Effects of the ferroptosis inducer erastin on osteogenic differentiation and biological pathways of primary osteoblasts.

BACKGROUND: Periodontitis is a chronic destructive inflammatory disease exacerbated by osteoblast dysfunction. Ferroptosis has emerged as a significant factor that could contribute to the pathological changes observed in periodontitis. However, the impact of ferroptosis on osteogenic differentiation and gene expression patterns of primary osteoblasts remain elusive. METHODS: In this study, osteoblasts were osteogenically induced for specific durations with and without the ferroptosis inducer erastin. Subsequently, cell proliferation, ferroptosis-related molecules, and osteogenic differentiation capacity were assessed. Furthermore, the differences in transcriptome expression following erastin treatment were analyzed by RNA sequencing. RESULTS: The results demonstrated that erastin treatment induced ferroptosis, resulting in suppressed cell proliferation and impaired osteogenic differentiation. Transcriptomic analysis revealed significant alterations in processes such as hydrogen peroxide catabolism, response to lipid peroxidation, and metal iron binding, as well as BMP receptor activity and collagen type XI trimer. CONCLUSION: The ferroptosis inducer erastin inhibited osteoblast proliferation and differentiation. Our study provides novel insights into the effect of ferroptosis on osteogenesis, suggesting that targeting ferroptosis may present a promising approach in the treatment of periodontitis.

Appreciable biosafety, biocompatibility and osteogenic capability of 3D printed nonstoichiometric wollastonite scaffolds favorable for clinical translation.

Background: Alveolar bone destruction due to periodontal disease often requires a bone graft substitute to reconstruct the anatomical structures and biological functions of the bone tissue. Despite significant advances in the development of foreign ion-doped nonstoichiometric wollastonite bioceramics (CaSiO3, nCSi) for alveolar bone regeneration over the past decade, the in vivo biosafety and osteogenesis of nCSi scaffolds remain uncertain. In this study, we developed a customized porous nCSi scaffold to investigate the in vivo biocompatibility and osteogenic properties of nCSi bioceramics. Methods: Six percent Mg-doped nCSi bioceramic scaffolds were fabricated by digital light processing (DLP), and the scaffold morphology, pore architecture, compressive strength, in vitro biodegradation, and apatite-forming ability of the bioceramic scaffolds were investigated systematically. Subsequently, an alveolar bone defect rabbit model was used to evaluate the biocompatibility and osteogenic efficacy of the nCSi bioceramics. Animal weight, hematological test, blood biochemical test, wet weight of the main organs, and pathological examination of the main organs were conducted. Micro-CT and histological staining were performed to analyze the osteogenic potential of the personalized bioceramic scaffolds. Results: The nCSi scaffolds exhibited appreciable initial compressive strength (>30 MPa) and mild mechanical decay over time during in vitro biodissolution. In addition, the scaffolds induced apatite remineralization in SBF. Bioceramic scaffolds have been proven to have good biocompatibility in vivo after implantation into the alveolar bone defect of rabbits. No significant effects on the hematological indices, blood biochemical parameters, organ wet weight, or organ histopathology were detected from 3 to 180 days postoperatively. The porous scaffolds exhibited strong bone regeneration capability in the alveolar bone defect model of rabbits. Micro-CT and histological examination showed effective maintenance of bone morphology in the bioceramic scaffold group; however, depressed bone tissue was observed in the control group. Conclusions: Our results suggest that personalized nCSi bioceramic scaffolds can be fabricated using the DLP technique. These newly developed strong bioceramic scaffolds exhibit good biocompatibility and osteogenic capability in vivo and have excellent potential as next-generation oral implants. The translational potential of this article: Tissue-engineered strategies for alveolar bone repair require a bone graft substitute with appreciable biocompatibility and osteogenic capability. This article provides a systematic investigation of the in vivo biosafety and osteogenic property of nCSi to further development of a silicate-based bioceramics materials for clinical applications.

Interleukin-17 alleviates erastin-induced alveolar bone loss by suppressing ferroptosis via interaction between NRF2 and p-STAT3.

