Pretargeted radiotherapy and synergistic treatment of metastatic, castration-resistant prostate cancer using cross-linked, PSMA-targeted lipoic acid nanoparticles.

Metastatic castration-resistant prostate cancer (CRPC) is a currently incurable disease associated with high mortality. Novel therapeutic approaches for CRPC are urgently needed to improve prognosis. In this study, we developed cross-linked, PSMA-targeted lipoic acid nanoparticles (cPLANPs), which can interact with transmembrane glycoprotein to accumulate inside prostate cancer cells, where they upregulate caspase-3, downregulate anti-apoptotic B-cell lymphoma-2 (BCL-2), and thereby induce apoptosis. The trans-cyclooctene (TCO) decoration on cPLANPs acts as a bioorthogonal handle allowing pretargeted single-photon emission computed tomography and radiotherapy, which revealed significantly enhanced tumor accumulation and minimal off-target toxicity in our experiments. The developed strategy showed a strong synergistic anti-cancer effect in vivo, with a tumor inhibition rate of up to 95.6% after 14 days of treatment. Our results suggest the potential of combining bioorthogonal pretargeted radiotherapy with suitable PSMA-targeted nanoparticles for the treatment of metastatic CRPC.

A bioorthogonal cell sorting strategy for isolation of desired cell phenotypes.

Here we describe a cost-effective and simplified cell sorting method using tetrazine bioorthogonal chemistry. We successfully isolated SKOV3 cells from complex mixtures, demonstrating efficacy in separating mouse lymphocytes expressing interferon and HeLa cells expressing virally transduced green fluorescent protein post-infection.

Trehalose improves palmitic acid-induced apoptosis of osteoblasts by regulating SIRT3-medicated autophagy via the AMPK/mTOR/ULK1 pathway.

Accumulation of lipid substances decreased the activity of osteoblasts. Trehalose is a typical stress metabolite to form a protective membrane on cell surface which has been demonstrated to regulate lipid metabolism. This activity of Trehalose indicates the potential effect of osteoporosis treatment. Our study aimed to determine the therapeutic effect of Trehalose in high fat-induced osteoporosis. We used palmitic acid (PA) to mimic the state of high fat and observed the apoptosis ratio of osteoblasts increased. After adding Trehalose, the apoptosis ratio decreased obviously. Autophagy is a regulatory means involved in the process of apoptosis. We detected the autophagy protein and found that the expression of Beclin-1, Atg5, and LC3 II increased, and p62 decreased after Trehalose treatment. When adding an autophagy inhibitor (3-MA), the expression of Beclin-1, Atg5, and LC3 II decreased, and p62 increased. These results indicated autophagy was an important factor involved in the preventive effect of Trehalose in PA-induced apoptosis. SIRT3 is a mitochondrial gene that can inhibit apoptosis, which has been reported to promote autophagy. We used SIRT3-siRNA to silence the expression of SIRT3 and found the effect of Trehalose was counteracted. The apoptosis ratio increased and the expression of Beclin-1, Atg5, and LC3 II decreased, p62 increased. Additionally, we also fed the mice with a high-fat diet (HFD) and intragastrical Trehalose. The results showed that Trehalose could inhibit the bone mass loss with HFD. Our study revealed the effect and mechanism of Trehalose in the treatment of osteoporosis.

Tuning the Physicochemical Properties of BODIPY for Bioimaging via meso-Amino Acylation.

A series of BODIPY probes with a wide emission range were prepared via aminoacylation at the meso-position. Functional moieties were also introduced to induce bathochromic shifts in emission, improve water solubility, increase Stokes shifts, and construct bioorthogonal turn-on probes. The developed analogues were successfully used in live-cell imaging, suggesting that the described strategy can be used to prepare probes with improved bioimaging potential.

Melatonin Mediates Osteoblast Proliferation Through the STIM1/ORAI1 Pathway.

