H2S Protects from Rotenone-Induced Ferroptosis by Stabilizing Fe-S Clusters in Rat Cardiac Cells.

Hydrogen sulfide (H2S) has been recently recognized as an important gasotransmitter with cardioprotections, and iron is vital for various cellular activities. This study explored the regulatory role of H2S on iron metabolism and mitochondrial functions in cultured rat cardiac cells. Rotenone, a mitochondrial complex I inhibitor, was used for establishing an in vitro model of ischemic cell damage. It was first found that rotenone induced oxidative stress and lipid peroxidation and decreased mitochondrial membrane potential and ATP generation, eventually causing cell death. The supplement of H2S at a physiologically relevant concentration protected from rotenone-induced ferroptotic cell death by reducing oxidative stress and mitochondrial damage, maintaining GPx4 expression and intracellular iron level. Deferiprone, an iron chelator, would also protect from rotenone-induced ferroptosis. Further studies demonstrated that H2S inhibited ABCB8-mediated iron efflux from mitochondria to cytosol and promoted NFS1-mediated Fe-S cluster biogenesis. It is also found that rotenone stimulated iron-dependent H2S generation. These results indicate that H2S would protect cardiac cells from ischemic damage through preserving mitochondrial functions and intracellular Fe-S cluster homeostasis.

MCL attenuates atherosclerosis by suppressing macrophage ferroptosis via targeting KEAP1/NRF2 interaction.

BACKGROUND: Micheliolide (MCL), which is the active metabolite of parthenolide, has demonstrated promising clinical application potential. However, the effects and underlying mechanisms of MCL on atherosclerosis are still unclear. METHOD: ApoE-/- mice were fed with high fat diet, with or without MCL oral administration, then the plaque area, lipid deposition and collagen content were determined. In vitro, MCL was used to pretreat macrophages combined by ox-LDL, the levels of ferroptosis related proteins, NRF2 activation, mitochondrial function and oxidative stress were detected. RESULTS: MCL administration significantly attenuated atherosclerotic plaque progress, which characteristics with decreased plaque area, less lipid deposition and increased collagen. Compared with HD group, the level of GPX4 and xCT in atherosclerotic root macrophages were increased in MCL group obviously. In vitro experiment demonstrated that MCL increased GPX4 and xCT level, improved mitochondrial function, attenuated oxidative stress and inhibited lipid peroxidation to suppress macrophage ferroptosis induced with ox-LDL. Moreover, MCL inhibited KEAP1/NRF2 complex formation and enhanced NRF2 nucleus translocation, while the protective effect of MCL on macrophage ferroptosis was abolished by NRF2 inhibition. Additionally, molecular docking suggests that MCL may bind to the Arg483 site of KEAP1, which also contributes to KEAP1/NRF2 binding. Furthermore, Transfection Arg483 (KEAP1-R483S) mutant plasmid can abrogate the anti-ferroptosis and anti-oxidative effects of MC in macrophages. KEAP1-R483S mutation also limited the protective effect of MCL on atherosclerosis progress and macrophage ferroptosis in ApoE-/- mice. CONCLUSION: MCL suppressed atherosclerosis by inhibiting macrophage ferroptosis via activating NRF2 pathway, the related mechanism is through binding to the Arg483 site of KEAP1 competitively.

Biomechanical Analysis of Axial Gradient Porous Dental Implants: A Finite Element Analysis.

The porous structure can reduce the elastic modulus of a dental implant and better approximate the elastic characteristics of the material to the alveolar bone. Therefore, it has the potential to alleviate bone stress shielding around the implant. However, natural bone is heterogeneous, and, thus, introducing a porous structure may produce pathological bone stress. Herein, we designed a porous implant with axial gradient variation in porosity to alleviate stress shielding in the cancellous bone while controlling the peak stress value in the cortical bone margin region. The biomechanical distribution characteristics of axial gradient porous implants were studied using a finite element method. The analysis showed that a porous implant with an axial gradient variation in porosity ranging from 55% to 75% was the best structure. Under vertical and oblique loads, the proportion of the area with a stress value within the optimal stress interval at the bone-implant interface (BII) was 40.34% and 34.57%, respectively, which was 99% and 65% higher compared with that of the non-porous implant in the control group. Moreover, the maximum equivalent stress value in the implant with this pore parameter was 64.4 MPa, which was less than 1/7 of its theoretical yield strength. Axial gradient porous implants meet the strength requirements for bone implant applications. They can alleviate stress shielding in cancellous bone without increasing the stress concentration in the cortical bone margin, thereby optimizing the stress distribution pattern at the BII.