AIM: To investigate the relationship between interleukin-17 (IL-17), ferroptosis and osteogenic differentiation. MATERIALS AND METHODS: We first analysed the changes in ferroptosis-related molecules in experimental periodontitis models. The effects of erastin, a small-molecule ferroptosis inducer, and IL-17 on alveolar bone loss and repair in animal models were then investigated. Primary mouse mandibular osteoblasts were exposed to erastin and IL-17 in vitro. Ferroptosis- and osteogenesis-related genes and proteins were detected. Further, siRNA, immunofluorescence co-localization and immunoprecipitation were used to confirm the roles of the nuclear factor erythroid-2-related factor 2 (NRF2) and phosphorylated signal transducer and activator of transcription 3 (p-STAT3), as well as their interaction. RESULTS: The levels of NRF2, glutathione peroxidase 4 and solute carrier family 7 member 11 were lower in the ligated tissues than in normal periodontal tissues. Alveolar bone loss in an in vivo experimental periodontitis model was aggravated by erastin and alleviated by IL-17. In vitro, IL-17 ameliorated erastin-inhibited osteogenic differentiation by reversing ferroptosis. Altered NRF2 expression correlated with changes in ferroptosis-related molecules and osteogenesis. Furthermore, the physical interaction between NRF2 and p-STAT3 was confirmed in the nucleus. In IL-17 + erastin-stimulated osteoblasts, the p-STAT3-NRF2 complex might actively participate in the downstream transcription of ferroptosis- and osteogenesis-related genes. CONCLUSIONS: IL-17 administration conferred resistance to erastin-induced osteoblast ferroptosis and osteogenesis. The possible mechanism may involve p-STAT3 directly interacting with NRF2.

Ferritin was involved in interleukin-17A enhanced osteogenesis through autophagy activation.

Periodontitis is a prevalent inflammatory immune disease that involves tissue inflammation and excessive bone loss. In murine periodontitis models and periodontitis patients, upregulated interleukin-17A (IL-17A) expression was observed, and its level seemed to correlate with the disease severity. In this study, we intended to investigate the specific role of ferritin, a critical iron storage protein, in IL-17A enhanced osteogenic differentiation as well as the underlying mechanism. Under osteogenic induction, IL-17A stimulation promoted differentiation and mineralization of murine calvarial osteoblasts. In addition, increased iron accumulation and ferritin expression were detected in osteoblasts treated with IL-17A, indicating an alteration in iron metabolism during osteogenesis. Administration of iron chelator deferoxamine (DFO) and transfection with small interfering RNA (siRNA) targeting ferritin heavy chain (FTH) further revealed that ferritin suppression consequently inhibited osteoblast differentiation. Autophagy activation was also found upon IL-17A stimulation, which played a positive role in osteogenic differentiation and was subsequently suppressed by DFO or siRNA targeting FTH. In conclusion, IL-17A induced ferritin expression in osteoblasts, which further enhanced osteogenic differentiation via autophagy activation. These findings may provide further insight into the role of IL-17A in osteoblast differentiation and demonstrate ferritin as a potential target in modulating alveolar bone homeostasis.

Predicting the Potential Impact of Emergency on Global Grain Security: A Case of the Russia-Ukraine Conflict.

Global emergencies have a profound impact on exacerbating food insecurity, and the protracted Russia-Ukraine conflict has emerged as a significant driver of a global food crisis. Accurately quantifying the impact of this conflict is crucial for achieving sustainable development goals. The multi-indicator comprehensive evaluation approach was used to construct a grain security composite index (GSCI). Moreover, econometric model was used to predict the potential impacts of the conflict on global grain security in 2030 under two scenarios: with and without the "Russia-Ukraine conflict". The results conclude that global food prices reached unprecedented levels as a consequence of the conflict, leading to notable fluctuations in food prices, especially with a significant surge in wheat prices. The conflict had a negative impact on global grain security, resulting in a decline in grain security from 0.538 to 0.419. Predictions indicate that the influence of the conflict on global grain security will be substantially greater compared to the scenario without the conflict in 2023-2030, ranging from 0.033 to 0.13. Furthermore, grain security will first decrease and then increase under the sustained consequences of the conflict. The achievement of the 2030 sustainable development goals will encounter significant challenges in light of these circumstances.

Modularized bioceramic scaffold/hydrogel membrane hierarchical architecture beneficial for periodontal tissue regeneration in dogs.

