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Cyclophilin A (CypA) is a cytosolic protein involved in multiple biological functions, such as inflammation, tissue remodeling, tumorigenesis, and vascular diseases. Human periapical lesions are induced by bacterial infections. However, the expression of CypA in human periapical lesions remains unclear. This study aimed to investigate the presence of CypA in human periapical lesions and the possible association of CypA with angiogenesis, inflammatory cell infiltration, and alveolar bone degradation during inflammatory development.Fifty-eight human periapical tissues, including periapical granulomas (PGs, n = 28), radicular cysts (RCs, n = 24), and healthy control tissues (control group, n = 6) were collected. Samples were fixed and analyzed. CypA expression was detected and analyzed by immunohistochemistry in different cross sections. Double immunofluorescence was assessed to colocalize CypA with CD34, CypA with matrix metalloproteinase 9 (MMP-9), and CD147 with MMP-9.CypA was significantly overexpressed in the RC and PG groups compared with the control group (P.05), but the difference between the RC and PG groups was insignificant (P.05). CypA-positive cells were mainly lymphocytes, endothelial cells, epithelial cells, and plasma cells. The double-labeling analysis of CypA with CD34 suggested that CypA expression was associated with angiogenesis during periapical lesions. MMP-9 colocalized with both CypA and CD147 indicated that CypA may colocalize with CD147 and may be associated with the degradation of soft and hard tissues around human periapical lesions.CypA may be involved in the development of periapical lesions with an increase in inflammatory cell infiltration, angiogenesis acceleration, and alveolar bone degradation.

Glioblastoma (GBM) remains the most lethal and common primary brain tumor, even after treatment with multiple therapies, such as surgical resection, chemotherapy, and radiation. Although great advances in medical development and improvements in therapeutic methods of GBM have led to a certain extension of the median survival time of patients, prognosis remains poor. The primary cause of its dismal outcomes is the high rate of tumor recurrence, which is closely related to its resistance to standard therapies. During the last decade, glioblastoma stem cells (GSCs) have been successfully isolated from GBM, and it has been demonstrated that these cells are likely to play an indispensable role in the formation, maintenance, and recurrence of GBM tumors, indicating that GSCs are a crucial target for treatment. Herein, we summarize the current knowledge regarding GSCs, their related signaling pathways, resistance mechanisms, crosstalk linking mechanisms, and microenvironment or niche. Subsequently, we present a framework of targeted therapy for GSCs based on direct strategies, including blockade of the pathways necessary to overcome resistance or prevent their function, promotion of GSC differentiation, virotherapy, and indirect strategies, including targeting the perivascular, hypoxic, and immune niches of the GSCs. In summary, targeting GSCs provides a tremendous opportunity for revolutionary approaches to improve the prognosis and therapy of GBM, despite a variety of challenges.

Aim. Cyclophilin A (CypA)/CD147 signaling plays critical roles in the regulation of inflammation and bone metabolism. This study aimed to investigate the participation of CypA/CD147 in mice periapical lesions progression and its relationship with bone resorption.Methodology. Periapical lesions were induced by pulp exposure in the first lower molars of 40 C57BL/6J mice. The mice were sacrificed on days 0, 7, 14, 21, 28, 35, 42, and 49. Mandibles were harvested for X-ray imaging, microcomputed tomography scanning, histologic observation, immunohistochemistry, enzyme histochemistry, and double immunofluorescence analysis. Western blot was employed to further detect the related molecular signaling pathways in LPS-stimulated RAW 264.7 cells treated with CypA inhibitor.Results. The volume and area of the periapical lesions increased from day 0 to day 35 and remained comparably stable until day 49. Immunohistochemistry demonstrated that the CypA expression levels also increased from day 0 to day 35 and decreased until day 49, similar to CD147 expression (R2= 0.4423, P < 0.05), osteoclast number (R2= 0.5101, P < 0.01), and the expression of osteoclastogenesis-related matrix metalloproteinase 9 (MMP-9) (R2= 0.4715, P < 0.05). Serial sections further confirmed the colocalization of CypA and CD147 on osteoclasts with immunohistochemistry. And the distribution of CypA-positive or CD147-positive cells was positively correlated with the dynamics of MMP-9-positive cells by using immunofluorescence analysis. Furthermore, CD147 and MMP-9 expression in RAW 264.7 cells were both downregulated with CypA inhibitor treatment (P < 0.05).Conclusions. The present study reveals the positive correlation of CypA/CD147 signaling and osteoclast-related MMP-9 expression in mice inflammatory periapical lesions progression. Therefore, intervention of CypA/CD147 signaling could probably provide a potential therapeutic target for attenuating inflammatory bone resorption.

