ROS/MMP-9 mediated CS degradation in BMSC inhibits citric acid metabolism participating in the dual regulation of bone remodelling.

It is necessary to figure out the abnormal energy metabolites at the cellular level of postmenopausal osteoporosis (PMOP) bone microenvironment. In this study, we constructed PMOP model by ovariectomy and identified 9 differential metabolites compared with control femur by energy metabolomic. The enrichment analysis of differential metabolites revealed that tricarboxylic acid cycle, glucagon pathway and purinergic signaling pathway were the main abnormal metabolic processes. Citric acid was identified as the key metabolite by constructing compound reaction-enzyme-gene network. The functional annotation of citric acid targets identified by network pharmacological tools indicated that matrix metalloproteinase 9 (MMP-9) may be involved in regulating citric acid metabolism in the osteogenic differentiation of bone marrow mesenchymal stem cell (BMSC). Molecular docking shows that the interaction forces between MMP-9 and citric acid synthase (CS) is -638, and there are multiple groups of residues used to form hydrogen bonds. Exogenous H2O2 promotes the expression of MMP-9 in BMSC to further degrade CS resulting in a decrease in mitochondrial citric acid synthesis, which leads to the disorder of bone remodeling by two underlying mechanisms ((1) the decreased histone acetylation inhibits the osteogenic differentiation potential of BMSC; (2) the decreased bone mineralization by citric acid deposition). MMP-9-specific inhibitor (MMP-9-IN-1) could significantly improve the amount of CS in BMSC to promote cellular citric acid synthesis, and further enhance bone remodeling. These findings suggest inhibiting the degradation of CS by MMP-9 to promote the net production of citric acid in osteogenic differentiation of BMSC may be a new direction of PMOP research.

Research Hot Spots and Trends on Melatonin From 2000 to 2019.

Research on melatonin remains one of the major hot spots in the field of disease treatment, but relevant data are numerous. The purpose of this study was to quantitatively and qualitatively analyze the progress of melatonin research through the method of bibliometrics and to predict hot spots and trends in melatonin research. This study retrieved all the studies on melatonin from 2000 to 2019 in the Web of Science and PubMed and analysed the publishing trends in the literature on a bibliometric online analysis platform and CiteSpace software. The research results were also visually analysed to summarize melatonin research hot spots through gCLUTO and pubMR. The study retrieved a total of 20,351 publications, of which the number of US publications ranked first, accounting for 21.46%, with the greatest impact (centrality = 0.31). The University of Texas Health Science Center at San Antonio and Harvard University had the highest average number of citations at 43.19 and 33.96, respectively. Journal of Pineal Research had the highest average number of citations in 2,993 journals. Professor Reiter made the largest contribution to this area. We further analysed 100 highly cited articles for clinical applications and ongoing related clinical drug trials based on the first hot spot. We systematically analysed melatonin for nearly 20 years while predicting the main research trends in the future, which may provide new directions and ideas for melatonin research. The structure and normal physiological functions of melatonin have been intensively studied in the past few years. And clinical application research and target of melatonin treatment for different diseases and target-based drug design will certainly become the focus of melatonin research.

Clinical Features and Laboratory Examination to Identify Severe Patients with COVID-19: A Systematic Review and Meta-Analysis.

