeutic effects of silibinin against type I diabetic periodontitis.

AIM: To investigate whether silibinin impacts diabetic periodontitis (DP) via mitochondrial regulation. MATERIALS AND METHODS: In vivo, rats were divided into control, diabetes, DP and DP combined with silibinin groups. Diabetes and periodontitis were induced by streptozocin and silk ligation, respectively. Bone turnover was evaluated by microcomputed tomography, histology and immunohistochemistry. In vitro, human periodontal ligament cells (hPDLCs) were exposed to hydrogen peroxide (H2 O2 ) with or without silibinin. Osteogenic function was analysed by Alizarin Red and alkaline phosphatase staining. Mitochondrial function and biogenesis were investigated by mitochondrial imaging assays and quantitative polymerase chain reaction. Activator and lentivirus-mediated knockdown of peroxisome proliferator-activated receptor gamma-coactivator 1-alpha (PGC-1α), a critical regulator of mitochondria biogenesis, was used to explore the mitochondrial mechanisms. RESULTS: Silibinin attenuated periodontal destruction and mitochondrial dysfunction and enhanced mitochondrial biogenesis and PGC-1α expression in rats with DP. Meanwhile, silibinin promoted cell proliferation, osteogenesis and mitochondrial biogenesis and increased the PGC-1α level in hPDLCs exposed to H2 O2 . Silibinin also protected PGC-1α from proteolysis in hPDLCs. Furthermore, both silibinin and activator of PGC-1α ameliorated cellular injury and mitochondrial abnormalities in hPDLCs, while knockdown of PGC-1α abolished the beneficial effect of silibinin. CONCLUSIONS: Silibinin attenuated DP through the promotion of PGC-1α-dependent mitochondrial biogenesis.

Silibinin Attenuates Experimental Periodontitis by Downregulation of Inflammation and Oxidative Stress.

Periodontitis is an oral microbiota-induced inflammatory disease, in which inflammation and oxidative stress play a critical role. Silibinin (SB), a Silybum marianum-derived compound, exhibits strong anti-inflammatory and antioxidative properties. We adopted a rat ligature-induced periodontitis model and a lipopolysaccharide- (LPS-) stimulated human periodontal ligament cells (hPDLCs) model to evaluate the protective effects of SB. In the in vivo model, SB reduced alveolar bone loss and apoptosis of PDLCs in the periodontal tissue. SB also maintained the expression of nuclear factor-E2-related factor 2 (Nrf2), a key regulator of cellular resistance to oxidative stress, and attenuated lipid, protein, and DNA oxidative damages in the periodontal lesion area. Meanwhile, in the in vitro model, SB administration reduced the production of intracellular reactive oxidative species (ROS). Furthermore, SB exerted a strong anti-inflammatory property in both in vivo and in vitro models by inhibiting the expression of inflammatory mediators including nuclear factor-κB (NF-κB) as well as nucleotide binding oligomerization domain- (NOD-) like receptor family pyrin domain-containing 3 (NLRP3) and downregulating the levels of proinflammatory cytokines. This study, for the first time, demonstrates that SB exhibits the anti-inflammatory and antioxidative properties against periodontitis by downregulating the expression of NF-κB and NLRP3 and upregulating Nrf2 expression, suggesting a promising potential clinical application of SB in periodontitis.

CypD-mediated mitochondrial dysfunction contributes to titanium ion-induced MC3T3-E1 cell injury.

Titanium (Ti) ion can stimulate osteoblast apoptosis and therefore have a high potential to play a negative role in the aseptic loosening of implants. Mitochondrial abnormalities are closely related to osteoblast dysfunction. However, the mitochondrial molecular mechanism of Ti ion induced osteoblastic cell apoptosis is still unclear. This study investigated in vitro mitochondrial oxidative stress (mtROS) mediated mitochondrial dysfunction involved in Ti ion-induced apoptosis of murine MC3T3-E1 osteoblastic cells. In addition to reducing mitochondrial membrane potential (MMP) and decreasing adenosine triglyceride production, exposure to Ti ions increased mitochondrial oxidative stress. Moreover, mitochondrial abnormalities significantly contributed to Ti ion induction of osteoblastic cellular apoptosis. A mitochondria-specific antioxidant, mitoquinone (MitoQ), alleviated Ti ion-induced mitochondrial dysfunction and apoptosis in osteoblastic cells, indicating that Ti ion mainly induces mitochondrial oxidative stress to produce a cytotoxic effect on osteoblasts. Here we show that the primary regulator of mitochondrial permeability transition pore (mPTP), cyclophilin D (CypD), is involved in mitochondrial dysfunction and osteoblast cell apoptosis induced by Ti ion. Overexpression of CypD exacerbates osteoblast apoptosis and impairs osteogenic function. Moreover, detrimental effects of CypD were rescued by cyclosporin A (CsA), an inhibitor of CypD, which shows its protective effect on mitochondrial and osteogenic osteoblast functions. Based on new insights into the mitochondrial mechanisms underlying Ti ion-induced apoptosis of osteoblastic cells, the findings of this study lay the foundation for the clinical use of CypD inhibitors to prevent or treat implant failure.

