Osteoarthritis (OA) is the most common degenerative musculoskeletal disorder worldwide. Diosmetin is the aglycone of diosmin, which is widely distributed in citrus fruits and olive leaves and expresses anti-inflammatory effects in many diseases. It was reported to alleviate OA through inhibiting subchondral bone remodeling, but its anti-inflammatory function in attenuating OA has not been determined. In this study, we established an OA mouse model by anterior cruciate ligament transection (ACLT) and destabilization of the medial meniscus (DMM) surgery. Diosmetin was then intragastrically administered twice a week for eight weeks. The effect of diosmetin on the mouse knee joint was determined via histopathological analysis. In vitro, diosmetin was applied to treat chondrocytes, fibroblast-like synoviocytes (FLSs), and macrophages. The effect of macrophage secretion on chondrocytes was evaluated using a coculture system. The activation of the PI3K/Akt pathway in macrophages was evaluated via Western blotting. The results showed that diosmetin attenuated OA in an OA mouse model without causing obvious organ toxicity. Diosmetin did not inhibit the degradation of the extracellular matrix or the upregulation of degrading enzymes in chondrocytes. Diosmetin also did not inhibit the expression of fibrosis-related proteins in FLSs. Diosmetin promoted the transition of macrophages from the M1 to the M2 phenotype through inhibiting the PI3K/Akt pathway. The coculture of chondrocytes and macrophages indicated that cytokines secreted by macrophages attenuated the degradation of the cartilage extracellular matrix. To conclude, diosmetin promoted the transition of macrophages from the M1 to the M2 phenotype. Diosmetin-treated macrophages attenuated the degradation of the cartilage extracellular matrix, which may be another mechanism underlying the protective effect of diosmetin on OA.

Osteoarthritis (OA) is the most common degenerative joint disease affecting millions of people worldwide. Garlic-derived exosomes (GDEs) are nanoparticles extracted from garlic that exhibit anti-inflammatory effects on other diseases, but the effect of GDEs on OA has not been elucidated. In this study, GDEs were extracted and characterized. Chondrocytes were treated with IL-1β and incubated with GDEs in vitro, and the expression of cartilage matrix components (collagen II and aggrecan) and matrix degrading enzymes (MMP3 and MMP9) was evaluated via Western blotting. Changes in the MAPK pathway was also examined using Western blotting. The transcriptomic changes associated with GDE intervention were evaluated using high-throughput RNA-seq method. In vivo, we used anterior cruciate ligament transection (ACLT) combined with destabilization of the medial meniscus (DMM) surgery to establish a mouse OA model, and GDEs was intraarticularly injected into the joint cavity. The therapeutic effect of GDE was evaluated by behavioral and histopathological analysis. The results showed that IL-1β treatment inhibited the expression of collagen II and aggrecan, and upregulated the expression of MMP3 and MMP9, while GDE intervention alleviated these effects. GDEs also inhibited the phosphorylation of ERK, JNK, and P38. In vivo, GDE alleviated the sensitivity to heat stimulation and altered walking gait in a mouse OA model. Histopathological analysis indicated that GDE intervention ameliorated joint destruction in the knee joint without obvious toxicity. The results proved that GDEs alleviated the progression of OA in vitro and in vivo, and may be a potential disease-modifying drug for OA.

At 18:00 on July 19, 2019, the ancient Yahuokou flow-like landslide in Dongshan Town, Zhouqu County, Gansu Province, China, was revived. The landslide mass of about 3.92 × 106 m3 was revived step by step, slid down the slope, and finally slipped into the Minjiang river, causing the Minjiang river to become a semi-blocked state, the water level of the river rose, and the riverside road was interrupted. The landslide is 1920 m long, with a height difference of 550 m and an apparent friction coefficient of 0.286. It is a typical push-type large-scale long-striped fault-fractured zone accumulation landslide, which is controlled by the Pingding-Huama fault zone. Under the action of long-term rainfall, the trailing edge of the upper section of the landslide first undergoes slow creep deformation, which eventually leads to the overall instability and decline of the upper section of the landslide, and then loads the upper part of the middle section of the sliding mass, which promotes the instability and decline of the middle section of the sliding mass. Finally, the sliding mass in the middle section exerts a load on the upper part of the sliding mass in the lower section, which revives the sliding mass in the lower section and gradually slides into the Minjiang river. Through field investigation, remote sensing interpretation, and borehole investigation, the basic characteristics and information of landslide deformation and movement are obtained. The limit equilibrium method is used to analyze the revival mechanism and the spring model is proposed to analyze the movement mechanism of the landslide. With the help of DNA-W numerical simulation software, the sliding process of the upper sliding mass is simulated by a frictional rheological model to verify the spring model. The analysis of the dynamic mechanism of the Yahuokou flow-like landslide will help provide a reference for the research on the instability and movement mechanism of the landslide in the Pingding-Huama fault zone, and provide the necessary scientific basis for the prevention and mitigation of landslide disasters.

