Resveratrol-enhanced SIRT1-mediated osteogenesis in porous endplates attenuates low back pain and anxiety behaviors.

Low back pain (LBP) is a major clinical problem that lacks effective treatments. The sensory innervation in porous vertebral endplates and anxiety contributes to spinal hyperalgesia. We hypothesized that SIRT1 activator resveratrol alleviates LBP and anxiety via promotion of osteogenesis in the porous endplates. The hyperalgesia and anxiety-related behaviors; sensory innervation, inflammation and porosity of endplates; and osteogenic/osteoclastic factors expression were measured following resveratrol treatment after lumbar spine instability (LSI) surgery. To explore whether resveratrol promotes endplates osteogenesis and thus alleviates LBP through activation of SIRT1 in the osteoprogenitor cells of endplates, SIRT1OSX-/- mice were employed. Additionally, the levels of inflammation markers, phosphorylation of cAMP response element-binding protein (pCREB), and brain-derived neurotrophic factor (BDNF) in hippocampus were evaluated. After 4 or 8 weeks LSI surgery, the mice suffered from hyperalgesia and anxiety, which were efficiently attenuated by resveratrol at 8 weeks. Resveratrol treatment-enhanced osteogenesis and decreased endplates porosities accompanied with the reduction of TNFα, IL-1ß, and COX2 levels and CGRP+ nerve fibers innervation in porous endplates. Resveratrol-mediated endplates osteogenesis, decreased endplates porosities, and analgesic and antianxiety effects were abrogated in SIRT1OSX-/- mice. Furthermore, resveratrol relieved inflammation and increased pCREB and BDNF expression in the hippocampus after 8 weeks, which alleviate anxiety-related behaviors. This study provides that resveratrol-mediated porous endplates osteogenesis via the activation of SIRT1 markedly blocked sensory innervation and inflammation in endplates, therefore, alleviating LSI surgery-induced LBP and hippocampus-related anxiety.

Protection against peripheral artery disease injury by Ruan Jian Qing Mai formula via metabolic programming.

Ruan Jian Qing Mai formula (RJQM), a multicomponent herbal formula, has been widely used to treat peripheral arterial disease (PAD) in China. However, its active compounds and mechanisms of action are still unknown. First, RNA sequencing analysis of 15 healthy and 16 PAD samples showed that 524 PAD differential genes were significantly enriched in Go Ontology (ribonucleotide metabolic process, oxidoreductase complex, and electron transfer activity), Kyoto Encyclopedia of Genes and Genomes (KEGG) and GSEA pathways (OXPHOS and TCA cycle), miRNA (MIR183), and kinase (PAK6). Fifty-three active ingredients in RJQM had similar structures to the seven drug molecules in CLUE. Then, network topology analysis of the 53 components-target-pathway-disease network yielded 10 active ingredients. Finally, computational toxicity estimations showed that the median lethal dose (LD50) of the 10 active ingredients was above 1000 mg/kg, and eight of them did not cause hepatotoxicity, mutagenicity, carcinogenicity, cytotoxicity, and immunotoxicity nor activate 12 toxic pathways. In conclusion, RJQM has a protection effect on PAD by regulating a complex molecular network. Part of the mechanism is associated with the regulation of OXPHOS by 10 active components, which may alleviate mitochondrial dysfunction and pathological metabolic programming.

Daphnetin ameliorates glucocorticoid-induced osteoporosis via activation of Wnt/GSK-3ß/ß-catenin signaling.

