FcRn inhibitors: a novel option for the treatment of myasthenia gravis.

Myasthenia gravis is an acquired, humoral immunity-mediated autoimmune disease characterized by the production of autoantibodies that impair synaptic transmission at the neuromuscular junction. The intervention-mediated clearance of immunoglobulin G (IgG) was shown to be effective in controlling the progression of the disease. The neonatal Fc receptor (FcRn) plays a key role in prolonging the serum half-life of IgG. Antagonizing FcRn to prevent its binding to IgG can accelerate the catabolism of the latter, resulting in decreased levels of IgG, including pathogenic autoantibodies, thereby achieving a therapeutic effect. In this review, we detail the substantial research progress, both basic and clinical, relating to the use of FcRn inhibitors in the treatment of myasthenia gravis.

A naphthalimide-based and Golgi-targetable fluorescence probe for quantifying hypochlorous acid.

The Golgi apparatus (GA) is a vital organelle in biological systems and excess reactive oxygen species (ROS) is produced during stress in the Golgi apparatus. Hypochlorous acid (HOCl) is a significant reactive oxygen species and has strong oxidative and antibacterial activity, but excessive secretion of hypochlorous acid can affect Golgi structure or function abnormally, it will lead to a series of diseases including Alzheimer's disease, neurodegenerative diseases, autoimmune diseases, and Parkinson's disease. In present work, a novel fluorescent probe for Golgi localization utilizing naphthalimide derivatives was constructed to detect hypochlorous acid. The fluorescent probe used a derivatived 1,8-naphthalimide as the emitting fluorescence group, phenylsulfonamide as the localization group and dimethylthiocarbamate as the sensing unit. When HOCl was absent, the intramolecular charge transfer (ICT) process of the developed probe was hindered and the probe exhibited a weak fluorescence. When HOCl was present, the ICT process occurred and the probe showed strong green fluorescence. When the HOCl concentration was altered from 5.0 × 10-7 to 1.0 × 10-5 mol·L-1, the fluorescence intensity of the probe well linearly correlated with the HOCl concentration. The detection limit of 5.7 × 10-8 mol·L-1 was obtained for HOCl. The HOCl fluorescent probe possessed a rapid reaction time, a high selectivity and a broad working pH scope. In addition, the probe possessed good biocompatibility and had been magnificently employed to image Golgi HOCl in Hela cells. These characteristics of the probe demonstrated its ability to be used for sensing endogenous and exogenous hypochlorous acids within the Golgi apparatus of living cells.

Influence of bone anatomical morphology of mandibular molars on dental implant based on CBCT.

BACKGROUND: To apply CBCT to investigate the anatomical relationship between the mandibular molar and alveolar bone, aimed to provide clinical guidelines for the design of implant restoration. METHODS: 201 CBCT data were reevaluated to measure height of the alveolar process (EF), width of the alveolar process (GH), width of the basal bone (IJ), the angle between the long axis of the first molar and the alveolar bone (∠a) and the angle between the long axis of the alveolar bone and basal bone (∠b). The angle and width were measured to determine the implant-prosthodontic classification of the morphology in the left lower first molar (36) and right lower first molar (46). All measurements were performed on the improved cross-sectional images. RESULTS: EF, GH and IJ were measured as (10.83 ± 1.31) mm, (13.93 ± 2.00) mm and (12.68 ± 1.96) mm for 36, respectively; and (10.87 ± 1.24) mm, (13.86 ± 1.93) mm and (12.60 ± 1.90) mm for 46, respectively. No statistical significance was observed in EF, GH, IJ, ∠a and ∠b between 36 and 46 (all P > 0.05). The morphology was divided into three categories including the straight (68.7-69.2%), oblique (19.9-20.4%) and concave types (11%). Each type was consisted of two subcategories. CONCLUSIONS: The proposed classification could provide evidence for appropriate selection and direction design of the mandibular molar implant in clinical. The concave type was the most difficult to implant with the highest risk of lingual perforation. The implant length, width, direction required more attention.

The survival rate of transcrestal sinus floor elevation combined with short implants: a systematic review and meta-analysis of observational studies.

BACKGROUND: Currently, insufficient bone volume always occurs in the posterior maxilla which makes implantation difficult. Short implants combined with transcrestal sinus floor elevation (TSFE) may be an option to address insufficient bone volume. PURPOSE: The clinical performance of short implants combined with TSFE was compared with that of conventional implants combined with TSFE according to the survival rate. METHOD: In this systematic review and meta-analysis, we followed the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Articles were identified through PubMed, Embase, the Cochrane Library, and manual searching. Eligibility criteria included clinical human studies. The quality assessment was performed according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. The odds ratio (OR) with its confidence interval (CI) was considered the essential outcome for estimating the effect of short implants combined with TSFE. RESULTS: The registration number is INPLASY202050092. Eleven studies met the inclusion criteria, including 1 cohort study and 10 cross-sectional studies. With respect to the 1-year survival rate, no significant effect was observed between short implants (length ≤ 8 mm) and conventional implants combined with TSFE (I2=0%, OR=1.04, 95% CI: 0.55-1.96). Similarly, no difference was seen between the two groups regarding the survival rate during the healing period (I2=10%, OR=0.74, 95% CI: 0.28-1.97) and 3-year loading (OR=1.76, 95% CI: 0.65-4.74). CONCLUSION: There was no evidence that the survival rate of short implants combined with TSFE was lower or higher than that of conventional implants combined with TSFE when the residual bone height was poor and the implant protrusion length of short implants was less than or similar to conventional implants. Nevertheless, the results should be interpreted cautiously due to the lack of random controlled trials in our meta-analysis.