BACKGROUND: With the COVID-19 epidemic breakout in China, up to 25% of diagnosed cases are considered to be severe. To effectively predict the progression of COVID-19 via patients' clinical features at an early stage, the prevalence of these clinical factors and their relationships with severe illness were assessed. METHODS: In this study, electronic databases (PubMed, Embase, Web of Science, and Chinese database) were searched to obtain relevant studies, including information on severe patients. Publication bias analysis, sensitivity analysis, prevalence, sensitivity, specificity, likelihood ratio, diagnosis odds ratio calculation, and visualization graphics were achieved through software Review Manager 5.3, Stata 15, Meta-DiSc 1.4, and R. RESULTS: Data of 3.547 patients from 24 studies were included in this study. The results revealed that patients with chronic respiratory system diseases (pooled positive likelihood 6.07, 95% CI: 3.12-11.82), chronic renal disease (4.79, 2.04-11.25), cardiovascular disease (3.45, 2.19-5.44), and symptoms of the onset of chest tightness (3.8, 1.44-10.05), shortness of breath (3.18, 2.24-4.51), and diarrhea (2.04, 1.38-3.04) exhibited increased probability of progressing to severe illness. C-reactive protein, ratio of neutrophils to lymphocytes, and erythrocyte sedimentation rate increased a lot in severe patients compared to nonsevere. Yet, it was found that clinical features including fever, cough, and headache, as well as some comorbidities, have little warning value. CONCLUSIONS: The clinical features and laboratory examination could be used to estimate the process of infection in COVID-19 patients. The findings contribute to the more efficient prediction of serious illness for patients with COVID-19 to reduce mortality.

Complication and Sequelae of COVID-19: What Should We Pay Attention to in the Post-Epidemic Era.

COVID-19 is widespread worldwide and seriously affects the daily life and health of humans. Countries around the world are taking necessary measures to curb the spread. However, COVID-19 patients often have at least one organ complication and sequelae in addition to respiratory symptoms. Controlling the epidemic is only a phased victory, and the complication and sequelae of COVID-19 will need more attention in the post-epidemic era. We collected general information from over 1000 articles published in 2020 after the COVID-19 outbreak and systematically analyzed the complication and sequelae associated with eight major systems in COVID-19 patients caused by ACE2 intervention in the RAS regulatory axis. The autoimmune response induced by 2019-nCoV attacks and damages the normal tissues and organs of the body. Our research will help medical workers worldwide address COVID-19 complication and sequelae.

The Role of Osteoclast Energy Metabolism in the Occurrence and Development of Osteoporosis.

In recent decades, the mechanism underlying bone metabolic disorders based on energy metabolism has been heavily researched. Bone resorption by osteoclasts plays an important role in the occurrence and development of osteoporosis. However, the mechanism underlying the osteoclast energy metabolism disorder that interferes with bone homeostasis has not been determined. Bone resorption by osteoclasts is a process that consumes large amounts of adenosine triphosphate (ATP) produced by glycolysis and oxidative phosphorylation. In addition to glucose, fatty acids and amino acids can also be used as substrates to produce energy through oxidative phosphorylation. In this review, we summarize and analyze the energy-based phenotypic changes, epigenetic regulation, and coupling with systemic energy metabolism of osteoclasts during the development and progression of osteoporosis. At the same time, we propose a hypothesis, the compensatory recovery mechanism (involving the balance between osteoclast survival and functional activation), which may provide a new approach for the treatment of osteoporosis.

The inhibitory effect of CTAB on human osteosarcoma through the PI3K/AKT signaling pathway.

Osteosarcoma (OS) metastasis and recurrence and multidrug resistance are three major obstacles in the clinic. New highly effective and low toxicity drugs for osteosarcoma are needed. The antitumoral efficacy of cetrimonium bromide (CTAB), a quaternary ammonium compound, is gradually being investigated. The aim of the present study was to investigate the effects of CTAB on OS cells and the underlying mechanisms. CTAB inhibited the proliferation of osteosarcoma cells in a concentration­ and time­dependent manner, resulting in cell cycle arrest in G1 phase. CTAB also suppressed the migration and invasion of HOS and MG63 cells at a low concentration without inhibiting the growth of human osteoblasts. Moreover, CTAB promoted caspase­mediated apoptosis of osteosarcoma cells through the PI3K/AKT cascade, and this effect was accompanied by obvious mitochondrial toxicity. In vivo, CTAB inhibited OS proliferation without inducing organ toxicity. In conclusion, this study reveals that CTAB has an inhibitory effect on OS by suppressing proliferation and metastasis and inducing apoptosis through the PI3K/AKT signaling pathway and identifies CTAB as a potential therapeutic drug.

A 10-year bibliometric analysis of osteosarcoma and cure from 2010 to 2019.

