Mechanisms of Bone Remodeling Disorder in Hemophilia.

Hemophilia is caused by a lack of antihemophilic factor(s), for example, factor VIII (FVIII; hemophilia A) and factor IX (FIX; hemophilia B). Low bone mass is widely reported in epidemiological studies of hemophilia, and patients with hemophilia are at an increased risk of fracture. The detailed etiology of bone homeostasis imbalance in hemophilia is unclear. Clinical and experimental studies show that FVIII and FIX are involved in bone remodeling. However, it is likely that antihemophilic factors affect bone biology through thrombin pathways rather than via their own intrinsic properties. In addition, among patients with hemophilia, there are pathophysiological processes in several systems that might contribute to bone loss. This review summarizes studies on the association between hemophilia and bone remodeling, and might shed light on the challenges facing the care and prevention of osteoporosis and fracture in patients with hemophilia.

Hydrogen sulfide promotes lipopolysaccharide-induced apoptosis of osteoblasts by inhibiting the AKT/NF-κB signaling pathway.

Apoptosis of osteoblasts plays a crucial role in osteomyelitis. Hydrogen sulfide (H2S) levels are increased in the pathophysiological processes of osteomyelitis. However, the effect of H2S on the apoptosis of osteoblasts remains unclear. To investigate the specific role of H2S in osteoblast apoptosis, MC3T3-E1 and hFOB cells were treated with NaHS or Na2S, a donor of H2S, and lipopolysaccharide (LPS), during osteomyelitis. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, flow cytometry analysis, western blotting, immunofluorescence, polymerase chain reaction, and Alizarin red staining were performed to examine the effects of H2S on osteoblast cell apoptosis, cell osteogenic differentiation, and AKT kinase (AKT)/nuclear factor kappa B (NF-κB) signaling. Hydrogen sulfide increased cell apoptosis, and inhibited the proliferation and osteogenic differentiation of osteoblast cells impaired by LPS. H2S increased apoptosis through upregulation of the FAS ligand (FASL) signaling pathway. H2S-induced apoptosis was alleviated using a FAS/FASL signaling pathway inhibitor. Treatment with NaHS also increased cell apoptosis by downregulating AKT/NF-κB signaling. In addition, treatment with an AKT signaling pathway activator decreased apoptosis and reversed the inhibitory effects of H2S on osteogenic differentiation. Hydrogen sulfide promotes LPS-induced apoptosis of osteoblast cells by inhibiting AKT/NF-κB signaling.

Design and Evaluation of Lyophilized Fibroblast Growth Factor 21 and Its Protection against Ischemia Cerebral Injury.

This study investigated the effect of the excipients, including glycine, mannitol, arginine, trehalose, sorbitol, and poloxamer188, on the stability of recombinant human fibroblast growth factor 21(FGF21) during the process of lyophilization and storage. The glass transition temperature (Tg), protein secondary structure, aggregation ratio, and the bioactivity of lyophilized FGF21 were measured. We furthermore investigated the effect of FGF21 against ischemia cerebral injury using the middle cerebral artery occlusion (MCAO) model in rats. The ischemia cerebral injury of MCAO rats was analyzed via 2,3,5-triphenyltetrazolium chloride and Nissl-staining. Endoplasmic reticulum (ER) stress related proteins were detected via Western blot. In this study, we found that aggregation was the primary mode of deterioration of lyophilized FGF21under accelerated storage conditions. Mannitol combined with trehalose and glycine formulations offers the most effective protein protection to reduce the aggregation. Administration of FGF21 protected cerebral ischemia and decreased ER stress related proteins in MCAO rats and PC12 cells.

Exosome-mediated repair of intervertebral disc degeneration: The potential role of miRNAs.

Intervertebral disc degeneration (IVDD) is a serious condition that manifests as low back pain, intervertebral disc protrusion, and spinal canal stenosis. At present, the main treatment methods for IVDD are surgical interventions such as discectomy, total disc replacement, and spinal fusion. However, these interventions have shown limitations, such as recurrent lumbar disc herniation after discectomy, lesions in adjacent segments, and failure of fixation. To overcome these shortcomings, researchers have been exploring stem cell transplantation therapy, such as mesenchymal stem cell (MSC) transplantation, but the treatment results are still controversial. Therefore, researchers are in search of new methods that are more efficient and have better outcomes. The exosomes from stem cells contain a variety of bioactive molecules that mediate cell interactions, and these components have been investigated for their potential therapeutic role in the repair of various tissue injuries. Recent studies have shown that MSC-derived miRNAs in exosomes and vesicles have therapeutic effects on nucleus pulposus cells, annulus fibrosus, and cartilage endplate. miRNAs play a role in many cell activities, such as cell proliferation, apoptosis, and cytokine release, by acting on mRNA translation, and they may have immense therapeutic potential, especially when combined with stem cell therapy. This article reviews the current status of research on intervertebral disc repair, especially with regard to the latest research findings on the molecular biological mechanisms of miRNAs in MSC-derived exosomes in intervertebral disc repair.

Profiling of metabolites, proteins, and protein phosphorylation in silica-exposed BEAS-2B epithelial cells.

Silicosis is an uncurable occupational disease induced by crystalline silica. Increased prevalence of silicosis has resulted in the increased need for development of treatment options. Although macrophages respond first to silica, epithelial cells are also involved in silicosis. However, changes in protein and metabolite levels have not been reported simultaneously. We used mass spectrometry to profile changes in metabolites, proteins, and phosphorylation in silica-exposed BEAS-2B epithelial cells. Silica exposure increased TCA cycle, alanine, aspartate and glutamate metabolism, and aerobic glycolysis activity. In addition, protein levels in the endoplasmic reticulum were significantly altered, and phosphorylation of MAPK signaling proteins was increased. The results of this study increased understanding the role of epithelial cells in silicosis.