Biodegradable Zn-Dy binary alloys with high strength, ductility, cytocompatibility, and antibacterial ability for bone-implant applications.

The unique combination of biodegradability, biocompatibility, and functionality of zinc (Zn)-based alloys makes them highly desirable for a wide range of medical applications. However, a long-standing problem associated with this family of biodegradable alloys in the as-cast state is their limited mechanical strength and slow degradation rate. Here we report the development of Zn-xDy (x = 1, 3, and 5 wt.%) alloys with high strength, ductility, cytocompatibility, antibacterial ability, and appropriate degradation rate for biodegradable bone-implant applications. Our results indicate that the mechanical properties of Zn-xDy alloys were effectively improved with increasing Dy addition and hot-rolling due to the second-phase strengthening. The hot-rolled (HR) Zn-3Dy alloy showed the best combined mechanical performance with an ultimate tensile strength of 270.5 MPa, a yield strength of 214.8 MPa, an elongation of 55.1%, and Brinell hardness of 75.9 HB. The corrosion and degradation rates of HR Zn-xDy alloys in Hanks' solution gradually increased with increasing Dy addition due to the intensification of galvanic corrosion. The HR Zn-3Dy alloy showed high antibacterial ability against S. aureus and cytocompatibility toward MC3T3-E1 cells among all the HR alloys. Overall, the HR Zn-3Dy alloy can be considered a promising biodegradable material for bone implants. STATEMENT OF SIGNIFICANCE: This work reports on Zn-xDy (x = 1, 3, and 5%) alloys fabricated by Dy alloying followed by hot-rolling for biodegradable bone-implant applications. Our findings demonstrate that the hot-rolled (HR) Zn-3Dy alloy showed the best combined mechanical performance with an ultimate tensile strength of 270.5 MPa, a yield strength of 214.8 MPa, an elongation of 55.1%, and Brinell hardness of 75.9 HB. The corrosion and degradation rates of HR Zn-xDy alloys in Hanks' solution gradually increased with increasing Dy addition due to the intensification of galvanic corrosion. Furthermore, the HR Zn-3Dy alloy showed greater antibacterial ability against S. aureus and the best cytocompatibility toward MC3T3-E1 cells among all the HR alloys.

Time Trends in the Incidence of Spinal Pain in China, 1990 to 2019 and Its Prediction to 2030: The Global Burden of Disease Study 2019.

BACKGROUND: With increasing life expectancy in China, the associated burden of low back and neck pain (spinal pain) on the healthcare system increases, posing a substantial public health challenge. This study aimed to investigate trends in spinal pain incidence across China from 1990 to 2019 and to predict incidence trends between 2020 and 2030. METHODS: Data were derived from the Global Burden of Disease Study (GBD) 2019. The annual percentage change (APC) and average annual percentage change (AAPC) between 1990 and 2019 were calculated using Joinpoint regression analysis. The effects of age, period, and cohort on spinal pain were estimated by an age-period-cohort model. An autoregressive integrated moving average (ARIMA) model was used to forecast incidence trends from 2020 to 2030. RESULTS: From 1990 to 2019, the age-standardized incidence rate (ASIR) of low back pain (LBP) significantly decreased in both male and female subjects, while the ASIR of neck pain (NP) slightly increased regardless of sex. Joinpoint regression analysis showed that the incidence rates of LBP decreased in all age groups, and incidence rates of NP increased after 45 years old among men and women. The age effects showed that the relative risks (RR) of LBP incidence increased with age, and the group aged 40-49 years had the highest RR for NP incidence, regardless of sex. Period effects showed that the risk of NP continuously increased with increasing time periods, but not in LBP. The cohort effect showed a continuously decreasing trend in later birth cohorts. The prediction results of the ARIMA model show that the ASIR of NP in both male and female subjects in China shows an increasing trend in the next 10 years, and the ASIR of LBP increased in male but decreased in female subjects. CONCLUSION: Spinal pain has remained a major public health burden over the past 30 years in China and will likely increase further with population aging. Therefore, spinal pain should be a priority for future research on prevention and therapy, and is especially critical as the aging population increases in China.