BACKGROUND: Destruction of alveolar bone and periodontal ligament due to periodontal disease often requires surgical treatment to reconstruct the biological construction and functions of periodontium. Despite significant advances in dental implants in the past two decades, it remains a major challenge to adapt bone grafts and barrier membrane in surgery due to the complicated anatomy of tooth and defect contours. Herein, we developed a novel biphasic hierarchical architecture with modularized functions and shape based on alveolar bone anatomy to achieve the ideal outcomes. METHODS: The integrated hierarchical architecture comprising of nonstoichiometric wollastonite (nCSi) scaffolds and gelatin methacrylate/silanized hydroxypropyl methylcellulose (GelMA/Si-HPMC) hydrogel membrane was fabricated by digital light processing (DLP) and photo-crosslinked hydrogel injection technique respectively. The rheological parameters, mechanical properties and degradation rates of composite hydrogels were investigated. L-929 cells were cultured on the hydrogel samples to evaluate biocompatibility and cell barrier effect. Cell scratch assay, alkaline phosphatase (ALP) staining, and alizarin red (AR) staining were used to reveal the migration and osteogenic ability of hydrogel membrane based on mouse mandible-derived osteoblasts (MOBs). Subsequently, a critical-size one-wall periodontal defect model in dogs was prepared to evaluate the periodontal tissue reconstruction potential of the biphasic hierarchical architecture. RESULTS: The personalized hydrogel membrane integrating tightly with the nCSi scaffolds exhibited favorable cell viability and osteogenic ability in vitro, while the scratch assay showed that osteoblast migration was drastically correlated with Si-HPMC content in the composite hydrogel. The equivalent composite hydrogel has proven good physiochemical properties, and its membrane exhibited potent occlusive effect in vivo; meanwhile, the hierarchical architectures exerted a strong periodontal regeneration capability in the periodontal intrabony defect models of dogs. Histological examination showed effective bone and periodontal ligament regeneration in the biomimetic architecture system; however, soft tissue invasion was observed in the control group. CONCLUSIONS: Our results suggested that such modularized hierarchical architectures have excellent potential as a next-generation oral implants, and this precisely tuned guided tissue regeneration route offer an opportunity for improving periodontal damage reconstruction and reducing operation sensitivity.

Interleukin-17 promotes osteoclastogenesis and periodontal damage via autophagy in vitro and in vivo.

OBJECTIVE: Because of its potent pro-inflammatory properties, interleukin-17 (IL-17) contributes to the pathogenesis of various inflammatory diseases. This study explored the effects of IL-17 on osteoclastogenesis in an osteoclast monoculture and osteoblast-osteoclast co-culture system, as tools to investigate the molecular mechanisms underlying the interactions between osteoclastogenesis and autophagy. METHODS: Various ratios of calvarial osteoblasts (OB) and osteoclast precursor cells (mouse macrophage cell line RAW264.7, hereinafter referred to as OC) were tested. Tartrate-resistant acid phosphatase (TRAP) staining was used to detect the optimum osteoblasts:osteoclasts ratio. IL-17 was added to the co-culture system to test its effects on multinucleated osteoclast formation and osteoclast-related proteins. We assessed the effects of IL-17 on receptor activator of nuclear factor-kappa B ligand (RANKL) expression in osteoblasts, and determined if IL-17 alone could modulate osteoclast formation in an osteoclast monoculture. Administration of exogenous RANKL combined with IL-17 was employed to stimulate RAW264.7 cells osteoclastogenesis and to determine production of osteoclasts and autophagy-related proteins. We knocked down Beclin1 expression in RAW264.7 cells and examined the expression of autophagy-related and osteoclast-related proteins in RAW264.7 cells and the co-culture system, and the TAK1-binding protein 3 (TAB3)/ extracellular signal regulated kinase (ERK) pathway. RESULTS: A ratio of 20 OB : 1 OC yielded the highest rate of osteoclast formation. Low IL-17 concentrations increased osteoclastogenesis in co-cultures significantly, but high levels of IL-17 had the opposite effect. IL-17 alone could not induce formation of TRAP+ multinucleated cells in RAW264.7 cells. Low IL-17 concentrations promoted osteoclast differentiation and autophagy in RAW264.7 cells induced by exogenous RANKL, but high IL-17 concentrations inhibited this process. Knockdown of Beclin1 reversed the enhanced effects of 0.1 ng/mL IL-17 on osteoclastogenesis and autophagy in RAW264.7 cells. The TAB3/ERK pathway was also blocked after autophagy inhibition. CONCLUSION: In the co-culture model used in this study, a ratio of 20 OB:1 OC proved to be the optimal ratio to facilitate osteoclast formation. IL-17 regulated RANKL-induced osteoclastogenesis via autophagy. The Beclin1/TAB3/ERK pathway was involved in osteoclast autophagy.

Inflamm-Aging-Related Cytokines of IL-17 and IFN-γ Accelerate Osteoclastogenesis and Periodontal Destruction.