BACKGROUND: In recent decades, the 5-year survival rate of osteosarcoma remains poor, despite the variety of operations, and exploration of drug therapy has become the key to improvement. This study investigates the contribution of different aspects in osteosarcoma and cure, and predicts research hotspots to benefit future clinical outcomes. METHODS: The Web of Science and PubMed databases were queried to collect all relevant publications related to osteosarcoma and cure from 2009 to 2019. These data were imported into CiteSpace and the Online Analysis Platform of Literature Metrology for bibliometric analysis. Bi-clustering was performed on Bibliographic Item co-occurrence Matrix Builder (BICOMB) and gCLUTO to identify hotspots. Additionally, completed clinical trials on osteosarcoma with results past phase II were collated. RESULTS: A total of 2258 publications were identified in osteosarcoma and cure from 2009 to 2019. China has the largest number of publications (38.49%), followed by the United States (23.03%) with the greatest impact (centrality = 0.44). The centrality of most institutions is < 0.1, and Central South University and Texas MD Anderson Cancer Center possess the highest average citation rates of 3.25 and 2.87. BMC cancer has the highest average citation rate of 3.26 in 772 journals. Four authors (Picci P, Gorlick R, Bielack SS and Bacci G) made the best contributions. We also identified eight hotspots and collected 41 clinical trials related to drug research on osteosarcoma. CONCLUSIONS: The urgent need exists to strengthen global academic exchanges. Overcoming multidrug resistance in osteosarcoma is the focus of past, present and future investigations. Transformation of the metastasis pattern, microenvironment genetics mechanism, alternative methods of systemic chemotherapy and exploration of traditional Chinese medicine is expected to contribute to a new upsurge of research.

Fecal and Serum Metabolomic Signatures and Microbial Community Profiling of Postmenopausal Osteoporosis Mice Model.

Background: Multiple studies have shown that an imbalance in the intestinal microbiota is related to bone metabolism, but the role of the intestinal microbiota in postmenopausal osteoporosis remains to be elucidated. We explored the effect of the intestinal microbiota on osteoporosis. Methods: We constructed a postmenopausal osteoporosis mouse model, and Micro CT was used to observe changes in bone structure. Then, we identified the abundance of intestinal microbiota by 16S RNA sequencing and found that the ratio of Firmicutes and Bacteroidetes increased significantly. UHPLC-MS analysis was further used to analyze changes in metabolites in feces and serum. Results: We identified 53 upregulated and 61 downregulated metabolites in feces and 2 upregulated and 22 downregulated metabolites in serum under OP conditions, and interestedly, one group of bile acids showed significant differences in the OP and control groups. Network analysis also found that these bile acids had a strong relationship with the same family, Eggerthellaceae. Random forest analysis confirmed the effectiveness of the serum and fecal models in distinguishing the OP group from the control group. Conclusions: These results indicated that changes in the gut microbiota and metabolites in feces and serum were responsible for the occurrence and development of postmenopausal osteoporosis. The gut microbiota is a vital inducer of osteoporosis and could regulate the pathogenesis process through the "microbiota-gut-metabolite-bone" axis, and some components of this axis are potential biomarkers, providing a new entry point for the future study on the pathogenesis of postmenopausal osteoporosis.

Septin4 regulates endoplasmic reticulum stress and apoptosis in melatonin­induced osteoblasts.

