LncRNA SNHG1 overexpression alleviates osteoarthritis via activating PI3K/Akt signal pathway and suppressing autophagy.

We hereby intend to further explore and confirm the underlying mechanism of Small nucleolar RNA Host Gene 1 (SNHG1) in osteoarthritis (OA). For in vitro assays, OA was induced in primary chondrocytes with interleukin-1ß (IL-1ß) treatment; while for in vivo tests, OA model was established in mice using the destabilization of the medial meniscus (DMM) method. Cell viability and apoptosis were assessed with MTT and flow cytometry assays, respectively. Cartilage tissue was stained by Safranin-O/Fast Green Staining. The mRNA and protein levels were separately determined via quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. SNHG1 overexpression promoted the viability yet inhibited the apoptosis of chondrocytes injured by IL-1ß. Moreover, the overexpression of SNHG1 promoted B-cell lymphoma-2 (Bcl-2) expression and activated phosphoinositol-3 kinase (PI3K)/protein kinase B (Akt) pathway but suppressed the process of autophagy, which led to down-regulation of light chain 3 (LC3)-II/I level and up-regulation of P62 level. However, rapamycin (RAPA, an autophagy activator) and LY294002 (a PI3K inhibitor) reversed the effects of SNHG1 overexpression on the viability and apoptosis of chondrocytes as well as on the proteins related to PI3K/Akt pathway and autophagy. In OA-modeled mice, SNHG1 overexpression prevented the loss of chondrocytes via the activation of PI3K/Akt pathway and the suppression of autophagy. SNHG1 overexpression might inhibit the apoptosis of chondrocytes by promoting PI3K/Akt pathway and inhibiting autophagy.

Apoptotic body-inspired nanotherapeutics efficiently attenuate osteoarthritis by targeting BRD4-regulated synovial macrophage polarization.

Bromodomain-containing protein 4 (BRD4) is the most well-studied BET protein that is important for the innate immune response. We recently revealed that targeting BRD4 triggers apoptosis in tumor-associated macrophages, but its role in synovial macrophages and joint inflammation is largely unknown. Herein, we demonstrated that BRD4 was highly expressed in the iNOS-positive M1 macrophages in the human and mouse osteoarthritis (OA) synovium, and conditional knockout of BRD4 in the myeloid lineage using Lyz2-cre; BRD4flox/flox mice significantly abolished anterior cruciate ligament transection (ACLT)-induced M1 macrophage accumulation and synovial inflammation. Accordingly, we successfully constructed apoptotic body-inspired phosphatidylserine-containing nanoliposomes (PSLs) loaded with the BRD4 inhibitor JQ1 to regulate inflammatory macrophages. JQ1-loaded PSLs (JQ1@PSLs) exhibited a higher cellular uptake by macrophages than fibroblast-like synoviocytes (FLSs) in vitro and in vivo, as well as the reduction in proinflammatory M1 macrophage polarization. Intra-articular injections of JQ1@PSLs showed prolonged retention within the joint, and remarkably reduced synovial inflammation and joint pain via suppressing M1 polarization accompanied by reduced TRPA1 expression by targeted inhibition of BRD4 in the macrophages, thus attenuating cartilage degradation during OA development. The results show that BRD4-inhibiting JQ1@PSLs can targeted-modulate macrophage polarization, which opens a new avenue for efficient OA therapy via a "Trojan horse".

Trim21 Regulates the Postnatal Development and Thermogenesis of Brown Adipose Tissue.

Brown adipose tissue undergoes rapid postnatal development to mature and plays a crucial role in thermoregulation and energy expenditure, which protects against cold and obesity. Herein, it is shown that the expression of Trim21 mRNA level of interscapular brown adipose tissue elevates after birth, and peaks at P14 (postnatal day 14). Trim21 depletion severely impairs the maturation of interscapular brown adipose tissue, decreases the expression of a series of thermogenic genes, and reduces energy expenditure. Consistently, the loss of Trim21 also leads to a suppression of white adipose tissue "browning", in response to cold exposure and a ß-adrenergic agonist, CL316,243. In addition, Trim21-/- mice are more prone to high-fat diet-induced obesity compared with the control littermates. Taken together, the study for the first time reveals a critical role of Trim21 in regulating iBAT postnatal development and thermogenesis.

Targeting YAP1-regulated Glycolysis in Fibroblast-Like Synoviocytes Impairs Macrophage Infiltration to Ameliorate Diabetic Osteoarthritis Progression.