Periodontal disease (PD), as an age-related disease, prevalent in middle-aged and elderly population, is characterized as inflammatory periodontal tissue loss, including gingival inflammation and alveolar bone resorption. However, the definite mechanism of aging-related inflammation in PD pathology needs further investigation. Our study is aimed at exploring the effect of inflamm-aging-related cytokines of interleukin-17 (IL-17) and interferon-γ (IFN-γ) on osteoclastogenesis in vitro and periodontal destruction in vivo. For receptor activator of nuclear factor-κB ligand- (RANKL-) primed bone marrow macrophages (BMMs), IL-17 and IFN-γ enhanced osteoclastogenesis, with the expression of osteoclastogenic mRNA (TRAP, c-Fos, MMP-9, Ctsk, and NFATc1) and protein (c-Fos and MMP-9) upregulated. Ligament-induced rat models were established to investigate the role of IL-17 and IFN-γ on experimental periodontitis. Both IL-17 and IFN-γ could enhance the local inflammation in gingival tissues. Although there might be an antagonistic interaction between IL-17 and IFN-γ, IL-17 and IFN-γ could facilitate alveolar bone loss and osteoclast differentiation.

TRAF6/ERK/p38 pathway is involved in interleukin-17-mediated autophagy to promote osteoclast precursor cell differentiation.

To investigate the effects of interleukin (IL)-17-mediated autophagy on the TNF receptor associated factor (TRAF6)/extracellular signal-regulated kinase (ERK)/p38 pathway and osteoclast differentiation. Mouse bone marrow-derived macrophages (BMM) were cultured with a medium containing 30 ng/mL macrophage colony stimulating factor and 50 ng/mL receptor activator of nuclear factor-kappa B ligard (RANKL), and IL-17 (0.01, 0.1, 1.0, 10 ng/mL) was added for intervention (IL-17 group). Tartrate-resistant acid phosphatase (TRAP) staining was used to observe TRAP positive multinucleated cells; phalloidin fluorescent staining was used to detect actin ring circumference; toluidine blue staining was used to analyze bone resorption lacuna formation. To further examine the mechanism of the effect of IL-17-mediated autophagy on the differentiation of osteoclasts, the control group used RANKL medium to culture mouse macrophage RAW264.7 cells, while the IL-17 group was treated with IL-17 (0.01, 0.1, 1.0, /mL). Western blot was used to detect the expression of autophagy-related proteins Beclin-1, microtubule-associated protein 1 light chain 3 (LC3) and osteoclast-related proteins c-fos and nuclear factor of activated T cell 1 (NFATc1) after treatment with different concentrations of IL-17. The expression of LC3, NFATc1, TRAF6/ERK/p38 signaling pathway related proteins were detected in IL-17 and autophagy inhibitor 3-MA group. The number of TRAP positive multinucleated cells, the circumference of the actin ring and the area of bone resorption lacuna in IL-17 group treated with IL-17 (0.01, 0.1, were significantly higher than those in the control group. In IL-17 treated RAW264.7 cells, the expression of c-fos, NFATc1, Beclin-1, LC3, TRAF6, p-ERK, and p-p38 was all significantly up-regulated (all 0.05). After treatment with the autophagy inhibitor 3-MA, the expression levels of LC3, NFATc1, TRAF6, p-ERK, and p-p38 all decreased significantly (all 0.05). IL-17 can promote the expression of autophagy proteins and enhance the differentiation ability of osteoclast precursor cells, and the TRAF6/ERK/p38 signaling pathway may be involved in this process.

Interleukin-17 induces pyroptosis in osteoblasts through the NLRP3 inflammasome pathway in vitro.

OBJECTIVE: Interleukin-17 (lL-17), a pro-inflammatory cytokine produced by Th17 cells, is also considered to play an important role in bone metabolism, but the exact mechanism of bone destruction remains unclear. In this study, we explored whether IL-17 could induce osteoblasts pyroptosis in vitro. METHODS: The murine primary osteoblasts were isolated from the calvarial bones of mice. The proliferation of osteoblasts was evaluated by cell counting kit-8 (CCK-8) assay. The mRNA levels of NOD-like receptor family pyrin domain containing 3 (NLRP3), apoptosis associated speck like protein containing a card (ASC), caspase-1, gasdermin-D (GSDMD), IL-1ß and receptor activator of nuclear factor-kappa B ligand (RANKL) were measured by real-time quantitative PCR. Pyroptosis after IL-17 treatment was evaluated by lactate dehydrogenase (LDH) Release Assay Kit and the morphological characteristics of osteoblasts were observed via Scanning Electron Microscopy (SEM). Pyroptosis associated proteins, cleaved IL-1ß and RANKL were evaluated through western blot. The release of IL-1ß and RANKL was measured by ELISA. In addition, calcium nodule was tested by alizarin red staining. RESULTS: High concentration IL-17 (100 ng/mL) could affect the proliferation of osteoblasts, promote the gene expression of NLRP3, caspase-1, GSDMD, IL-1ß and RANKL. In contrast to control group, osteoblasts treated with IL-17 had the appearance of numerous pores, swelling and rupture. Also, the release of LDH, IL-1ß and RANKL increased in the presence of IL-17. However, inhibition of NLRP3 prevented activation of the NLRP3 inflammasome, thereby restoring osteoblasts morphology and function. CONCLUSION: IL-17 induced osteoblasts pyroptosis, and the pyroptosis of osteoblasts may prompt the release of IL-1ß and RANKL,which may further contribute to disruption of bone metabolism. Besides, the NLRP3 inflammasome pathway was involved in the pyroptosis of osteoblasts.