Microwave-assisted synthesis of composites based on titanium and hydroxyapatite for dental implantation.

Titanium (Ti) and its alloys are widely used in clinical practice. As they are not bioactive, hydroxyapatite (HA) is commonly used to modify them. This study offered a review of microwave-assisted synthesis of composites based on Ti and HA for dental implantation by exploring their interaction mechanisms with microwave and features of two main techniques, namely microwave coating and sintering, along with current challenges and potential solutions in the field. It was shown that microwave coating enables rapid deposition of HA, but suffers from problems such as uneven coating thickness, poor integrity and unstable composition of the products. They can be solved by creating interlayers, combining the spin coating technique, etc. Unlike microwave coating, microwave sintering can effectively modify the mechanical properties of the composites, despite the shortcomings of excessive elastic moduli and potential HA decomposition. These issues are expected to be addressed by adding alloying elements and employing appropriate materials as space holders and ion-doped HA for sintering.

H2S regulation of iron homeostasis by IRP1 improves vascular smooth muscle cell functions.

Either H2S or iron is essential for cellular processes. Abnormal metabolism of H2S and iron has increased risk for cardiovascular diseases. The aim of the present study is to examine the mutual interplay of iron and H2S signals in regulation of vascular smooth muscle cell (SMC) functions. Here we found that deficiency of cystathionine gamma-lyase (CSE, a major H2S-producing enzyme in vascular system) induced but NaHS (a H2S donor) administration attenuated iron accumulation in aortic tissues from angiotensin II-infused mice. In vitro, iron overload induced labile iron levels, promoted cell proliferation, disrupted F-actin filaments, and inhibited protein expressions of SMC-specific markers (αSMA and calponin) more significantly in SMCs from CSE knockout mice (KO-SMCs) than the cells from wild-type mice (WT-SMCs), which could be reversed by exogenously applied NaHS. In contrast, KO-SMCs were more vulnerable to iron starvation-induced cell death. Either iron overload or NaHS did not affect elastin level and gelatinolytic activity. We further found that H2S induced more aconitase activity of iron regulatory protein 1 (IRP1) but inhibited its RNA binding activity accompanied with increased protein levels of ferritin and ferriportin, which would contribute to the lower level of labile iron level inside the cells. In addition, iron was able to suppress CSE-derived H2S generation, while iron also non-enzymatically induced H2S release from cysteine. This study reveals the mutual interaction between iron and H2S signals in regulating SMC phenotypes and functions; CSE/H2S system would be a target for preventing iron metabolic disorder-related vascular diseases.

SETD4 Confers Cancer Stem Cell Chemoresistance in Nonsmall Cell Lung Cancer Patients via the Epigenetic Regulation of Cellular Quiescence.

Increasing evidence indicates that quiescent cancer stem cells (CSCs) are a root cause of chemoresistance. SET domain-containing protein 4 (SETD4) epigenetically regulates cell quiescence in breast cancer stem cells (BCSCs), and SETD4-positive BCSCs are chemoradioresistant. However, the role of SETD4 in chemoresistance, tumor progression, and prognosis in nonsmall cell lung cancer (NSCLC) patients is unclear. Here, SETD4-positive cells were identified as quiescent lung cancer stem cells (qLCSCs) since they expressed high levels of ALDH1 and CD133 and low levels of Ki67. SETD4 expression was significantly higher in advanced-stage NSCLC tissues than in early-stage NSCLC tissues and significantly higher in samples from the chemoresistant group than in those from the chemosensitive group. Patients with high SETD4 expression had shorter progression-free survival (PFS) times than those with low SETD4 expression. SETD4 facilitated heterochromatin formation via H4K20me3, thereby leading to cell quiescence. RNA-seq analysis showed upregulation of genes involved in cell proliferation, glucose metabolism, and PI3K-AKT signaling in activated qLCSCs (A-qLCSCs) compared with qLCSCs. In addition, SETD4 overexpression facilitated PTEN-mediated inhibition of the PI3K-mTOR pathway. In summary, SETD4 confers chemoresistance, tumor progression, and a poor prognosis by regulating CSCs in NSCLC patients.