Lumbar Sympathetic Trunk Injury: An Underestimated Complication of Oblique Lateral Interbody Fusion.

OBJECTIVE: Lumbar sympathetic trunk (LST) injury is one of the major complications after oblique lumbar interbody fusion (OLIF). LST injury often manifests as unequal skin temperature in lower limbs after operation, and there may be a large number of missed diagnoses due to the lack of attention and different diagnostic methods. The study aimed to investigate the incidence and clinical characteristics of LST injury after OLIF. METHODS: The data of patients with lumbar degenerative diseases who underwent OLIF in our hospital from April 2016 to October 2017 were retrospectively analyzed. Finally, a total of 54 patients were included. There were 10 males and 44 females, aged 58.4 ± 10.9 years. The skin temperature of lower limbs was measured before and a day after surgery. The patients were followed up at 1 week, 6 weeks, 6 months, and 2 years after the surgery. Likert five-point scale was used to evaluate the discomfort caused by LST injury. Injury severity score was introduced to grade injury degree according to the recovery time of postoperative symptoms. The chi-square test was used to analyze the association of incidence of lumbar sympathetic trunk (LST) injury with contributing factors, such as gender and number of surgical segments. RESULTS: The unequal temperature was not found before surgery in all the patients. Postoperatively, 16 cases (29.6%) had difference of skin temperature more than 0.5 °C and were diagnosed with LST injury. Eight patients (14.8%) had self-perception of skin temperature differences, and 12 patients (22.2%) had other symptoms, such as muscle pain, numbness, and weakness, which were not statistically different between patients with and without lumbar sympathetic trunk injury (p > 0.05). In the 16 patients with LST injury, the difference of skin temperature between the two legs was 0.6 ± 0.1 °C on the first day, and the temperature difference lasted for 1.5-~12 months. According to Likert five-point scale, two cases (12.5%) were poor, and 14 cases (87.5%) were moderate immediately after surgery. Fifteen cases improved to some extent 6 weeks to 12 months after surgery. CONCLUSION: Postoperative LST injury is mainly manifested by different temperature of lower limbs. The incidence was higher in patients with multi-segment OLIF than in those with single-segment OLIF, and the subjective experience of most patients with LST injury was moderate discomfort.

Osteoporosis treatment using stem cell-derived exosomes: a systematic review and meta-analysis of preclinical studies.

BACKGROUND: The increasing incidence of osteoporosis in recent years has aroused widespread public concern; however, existing effective treatments are limited. Therefore, new osteoporosis treatment methods, including stem cell transplantation and exosome therapy, have been proposed and are gaining momentum. Exosomes are considered to have greater potential for clinical application owing to their immunocompatibility. This study summarises the latest evidence demonstrating the efficacy of exosomes in improving bone loss in the treatment of osteoporosis. MAIN TEXT: This systematic review and meta-analyses searched PubMed, Embase, and Cochrane Library databases from inception to 26 March 2022 for osteoporosis treatment studies using stem cell-derived exosomes. Six endpoints were selected to determine efficacy: bone mineral density, trabecular bone volume/tissue volume fraction, trabecular number, trabecular separation, trabecular thickness, and cortical thickness. The search generated 366 citations. Eventually, 11 articles that included 15 controlled preclinical trials and 242 experimental animals (rats and mice) were included in the meta-analysis. CONCLUSION: The results were relatively robust and reliable despite some publication biases, suggesting that exosome treatment increased bone mass, improved bone microarchitecture, and enhanced bone strength compared with placebo treatments. Moreover, stem cell-derived exosomes may favour anabolism over catabolism, shifting the dynamic balance towards bone regeneration.

Chronic giant cranial diploe hematoma in hemophiliac.

Cranial diploe hematoma is a hematoma that occurs between the inner and outer layer of the skull and is often in infants and young children. Hemophilia A is an inherited X-linked bleeding disorder caused by a deficiency of coagulation factor VIII (FVIII) . Epidemiological survey results show that the prevalence of hemophilia in 24 provinces and cities in China is 2.73/100,000, while only about 5% of patients are registered . Hemophilia is mainly characterized by bleeding, which can occur anywhere in the pa-tient's body and manifest as intracranial, gastrointestinal, or pharyngeal bleeding, which can be life-threatening in severe cases. This article shares a case of a patient with he-mophilia A complicated by a chronic giant diploe hematoma.

A weighted multipath measurement based on gene ontology for estimating gene products similarity.

Many different methods have been proposed for calculating the semantic similarity of term pairs based on gene ontology (GO). Most existing methods are based on information content (IC), and the methods based on IC are used more commonly than those based on the structure of GO. However, most IC-based methods not only fail to handle identical annotations but also show a strong bias toward well-annotated proteins. We propose a new method called weighted multipath measurement (WMM) for estimating the semantic similarity of gene products based on the structure of the GO. We not only considered the contribution of every path between two GO terms but also took the depth of the lowest common ancestors into account. We assigned different weights for different kinds of edges in GO graph. The similarity values calculated by WMM can be reused because they are only relative to the characteristics of GO terms. Experimental results showed that the similarity values obtained by WMM have a higher accuracy. We compared the performance of WMM with that of other methods using GO data and gene annotation datasets for yeast and humans downloaded from the GO database. We found that WMM is more suited for prediction of gene function than most existing IC-based methods and that it can distinguish proteins with identical annotations (two proteins are annotated with the same terms) from each other.