Idiopathic scoliosis (IS) is a spinal 3­dimensional deformity with an unknown cause. Melatonin is secreted by the pineal body and contributes to the occurrence and progression of IS. In our previous preliminary study, it was reported that high concentrations of melatonin can induce osteoblast apoptosis, thus acting as an IS treatment, but the mechanism of action is unknown. Therefore, the present study was performed to further investigate the possible mechanism underlying the efficacy of melatonin as a treatment for IS. The present results indicated that high concentrations of melatonin mediate endoplasmic reticulum stress (ERS)­induced apoptosis in hFOB 1.19 cells, and this resulted in a significant and dose­dependent increase in the expression of Septin4, as well as the expression levels of glucose­regulated protein (GRP)78, GRP94 and cleaved caspase­3. Furthermore, osteoblasts were overexpressed with Septin4 and the mechanism via which melatonin induces osteoblast ERS was demonstrated to be via the regulation of Septin4. In addition, it was indicated that cytoskeleton destruction, cell morphology changes and the decrease in the number of cells were aggravated after osteoblasts were overexpressed with Septin4, as indicated by phalloidin and DAPI staining. Collectively, the present results suggest that the Septin4 protein may be a target of ERS in melatonin­induced osteoblast apoptosis, which is involved in bone metabolism diseases, thus providing novel evidence for clinical melatonin treatment of IS.

Protective Role of Melatonin Against Postmenopausal Bone Loss via Enhancement of Citrate Secretion From Osteoblasts.

A negative correlation exists between the severity of osteoporosis and citrate levels in bone. Our previous research found that melatonin can significantly improve bone mass in mice with osteoporosis, but the underlying mechanism involving citrate remains unknown. Herein, we demonstrated that melatonin increased bone volume and citrate levels in ovariectomized osteoporosis mice. Melatonin increased citrate and mineralized nodules in osteoblasts induced from primary mouse bone marrow mesenchymal stem cells in vitro. ZIP-1 knockdown and overexpression confirmed that melatonin specifically upregulated ZIP-1 to rescue citrate levels and bone mass. In general, we verified that melatonin can improve bone mass by enhancing matrix mineralization, which is highly related to increased citrate secretion from osteoblasts, and that ZIP-1 is the target of melatonin. These findings reveal another role of melatonin in regulating bone remodeling and provide a research base for its possible application in the treatment of clinical osteoporosis in the future.

Pycnogenol achieves neuroprotective effects in rats with spinal cord injury by stabilizing the mitochondrial membrane potential.

OBJECTIVES: In this study, we aimed to verify the neuroprotective effects of pycnogenol (PYC) on spinal cord injury (SCI) and to determine the underlying mechanisms. METHODS: Male Wistar rats were selected to establish a model of SCI in accordance with the Allen's protocol. The rats in the PYC group were treated with 100 mg/kg PYC by intraperitoneal injection 15 minutes after SCI. The Basso, Beattie and Bresnahan (BBB) scale was used to evaluate locomotor activity. The superoxide dismutase (SOD) activity and malondialdehyde (MDA) production were detected by ELISA. The expression of Cleaved-caspase 3, Bcl-2, Bax and the levels of Cytochrome c (Cyt-c) were analysed by Western blot or Immunohistochemistry. Furthermore, we used the JC-1 fluorescent probe to analyse the mitochondrial membrane potential (ΔΨm). RESULTS: The rats that received PYC had significantly higher BBB scores than the control lesion rats. PYC treatment resulted in reduced bleeding in spinal cord tissue and proliferation of glial cells, greater numbers of anterior horn neurons, more complete structures of residual neurons, and significant improvement in Nissl body morphology. In addition, PYC reduced MDA production and increased SOD activity. The mitochondrial membrane potential (MMP) was significantly increased in the PYC treatment group compared with the SCI group. In addition, PYC decreased the expression of Cleaved-caspase 3 and Bax and the release of Cyt-c and increased the expression of Bcl-2 in the SCI rats. CONCLUSIONS: The above findings suggested that PYC can improve motor function and reduce neuronal apoptosis after SCI by stabilizing the MMP through the inhibition of oxidative stress. ABBREVIATIONS: DMSO: dimethyl sulfoxide; IHC: immunological histological chemistry; MDA: malondialdehyde; PBS: phosphate buffered saline; PMSF: phenylmethanesulfonyl fluoride; PVDF: polyvinylidene difluoride; PYC: Pycnogenol; RIPA: radio immunoprecipitation assay; SCI: spinal cord injury; SOD: superoxide dismutase.

COVID-19 will stimulate a new coronavirus research breakthrough: a 20-year bibliometric analysis.