Quantitative analysis of a novel DNA hypermethylation panel using bronchial specimen for lung cancer diagnosis.

Non-diagnostic findings are common in transbronchial lung biopsy (TBLB) and endobronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB). One of the challenges is to improve the detection of lung cancer using these techniques. To address this issue, we utilized an 850 K methylation chip to identify methylation sites that distinguish malignant from benign lung nodules. Our study found that a combination of HOXA7, SHOX2 and SCT methylation analysis has the best diagnostic yield in bronchial washing (sensitivity: 74.1%; AUC: 0.851) and brushing samples (sensitivity: 86.1%; AUC: 0.915). We developed a kit comprising these three genes and validated it in 329 unique bronchial washing samples, 397 unique brushing samples and 179 unique patients with both washing and brushing samples. The panel's accuracy in lung cancer diagnosis was 86.9%, 91.2% and 95% in bronchial washing, brushing and washing + brushing samples, respectively. When combined with cytology, rapid on-site evaluation (ROSE), and histology, the panel's sensitivity in lung cancer diagnosis was 90.8% and 95.8% in bronchial washing and brushing samples, respectively, and 100% in washing + brushing samples. Our findings suggest that quantitative analysis of the three-gene panel can improve the diagnosis of lung cancer using bronchoscopy.

Hydrogen sulfide alleviates mitochondrial damage and ferroptosis by regulating OPA3-NFS1 axis in doxorubicin-induced cardiotoxicity.

Ferroptosis is a major cause of cardiotoxicity induced by doxorubicin (DOX). Previous studies have shown that hydrogen sulfide (H2S) inhibits ferroptosis in cardiomyocytes and myoblasts, but the underlying mechanism has not been fully elucidated. In this study, we investigated the role of H2S in protecting against DOX-induced cardiotoxicity both in vivo and in vitro, and elucidated the potential mechanisms involved. We found that DOX downregulated the expression of glutathione peroxidase 4 (GPX4) and NFS1, and upregulated the expression of acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) expression level, resulting in increased lipid peroxidation and ferroptosis. Additionally, DOX inhibited MFN2 expression and increased DRP1 and FIS1 expression, leading to abnormal mitochondrial structure and function. In contrast, exogenous H2S inhibited DOX-induced ferroptosis by restoring GPX4 and NFS1 expression, and reducing lipid peroxidation in H9C2 cells. This effect was similar to that of the ferroptosis antagonist ferrostatin-1 (Fer-1) in protecting against DOX-induced cardiotoxicity. We further demonstrated that the protective effect of H2S was mediated by the key mitochondrial membrane protein optic atrophy 3 (OPA3), which was downregulated by DOX and restored by exogenous H2S. Overexpression of OPA3 alleviated DOX-induced mitochondrial dysfunction and ferroptosis both in vivo and in vitro. Mechanistically, NFS1 has an inhibitory effect on ferroptosis, and NFS1 deficiency increases the susceptibility of cardiomyocytes to ferroptosis. OPA3 is involved in the regulation of ferroptosis by interacting with NFS1. Post-translationally, DOX promoted OPA3 ubiquitination, while exogenous H2S antagonized OPA3 ubiquitination by promoting OPA3 s-sulfhydration. In summary, our findings suggested that H2S protects against DOX-induced cardiotoxicity by inhibiting ferroptosis via targeting the OPA3-NFS1 axis. This provides a potential therapeutic strategy for the treatment of DOX-induced cardiotoxicity.