Glucocorticoids have been widely used in multiple inflammatory and autoimmune diseases. However, long-term glucocorticoid therapy may result in osteoporosis. The present study aimed to evaluate the potential therapeutic effects and investigate the underlying mechanisms of Daphnetin (Daph) on glucocorticoid-induced osteoporosis (GIOP). In vivo, male Sprague Dawley rats were intramuscularly injected with dexamethasone (DEX) to induce GIOP and Daph was given intraperitoneally. Bone histological changes, mineral content, microstructure parameters and bone turnover markers were detected. Gut microbiota composition and intestinal barrier function were further assessed. In vitro, MC3T3-E1 pre-osteoblasts were treated with DEX and the abilities of Daph on osteoblast proliferation, differentiation and mineralization were assessed. A Wnt signaling inhibitor, XAV939, was added additionally to evaluate the effect of Daph on Wnt signaling. The results showed that in vivo, Daph increased the DEX-induced reduction in body weight gain, bone mineral content and microstructure parameters and restored the levels of bone turnover markers in GIOP rats. In vitro, Daph promoted osteoblast proliferation, differentiation and mineralization in DEX-treated MC3T3-E1 pre-osteoblasts. Moreover, Daph activated the Wnt/GSK-3ß/ß-catenin signaling pathway. XAV939 successfully abolished the beneficial effects of Daph on GIOP in vitro. Besides, Daph showed improvement on gut microbiota disorder and intestinal barrier dysfunction post GIOP. Collectively, these data demonstrated that Daph effectively ameliorates GIOP and the possible mechanism may be that Daph activated Wnt/GSK-3ß/ß-catenin signaling.

Osteoblasts support megakaryopoiesis through production of interleukin-9.

Severe thrombocytopenia is a significant challenge in patients undergoing myelosuppressive chemotherapy for malignancies. Understanding the biology of platelet-producing megakaryocytes development in the bone marrow microenvironment may facilitate the development of novel therapies to stimulate platelet production and prevent thrombocytopenia. We report here that osteoblasts supported megakaryopoiesis by secreting interleukin-9 (IL-9), which stimulated IL-9 receptor (IL-9R)/Stat3 signaling in promoting megakaryopoiesis. IL-9 production in osteoblasts was negatively regulated by the mechanistic target of rapamycin complex 1 (mTORC1) signaling in a NF-κB-dependent manner. Constitutive activation of mTORC1 inhibited IL-9 production in osteoblasts and suppressed megakaryocytic cells expansion, whereas mTORC1 inactivation increased IL-9 production and enhanced megakaryocyte and platelet numbers in mice. In mouse models, we showed that IL-9 administration stimulated megakaryopoiesis, whereas neutralizing endogenous IL-9 or IL-9R depletion inhibited the process. Importantly, we found that low doses of IL-9 efficiently prevented chemotherapy-induced thrombocytopenia (CIT) and accelerated platelet recovery after CIT. These data indicate that IL-9 is an essential regulator of megakaryopoiesis and a promising therapeutic agent for treatment of thrombocytopenia such as CIT.

mTORC1 Prevents Preosteoblast Differentiation through the Notch Signaling Pathway.

The mechanistic target of rapamycin (mTOR) integrates both intracellular and extracellular signals to regulate cell growth and metabolism. However, the role of mTOR signaling in osteoblast differentiation and bone formation is undefined, and the underlying mechanisms have not been elucidated. Here, we report that activation of mTOR complex 1 (mTORC1) is required for preosteoblast proliferation; however, inactivation of mTORC1 is essential for their differentiation and maturation. Inhibition of mTORC1 prevented preosteoblast proliferation, but enhanced their differentiation in vitro and in mice. Activation of mTORC1 by deletion of tuberous sclerosis 1 (Tsc1) in preosteoblasts produced immature woven bone in mice due to excess proliferation but impaired differentiation and maturation of the cells. The mTORC1-specific inhibitor, rapamycin, restored these in vitro and in vivo phenotypic changes. Mechanistically, mTORC1 prevented osteoblast maturation through activation of the STAT3/p63/Jagged/Notch pathway and downregulation of Runx2. Preosteoblasts with hyperactive mTORC1 reacquired the capacity to fully differentiate and maturate when subjected to inhibition of the Notch pathway. Together, these findings identified the role of mTORC1 in osteoblast formation and established that mTORC1 prevents preosteoblast differentiation and maturation through activation of the Notch pathway.