The interplay between immune cells/macrophages and fibroblast-like synoviocytes (FLSs) plays a pivotal role in initiating synovitis; however, their involvement in metabolic disorders, including diabetic osteoarthritis (DOA), is largely unknown. In this study, single-cell RNA sequencing (scRNA-seq) is employed to investigate the synovial cell composition of DOA. A significant enrichment of activated macrophages within eight distinct synovial cell clusters is found in DOA synovium. Moreover, it is demonstrated that increased glycolysis in FLSs is a key driver for DOA patients' synovial macrophage infiltration and polarization. In addition, the yes-associated protein 1 (YAP1)/thioredoxin-interacting protein (TXNIP) signaling axis is demonstrated to play a crucial role in regulating glucose transporter 1 (GLUT1)-dependent glycolysis in FLSs, thereby controlling the expression of a series of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) which may subsequently fine-tune the infiltration of M1-polarized synovial macrophages in DOA patients and db/db diabetic OA mice. For treatment, M1 macrophage membrane-camouflaged Verteporfin (Vt)-loaded PLGA nanoparticles (MVPs) are developed to ameliorate DOA progression by regulating the YAP1/TXNIP signaling axis, thus suppressing the synovial glycolysis and the infiltration of M1-polarized macrophages. The results provide several novel insights into the pathogenesis of DOA and offer a promising treatment approach for DOA.

From cells to organs: progress and potential in cartilaginous organoids research.

While cartilage tissue engineering has significantly improved the speed and quality of cartilage regeneration, the underlying metabolic mechanisms are complex, making research in this area lengthy and challenging. In the past decade, organoids have evolved rapidly as valuable research tools. Methods to create these advanced human cell models range from simple tissue culture techniques to complex bioengineering approaches. Cartilaginous organoids in part mimic the microphysiology of human cartilage and fill a gap in high-fidelity cartilage disease models to a certain extent. They hold great promise to elucidate the pathogenic mechanism of a diversity of cartilage diseases and prove crucial in the development of new drugs. This review will focus on the research progress of cartilaginous organoids and propose strategies for cartilaginous organoid construction, study directions, and future perspectives.

BRD4 facilitates osteogenic differentiation of human bone marrow mesenchymal stem cells through WNT4/NF-κB pathway.

BACKGROUND: Human bone marrow mesenchymal stem cells (hBMSCs) are a major source of osteoblast precursor cells and are directly involved in osteoporosis (OP) progression. Bromodomain-containing protein 4 (BRD4) is an important regulator for osteogenic differentiation. Therefore, its role and mechanism in osteogenic differentiation process deserve further investigation. METHODS: hBMSCs osteogenic differentiation was evaluated by flow cytometry, alkaline phosphatase assay and alizarin red staining. Western blot was used to test osteogenic differentiation-related proteins, BRD4 protein, WNT family members-4 (WNT4)/NF-κB-related proteins, and glycolysis-related proteins. Metabolomics techniques were used to detect metabolite changes and metabolic pathways. BRD4 and WNT4 mRNA levels were determined using quantitative real-time PCR. Dual-luciferase reporter assay and chromatin immunoprecipitation assay were performed to detect BRD4 and WNT4 interaction. Glycolysis ability was assessed by testing glucose uptake, lactic acid production, and ATP levels. RESULTS: After successful induction of osteogenic differentiation, the expression of BRD4 was increased significantly. BRD4 knockdown inhibited hBMSCs osteogenic differentiation. Metabolomics analysis showed that BRD4 expression was related to glucose metabolism in osteogenic differentiation. Moreover, BRD4 could directly bind to the promoter of the WNT4 gene. Further experiments confirmed that recombinant WNT4 reversed the inhibition effect of BRD4 knockdown on glycolysis, and NF-κB inhibitors (Bardoxolone Methyl) overturned the suppressive effect of BRD4 knockdown on hBMSCs osteogenic differentiation. CONCLUSION: BRD4 promoted hBMSCs osteogenic differentiation by inhibiting NF-κB pathway via enhancing WNT4 expression.

Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/ß-catenin signaling.

Despite the diverse roles of tripartite motif (Trim)-containing proteins in the regulation of autophagy, the innate immune response, and cell differentiation, their roles in skeletal diseases are largely unknown. We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast (OB) differentiation in osteosarcoma. However, how Trim21 contributes to skeletal degenerative disorders, including osteoporosis, remains unknown. First, human and mouse bone specimens were evaluated, and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients. Next, we found that global knockout of the Trim21 gene (KO, Trim21-/-) resulted in higher bone mass compared to that of the control littermates. We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and elevating the activity of OBs; moreover, Trim21 depletion suppressed osteoclast (OC) formation of RAW264.7 cells. In addition, the differentiation of OCs from bone marrow-derived macrophages (BMMs) isolated from Trim21-/- and Ctsk-cre; Trim21f/f mice was largely compromised compared to that of the littermate control mice. Mechanistically, YAP1/ß-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs. More importantly, the loss of Trim21 prevented ovariectomy (OVX)- and lipopolysaccharide (LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling. Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption, thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.