Factors Associated with Poor Outcomes in Patients Undergoing Endovascular Therapy for Acute Ischemic Stroke due to Large-Vessel Occlusion in Acute Anterior Circulation: A Retrospective Study.

OBJECTIVE: To investigate factors associated with poor clinical outcomes in patients with acute ischemic stroke undergoing endovascular therapy. METHODS: A retrospective review of 265 patients with acute ischemic stroke treated in the First Hospital of Jilin University between January 1, 2016, and November 1, 2019, was performed. The primary outcome was the proportion of patients with a modified Rankin score of 0-2 at 90 days. Univariate and multivariate analyses were performed to assess potential clinical factors associated with a poor 90-day outcome. RESULTS: The rates of successful revascularization, good prognosis, symptomatic intracranial hemorrhage, and mortality were 84.5%, 46.0%, 9.8%, and 12.8%, respectively. As per univariate analysis, age, diagnosis of atrial fibrillation, diagnosis of diabetes, high baseline glucose level, tandem occlusion, high National Institutes of Health Stroke Scale (NIHSS) score at admission, general anesthesia, number of passes, high NIHSS score on discharge, unsuccessful recanalization (modified treatment in cerebral ischemia score <2b), and development of symptomatic intracranial hemorrhage, hemorrhagic infarction, parenchymal hematoma, and subarachnoid hemorrhage were associated with poor prognosis. Tobacco use was positive in correlation with good prognosis in univariate analysis. Diabetes, tandem occlusion, high NIHSS score at admission, and general anesthesia were independent factors associated with a poor 90-day outcome in multivariate analysis. CONCLUSIONS: Diabetes, tandem occlusion, high NIHSS score at admission, and general anesthesia were independent risk factors associated with a poor 90-day outcome and should be considered a reference by neurointerventionalists in guiding their clinical decision-making.

Global burden of periodontal disease and its relation with socioeconomic development during 1990-2019.

To analyze the global burden of periodontal disease and its relation with socioeconomic development. Data of global disability-adjusted life year (DALY) due to periodontal disease and human development index (HDI) from 1990 to 2019 were obtained from Global Health Data Exchange (GHDx) and human development reports. The trend of the global burden of periodontal disease from 1990 to 2019 was described. The correlation between age-standardized DALY rates and HDI were examined in 2019, and between-country periodontal disease burden inequality from 1990 to 2019 was measured using health-related Gini coefficients and concentration indexes. From 1990 to 2019, the global DALY rate due to periodontal disease increased from 78.63 to 85.48, and the epidemiological burden did not increase significantly. Statistical differences were found across different HDI categories for age-standardized DALY rates of periodontal disease ( 44.315, <0.01) in 2019. Linear regression analysis also revealed a negative correlation between age-standardized DALY rate of periodontal disease and HDI ( = -0.417, <0.01) . Gini coefficients decreased from 0.361 to 0.281 and concentration indexes fell from 0.0339 to -0.0538 between 1990 and 2019. The global burden of periodontal disease did not increase between 1990 and 2019, though the socioeconomic-associated inequality still existed. The burden of periodontal disease was more concentrated in less developed countries, and the socioeconomic-associated inequality has increased since 2000.

A Case Series and Literature Review of Vertebral Artery Stump Syndrome.

PURPOSE: Stump syndrome refers to cerebral ischaemic symptoms caused by an embolus from a previously occluded ipsilateral artery that occludes a down-stream artery. It can be divided into two types: carotid stump syndrome and vertebral artery stump syndrome (VASS). At present, there is limited clinical experience with VASS. We aimed to propose a more precise diagnostic standard for VASS, and to share our experience with handling this condition. MATERIALS AND METHODS: We retrospectively collected data of patients who were treated with endovascular thrombectomy in the stroke centre of the First Hospital of Jilin University from January 2016 to March 2020. After screening patients with posterior-circulation acute ischaemic stroke, we selected patients who had an acute occlusion of an intracranial artery in the context of a previously occluded ipsilateral vertebral artery origin, as confirmed by digital subtraction angiography. RESULTS: Eleven patients met our inclusion criteria. Nine patients achieved recanalization of both extracranial and intracranial occluded arteries, one patient had modified thrombolysis in cerebral infarction grade 3, and eight patients had grade 2b. Residual stenosis of recanalized intracranial arteries was less than 30% in all cases, while three patients had embolism of distal arteries. No dissection or subarachnoid haemorrhage occurred. Two patients didn't reach vascular recanalization. Among the nine patients with recanalized artery, four had a 90-day modified Rankin Scale score ≤ 3 (favourable outcome), and four patients died; As for the two non-recanalized patients, one had a mRS score of 5 and one died. CONCLUSION: VASS is a clinical syndrome caused by embolic occlusion of a distal intracranial artery occluded ipsilateral extracranial vertebral artery. Antegrade blood flow from the collateral vessels, distal embolic occlusion and mild or no residual stenosis of the occluded intracranial artery after recanalization are notable features of this clinical event. Endovascular thrombectomy may be effective for treating VASS.