Two-stage transcrestal sinus floor elevation-insight into replantation: Six case reports.

BACKGROUND: Transcrestal sinus floor elevation (TSFE) has been widely used in the oral clinic when the residual bone height (RBH) exceeds 5 mm. However, when there is insufficient RBH in the posterior maxilla, two-stage TSFE may be an option. CASE SUMMARY: This article introduces the concept of two-stage TSFE. Six patients had osseointegration failure after TSFE. For the first-stage surgery, we restricted the vertical bone augmentation as much as possible. At the second-stage surgery, the increased RBH was 3.28 ± 1.55 mm, which was beneficial for surgery. Five implants functioned successfully on schedule, but one implant failed again during the healing period. A third surgery was performed, and the implant functioned successfully. CONCLUSION: When RBH was less than 5 mm, two or more procedures of TSFE might result in a higher RBH.

Cyclic tensile forces enhance the angiogenic properties of HUVECs by promoting the activities of human periodontal ligament cells.

BACKGROUND: This study aimed to investigate whether human periodontal ligament (PDL) cells secrete pro-angiogenic factors that induce the vascularization of surrounding bone tissue under tensile stress. METHODS: Quantitative real-time PCR and Western blotting were used to analyze the mRNA and protein expression levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), Angiopoietin-I (Ang-I), connective tissue growth factor （CTGF）, and macrophage colony-stimulating factor (M-CSF) in PDL cells after tensile force treatments of different durations. Enzyme-linked immunosorbent assay was used to measure the VEGF concentration in the supernatants of cell cultures. Cell viability assay, wound healing assay, and tube formation assay were performed to evaluate the angiogenic behaviors of human umbilical vein endothelial cells (HUVECs). RESULTS: The mRNA expression and protein expression of VEGF, bFGF, Ang-I, and M-CSF was increased in the cells that received 6 to 48 hours of tensile force treatment. And, the VEGF level in the supernatant significantly increased in the human PDL cell cultures stressed for 6 to 48 hours. The abilities of HUVECs to proliferate, migrate, and form tubes were enhanced in media conditioned with tensile-stressed human PDL cells. Hence, tensile force induced human PDL cells to express and release pro-angiogenic factors enhancing the proliferation, migration, and angiogenic capacity of HUVECs. CONCLUSION: Tensile stress induced human PDL cells to express and release pro-angiogenic factors, including VEGF, bFGF, Ang-I, and M-CSF, thereby enhancing the proliferation, migration, and angiogenic capacity of HUVECs.

Folium Sennae and emodin reverse airway smooth muscle contraction.

The objective of this project was to find a bronchodilatory compound from herbs and clarify the mechanism. We found that the ethanol extract of Folium Sennae (EEFS) can relax airway smooth muscle (ASM). EEFS inhibited ASM contraction, induced by acetylcholine, in mouse tracheal rings and lung slices. High-performance liquid chromatography assay showed that EEFS contained emodin. Emodin had a similar reversal action. Acetylcholine-evoked contraction was also partially reduced by nifedipine (a selective inhibitor of L-type voltage-dependent Ca2+ channels, LVDCCs), YM-58483 (a selective inhibitor of store-operated Ca2+ entry, SOCE), as well as Y-27632 (an inhibitor of Rho-associated protein kinase). In addition, LVDCC- and SOCE-mediated currents and cytosolic Ca2+ elevations were inhibited by emodin. Emodin reversed acetylcholine-caused increases in phosphorylation of myosin phosphatase target subunit 1. Furthermore, emodin, in vivo, inhibited acetylcholine-induced respiratory system resistance in mice. These results indicate that EEFS-induced relaxation results from emodin inhibiting LVDCC, SOCE, and Ca2+ sensitization. These findings suggest that Folium Sennae and emodin may be new sources of bronchodilators.

NS8593 inhibits Ca2+ permeant channels reversing mouse airway smooth muscle contraction.