Mycobacterium infection secondary to exogenous lipoid pneumonia caused by nasal drops: a case report and literature review.

BACKGROUND: Exogenous lipoid pneumonia (ELP) is a rare disease and its diagnosis is often mistaken or delayed. Secondary infection with rapidly growing non-tuberculous mycobacteria is a rare complication of lipoid pneumonia. CASE PRESENTATION: A 38-year-old man presented with fever, cough, sputum, chest tightness, and shortness of breath. He had a 2-year history of allergic rhinitis and used liquid paraffin-containing menthol nasal drops daily. A chest CT scan showed multiple patchy ground glass opacities with blurred borders in both lungs, which were located in the inner pulmonary field and distributed along the bronchi. His ambient air PO2 was 63 mmHg. The patient was diagnosed with ELP by CT-guided lung biopsy. The nasal drops were discontinued, and systemic glucocorticoids were administered. During treatment, the pulmonary lesions deteriorated, and bronchoalveolar lavage was performed during bronchoscopy. Additionally, Mycobacterium abscessus was detected in the lavage fluid. Upon detection of a secondary M. abscessus infection, glucocorticoids were gradually discontinued, and anti-M. abscessus treatment was implemented. The patient's symptoms rapidly ameliorated. After 11 months of anti-M. abscessus treatment, a repeat CT scan showed clear regression of the lung lesions. CONCLUSION: Routine microbiological examination of samples, including sputum or alveolar lavage fluid, is necessary for patients with diagnosed or suspected ELP.

Optimization of stress distribution of bone-implant interface (BII).

Many studies have found that the threshold of occlusal force tolerated by titanium-based implants is significantly lower than that of natural teeth due to differences in biomechanical mechanisms. Therefore, implants are considered to be susceptible to occlusal trauma. In clinical practice, many implants have shown satisfactory biocompatibility, but the balance between biomechanics and biofunction remains a huge clinical challenge. This paper comprehensively analyzes and summarizes various stress distribution optimization methods to explore strategies for improving the resistance of the implants to adverse stress. Improving stress resistance reduces occlusal trauma and shortens the gap between implants and natural teeth in occlusal function. The study found that: 1) specific implant-abutment connection design can change the force transfer efficiency and force conduction direction of the load at the BII; 2) reasonable implant surface structure and morphological character design can promote osseointegration, maintain alveolar bone height, and reduce the maximum effective stress at the BII; and 3) the elastic modulus of implants matched to surrounding bone tissue can reduce the stress shielding, resulting in a more uniform stress distribution at the BII. This study concluded that the core BII stress distribution optimization lies in increasing the stress distribution area and reducing the local stress peak value at the BII. This improves the biomechanical adaptability of the implants, increasing their long-term survival rate.

Uptake and distribution of microplastics of different particle sizes in maize (Zea mays) seedling roots.

Microplastics (MPs) pollution may be harmful to terrestrial ecosystems and is receiving increasing attention. A microcosm study on the uptake of MPs in maize (Zea mays) seedling roots exposed to small polystyrene (PS) beads (0.2, 0.5 and 1.0 µm) and large PS beads (2.0 and 5.0 µm) at 50 mg L-1 for 7 d was performed. Additionally, the absorption ability of different parts of the roots was also investigated after 10 d of exposure with 0.2 µm PS beads. The results showed that root and shoot biomass remained unchanged under different particle sizes of PS beads. The small PS beads markedly increased the accumulation and distribution of PS beads in roots more than large ones. Confocal laser scanning micrographs confirmed that strong fluorescence signals from small PS beads (0.2 µm) were seen in all tissues, as compared with the control. Large PS beads (2.0 µm) were mainly distributed in the xylem, and no PS beads were detected in any root tissues when treated with 5.0 µm PS beads. More PS beads were absorbed by the root maturation zone than by the root tip zone. Fluorescence intensity values of PS bead accumulations measured across the tissues further confirmed these results. As seen in scanning electron microscopy images, small PS beads assembled on the cell wall of the xylem, while large PS beads (2.0 µm) were scattered on the cell walls of root xylem. The present study revealed the effects of different PS bead sizes on accumulation and distribution in maize roots, as well as the absorption ability of different positions of the roots. Moreover, fluorescence intensity could be a useful method to evaluate the uptake and distribution of MPs accurately.