Hypertension is common in patients with aneurysmal subarachnoid hemorrhage (SAH). However, it is still unclear whether premorbid antihypertensive therapy can help to reduce the risk of severe aneurysmal bleeding. Therefore, this study aims to assess the effect of premorbid hypertension control on outcome of patients with aneurysmal SAH. We retrospectively reviewed the clinical data of patients with intracranial aneurysms admitted to our institution from February 2012 to December 2017. Based on premorbid hypertension history and use of antihypertensive agents, all patients with aneurysmal SAH were divided into antihypertensive group and uncontrolled group. Patient characteristics, imaging features, clinical complication, and outcome were analyzed between the two groups. A total of 348 patients with ruptured aneurysms were included in this study. Compared to those with premorbid controlled hypertension, patients with premorbid uncontrolled hypertension presented worse clinical grade, with more severe aneurysmal SAH and more frequent intracerebral hematoma. Patients receiving a treatment for ACEI type or ARB type of drugs in the antihypertensive group suffered from less amount of aneurysmal bleeding, while patients with grade 3 hypertension in the uncontrolled group suffered from more amount of aneurysmal bleeding. Patients with premorbid controlled hypertension had a lower incidence of rebleeding, hydrocephalus, and cerebral vasospasm, and had a lower rate of disability and mortality. Premorbid hypertension control is associated with favorable clinical outcome of patients with aneurysmal SAH. Besides, the ACEI type or ARB type of antihypertensive agents is associated with the less amount of bleeding after aneurysm rupture.

Objective To detect cerebral autoregulation (CA) in patients with aneurysmal subarachnoid hemorrhage (aSAH) by near-infrared spectroscopy and to assess its association with delayed cerebral ischemia (DCI). Methods From January to August 2017, 81 patients (average age 53.25 ± 10.27 years) were studied. Near-infrared spectroscopy was used to monitor CA, and associated factors were evaluated. Monitoring of CA was carried out at 5 time points (preoperative day 1 and postoperative days 1, 2, 3, and 7). Patients were sorted into 2 groups according to whether DCI occurred (DCI group and non-DCI group). The relationship between CA and DCI in patients with aSAH was analyzed. Results Among 81 patients, CA trended toward being impaired in patients with aSAH with a poorer grade. DCI occurred in 39 of 51 (48.15%) patients with impaired CA. DCI occurred in 6 of 30 (7.4%) patients with intact CA. Conclusions Impaired CA monitored by near-infrared spectroscopy was shown in patients with aSAH before and after surgical intervention. Older age, smoking, hypertension, and especially impaired CA are independent risk factors for patients with DCI.

Aim To investigate the shift in the subgingival microbiota under scaling and root planing (SRP) in patients with generalized aggressive periodontitis (GAgP). Materials and methods After undergoing supragingival scaling, 12 individuals with GAgP were enrolled in this longitudinal study. Full-mouth SRP was accomplished in 3 weeks and re-evaluated 6 weeks later. Pooled subgingival samples (posterior-mesial, posterior-buccal, anterior-mesial, and anterior-buccal) were obtained from each patient before SRP (pre-treatment group) and at the time of re-evaluation (post-treatment group). 16S rRNA PCR products were generated and sequenced after DNA isolation. Results Under SRP, the diversity of the subgingival community was consistent, whereas genus-level biomarkers transformed from Porphyromonas, Treponema, and Fretibacterium to Actinomyces, Streptococcus, and Haemophilus. In a network analysis, pathogen-related and non-pathogen-related components were identified in both the pre- and post-treatment groups; the pathogen component was dramatically augmented, while the non-pathogen component shrank after treatment. Hubs were also distributed in both components pre-treatment and were confined to the pathogen component post-treatment. Conclusions Scaling and root planing decreased periodontal pathogens in the subgingival microbiota of patients with GAgP. However, the shift in the microbiota composition was characterized by the expansion of pathogen-related components and the contraction of non-pathogen-related components 6 weeks after SRP. Clinicaltrials.gov #NCT03090282.