A biodegradable in situ Zn-Mg2Ge composite for bone-implant applications.

Zinc (Zn)-based composites have received extensive attention as promising biodegradable materials due to their unique combination of moderate biodegradability, biocompatibility, and functionality. Nevertheless, the low mechanical strength of as-cast Zn-based composites impedes their practical clinical application. Here we reported the mechanical properties, corrosion behavior, wear properties, and cytotoxicity of in situ synthesized biodegradable Zn-xMg2Ge (x = 1, 3, and 5 wt.%) composites for bone-implant applications. The mechanical properties of Zn-xMg2Ge composites were effectively improved by alloying and hot-rolling due to particle reinforcement of the Mg2Ge intermetallic phase and dynamic recrystallization. The hot-rolled (HR) Zn-3Mg2Ge composite exhibited the best mechanical properties, including a yield strength of 162.3 MPa, an ultimate tensile strength of 264.3 MPa, an elongation of 10.9%, and a Brinell hardness of 83.9 HB. With an increase in Mg2Ge content, the corrosion and degradation rates of the HR Zn-xMg2Ge composites gradually increased, while their wear rate decreased and then increased in Hanks' solution. The diluted extract (12.5% concentration) of the HR Zn-3Mg2Ge composite showed the highest cell viability compared to the other HR composites and their as-cast pure Zn counterparts. Overall, the HR Zn-3Mg2Ge composite can be considered a promising biodegradable Zn-based composite for bone-implant applications. STATEMENT OF SIGNIFICANCE: This paper reports the mechanical properties, corrosion behavior, wear properties, and cytotoxicity of in situ synthesized biodegradable Zn-xMg2Ge (x = 1, 3, and 5 wt.%) composites for bone-implant applications. Our findings demonstrated that the mechanical properties of Zn-xMg2Ge composites were effectively improved by alloying and hot-rolling due to Mg2Ge particle reinforcement and dynamic recrystallization. The hot-rolled Zn-3Mg2Ge composite showed superior cytocompatibility, satisfying corrosion and degradation rates, and the best mechanical properties including a yield strength of 162.3 MPa, an ultimate tensile strength of 264.3 MPa, and an elongation of 10.9%.

A biodegradable Fe/Zn-3Cu composite with requisite properties for orthopedic applications.

Zinc (Zn)-based metals and alloys are emerging as promising biodegradable implant materials due to their inherent biodegradability and good biocompatibility. However, this class of materials exhibits low mechanical strength and a slow degradation rate, which hinders their clinical application. Here we report the development of a new biodegradable Fe/Zn-3Cu composite fabricated by infiltration casting of a Zn-3Cu alloy into an Fe foam followed by hot-rolling. Our results indicate that the hot-rolled (HR) Fe/Zn-3Cu composite exhibited an α-Zn matrix phase, a secondary CuZn5 phase, and an α-Fe phase. The HR Fe/Zn-3Cu composite exhibited an ultimate tensile strength of 269 MPa, a tensile yield strength of 210 MPa, and an elongation of 27%. The HR Fe/Zn-3Cu composite showed a degradation rate of 228 µm/year after immersion in Hanks' solution for 30 d The diluted extract of the HR Fe/Zn-3Cu composite exhibited a higher cell viability than that of the HR Zn-3Cu alloy in relation to MC3T3-E1 and MG-63 cells. Furthermore, the HR Fe/Zn-3Cu composite showed significantly better antibacterial ability than that of the HR Zn-3Cu alloy in relation to S. aureus. Overall, the HR Fe/Zn-3Cu composite can be anticipated to be a promising biodegradable implant material for bone-fixation applications. STATEMENT OF SIGNIFICANCE: This work reports a new biodegradable Fe/Zn-3Cu composite fabricated by infiltration casting and followed by hot-rolling for biodegradable bone-fixation application. Our findings demonstrated that the hot-rolled (HR) Fe/Zn-3Cu composite exhibited an ultimate tensile strength of 269.1 MPa, a tensile yield strength of 210.3 MPa, and an elongation of 26.7%. HR Fe/Zn-3Cu composite showed a degradation rate of 227.6 µm/a, higher than HR Zn-3Cu alloy after immersion in Hanks' solution for 30 d The diluted extracts of the HR Fe/Zn-3Cu composite exhibited a higher cell viability than HR Zn-3Cu alloy toward MC3T3-E1 cells. Furthermore, the HR Fe/Zn-3Cu composite showed significantly better antibacterial ability than the HR Zn-3Cu alloy toward S. aureus.