Based on the positive correlation between bone mineral density and melatonin levels in blood, this study confirmed that melatonin supplementation prevents postmenopausal osteoporosis. We further confirmed that melatonin promotes an increase in intracellular calcium concentrations through the STIM1/ORAI1 pathway, thereby inducing the proliferation of osteoblasts. Introduction: Osteoporosis (OP) is a progressive, systemic bone disease that is one of the main causes of disability and death in elderly female patients. As an amine hormone produced by the human pineal gland, melatonin plays an important role in regulating bone metabolism. This study intends to investigate the relationship between melatonin levels in human blood and bone density and to suggest the efficacy of melatonin in treating osteoporosis by performing in vivo and in vitro experiments. Methods: We used liquid chromatography-tandem mass spectrometry to determine the serum melatonin levels in postmenopausal women with osteoporosis and young women with a normal bone mass. The bone density, BV/TV, Tb.Th, Tb.Sp and other indicators of postmenopausal osteoporosis and mice with a normal bone mass were detected by measuring bone density and micro-CT. The intracellular calcium ion concentration was detected using fluorescence microscopy and a full-wavelength multifunctional microplate reader, and the expression of SOCE-related genes and STIM1/ORAI1 proteins was detected using PCR and WB. Results: This study confirmed that bone density positively correlates with the melatonin level in human blood. In the animal model, melatonin supplementation reverses postmenopausal osteoporosis. We explored the internal mechanism of melatonin treatment of osteoporosis. Melatonin promotes an increase in intracellular calcium ion concentrations through the STIM1/ORAI1 pathway to induce osteoblast proliferation. Conclusions: This study provides an important theoretical basis for the clinical application of melatonin in patients with osteoporosis and helps to optimize the diagnosis and treatment of postmenopausal osteoporosis.

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.

Metformin attenuates H2O2-induced osteoblast apoptosis by regulating SIRT3 via the PI3K/AKT pathway.

Osteoporosis is a common metabolic disease that has a high incidence in postmenopausal women. Studies have indicated that oxidative damage plays an important role in the development of postmenopausal osteoporosis. Metformin has been showed to have the ability to relieve excessive oxidation. The aim of the present was to determine the therapeutic effect and potential mechanism of metformin in postmenopausal osteoporosis. Oxidative damage was stimulated in vitro by the addition of H2O2 to MC3T3-E1 cells and a mouse menopausal model was also constructed. Cell viability and flow cytometry experiments were performed to determine the effects of H2O2 and metformin treatment on apoptosis. Mitochondrial membrane potential was tested by JC-1 assays. Western blotting was used to detect the expression of mitochondrial apoptosis markers and antioxidant enzymes. Small interfering RNA was used to knockdown sirtuin3 (SIRT3), which was verified at the mRNA and protein levels. Bilateral ovariectomy was used to prepare menopausal mice, which were analyzed using micro-computed tomography. The results indicated that metformin is able to repair mitochondrial damage and inhibit the apoptosis of osteoblasts induced by H2O2, and also reverse bone mass loss in ovariectomized mice. Western blotting results demonstrated the involvement of SIRT3 in the production of antioxidant enzymes that are essential in protecting against mitochondrial injury. In addition, experiments with SIRT3 knockdown indicated that metformin reverses H2O2-induced osteoblast apoptosis by upregulating the expression of SIRT3 via the PI3K/AKT pathway. The results of the present reveal the pathogenesis of oxidative damage and the therapeutic effect of metformin in postmenopausal osteoporosis. They also suggest that SIRT3 is a potential drug target in the treatment of osteoporosis, with metformin being a candidate drug for modification and/or clinical application.

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.

Investigating Research Hotspots and Publication Trends of Spinal Stenosis: A Bibliometric Analysis During 2000-2018.