Effect of nitrate addition on reductive transformation of pentachlorophenol in paddy soil in relation to iron(III) reduction.

Reductive dechlorination is a crucial pathway for anaerobic biodegradation of highly chlorinated organic contaminants. Under an anoxic environment, reductive dechlorination of organic contaminants can be affected by many redox processes such as nitrate reduction and iron reduction. In the present study, batch incubation experiments were conducted to investigate the effect of nitrate addition on reductive dechlorination of PCP in paddy soil with consideration of iron transformation. Study results demonstrate that low concentrations (0, 0.5 and 1 mM) of nitrate addition can enhance the reductive dechlorination of PCP and Fe(III) reduction, while high concentrations (5, 10, 20 and 30 mM) of nitrate addition caused the contrary. Significant positive correlations between PCP degradation rates and the formation rates of dissolved Fe(II) (pearson correlation coefficients r = 0.965) and HCl-extractable Fe(II) (r = 0.921) suggested that Fe(III) reduction may enhance PCP dechlorination. Furthermore, consistent variation trends of PCP degradation and the abundances of the genus Comamonas, capable of Fe(III) reduction coupled to reductive dechlorination, and of the genus Dehalobacter indicated the occurrence of microbial community variation induced by nitrate addition as a response to PCP dechlorination.

The impact of enhancing publicity and commemoration of body donors at Zhengzhou University, China.

As a fundamental subject of medical education, human anatomy plays a critical role in the development of medical science. However, because of multiple factors including cultural conservativism and limited social understanding, China is facing a particularly severe shortage of bodies donated for anatomy education. Zhengzhou University (ZZU) has continued to uphold whole-body dissection as the preferred method for medical students to learn anatomy. For this study, records of registered individuals (who have signed a body donation agreement) and donors (whose bodies have been received) from 2001 to 2020 were collected and analyzed. The aim of this study was to explore the factors influencing the body donation program (BDP) at ZZU, and then reinforce the social understanding for the BDP. The results showed a significant increase in the numbers of both registered individuals and donors since 2015, which is the year the publicity and commemoration in honor of donors were increased. There were no significant differences between the biological male and female sexes in the registered individuals, but the number of male donors (12.85 ± 10.86, per year) was significantly higher than that of female donors (4.75 ± 4.53, per year). The current donor profile at ZZU is male in his 60/70s, while the profile of registered individuals is male or female in their 60s. Strengthening the publicity and commemoration in honor of donors may contribute to the implementation of BDPs.

Cervical microendoscopic laminoplasty-induced clinical resolution of disc herniation in patients with single- to three-level myelopathy.

This study aimed to explore the effects on resorption of cervical disc herniation (CDH) and clinical outcomes of surgery. Cervical microendoscopic laminoplasty (CMEL), which is commonly preferable to anterior corpectomy and fusion, was applied to patients with 1- to 3-level degenerative cervical myelopathy (DCM). DCM patients with 1-3 levels DCM underwent either conservation treatment or CMEL. In conservation-treated patients (53 cases), CDH volume remained unchanged with no improvement in JOA and VAS scores. Conversely, 63 patients with 1-3 levels DCM were prospectively enrolled and exhibited a profound decrease in CDH volume: 89.1% of CDHs (123/138) regressed over 10%, 64.5% of CDHs (89/138) regressed over 25%, while 27.5% and 6.5% of CDHs (38/138 and 9/138) largely regressed over 50% and 75%, respectively. Meanwhile, the JOA and VAS scores were improved in different ways. Intriguingly, CDH volume changes correlated significantly with elevations in JOA scores, indicating an association of clinical CDH resolution with neurological recovery. We showed that CMEL induced clinically related diminishment of CDH and alleviation of clinical symptoms in patients with 1- to 3-level myelopathy and that it could help avoid anterior dissection of the disc to some extent.

Volumetric Changes in Cervical Disc Herniation: Comparison of Cervical Expansive Open-door Laminoplasty and Cervical Microendoscopic Laminoplasty.