Clinical outcomes and risk factor of immune checkpoint inhibitors-related pneumonitis in non-small cell lung cancer patients with chronic obstructive pulmonary disease.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is the most common co-morbidity associated with non-small cell lung cancer (NSCLC) patients. Immune checkpoint inhibitors related pneumonitis (CIP) is a common immune-related adverse event that can be life-threatening. The study aims to evaluate the association of COPD with the incidence and outcome of CIP in NSCLC patients receiving immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS: We retrospectively collected data from 122 patients diagnosed with NSCLC and treated with ICIs in our department. Baseline pulmonary function was performed in the whole cohort. The incidence, risk factors, treatment and outcome of CIP patients were evaluated. Furthermore, the efficacy of ICIs in patients with COPD was analyzed. RESULTS: Nineteen patients (15.5%, 19/122) developed CIP during ICIs treatment, most patients with CIP were grade 1-2, and the incidence of CIP was comparable in patients with COPD and those without COPD (18.0% vs. 13.1%, P = 0.618). In addition, an increasing trend in the incidence of CIP among patients with pulmonary fibrosis on baseline chest CT scans (27.3% vs. 13.0%, P = 0.093). There is a longer progression-free survival in COPD patients than the non-COPD patients. CONCLUSION: Coexisting COPD did not predict the higher risk of CIP in NSCLC treated with ICIs therapy. Nevertheless, pre-existing pulmonary fibrosis on CT scan may increase the risk of CIP, close monitoring is advised in these patients during ICIs.

ALK-R3HDM1 and EML4-ALK fusion as a mechanism of acquired resistance to gefitinib: A case report and literature review.

We report a case with a novel ALK-R3HDM1 and EML4-ALK dual fusion that might be a delicate mechanism for the acquired resistance of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI). A patient with EGFR L858R lung adenocarcinoma developed disease progression after 72.7 months of gefitinib therapy; rebiopsy was done, and next-generation sequencing showed the disappearance of the previous EGFR mutations. In addition, two new ALK fusions emerged, indicating that the emergence of dual ALK rearrangement may be the underlying mechanism of gefitinib resistance. The patient exhibits an excellent response to second-line alectinib treatment with a significant clinical benefit and a high quality of life. Finally, we summarized previous studies in which ALK fusion is a required resistance mechanism to EGFR-TKI.

FAM201A Promotes Cervical Cancer Progression and Metastasis through miR-1271-5p/Flotillin-1 Axis Targeting-Induced Wnt/ß-Catenin Pathway.

This study investigated the role of the family with sequence similarity 201-member A (FAM201A), as previously reported oncogenic, in cervical cancer (CC). FAM201A expression in CC was analyzed through bioinformatics analyses, and its distribution in CC tissues/cells was determined by in situ hybridization. CC cells were transfected/cotransfected with FAM201A/flotillin-1 (FLOT1) overexpression plasmids and miR-1271-5p mimics, followed by functional analysis on viability, migration and invasion. Pearson's correlation tests were performed to analyze the correlation between FAM201A and miR-1271-5p in CC tissues. The targeting relationship between miR-1271-5p and FLOT1 was confirmed by dual-luciferase reporter assay. The expressions of FAM201A, miR-1271-5p, FLOT1, matrix metalloproteinases (MMP)-9, MMP-2, E-cadherin, N-cadherin, and the Wnt/ß-catenin pathway-related molecules (Wnt1, ß-catenin and p-ß-catenin) in CC cells or tissues were assessed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and/or western blot. The results showed that FAM201A was abundantly expressed and miR-1271-5p expression was downregulated in CC. FAM201A was enriched in CC cell cytoplasm and negatively correlated with miR-1271-5p in CC tissues. FAM201A overexpression enhanced the cell viability, migration, invasion, and tumorigenesis of CC in vivo and increased FLOT1 expression. These trends were all reversed by upregulating miR-1271-5p, which induced opposite effects to FAM201A overexpression. MiR-1271-5p upregulation depleted the levels of MMP-9, MMP-2, N-cadherin, and the Wnt/ß-catenin pathway-related molecules and upregulated E-cadherin expression. FLOT1 was a direct target of miR-1271-5p. FLOT1 overexpression induced effects contrary to the upregulation of miR-1271-5p and abolished miR-1271-5p upregulation-induced effects in CC cells. Overall, this study showed that FAM201A promoted cervical cancer progression and metastasis by targeting the miR-1271-5p/FLOT1 axis-induced Wnt/ß-catenin pathway.