RANKL expression of primary osteoblasts is enhanced by an IL-17-mediated JAK2/STAT3 pathway through autophagy suppression.

Objective: Interleukin-17 (IL-17), produced by T helper (Th)-17 cells, is a potent regulator of bone homeostasis. Osteoblasts are key cells that orchestrate inflammatory bone destruction and bone remodeling. This study examines the effect of different concentrations of IL-17 on osteogenesis and receptor activator of nuclear factor-kappa B ligand (RANKL) expression of primary osteoblasts.Methods: First, the growth of primary osteoblasts was evaluated. Second, we assessed the effects of IL-17 on the level of autophagy and the related Janus activated kinase 2 (JAK2) and downstream signal transducer and activator of transcription 3 (STAT3) signaling pathway. Next, osteogenic activity in different concentrations of IL-17 was tested. Finally, the specific JAK2/STAT3 signaling pathway inhibitor AG490 and autophagy inhibitor 3-MA were used to investigate the involvement of this pathway and autophagy in IL-17-induced regulation of RANKL expression.Results: Initially, we found that IL-17 treatment promoted growth of osteoblasts in a time- and dose-dependent manner. Next, we showed that low levels of IL-17 promoted autophagy activity, whereas the opposite was observed at high levels of IL-17. Moreover, high levels of IL-17 activated the JAK2/STAT3 signaling pathway, although this effect was reversed by upregulation of autophagy. Furthermore, our findings indicated that high concentrations of IL-17 promoted the differentiation, calcification, and RANKL expression of murine osteoblasts via activation of the JAK2/STAT3 pathway. Importantly, downregulation of autophagy at high IL-17 concentrations further enhanced RANKL expression via suppressing the JAK2/STAT3 cascade.Conclusion: Overall, our findings demonstrate, for the first time, that IL-17 modulates RANKL expression of osteoblasts through an autophagy-JAK2-STAT3 signaling pathway, thus affecting bone metabolism.

Impact of leukoaraiosis severity on the association of outcomes of mechanical thrombectomy for acute ischemic stroke: a systematic review and a meta-analysis.

BACKGROUND: Leukoaraiosis (LA) severity is associated with poor outcome after mechanical thrombectomy (MT) for acute ischemic stroke (AIS) caused by large vessel occlusion. This meta-analysis aimed to assess the association of LA severity with AIS-related risk factors and outcomes of MT. METHODS: PubMed, Web of Science, EMBASE, and Cochrane Collaboration Database was searched for studies on MT for AIS with LA. We conducted a random-effects meta-analysis for the prevalence of stroke risk factors and the MT outcome in the absent to moderate LA and severe LA groups. RESULTS: We included seven cohort studies involving 1294 participants (1019 with absent to moderate LA and 275 with severe LA). The absent to moderate LA group had a significantly lower prevalence of coronary artery disease (odds ratio [OR] 0.43; 95% CI 0.29-0.66), atrial fibrillation (OR, 0.26; 95% CI 0.17-0.38), hypertension (OR, 0.39; 95% CI 0.24-0.61), and ischemic stroke (OR, 0.27; 95% CI 0.15-0.50) than the severe LA group. There were no significant between-group differences in symptom onset to recanalization time (364.4 versus 356.2 min, mean difference 19.4; 95% CI - 28.3 to 67.2), final recanalization rate (modified thrombolysis in cerebral infarction score of 2b/3; OR, 0.87; 95% CI 0.55-1.38), and symptomatic intracranial hemorrhage (OR, 0.62; 95% CI 0.34-1.11). The absent to moderate LA group had a higher good functional outcome (modified Rankin Scale score of 0-2 at 90 days; OR, 4.55; 95% CI 3.20-6.47) and a lower mortality rate (179/1019 vs 108/275; OR, 0.28; 95% CI 0.20-0.39). CONCLUSION: There are unique differences in the characteristics of risk factors and clinical outcomes of ischemic stroke across patients with LA of different severity. Patients with severe LA are more likely to be associated with risk factors for cerebrovascular disease and have a poor post-MT outcome.