2-hydroxyethyl methacrylate (HEMA) is the major resin monomer that is released from incomplete polymerized dental restorative and adhesive biomaterials during dental therapy. Autophagy and apoptosis are biologically connected and the relationship between autophagy and apoptosis is complex under various circumstances. This study aimed to determine whether autophagy is activated by HEMA and further explore the function of autophagy during the HEMA-induced apoptosis of dental mesenchymal cells (DMCs). We exposed DMCs to different concentrations of HEMA. Cell viability showed a time- and concentration-dependent decrease when exposed to HEMA. We showed that HEMA exposure increased autophagic vacuoles and the expression of autophagic biomarkers (Beclin1, Atg5 and LC3). Pre-incubated with autophagy inhibitors (3-methyladenine and chloroquine) significantly prevented HEMA-induced apoptosis. Interestingly, HEMA initiated nuclear factor-κB (NF-κB) expression and nuclear translocation, whereas the NF-κB inhibitor (Bay 11-7082) markedly suppressed HEMA-induced autophagic activation and apoptosis. As is consistent with the in vitro results, HEMA treatment resulted in dental pulp tissue toxicity and activation of typical autophagic vacuoles in the tooth slice organ culture model ex vivo. In summary, we demonstrated that NF-κB signaling functioned upstream of HEMA-inducecd autophagy in DMCs and that the activation of NF-κB-autophagy axis was responsible for HEMA-induced apoptosis. Our findings provide novel insights into the mechanisms of resin monomer-mediated dental pulp damage during dental treatment, highlighting the activation of NF-κB-autophagy axis as an important mechanism of HEMA-mediated apoptosis.

The aim was to investigate the role of rabeprazole on the pharmacokinetics (PK) and pharmacodynamics (PD) of metformin. The in vitro inhibition assays on metformin transport were carried out and showed that the half maximal inhibitory concentration (IC 50 ) of rabeprazole on OCT2-mediated metformin transport was 26.0 μM, whereas the IC 50 on MATE1-mediated metformin transport inhibition was 4.6 μM. Fifteen healthy Chinese male volunteers were enrolled and given two different doses of metformin plus the co-administration of placebo or rabeprazole. Plasma concentrations of metformin were measured up to 12 h after the second dose. The glucose-lowering effects and the variation of insulin concentrations were evaluated during the oral glucose tolerance test (OGTT). The AUC 0–12 of metformin plus rabeprazole were 28,276 ± 5187 ng/ml·h, which was significantly higher than AUC 0–12 of metformin plus placebo (24,691 ± 3129 ng/ml·h). Thus, rabeprazole can modestly influence the PK of metformin, suggesting the precaution of using the two drugs together. In OGTTs, rabeprazole decreased the values of AUC insulin and the maximum insulin concentration. Although rabeprazole showed inhibition effect on OCT2-mediated metformin transport, the glucose-lowering effect of metformin remained the same regardless of its PK changes. Further studies are needed to warrant the effect of rabeprazole on metformin.

miR-3188, one of the earliest discovered microRNAs, is involved in regulating the mTOR-p-PI3K/AKT pathway, thus affecting the progression of diabetic complications. In this study, we observed that the miR-3188 (rs7247237-C>T) polymorphism not only affected the production of nitric oxide (NO) production in endothelial cells, but also significantly associated with the incidence of vascular complications in Chinese patients with type 2 diabetes. Mechanistic analyses indicate that miR-3188 (rs7247237-T) polymorphism inhibited its own expression and upregulated the expression of gstm1 and trib3, which impairs NO production in human endothelial cells through inactivating AKT/eNOS signal transduction pathway. In addition, our clinical retrospective study indicated that, compared with patients with the CC genotype (n = 351), patients with rs7247237 TT + CT genotypes (n = 580) exhibited an increased risk of major vascular events during intensive glucose control treatment (hazard ratio = 1.560; 95% CI: 1.055-2.307, P = 0.025). Simultaneously, the risk of major vascular events was marginally decreased in patients with the CC genotype during intensive glucose control treatment compared with standard treatment (hazard ratio = 0.666; 95% CI: 0.433-1.016, P = 0.053). Our findings indicate that the miR-3188 (rs7247237-C>T) polymorphism is associated with the incidence of vascular complications in Chinese patients with type 2 diabetes, likely due to its remarkable effect on miR-3188 expression.