Adult neurogenesis occurs in two specialized regions of the mammalian brain,the subventricular zone(SVZ)and the subgranular zone(SGZ)of the dentate gyrus(DG).1 Adult hippocampal neural stem cells(NSCs),referred to as Type 1 cells represented by radial glia-like cells(RGLs),generate Type 2 cells that are divided into Type 2a and Type 2 b subpopulations,the latter of which give rise to Type 3 cells(neuroblasts).

On one hand, anti-slide shaft technology can overcome the problems of blocking the seepage and drainage path in the slope by traditional anti-slide piles. On the other hand, it can reduce the excavation quantities when the vertical drainage and anti slide structures are separately constructed. Besides, it can fully provide the hydration-heat dissipation surface to ensure the overall structure quality. It has been an important technology in modern landslide prevention engineering, and the novel one of geological disaster, hydrogeology and underground engineering in recent years. The anti-slide shaft technology involves hydrodynamic mechanics and solid mechanics, as well as hydrodynamic model, structural model, engineering geological model, etc. Besides, its promoted application is restricted by some problems, such as the lack of mature theoretical system, the relatively complex of this spatial structural combination, and the difficulty of the construction technology. Thus, it is necessary to carry out targeted current status summary research. Based on a large number of relevant documents,patents and practical engineering applications at home and abroad, we summarize the characteristics and classification of anti-slide shaft structure（anti-liquefaction pile, hollow anti-slide shaft, box anti-slide shaft, etc）,and find that the anti-slide shaft structure are mostly pile-type or tie-type, forming a 3-D structure system with the combination characteristics of seepage, collection, drainage and anti-slide. This kind of seepage-collectiondrainage structures usually include water permeable holes, radiant seepage holes and drainage pipes. The demonstration of typical application examples show that although the anti-slide shafts have the advantage of significant improvement on the stability, there is still a large optimization space from its extensive use and diversification. Thus, the current complex construction process, unclear mechanical properties and drainage characteristics, imperfect stability calculation theory, plane layout optimization method to be improved in antislide shaft technology are important scientific issues and research trend, which need to be paid attention in the future. The solutions of these scientific problems are not only beneficial to improving the mechanical and drainage theory, but also beneficial to improving the overall application level of anti-slide shaft technology.

[Erratum to: BMB Reports 2012; 45(9): 509-514, PMID: 23010171] The BMB Reports would like to correct in the Figure 2 of BMB Rep. 2012; 45(9): 509-514 titled "Biphasic effects of TGFβ1 on BMP9-induced osteogenic differentiation of mesenchymal stem cells." The original version of this article unfortunately contained image assembling error in the Figure 2. The image for "GFP-Day13" group was inadvertently duplicated from that for "BT20-Day 5" group, and an incorrect image was used for "GFP-Day 17" group. This article has been updated to correct this error in Figure 2.

Remdesivir (RDV; GS-5734, Veklury), the first FDA-approved antiviral to treat COVID-19, is a single-diastereomer monophosphoramidate prodrug of an adenosine analogue. RDV is taken up in the target cells and metabolized in multiple steps to form the active nucleoside triphosphate (TP) (GS-443902), which, in turn, acts as a potent and selective inhibitor of multiple viral RNA polymerases. In this report, we profiled the key enzymes involved in the RDV metabolic pathway with multiple parallel approaches: (i) bioinformatic analysis of nucleoside/nucleotide metabolic enzyme mRNA expression using public human tissue and lung single-cell bulk mRNA sequence (RNA-seq) data sets, (ii) protein and mRNA quantification of enzymes in human lung tissue and primary lung cells, (iii) biochemical studies on the catalytic rate of key enzymes, (iv) effects of specific enzyme inhibitors on the GS-443902 formation, and (v) the effects of these inhibitors on RDV antiviral activity against SARS-CoV-2 in cell culture. Our data collectively demonstrated that carboxylesterase 1 (CES1) and cathepsin A (CatA) are enzymes involved in hydrolyzing RDV to its alanine intermediate MetX, which is further hydrolyzed to the monophosphate form by histidine triad nucleotide-binding protein 1 (HINT1). The monophosphate is then consecutively phosphorylated to diphosphate and triphosphate by cellular phosphotransferases. Our data support the hypothesis that the unique properties of RDV prodrug not only allow lung-specific accumulation critical for the treatment of respiratory viral infection such as COVID-19 but also enable efficient intracellular metabolism of RDV and its MetX to monophosphate and successive phosphorylation to form the active TP in disease-relevant cells.