Effects of Early Changes in Blood Pressure During Intravenous Thrombolysis on the Prognosis of Acute Ischemic Stroke Patients.

Background: Intravenous thrombolysis (IVT) therapy is currently one of the best medical treatments available for patients with acute ischemic stroke. Studies have shown that blood pressure (BP) changes in patients treated with IVT are significantly correlated with prognosis. Objective: Our study aimed to determine the relationship between BP changes during recombinant tissue plasminogen activator (rt-PA) infusion and the 3-month prognosis evaluated using the modified Rankin Scale (mRS) and determine the factors influencing BP changes during rt-PA infusion. Methods: Consecutive patients who were treated with IVT and admitted to our stroke center between May 2015 and October 2017 were analyzed retrospectively. Patients were divided into two groups according to their 3-month prognosis status: patients with mRS ≤ 2 were defined as "favorable outcome group" and those with mRS ≥ 3 as "unfavorable outcome group". First, the factors affecting prognosis after thrombolysis were analyzed. Second, we analyzed the relationship between BP and the prognosis. BP was taken before and at regular intervals of 15 min during the rt-PA infusion (1 h). The average value of BP during thrombolysis was calculated and compared to the baseline BP. BP decrease was defined as the difference between the baseline BP and the average BP, provided it was greater than 0 mmHg. Third, univariate and multivariate analyses were performed to identify factors that may contribute to BP decrease. Results: In total, 458 patients were included. Patients with a lower baseline National Institute of Health Stroke Scale (NIHSS) score (8.25 ± 5.57 vs. 13.51 ± 7.42, P < 0.001), a higher Alberta Stroke Program Early CT Score (ASPECTS; 8.65 ± 1.82 vs. 8.13 ± 2.00, P = 0.005), decreased BP during thrombolysis (69.4% vs. 59.8%, P = 0.037), and steady BP (SD < 10 mmHg) were more likely to have a favorable outcome (73.9% vs. 60.6%, P = 0.019). High baseline BP (OR > 1), hypertension history (OR < 1), and baseline ASPECTS (OR > 1) were independent factors of BP change during thrombolysis. Conclusion: Patients with decreased or steady BP during thrombolysis were more likely to have a favorable outcome. Baseline ASPECTS, baseline NIHSS score, and hypertension history influenced BP changes during thrombolysis.

The Therapeutic Effects of Endovascular Therapy with mTICI2b and 3 Recanalization for Acute Anterior Circulation Stroke Patients.

BACKGROUND AND PURPOSE: Modified Thrombolysis in Cerebral Infarction (mTICI)2b/3 has been considered the criterion for successful reperfusion in endovascular treatment. This study aimed to compare the therapeutic safety and efficacy of mTICI2b and mTICI3 recanalization, and to analyze the factors related to outcomes in everyday clinical practice. MATERIALS AND METHODS: This is a single-center retrospective analysis of 224 patients who underwent successful thrombectomy (achieving a mTICI score ≥2b). The primary outcomes included a modified Rankin score (mRS) of 0-2 at 90-day, mortality, and symptomatic intracranial hemorrhage. RESULTS: A total of 111 patients achieved mTICI2b status (49.6%), and 113 achieved mTICI3 status (50.4%). The comparison between mTICI2b and 3 reperfusions showed no differences in short-term outcomes, 90-day mRS, complications, and mortality. There was a trend toward more passes in mTICI2b patients, although the difference was not significant. The univariate analysis showed that poor outcomes after endovascular treatment were associated with older age, previous history of coronary heart disease, atrial fibrillation, diabetes, tandem occlusions, high National Institutes of Health Stroke Scale (NIHSS) score on admission, and general anesthesia. A previous history of coronary heart disease, a high NIHSS score on admission, and the use of general anesthesia were independent factors that affected the therapeutic effects. CONCLUSION: The superiority (efficacy and safety) of mTICI3 reperfusion was not significant compared with that of mTICI2b reperfusion. Prolonged efforts to achieve mTICI3 after achieving mTICI2b should be considered prudently for those with difficulty achieving 100% reperfusion.

Autophagy was involved in tumor necrosis factor-α-inhibited osteogenic differentiation of murine calvarial osteoblasts through Wnt/ß-catenin pathway.