Objective. The opinions about the application of pulse oximetry in diagnosis of congenital heart disease (CHD) were debatable. We performed this meta-analysis to confirm the diagnostic role of pulse oximetry screening for CHD. Methods. Relevant articles were searched in the databases of Pubmed, Embase, Google Scholar, and Chinese National Knowledge Infrastructure (CNKI) up to April 2017. Data was processed in the MetaDiSc 1.4 software. Pooled sensitivity and specificity with 95% confidence interval (95% CI) were calculated to explain the diagnostic role of pulse oximetry screening for CHD. I2⩾50% or p<0.05 indicated significant heterogeneity. Area under curve (AUC) of summary receiver operating characteristics (SROC) was calculated to assess its diagnostic accuracy. The robustness of overall results was evaluated by sensitivity analysis. Publication bias was evaluated by Deek’s funnel plot. Results. 22 eligible articles were selected. Pooled sensitivity and specificity were 0.69 (0.67–0.72) and 0.99 (0.99-0.99), respectively. The corresponding AUC was 0.9407, suggesting high diagnostic accuracy of pulse oximetry screening for CHD. Sensitivity analysis demonstrated that the pooled results were robust. Deek’s funnel plot seemed to be symmetrical. Conclusions. Pulse oximetry screening could be used to diagnose CHD. It shows high diagnosis specificity and accuracy.

The link between single-cell variation and population-level fate choices lacks a mechanistic explanation despite extensive observations of gene expression and epigenetic variation among individual cells. Here, we found that single human embryonic stem cells (hESCs) have different and biased differentiation potentials toward either neuroectoderm or mesendoderm depending on their G1 lengths before the onset of differentiation. Single-cell variation in G1 length operates in a dynamic equilibrium that establishes a G1 length probability distribution for a population of hESCs and predicts differentiation outcome toward neuroectoderm or mesendoderm lineages. Although sister stem cells generally share G1 lengths, a variable proportion of cells have asymmetric G1 lengths, which maintains the population dispersion. Environmental Wingless-INT (WNT) levels can control the G1 length distribution, apparently as a means of priming the fate of hESC populations once they undergo differentiation. As a downstream mechanism, global 5-hydroxymethylcytosine levels are regulated by G1 length and thereby link G1 length to differentiation outcomes of hESCs. Overall, our findings suggest that intrapopulation heterogeneity in G1 length underlies the pluripotent differentiation potential of stem cell populations., The link between single-cell variation and population-level fate choices lacks a mechanistic explanation. This study finds that the duration of the G1 cell cycle phase in stem cells varies within the population, giving rise to a probability distribution of G1 length that is responsive to Wnt signalling and that predicts cells’ differentiation potential upon exit from pluripotency.

Introduction Mineral trioxide aggregate (MTA) regulates bone remodeling, particularly osteoclast differentiation. However, intracellular mechanisms underlying the anti-osteoclastogenesis of MTA remain unclear. This study aimed to evaluate the potential alterations of autophagic pathway during anti-osteoclastogenic effects by MTA in vitro and investigate their underlying mechanisms. Methods Osteoclast precursors were treated with MTA extracts containing the receptor activator of nuclear factor-kappa B ligand (RANKL). Rapamycin was used to activate autophagy. RANKL-induced osteoclast differentiation was stained with tartrate-resistant acid phosphatase. Several specific autophagy features in osteoclast precursors were measured by using immunofluorescence, monodansylcadaverine, and transmission electron microscope. Autophagy-related proteins were investigated via Western blot analysis. The mRNA expression involved in autophagic and osteoclastic activities was detected with quantitative real-time polymerase chain reaction. Results MTA extracts inhibited osteoclast differentiation via preventing the fusion of osteoclast precursors without cytotoxicity. MTA extracts interrupted RANKL-induced acidic vesicular organelle formation and autophagic vacuole appearance in osteoclast precursors. Moreover, autophagic genes and proteins stimulated with RANKL diminished with MTA extracts. Notably, autophagy activation through rapamycin promoted multinucleated osteoclasts formation and increased osteoclastic genes expression, which almost reversed MTA-mediated anti-osteoclastogenic effects. Conclusions MTA inhibited osteoclastogenesis for bone repair through attenuating the autophagic pathway.