Long non-coding RNAs are important regulators of biological processes, but their roles in the osteogenic differentiation of mesenchymal stem cells (MSCs) remain unclear. Here we investigated the role of murine HOX transcript antisense RNA (mHotair) in BMP9-induced osteogenic differentiation of MSCs using immortalized mouse adipose-derived cells (iMADs). Touchdown quantitative polymerase chain reaction analysis found increased mHotair expression in bones in comparison with most other tissues. Moreover, the level of mHotair in femurs peaked at the age of week-4, a period of fast skeleton development. BMP9 could induce earlier peak expression of mHotair during in vitro iMAD osteogenesis. Silencing mHotair diminished BMP9-induced ALP activity, matrix mineralization, and expression of osteogenic, chondrogenic and adipogenic markers. Cell implantation experiments further confirmed that knockdown of mHotair attenuated BMP9-induced ectopic bone formation and mineralization of iMADs, leading to more undifferentiated cells. Crystal violet staining and cell cycle analysis revealed that silencing of mHotair promoted the proliferation of iMAD cells regardless of BMP9 induction. Moreover, ectopic bone masses developed from mHotair-knockdown iMAD cells exhibited higher expression of PCNA than the control group. Taken together, our results demonstrated that murine mHotair is an important regulator of BMP9-induced MSC osteogenesis by targeting cell cycle and proliferation.

Background: Reactive oxygen species (ROS), as a category of highly reactive molecules, are attractive for eliminating tumor cells in situ. However, the intrinsic tumor microenvironment (TME) always compromises treatment efficacy. In another aspect, silk fibroin (SF), as a category of natural biomacromolecules, is highly promising for synthesis of metallic nanocrystals via biomineralization. Methods: As a proof-of-concept study, AuPt bimetallic nanozyme derived from bioinspired crystallization of chloroauric acid and chloroplatinic acid was facilely developed in the presence of silk fibroin (SF). Antitumor effects caused by the as-synthesized AuPt@SF (APS) nanozyme were demonstrated in 4T1 tumor cells in vitro and xenograft tumor models in vivo. Results: APS nanozyme can decompose glucose to constantly supply H2O2 and deplete intracellular glutathione (GSH). APS nanozyme can simultaneously convert adsorbed O2 and endogenic H2O2 into superoxide radicals (•O2-) and hydroxyl radical (•OH), respectively, upon highly efficient catalytic reaction. Subsequently, these cytotoxic ROS cause irreversible damage to the cell membrane, nucleic acid and mitochondria of tumors. Upon fluorescence/photoacoustic (FL/PA)-imaging guidance, remarkable tumor damage based on the current nanoplatform was confirmed in vivo. Conclusion: The objective of our investigation is to supply more useful insights on the development of SF-based nanocatalysts, which are specifically responsive to TME for extremely efficient tumor theranostics.

Traditional techniques for the synthesis of nickel sulfide (NiS) nanoparticles (NPs) always present drawbacks of morphological irregularity, non-porous structure and poor long-term stability, which are extremely unfavorable for establishing effective therapeutic agents. Here, a category of hollow mesoporous NiS (hm-NiS) NPs with uniform spherical structure and good aqueous dispersity were innovatively developed based on a modified solvothermal reaction technique. Upon the successful synthesis of hm-NiS NPs, dopamine was seeded and in situ polymerized into polydopamine (PDA) on the NP surface, followed by functionalization with thiol-polyethylene glycol (SH-PEG) and encapsulation of the chemotherapeutic drug, doxorubicin (DOX), to form hm-NiS@PDA/PEG/DOX (NiPPD) NPs. The resultant NiPPD NPs exhibited a decent photothermal response and stability, attributed to the optical absorption of the hm-NiS nanocore and PDA layer in the near-infrared (NIR) region. Furthermore, stimulus-responsive drug release was achieved under both acidic pH conditions and NIR laser irradiation, owing to the protonation of -NH2 groups in the DOX molecules and local thermal shock, respectively. Lastly, a strong combinatorial photothermal-chemotherapeutic effect was demonstrated for tumor suppression with minimal systemic toxicity in vivo. Collectively, this state-of-the-art paradigm may provide useful insights to deepen the application of hm-NiS NPs for disease management and precision medicine.