Periodontitis is an inflammatory disease with a high incidence characterized by irreversible destruction of alveolar bone. This study aimed to investigate the effect of tumor necrosis factor-α (TNF-α) on osteogenic differentiation and its molecular mechanism. TNF-α inhibited osteogenic differentiation as revealed by the lower accumulation of osteoblastic genes like runt-related transcription factor (Runx2), alkaline phosphatase (ALP), osteoprotegerin (OPG), and osteocalcin (OCN). Moreover, TNF-α down-regulated the expressions of LC3II, ATG7, and beclin 1 (BECN1); suggesting that autophagy was inhibited during the process of osteogenic differentiation. Consistently, Wnt/ß-catenin signaling pathway members such as low-density lipoprotein receptor-related protein 5 (LRP5), ß-catenin, and phosphorylated-ß-catenin (p-ß-catenin) were reduced by TNF-α. Furthermore, the inhibitory effect of TNF-α on osteogenic differentiation and the Wnt/ß-catenin signaling pathway could be abated by autophagy inducers but exacerbated by autophagy inhibitors. The most intriguing finding of all was that TNF-α inhibited osteoblastic differentiation and the Wnt/ß-catenin signaling pathway by down-regulating autophagy, and autophagy positively regulated the Wnt/ß-catenin pathway and thus influenced osteoblastic differentiation. Our study provides a theoretical basis for autophagy-inducer therapy for the alveolar bone loss caused by periodontitis.

Autophagy negative-regulating Wnt signaling enhanced inflammatory osteoclastogenesis from Pre-OCs in vitro.

Periodontitis thereby the alveolar bone loss induced by inflammation, is a wide-spread phenomenon around the world. It is an ongoing challenge faced by clinicians worldwide. This study aimed to identify the effects of lipopolysaccharide (LPS) on osteoclasts (OCs) differentiation in vitro and to investigate its molecular mechanism. For bone marrow derived macrophages (considered as Pro-OCs), LPS impaired their differentiation into OCs in a dose-dependent manner. In contrast, it promoted Pre-OCs (referred to receptor activator of nuclear factor-κB ligand (RANKL) pretreated Pro-OCs) and differentiated to OCs with increased maximum diameter, quantity, the covering area and the fusion index in vitro. It also facilitated OCs proliferation, bone resorption and OCs related genes expression. Furthermore, it was revealed that LPS enhanced OCs genesis from Pre-OCs via activating autophagy pathway consequently elevated the accumulation of TRAP, Cts K and NFATC1, specific genes of OCs. The members of Wnt signaling were expressed as at lower states during the LPS induced OCs formation, but they could be rescued in the presence of autophagy inhibitor. The most promising observation was the direct interaction of LC3B and Dvl2, indicating that the crosstalk between above pathways existed in OCs. Taken together, we consider that LPS activates autophagy which negatively regulates Wnt signaling via autophagic degradation of Dvl2 is significant for osteoclastogenesis from Pre-OCs in vitro. Our study sheds light on the fact that autophagy inhibitors will become a new, potentially applicable therapeutic option in the treatment of periodontal bone loss.

Stenting for Symptomatic Intracranial Vertebrobasilar Artery Stenosis in Northeast of China: A Single-Center Study.

Objective: We described the incidence of surgery-related complications to evaluate the safety of endovascular therapy for severe symptomatic intracranial vertebral basilar artery stenosis (IVBS) in our stroke center in Northeast of China. Methods: Consecutive patients with symptomatic IVBS caused by 70-99% stenosis despite standard medical treatment of antiplatelet agents plus statin were enrolled. Either balloon-mounted stent or balloon predilation plus self-expanding stent was performed. Clinical adverse events such as stroke, transient ischemic attack (TIA), and death after the surgery were documented. Radiological events such as in-stent thrombosis, dissection, and guide-wire perforation during the process were recorded as complications as well. The baseline characteristics and outcomes of patients among different Mori types were compared. Results: From January 2017 to December 2018, 97 patients with stroke or TIA due to intracranial IVBS were treated by stenting, including 30 patients with basilar artery (BA) stenosis, 55 patients with intracranial vertebral artery (V4) stenosis, and 12 patients with V4-BA stenosis. The primary events include two intracranial hemorrhage (2.1%, 2/97), seven ischemic events (7.2%, 7/97), and two death (2.1%, 2/97). The successful stent deployment rate was 98.9% (96/97). The Apollo stents were used more for Mori A lesions. Self-expanding stents were more used in Mori C lesions. Mori C lesions were more vulnerable to endovascular procedure and showed higher rate of complications than A (p = 0.008) and B type (p = 0.047). Conclusion: A high technical success rate of IVBS stenting could be achieved, and the safety was acceptable, whereas Mori C lesions were more vulnerable to endovascular procedure and showed a higher rate of complications than A and B types.