STUDY DESIGN: Retrospective study on 185 patients with 490 cervical disc herniation (CDH). OBJECTIVE: The aim of this study was to compare the changes in volumes of CDH in patients with degenerative cervical myelopathy (DCM) surgically treated by expansive open-door laminoplasty (EOLP) or cervical microendoscopic laminoplasty (CMEL). SUMMARY OF BACKGROUND DATA: Spontaneous resorption of CDH was shown in patients with DCM after conservation treatment, but very few in surgically treated patients. Our previous study identified the clinical efficiency of CMEL to treat DCM but how CDH sized postoperatively, as well as comparing to EOLP, was unknown. METHODS: Consecutive patients with DCM from December 2015 to December 2019, who underwent MRI evaluation, receiving CMEL or EOLP, and repeat MRI in follow-up were included. The volume of CDH were monitored using the picture archiving and communication system, further calculating the incidence of CDH with volume regression and the percentage changes of CDH volume. The correlations of possible determines with CDH volume changes were analyzed by Spearman rank correlation coefficient. RESULTS: A total of 89 patients (215 CDHs, EOLP-group) and 96 patients (275 CDHs, CMEL-group) was surveyed, respectively. Resultantly, volume of CDH was decreased postoperatively in both EOLP and CMEL cases. But this CDH volume regression was more profound in CMEL groups (incidence of 81.2% from 223/275, median volume change ratio of -26.7%, occurring from 1 month after CMEL), statistically different from EOLP group (50.2% from 108/215, median volume change ratio of -5.4%, none-appearance within 1 month). Patients information as sex, age, and follow-up time, not CDH significant, was significantly correlated with CDH volume changes. CONCLUSION: Patients who underwent CMEL developed a postoperative reduction of CDH volume, with more popularity, greater degree and earlier-staged than EOLP-patients. Young females with longer follow-up time were more likely occur.Level of Evidence: 4.

Accumulation Mechanism and Risk Assessment of Artemisia selengensis Seedling In Vitro with the Hydroponic Culture under Cadmium Pressure.

Artemisia selengensis is a perennial herb of the Compositae with therapeutic and economic value in China. The cadmium (Cd) accumulation mechanism and healthy risk evaluation of A. selengensis were investigated in this study. Tissue culture seedlings were obtained by plant tissue culture in vitro, and the effect of Cd stress (Cd concentration of 0.5, 1, 5, 10, 25, 50 and 100 µM) on A. selengensis was studied under hydroponic conditions. The results showed that low-Cd (0.5-1 µM) stress caused a rare effect on the growth of A. selengensis seedlings, which regularly grew below the 10 µM Cd treatment concentration. The biomass growth rate of the 0.5, 1, and 5 µM treatment groups reached 105.8%, 96.6%, and 84.8% after 40 days of cultivation, respectively. In addition, when the concentration of Cd was greater than 10 µM, the plant growth was obviously inhibited, i.e., chlorosis of leaves, blackening roots, destroyed cell ultrastructure, and increased malondialdehyde (MDA) content. The root could be the main location of metal uptake, 57.8-70.8% of the Cd was concentrated in the root after 40 days of cultivation. Furthermore, the root cell wall was involved in the fixation of 49-71% Cd by subcellular extraction, and the involvement of the participating functional groups of the cell wall, such as -COOH, -OH, and -NH2, in metal uptake was assessed by FTIR analysis. Target hazard quotient (THQ) was used to assess the health risk of A. selengensis, and it was found that the edible part had no health risk only under low-Cd stress (0.5 to 1 µM) and short-term treatment (less than 20 days).

A New Automated AI-Assisted System to Assess Cervical Disc Herniation.