Our previous study revealed that 3T3-L1 preadipocytes can differentiate to either osteoblasts or adipocytes in response to bone morphogenic protein 9 (BMP9). In the present study, we try to further investigate whether the Wnt/β-catenin signaling plays a crucial role in this process. It was found that BMP9 effectively activated the Wnt/β-catenin signaling, and induced the expression levels of certain canonical Wnt ligands and their receptors in preadipocytes. Exogenous expression of β-catenin, Wnt1, Wnt3a, and Wnt10b potentiated BMP9-induced alkaline phosphatase (ALP) activity, while β-catenin knockdown or Dickkopf 1 (Dkk1) diminished BMP9-induced ALP activity. Moreover, it was demonstrated that β-catenin overexpression promoted BMP9-induced mineralization, and increased the expression levels of late osteogenic markers osteopontin and osteocalcin. Furthermore, β-catenin inhibited BMP9-induced lipid accumulation and the adipogenic marker adipocyte fatty acid binding protein (aP2). The cell-implantation assay results identified that β-catenin not only augmented BMP9-induced ectopic bone formation, but also blocked adipogenesis in vivo. Mechanistically, it was found that β-catenin and BMP9 synergistically stimulated the osteogenic transcription factors runt-related transcription factor 2 (Runx2) and Osterix (OSX). However, BMP9-induced adipogenic transcription factors, peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT enhancer-binding protein α (C/EBPα), were inhibited by β-catenin. Therefore, these findings suggested that the Wnt/β-catenin signaling, potentially via the modulation of osteogenic and adipogenic transcriptional factors, exerts an opposite effect on BMP9-induced osteogenic and adipogenic differentiation in preadipocytes.

Reconstruction of bone defects is one of the most substantial and difficult clinical challenges in orthopedics. Transforming growth factor beta 1 (TGFβ1) might play an important role in stimulating osteogenic differentiation of bone morphogenetic protein 9 (BMP9)-induced C3H10T1/2 mesenchymal stem cells. In our current study, we examined the potential synergy between TGFβ1 and BMP9 in promoting the osteogenesis of C3H10T1/2 cells, and whether such effects could contribute to bone formation in vivo. Our experiment data indicated that TGFβ1 could increase the expression of osteogenic markers and the formation of mineralized calcium nodules in, while suppressing the proliferation of, BMP9-induced C3H10T1/2 cells. Furthermore, mice intramuscularly injected with BMP9/TGFβ1-transduced C3H10T1/2 cells into the gastrocnemius muscle on their tibiae developed ectopic bone masses with more mature osteoid structures, compared to those grafted with cells expressing BMP9/RFP. Subsequent mechanistic studies found that TGFβ1-induced enhancement of osteogenesis in BMP9-overexpressing C3H10T1/2 cells was accompanied by augmented expression of heat shock protein 47 (HSP47), a collagen-specific molecular chaperone essential for collagen biosynthesis, and can be attenuated by pirfenidone, a known anti-fibrotic inhibitor. Interestingly, protein microarray analysis suggested that TGFβ1/BMP9-dependent osteogenesis of C3H10T1/2 cells seemed to involve several non-canonical signaling pathways such as Janus kinase-signal transducer and activator of transcription, phosphoinositide-3-kinase-protein kinase B, and mitogen-activated protein kinase. These results provided further evidence that TGFβ1 could promote bone formation from BMP9-induced C3H10T1/2 cells and shed important light on the underlying molecular mechanisms.

PURPOSE:Postoperative anemia has been a threat to total hip arthroplasty patients. We introduced a novel medullary cavity hemostasis (MCH) technique and combined it with tranexamic acid (TXA) to prevent postoperative anemia in elder patients. This trial was conducted to evaluate the effectiveness and safety of this technique.METHODS:In this retrospective consecutive study, each group has 88 patients who were all over 70 years old. In the control group, patients were given TXA. In the experimental group, the MCH technique and same TXA application were used.RESULTS:The average of total blood loss, drainage volume, and hidden blood loss were significantly less in the experimental group. The postoperative hemoglobin (Hb) level was significantly higher in the experimental group (100.6 g/dL) than it is in the control group (81.4 g/dL). None of the patient has shown signs of prosthesis subsidence, periprosthetical osteolysis, or stem loosening during follow-ups in the average follow-up time of 3 years.CONCLUSION:We discovered that application of TXA alone is not sufficient to prevent postoperative moderate anemia in patients over 70 years old. Combination of TXA and MCH is an effective and safe way to alleviate the severity of postoperative anemia.