Cellular Senescence and Periodontitis: Mechanisms and Therapeutics.

Periodontitis is a chronic inflammatory disease which increases in prevalence and severity in the older population. Aging is a leading risk factor for periodontitis, which exacerbates alveolar bone loss and results in tooth loss in the elderly. However, the mechanism by which aging affects periodontitis is not well understood. There is considerable evidence to suggest that targeting cellular senescence could slow down the fundamental aging process, and thus alleviate a series of age-related pathological conditions, likely including alveolar bone loss. Recently, it has been discovered that the senescent cells accumulate in the alveolar bone and promote a senescence-associated secretory phenotype (SASP). Senescent cells interacting with bacteria, together with secreted SASP components altering the local microenvironment and inducing paracrine effects in neighboring cells, exacerbate the chronic inflammation in periodontal tissue and lead to more alveolar bone loss. This review will probe into mechanisms underlying excessive alveolar bone loss in periodontitis with aging and discuss potential therapeutics for the treatment of alveolar bone loss targeting cellular senescence and the SASP. Inspecting the relationship between cellular senescence and periodontitis will lead to new avenues of research in this field and contribute to developing potential translatable clinical interventions to mitigate or even reverse the harmful effects of aging on oral health.

Nitroimidazopyrazinones with Oral Activity against Tuberculosis and Chagas Disease in Mouse Models of Infection.

Tuberculosis and parasitic infections continue to impose a significant threat to global public health and economic growth. There is an urgent need to develop new treatments to combat these diseases. Here, we report the in vitro and in vivo profiles of a new bicyclic nitroimidazole subclass, namely, nitroimidazopyrazinones, against mycobacteria and Trypanosoma cruzi. Derivatives with monocyclic side chains were selective against Mycobacterium tuberculosis and were able to reduce the bacterial load when dosed orally in mice. We demonstrated that deazaflavin-dependent nitroreductase (Ddn) could act effectively on nitroimidazopyrazinones, indicating the potential of Ddn as an activating enzyme for these new compounds in M. tuberculosis. Oral administration of compounds with extended biaryl side chains (73 and 74) was effective in suppressing infection in an acute T. cruzi-infected murine model. These findings demonstrate that active nitroimidazopyrazinones have potential to be developed as orally available clinical candidates against both tuberculosis and Chagas disease.

Synthesis of Ti6Al4V/SrFHA Composites by Microwave-Assisted Liquid Phase Deposition and Calcination.

The feasibility of synthesis of Ti6Al4V/SrFHA (Ca9.37Sr0.63(PO4)6F2) composites via coating strontium and fluorine co-doped HA to Ti6Al4V substrate by microwave-assisted liquid phase deposition and calcination was evaluated, with a focus on the effect of the deposition temperature from 30 °C to 70 °C. The outcomes demonstrate that strontium and fluorine can be successfully doped into HA to form a SrFHA coating with modified micromorphology which is deposited on the alloy. When the deposition temperature was 50 °C, the coating with the largest uniform continuous SrFHA coverage was obtained. After calcination, the adhesion strength and Vickers microhardness of the Ti6Al4V/SrFHA composite increased from 0.68 MPa and 323 HV to 2.41 MPa and 329 HV, respectively, with a decrease in the water contact angle from 10.88° to 7.24°, exhibiting enhancement of both mechanical properties and wettability. Moreover, the composite obtained at the deposition temperature of 50 °C exhibited good bioactivity based on the simulate body fluid (SBF) test. On account of the above features primarily as a result of the combined effect of the co-doping of strontium and fluorine, high crystallinity of SrFHA, large surface roughness, and formation of the titanium oxide transition layer, the Ti6Al4V/SrFHA composite shows great potential in dental implantology.