STUDY DESIGN: An algorithm was developed with MATLAB platform to automatically quantify the volume of cervical disc herniation (CDH) based on the sagittal magnetic resonance images. This automated program was used for CDH data set, and then compared with manual measurement results confirming its reliability. OBJECTIVE: The aim was to develop a new software for automated CDH volume measurement. SUMMARY OF BACKGROUND DATA: CDH compresses the spinal cord, regarding as the leading cause of cervical myelopathy. However, the CDH volume, of great value to clinical symptoms, can be only manually measured with no-excellent but acceptable interobserver reliability. This was due to the manual error of outlining CDH area and inclusion of structure posterior vertebra. No studies has proposed such an automated algorithm of CDH volume quantification which is standardised to quantify the accurate volume of CDH thus helping doctors easily evaluate CDH progressing. METHODS: The algorithm of CDH volume measurement was proposed. This program was then tested for 490 CDHs data set, from 185 patients with two repeated magnetic resonance imaging detections. Three individual observers manually measured the volumes of these CDHs, to justify the accuracy of this software. CDH volume was either in the classic way or the revised way excluding the influence of structure posterior vertebra. RESULTS: The automated software was successfully developed on MATLAB platform, with no difference found with manual measurements (average level) in CDH volume measurement. The change ratios in CDH volumes were profoundly consistent with manual observation, showing the error of 5.8% in median. The revised method elevated the absolute value of ratio by amplifying the percentage change. CONCLUSION: Our developed automated volumetry system was an standardized and accurate way, with selective removal module of structure posterior vertebra, replaceable for manual volume measurement of CDH, which was useful for spinal surgeons diagnosing and treating CDH disease.

Repair of bone defects in rhesus monkeys with α1,3-galactosyltransferase-knockout pig cancellous bone.

Introduction: Since xenografts offer a wide range of incomparable advantages, they can be a better option than allografts but only if the possibility of immunological rejection can be eliminated. In this study, we investigated the ability of α1,3-galactosyltransferase (α1,3-GT) gene knockout (GTKO) pig cancellous bone to promote the repair of a femoral condyle bone defect and its influence on heterologous immune rejection. Materials and methods: Cylindrical bone defects created in a rhesus monkey model were transplanted with GTKO bone, WT bone or left empty. For immunological evaluation, T lymphocyte subsets CD4+ and CD8+ in peripheral blood were assayed by flow cytometry, and the IL-2 and IFN-γ contents of peripheral blood serum were analyzed by ELISA at 2, 5, 7, 10, and 14 days post-surgery. Micro-CT scans and histological assessment were conducted at 4 and 8 weeks after implantation. Results: Compared with WT-pig bone, the heterologous immunogenicity of GTKO-pig bone was reduced. The defect filled with fresh GTKO-pig bone was tightly integrated with the graft. Histological analysis showed that GTKO-pig cancellous bone showed better osseointegration and an appropriate rate of resorption. Osteoblast phenotype progression in the GTKO group was not affected, which revealed that GTKO-pig bone could not only fill and maintain the bone defect, but also promote new bone formation. Conclusion: GTKO-pig cancellous bone decreased the ratio of CD4+ to CD8+ T cells and cytokines (IFN-γ and IL-2) to inhibit xenotransplant rejection. Moreover, GTKO group increased more bone formation by micro-CT analysis and osteoblastic markers (Runx2, OSX and OCN). Together, GTKO-pig cancellous bone showed better bone repair than WT-pig cancellous bone.

Primary Cilia as a Biomarker in Mesenchymal Stem Cells Senescence: Influencing Osteoblastic Differentiation Potency Associated with Hedgehog Signaling Regulation.