Spinal stenosis is a common disease affecting the elderly that is present in a various forms. Its high incidence forces researchers to pay more attention and offer countermeasures. We used the Web of Science Core collection and PubMed database to obtain 5,606 scientific studies concerning spinal stenosis, and the number of publications maintained a roughly increasing trend from 108 in 2000 to 512 in 2018, only declining in 2011. Bibliometric analysis was conducted using the online analysis software CiteSpace and Bibliographic Item Co-Occurrence Matrix Builder (BICOMB). The United States maintains academic leadership in this field. The journal SPINE was the most authoritative, with 695 articles and an average of 12.73 citations. The exported major MeSH terms were further biclustered with gCLUTO according to co-word analysis to reveal research hotspots, including etiology, pathogenesis, clinical manifestation, conservative treatment, operative indication, internal implantation, and postoperative complications. After combination, the main topics focused on pathogenesis and surgical treatment. Narrowing causes flavum ligamentum hypertrophy, and posterior longitudinal ligament ossification is widely accepted. Additionally, minimally invasive surgery and internal implantation fixation are more valid in the clinic. Refining pathological classification and optimizing surgical methods and instrument properties will be important future research directions for spinal stenosis.

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.

Research hotspots and trends analysis of ankylosing spondylitis: a bibliometric and scientometric analysis from 2009 to 2018.

BACKGROUND: This study utilized bibliometric analysis to qualitatively and quantitatively analyze hotspots and predict trends in the field of ankylosing spondylitis (AS) research. METHODS: Articles about AS were obtained from the Web of Science Core Collection and PubMed database, and bibliometric analysis was carried out through CiteSpace and the Online Analysis Platform of Literature Metrology and Bibliographic Item Co-Occurrence Matrix Builder (BICOMB). Then, co-word biclustering analysis was conducted to obtain research hotspots and predict trends using gCLUTO software. RESULTS: A total of 6,818 articles on AS from 2009 to 2018 were analyzed, showing an increasing publication trend (558 articles in 2009 to 851 articles in 2018). The Journal of Rheumatology was the leading journal in AS research, with an impact factor (IF) of 3.634 and H-index value of 49. In terms of region, the United States led the world in this field, and The University of Toronto was the leading institution for AS research. Van Der Heijde, D was the most prolific author in the field. Eight research hotspots in the field of AS were also identified. CONCLUSIONS: Our analysis identified eight research hotspots, and predicted that surgical treatment and etiology will be the main AS research trends in the future. This study provides new directions and ideas for future research in AS.

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.

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.

Mapping theme trends and recognizing hot spots in postmenopausal osteoporosis research: a bibliometric analysis.

BACKGROUND: This study aimed to draw a series of scientific maps to quantitatively and qualitatively evaluate hot spots and trends in postmenopausal osteoporosis research using bibliometric analysis. METHODS: Scientific papers published on postmenopausal osteoporosis were extracted from the Web of Science Core Collection and PubMed database. Extracted information was analyzed quantitatively with bibliometric analysis by CiteSpace, the Online Analysis Platform of Literature Metrology and Bibliographic Item Co-Occurrence Matrix Builder (BICOMB). To explore the hot spots in this field, co-word biclustering analysis was conducted by gCLUTO based on the major MeSH terms/MeSH subheading terms-source literatures matrix. RESULTS: We identified that a total of 5,247 publications related to postmenopausal osteoporosis were published between 2013 and 2017. The overall trend decreased from 1,071 literatures in 2013 to 1,048 literatures in 2017. Osteoporosis International is the leading journal in the field of postmenopausal osteoporosis research, both in terms of impact factor score (3.819) and H-index value (157). The United States has retained a top position and has exerted a pivotal influence in this field. The University of California, San Francisco was identified as a leading institution for research collaboration, and Professors Reginster and Kanis have made great achievements in this area. Eight research hot spots were identified. CONCLUSIONS: Our study found that in the past few years, the etiology and drug treatment of postmenopausal osteoporosis have been research hot spots. They provide a basis for the study of the pathogenesis of osteoporosis and guidelines for the drug treatment of osteoporosis.