Tooth development is regulated by sequential and reciprocal epithelium-mesenchymal interactions and their related molecular signaling pathways, such as bone morphogenetic proteins (BMPs). Among the 14 types of BMPs, BMP9 (also known as growth differentiation factor 2) is one of the most potent BMPs to induce osteogenic differentiation of mesenchymal stem cells. The purpose of this study was to examine potential roles of BMP9 signaling in tooth development. First, we detected the expression pattern of BMP9 in tooth germ during postnatal tooth development, and we found that BMP9 was widely expressed in odontoblasts, ameloblasts, dental pulp cells, and osteoblasts in alveolar bones. Then, we established a BMP9-KO mouse model. Gross morphological examination revealed that the tooth cusps of BMP9-KO mice were significantly abraded with shorter roots. Micro-computed tomography and three-dimensional reconstruction analysis indicated that the first molars of the BMP9-KO mice exhibited a reduced thickness dentin, enlarged pulp canals, and shortened roots, resembling the phenotypes of the common hereditary dental disease dentinogenesis imperfecta. Further, the alveolar bone of the BMP9-KO mutants was found to be shorter and had a decreased mineral density and trabecular thickness and bone volume fraction compared with that of the wild-type control. Mechanistically, we demonstrated that both dentin sialophosphoprotein and dentin matrix protein 1 were induced in dental stem cells by BMP9, whereas their expression was reduced when BMP9 was silenced. Further studies are required to determine whether loss of or decreased BMP9 expression is clinically associated with dentinogenesis imperfecta. Collectively, our results strongly suggest that BMP9 may play an important role in regulating dentinogenesis and tooth development. Further research is recommended into the therapeutic uses of BMP9 to regenerate traumatized and diseased tissues and for the bioengineering of replacement teeth.

Introduction Although nonsurgical methods and many surgical techniques have been developed for repairing a ruptured Achilles tendon, there is no consensus on its best treatment. In this article, a novel minimally invasive technique called the Panda Rope Bridge Technique (PRBT) is described. Methods Patient with acute Achilles tendon rupture was operated on in the prone position. The PRBT begin with making the proximal bridge anchor (Krackow sutures in the myotendinous junction), the distal bridge anchor (two suture anchors in the calcaneus bone) and the ropes (threads of the suture anchors) stretched between the anchor sites. Then a small incision was made to debride and reattach the stumps of ruptured tendon. After the surgery, no cast or splint fixation was applied. All patients performed enhanced recovery after surgery (ERAS), which included immediate ankle mobilisation from day 1, full weight-bearing walking from day 5 to 7, and gradually take part in athletic exercises from 8 weeks postoperatively. Results PBRT was performed in 11patients with acute Achilles tendon rupture between June 2012 and June 2015. No wound infection, fistula, skin necrosis, sural nerve damage, deep venous thrombosis or tendon re-rupture was found. One year after the surgery, all patients reported 100 AOFAS ankle-hindfoot score points and the mean ATRS was 96.6. Conclusion The PRBT is a simple, effective and minimally invasive technique, with no need for immobilisation of the ankle, making possible immediate and aggressive postoperative rehabilitation.

Mesenchymal stem cells (MSCs) are multipotent progenitors that can differentiate into multiple lineages including osteoblastic lineage. Osteogenic differentiation of MSCs is a cascade that recapitulates most, if not all, of the molecular events occurring during embryonic skeletal development, which is regulated by numerous signaling pathways including bone morphogenetic proteins (BMPs). Through a comprehensive analysis of the osteogenic activity, we previously demonstrated that BMP9 is the most potent BMP for inducing bone formation from MSCs both in vitro and in vivo. However, as one of the least studied BMPs, the essential mediators of BMP9-induced osteogenic signaling remain elusive. Here we show that BMP9-induced osteogenic signaling in MSCs requires intact Notch signaling. While the expression of Notch receptors and ligands are readily detectable in MSCs, Notch inhibitor and dominant-negative Notch1 effectively inhibit BMP9-induced osteogenic differentiation in vitro and ectopic bone formation in vivo. Genetic disruption of Notch pathway severely impairs BMP9-induced osteogenic differentiation and ectopic bone formation from MSCs. Furthermore, while BMP9-induced expression of early-responsive genes is not affected by defective Notch signaling, BMP9 upregulates the expression of Notch receptors and ligands at the intermediate stage of osteogenic differentiation. Taken together, these results demonstrate that Notch signaling may play an essential role in coordinating BMP9-induced osteogenic differentiation of MSCs.