Bone tissue engineering-based therapy for bone lesions requires the expansion of seeding cells, such as autologous mesenchymal stem cells (MSCs). A major obstacle to this process is the loss of the phenotype and differentiation capacity of MSCs subjected to passage. Recent studies have suggested that primary cilia, primordial organelles that transduce multiple signals, particularly hedgehog signals, play a role in senescence. Therefore, we explored the relationships among senescence, primary cilia, and hedgehog signaling in MSCs. Ageing of MSCs by expansion in vitro was accompanied by increased cell doubling time. The osteogenic capacity of aged MSCs at passage 4 was compromised compared to that of primary cells. P4 MSCs exhibited reductions in the frequency and length of primary cilia associated with decreased intensity of Arl13b staining on cilia. Senescence also resulted in downregulation of the expression of hedgehog components and CDKN2A. Suppression of ciliogenesis reduced the gene expression of both Gli1, a key molecule in the hedgehog signaling pathway and ALP, a marker of osteoblastic differentiation. This study demonstrated that the senescence of MSCs induced the loss of osteoblastic differentiation potency and inactivated hedgehog signaling associated with attenuated ciliogenesis, indicating that primary cilia play a mediating role in and are biomarkers of MSC senescence; thus, future antisenescence strategies involving manipulation of primary cilia could be developed.

Blood eosinophils and mortality in patients with acute respiratory distress syndrome: A propensity score matching analysis.

BACKGROUND: The effect of blood eosinophils (EOSs) on mortality in acute respiratory distress syndrome (ARDS) patients and whether corticosteroids affect this effect are unclear. METHODS: The Medical Information Mart for Intensive Care III database (version 1.4) was used to extract data. Patients with ARDS were selected for inclusion. Cox regression models using the backward stepwise method and propensity score matching (PSM) were used to assess the relationship between blood EOS counts and 28-day mortality. RESULTS: A total of 2,567 patients with ARDS were included, and the 28-day mortality rate was 24.19%. The crude 28-day mortality was significantly lower in patients with EOS counts ≥2% (18.60% [85/457] vs. 25.40% [536/2,110], P=0.002) than in those with EOS counts <2%. In the Cox regression model, the EOS counts ≥2% showed a significant association with the decreased 28-day mortality (hazard ratio [HR] 0.731; 95% confidence interval [95% CI] 0.581-0.921, P=0.008). In the corticosteroid non-use subgroup, EOS counts ≥2% was significantly related to decreased 28-day mortality (HR 0.697, 95% CI 0.535-0.909, P=0.008), but the result was not significant in the corticosteroid non-use subgroup model (P=0.860). A total of 457 well-matched pairs were obtained by a 1:1 matching algorithm after PSM. The 28-day mortality remained significantly lower in the EOS counts ≥2% group (18.60% [85/457] vs. 26.70% [122/457], P=0.003). CONCLUSIONS: Higher EOS counts are related to lower 28-day mortality in ARDS patients, and this relationship can be counteracted by using corticosteroids.

Curcumin Modulates the Crosstalk Between Macrophages and Bone Mesenchymal Stem Cells to Ameliorate Osteogenesis.

Bone healing is thought to be influenced by the cross-talk between bone forming and immune cells. In particular, macrophages play a crucial role in the regulation of osteogenesis. Curcumin, the major bioactive polyphenolic ingredient of turmeric, has been shown to regulate inflammatory response and osteogenic activities. However, whether curcumin could regulate macrophage polarization and subsequently influence osteogenesis remain to be elucidated. In this study, the potential immunomodulatory capability of curcumin on inflammatory response and phenotype switch of macrophages and the subsequent impact on osteogenic differentiation of MSCs are investigated. We demonstrated that curcumin exhibited significant anti-inflammatory effect by polarizing the macrophages toward anti-inflammatory phenotype, with increased expression of IL-4, IL-10, and CD206, and decreased expression of IL-1ß, TNF-α, CCR7, and iNOS. In addition, curcumin could improve the osteo-immune microenvironment via promoting osteogenesis-related regenerative cytokine BMP-2 and TGF-ß production. Moreover, the co-cultured test of macrophages and BMSCs showed that curcumin-modulated macrophages conditioned medium could promote osteogenic differentiation of BMSCs with increased gene (ALP, Runx-2, OCN, and OPN) and protein (Runx-2 and OCN) expression levels, enhanced ALP activity, and obvious formation of mineralized nodules. Taken together, with the interaction between curcumin-conditioned macrophage and curcumin-stimulated BMSCs, curcumin could remarkably enhance the osteogenic differentiation of BMSCs in LPS-activated inflammatory macrophage-BMSCs coculture system.