Osteogenesis Performance of Boronized Ti6Al4V/HA Composites Prepared by Microwave Sintering: In Vitro and In Vivo Studies.

The boronized Ti6Al4V/HA composite is deemed to be an important biomaterial because of its potential remarkable mechanical and biological properties. This paper reports the osteogenesis performance of the boronized Ti6Al4V/HA composite, which was prepared by microwave sintering of powders of Ti6Al4V, hydroxyapatite (HA), and TiB2 in high-purity Ar gas at 1050 °C for 30 min, as dental implant based on both cell experiments in vitro and animal experiments in vivo. The comparison between the boronized Ti6Al4V/HA composite and Ti, Ti6Al4V, and boronized Ti6Al4V in the terms of adhesion, proliferation, alkaline phosphate (ALP) activity, and mineralization of MG-63 cells on their surfaces confirmed that the composite exhibited the best inductive osteogenesis potential. It exerted a more significant effect on promoting the early osteogenic differentiation of osteoblasts and exhibited the maximum optical density (OD) value in the MTT assay and the highest levels of ALP activity and mineralization ability, primarily ascribed to its bioactive HA component, porous structure, and relatively rough micro-morphology. The in vivo study in rabbits based on the micro-computed tomography (micro-CT) analysis, histological and histomorphometric evaluation, and biomechanical testing further confirmed that the boronized Ti6Al4V/HA composite had the highest new bone formation potential and the best osseointegration property after implantation for up to 12 weeks, mainly revealed by the measured values of bone volume fraction, bone implant contact, and maximum push-out force which, for example, reached 48.64%, 61%, and 150.3 ± 6.07 N at the 12th week. Owing to these inspiring features, it can serve as a highly promising dental implant.

Deficiency of cystathionine gamma-lyase promotes aortic elastolysis and medial degeneration in aged mice.

Enzymatic degradation of elastin by matrix metalloproteinases (MMPs) leads to the permanent dilation of aortic wall and constitutes the most prominent characters of aortic aneurysm and aging-related medial degeneration. Hydrogen sulfide (H2S) as a gasotransmitter exhibits a wide variety of cardio-protective functions through its anti-inflammatory and anti-oxidative actions. Cystathionine gamma-lyase (CSE) is a main H2S-generating enzyme in cardiovascular system. The regulatory roles of CSE/H2S system on elastin homeostasis and blood vessel degeneration have not yet been explored. Here we found that aged CSE knockout mice had severe aortic dilation and elastic degradation in abdominal aorta and were more sensitive to angiotensin II-induced aortic elastolysis and medial degeneration. Administration of NaHS would protect the mice from angiotensin II-induced inflammation, gelatinolytic activity, elastin fragmentation, and aortic dilation. In addition, human aortic aneurysm samples had higher inflammatory infiltration and lower expression of CSE. In cultured smooth muscle cells (SMCs), TNFα-induced MMP2/9 hyperactivity and elastolysis could be attenuated by exogenously applied NaHS or CSE overexpression while further deteriorated by complete knockout of CSE. It was further found that H2S inhibited MMP2 transcription by posttranslational modification of Sp1 via S-sulfhydration. H2S also directly suppressed MMP hyperactivity by S-sulfhydrating the cysteine switch motif. Taken together, this study revealed the involvement of CSE/H2S system in the pathogenesis of aortic elastolysis and medial degeneration by maintaining the inactive form of MMPs, suggesting that CSE/H2S system can be a target for the prevention of age-related medial degeneration and treatment of aortic aneurysm.