BACKGROUND: COVID-19 is currently rampant in China, causing unpredictable harm to humans. This study aimed to quantitatively and qualitatively investigate the research trends on coronaviruses using bibliometric analysis to identify new prevention strategies. METHODS: All relevant publications on coronaviruses were extracted from 2000-2020 from the Web of Science database. An online analysis platform of literature metrology, bibliographic item co-occurrence matrix builder (BICOMB) and CiteSpace software were used to analyse the publication trends. VOSviewer was used to analyse the keywords and research hotspots and compare COVID-19 information with SARS and MERS information. RESULTS: We found a total of 9,760 publications related to coronaviruses published from 2000 to 2020. The Journal of Virology has been the most popular journal in this field over the past 20 years. The United States maintained a top position worldwide and has provided a pivotal influence, followed by China. Among all the institutions, the University of Hong Kong was regarded as a leader for research collaboration. Moreover, Professors Yuen KY and Peiris JSM made great achievements in coronavirus research. We analysed the keywords and identified 5 coronavirus research hotspot clusters. CONCLUSIONS: We considered the publication information regarding different countries, institutions, authors, journals, etc. by summarizing the literature on coronaviruses over the past 20 years. We analysed the studies on COVID-19 and the SARS and MERS coronaviruses. Notably, COVID-19 must become the research hotspot of coronavirus research, and clinical research on COVID-19 may be the key to defeating this epidemic.

The publication trends and hot spots of scoliosis research from 2009 to 2018: a 10-year bibliometric analysis.

BACKGROUND: This study aims to quantitatively and qualitatively investigate the trends in scoliosis research and evaluate research hotspots using bibliometric analysis. METHODS: All relevant publications on scoliosis from the period from 2009 to 2018 were extracted from the Web of Science and PubMed databases. Publication trends were analyzed using an Online analysis platform of literature metrology, Bibliographic Item Co-occurrence Matrix Builder (BICOMB), and CiteSpace software. Hotspots were analyzed and visualized using the gCLUTO software package. RESULTS: A total of 7,445 scoliosis research publications dated between 2009 and 2018 were found. The spine was the most popular journal in this field during this period. The United States maintained a top position in global scoliosis research throughout the 10 years and has had a pivotal influence, followed by China and Canada. Among all institutions, the University of California, San Francisco, was a leader in research collaboration. At the same time, Professors Yong Qiu and Lawrence G. Lenke made great achievements in scoliosis research. We analyzed the major Medical Subject Headings (MeSH) terms/MeSH subheadings and identified eight hotspots in scoliosis research. CONCLUSIONS: We summarized the publication information of scoliosis-related literature in the 10 years from 2009 to 2018, including country and institution of origin, authors, and publication journal. We analyzed former research hotspots in the field of scoliosis and predicted future areas of interest. The development of various new orthopedic plants, artificial intelligence diagnosis, and genetic research will be future hotspots in scoliosis research.

Pyroptosis in Osteoblasts: A Novel Hypothesis Underlying the Pathogenesis of Osteoporosis.

Osteoporosis has become a worldwide disease characterized by a reduction in bone mineral density and the alteration of bone architecture leading to an increased risk of fragility fractures. And an increasing number of studies have indicated that osteoblasts undergo a large number of programmed death events by many different causes in osteoporosis and release NLRP3 and interleukin (e.g., inflammatory factors), which play pivotal roles in contributing to excessive differentiation of osteoclasts and result in exaggerated bone resorption. NLRP3 is activated during pyroptosis and processes the precursors of IL-1ß and IL-18 into mature forms, which are released into the extracellular milieu accompanied by cell rupture. All of these compounds are the classical factors of pyroptosis. The cellular effects of pyroptosis are commonly observed in osteoporosis. Although many previous studies have focused on the pathogenesis of these inflammatory factors in osteoporosis, pyroptosis has not been previously evaluated. In this review, pyroptosis is proposed as a novel hypothesis of osteoporosis pathogenesis for the first time, thus providing a new direction for the treatment of osteoporosis in the future.