Anagliptin stimulates osteoblastic cell differentiation and mineralization.

Osteoporosis is a common debilitating bone disease characterized by loss of bone mass and degradation of the bone architecture, which is primarily driven by dysregulated differentiation of mesenchymal stem cells into bone-producing osteoblasts. Osteoblasts contribute to bone formation by secreting various proteins that guide the deposition of bone extracellular matrix, such as alkaline phosphatase (ALP), osteocalcin (OCN), and osteopontin (OPN). The Wnt/ß-catenin pathway is widely recognized as a regulator of bone mass and is required to maintain bone homeostasis. Hormones have long been recognized as playing a key role in bone metabolism, and in recent years, growing evidence has shown that diabetes is a risk factor for osteoporosis. In the present study, we investigated the effects of the antidiabetic drug anagliptin on the differentiation and mineralization of osteoblasts induced by osteogenic medium. Anagliptin promotes insulin production via inhibition of dipeptidyl peptidase IV (DPP-4), an enzyme that targets the incretin hormone glucagon-like peptide 1 (GLP-1) for degradation. Our findings show that anagliptin significantly increases the differentiation of MSCs into osteoblasts via activation of RUNX2. Anagliptin significantly increased matrix deposition and mineralization by osteoblasts, as evidenced by elevated levels of ALP, OCN, OPN, and BMP-2. We further demonstrate that anagliptin activates the canonical and noncannonical Wnt signaling pathways and that silencing of Wnt/ß-catenin signaling completely abolished the effects of anagliptin. Thus, anagliptin might be a safe, effective therapy for type II diabetes that might show promise as a therapy against osteoporosis.

Protection against COVID-19 injury by qingfei paidu decoction via anti-viral, anti-inflammatory activity and metabolic programming.

Qingfei Paidu decoction (QFPD), a multi-component herbal formula, has been widely used to treat COVID-19 in China. However, its active compounds and mechanisms of action are still unknown. Firstly, we divided QFPD into five functional units (FUs) according to the compatibility theory of traditional Chinese medicine. The corresponding common targets of the five FUs were all significantly enriched in Go Ontology (oxidoreductase activity, lipid metabolic process, homeostatic process, etc.), KEGG pathways (steroid biosynthesis, PPAR signaling pathway, adipocytokine signaling pathway, etc.), TTD diseases (chronic inflammatory diseases, asthma, chronic obstructive pulmonary Disease, etc.), miRNA (MIR183), kinase (CDK7) and TF (LXR). QFPD contained 257 specific targets in addition to HCoV, pneumonia and ACE2 co-expression proteins. Then, network topology analysis of the five components-target-pathway-disease networks yielded 67 active ingredients. In addition, ADMET estimations showed that 20 compounds passed the stringent lead-like criteria and in silico drug-likeness test with high gastrointestinal absorption and the median lethal dose (LD50 > 1600 mg/kg). Moreover, 4 specific ingredients (M3, S1, X2 and O2) and 5 common ingredients (MS1, MX16, SX1, WO1 and XO1) of QFPD presented good molecular docking score for 2019-nCov structure and non-structure proteins. Finally, drug perturbation of COVID-19 network robustness showed that all five FUs may protect COVID-19 independently, and target 8 specifically expressed drug-attacked nodes which were related to the bacterial and viral responses, immune system, signaling transduction, etc. In conclusion, our new FUNP analysis showed that QFPD had a protection effect on COVID-19 by regulating a complex molecular network with safety and efficacy. Part of the mechanism was associated with the regulation of anti-viral, anti-inflammatory activity and metabolic programming.

Osteocyte TSC1 promotes sclerostin secretion to restrain osteogenesis in mice.