AIMS: This study focused on investigating whether NS8593 reverses airway smooth muscle (ASM) contraction and the underlying mechanism. MAIN METHODS: ASM contraction in mouse tracheal rings and lung slices was measured. Currents mediated by voltage dependent Ca2+ channels (VDCCs) and ACH-activated channels were measured using the whole-cell patch-clamp technique in single tracheal smooth muscle cells (TSMCs). Intracellular Ca2+ level and cell length were measured using an LSM 700 laser confocal microscope and a Zen 2010 software. Mouse respiratory system resistance (Rrs) was assessed using a FlexiVent FX system. KEY FINDINGS: High K+ (80 mM K+) and ACH induced ASM contraction in mouse tracheal rings and lung slices, which was partially relaxed by nifedipine (blocker of L-type VDCCs, LVDCCs), YM-58483 (blocker of store-operated Ca2+ entry (SOCE), transient receptor potential C3 (TRPC3) and TRPC5 channels), respectively. However, the contraction was completely reversed by NS8593, whereas, slightly relaxed by formoterol. ACH activated inward currents, which displayed linear and reversed around 0 mV, indicating the currents were mediated by non-selective cation channels (NSCCs). Moreover, these currents were blocked by YM-58483. In addition, such currents were abolished by NS8593, implicating that NS8593 inhibits the same channels. Besides, NS8593 inhibited increases of intracellular Ca2+ and the associated cell shortening. Finally, NS8593 inhibited ACH-induced increases of mouse respirator system resistance (Rrs). SIGNIFICANCE: Our results indicate that NS8593 inhibits LVDCCs and NSCCs, resulting in decreases of intracellular Ca2+ and then leading to ASM relaxation. These data suggest that NS8593 might be a new bronchodilator.

Nell-1 Enhances Osteogenic Differentiation of Pre-Osteoblasts on Titanium Surfaces via the MAPK-ERK Signaling Pathway.

BACKGROUND/AIMS: This study aimed to investigate the effect of Nell-1 on the osteogenic behaviors of pre-osteoblasts on titanium (Ti) surfaces and to identify the underlying signaling pathway. METHODS: Nell-1 at different concentrations was added to culture medium to stimulate MC3T3-E1 subclone 14 on Ti surfaces. A CCK-8 colorimetric assay was used to detect cell proliferation. Alkaline phosphatase activity (ALP) assay and enzyme-linked immunosorbent assay (ELISA) were used to evaluate ALP activity and the osteocalcin (OCN) secretion, respectively. Indicators of osteoblastic differentiation were assessed using real-time polymerase chain reaction analysis (RT-PCR). Western blot (WB) assay was used to analyze the expression changes of the osteogenic proteins and the mitogen-activated protein kinase (MAPK) pathway. RESULTS: Nell-1 significantly increased the osteogenic gene and protein expression levels of ALP, OCN, Runx2, osteoprotegerin (OPG), collagen type I (Col-I), and Osterix (Osx) in pre-osteoblasts on Ti surfaces. The optimal concentration of Nell-1 was 100 ng/ ml. In addition, Nell-1 activated ERK and JNK, but not P38, in MC3T3-E1 cells on the Ti surface. Except for ALP and Col-I, the promotive effects of Nell-1 on the expression of osteogenic markers were suppressed by ERK inhibitor U0126. CONCLUSION: Certain concentrations of Nell-1 can promote the osteogenic differentiation of pre-osteoblasts on Ti surfaces by activating the MAPK/ERK signaling pathway.

Plasmodium chabaudi AS: distinct CD4(+)CD25(+)Foxp3(+) regulatory T cell responses during infection in DBA/2 and BALB/c mice.

Malaria infections display variation patterns of clinical course and outcome. Although CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells play an essential role in immune homeostasis, the immune regulatory roles involved in malaria infection remains to be elucidated. Herein, we compared the disparity in Treg cells response during the course of blood stage Plasmodium chabaudi chabaudi AS (P. c chabaudi AS) infection in DBA/2 and BALB/c mice. BALB/c mice initiated a Th1/Th2 profile respond to P. c chabaudi AS infection, but DBA/2 mice failed to control P. c chabaudi AS infection and almost of them died post-peak parasitemia. At the peak parasitemia, we found that higher proportion of Treg cells with elevated Foxp3 expression in DBA/2 than in BALB/c mice. We used anti-CD25 mAb to deplete Treg cells and found that the survival time and rate were prolonged in DBA/2 mice treated with anti-CD25 mAb. Treatment with anti-CD25 mAb in vivo led to enhanced pro-inflammation responses and Foxp3 expression decline on Treg cells. In contrast, after DBA/2 was treatment with anti-IL-10R mAb, IL-10R blockade in vivo caused excessive pro-inflammation responses and Foxp3 expression loss on CD4(+)CD25(+) T cells. Earlier death was found in all of DBA/2 mice with anti-IL-10R mAb. It suggested that IL-2 and IL-10 signal involved in maintaining Foxp3 expression on Treg cells. In all, the moderate suppressive activity of Treg cells may facilitate resistance to P. c chabaudi AS infection.