Osteocytes secrete the glycoprotein sclerostin to inhibit bone formation by osteoblasts, but how sclerostin production is regulated in osteocytes remains unclear. Here, we show that tuberous sclerosis complex 1 (TSC1) in osteocytes promotes sclerostin secretion through inhibition of mechanistic target of rapamycin complex 1 (mTORC1) and downregulation of Sirt1. We generated mice with DMP1-Cre-directed Tsc1 gene deletion ( Tsc1 CKO) to constitutively activate mTORC1 in osteocytes. Although osteocyte TSC1 disruption increased RANKL expression and osteoclast formation, it markedly reduced sclerostin production in bone, resulting in severe osteosclerosis with enhanced bone formation in mice. Knockdown of TSC1 activated mTORC1 and decreased sclerostin, while rapamycin inhibited mTORC1 and increased sclerostin mRNA and protein expression levels in MLO-Y4 osteocyte-like cells. Furthermore, mechanical loading activated mTORC1 and prevented sclerostin expression in osteocytes. Mechanistically, TSC1 promotes sclerostin production and prevents osteogenesis through inhibition of mTORC1 and downregulation of Sirt1, a repressor of the sclerostin gene Sost. Our findings reveal a role of TSC1/mTORC1 signalling in the regulation of osteocyte sclerostin secretion and bone formation in response to mechanical loading in vitro. Targeting TSC1 represents a potential strategy to increase osteogenesis and prevent bone loss-related diseases.

The modification and characterization of thermal-treated sericite by fluorosilicate.

In this article, the thermal-treated sericite was modified by both fluorosilicate and the combination of fluorosilicate and nitric acid in order to reduce its layer charge and gain cation exchange capabilities for the preparation of sericite/polymer nanocomposites. After several orthogonal experiments and single factor experiments, the optimal experimental conditions were set up and we found that the combination of nitric acid and fluorosilicate is much more effective than fluorosilicate alone. Chemical composition analysis showed Al3+ was dissolved out from sericite and the dissolving amount is 65 mg/g under optimal experimental conditions. Combining the NMR test, it is considered that the Si/Al ratio in the tetrasheet of the modified product increased from 3.48 to 10. The layer charge reduced and the CEC value increased after fluorosilicate modification, which means the modified sericite is a promising matrix for clay-polymer nanocomposites.

Stopping at Sacrum Versus Nonsacral Vertebra in Long Fusion Surgery for Adult Spinal Deformity: Meta-Analysis of Revision with Minimum 2-Year Follow-Up.

OBJECTIVE: A pooled comparison was conducted on a revision to the sacrum (S) versus a nonsacral (NS) surgical strategy in adult spinal deformity (ASD). METHODS: Strictly following the PRISMA 2009 guidelines, the MEDLINE, EMBASE, and Cochrane Library databases were used to search for studies published in English up to March 2018 that addressed the S versus NS surgical approach for a long fusion to treat ASD. Data on total revisions and revision reasons were extracted from the included studies and were pooled analyzed. RESULTS: Eight retrospective studies with a total of 1846 ASD patients (528 S and 1318 NS) were included. The total revision rate was 11.38% (S: 17.80% and NS: 8.80%), and implant failure, pseudarthrosis, adjacent segment degeneration, and proximal junctional kyphosis (PJK) were common reasons for revision. The pooled results indicated that the NS group had decreased incident rates of total revision (95% confidence interval [CI] 1.20-2.32, P = 0.002; I2 = 0%) and pseudarthrosis (95% CI 2.16-15.44, P = 0.0005; I2 = 0%) compared with the S group. No significant differences were observed in implant failure (95% CI 0.86-3.90, P = 0.12; I2 = 0%), adjacent segment degeneration (95% CI 0.08-1.25, P = 0.10; I2 = 0%), and PJK (95% CI 0.54-6.88, P = 0.35; I2 = 0%) between the 2 groups. CONCLUSIONS: Revision in ASD patients is a serious problem with a total rate of 11.38%, and implant failure, pseudarthrosis, adjacent segment degeneration, and PJK are common reasons for revision. Stopping at the sacrum vertebra in long fusion surgery on ASD patients seems to increase the incidence rates of total revision and pseudarthrosis.