Treatment of Morel-Lavallée Lesions (MLLs) with Mesh Incisions Combined with Quilting Sutures and Negative Pressure Wound Therapy (NPWT).

Purpose: The objective of this retrospective study was to evaluate the clinical effects of a novel treatment approach for Morel-Lavallée lesions (MLL) using a combination of suturing techniques and Negative Pressure Wound Therapy (NPWT) with mesh incisions. To summarize the clinical effects of a combination of suturing techniques and (Negative Pressure Wound Therapy) NPWT on the wall of Morel-Lavallée lesions (MLL) fibrotic pseudocapsules with mesh incisions in the treatment of MLLs. A retrospective analysis was performed on MLL patients from April 2017 to March 2021. Methods: This a retrospective case-control study and thirteen MLL patients were included in this retrospective analysis conducted between April 2017 and March 2021, who were treated with mesh incisions on the wall of the pseudocapsule, quilting suturing to degloved soft tissues, and NPWT. Physical examination, MRI, or ultrasound before surgery confirmed the diagnosis. Wound healing, secondary infection, recurrence, visual analog scale (VAS) scores before and after surgery, and skin and soft tissue condition were observed and evaluated. Results: The combination of mesh incisions, quilting sutures, and NPWT led to successful wound healing in 11 out of 13 cases without recurrent hematoma or secondary infection. Visual analog scale (VAS) scores significantly decreased after the operation, and the aesthetic and tactile qualities of the injured area improved. One case of skin and soft tissue necrosis infection before the operation, which healed after second-stage full-thickness skin grafting, 1 case healed after a dressing change, and the remaining 11 cases had wounds that healed by the first stage without secondary infection or recurrent hematoma formation. VAS scores decreased significantly after the operation, the appearance of the injured area was as expected, and the skin feel and elasticity recovered satisfactorily. Conclusion: The study demonstrates that the mesh incision technique, along with mattress sutures and NPWT, presents a feasible and effective approach for treating MLL with fibrotic pseudocapsules. This could shorten healing times, reduce risk of complications, and improve patient satisfaction.

Preliminary study of short-term outcomes and learning curves of robotic-assisted THA: comparison between closed platform robotic system and open platform robotic system.

BACKGROUND: Both closed platform and open platform robotic-assisted total hip arthroplasty (THA) have recently been recommended as a viable treatment option for achieving accurate positioning of components. Yet, limited studies paid attention to the differences between the closed platform robotic system and the open platform robotic system. Hence, this study aimed to investigate clinical outcomes, radiographic outcomes, complication rates and learning curve of two systems. MATERIALS AND METHODS: We retrospectively included 62 patients (31 closed robotic system and 31 open robotic system) who underwent THA between February 2021 and January 2023. The demographics, operating time, cup positioning, complications and hip Harris score were evaluated. Learning curves of operation time was conducted using cumulative sum (CUSUM) analysis. RESULTS: There were no differences in surgical time (76.7 ± 12.1 min vs. 72.3 ± 14.8 min), estimated blood loss (223.2 ± 13.2 ml vs. 216.9 ± 17 ml) and Harris Hip score (HHS) between closed platform robotic system and the open platform robotic system. The closed robotic system and the open robotic system were associated with a learning curve of 9 cases and 7 cases for surgical time respectively, based on the satisfying rate of Lewinnek's safe zone outliers (1/31, 96.8%) and no occurrence of complication. Both robotic systems had significant reduction in overall surgical time, the duration of acetabulum registration, and estimated blood loss between learning phase and proficiency phase. CONCLUSION: The authors suggest that the surgical outcomes and safe zone outlier rate of the open robotic-assisted THA were similar to those of the closed robotic-assisted THA. These two robotic-assisted are associated with comparable learning curves and both have the precise positioning of acetabular component. From learning phase to proficiency phase, the rate of positions within the safe zone differed only marginally (88.9-100% vs. 85.7-100%) based on a rather low number of patients. This is not a statistically significant difference. Therefore, we suggest that THA undergoing with the robotic-assisted system is the relatively useful way to achieve planned acetabular cup position so far.

Hippo/YAP1 inhibition by verteporfin attenuates osteophyte formation in a mouse surgical osteoarthritis model.

Osteophyte is an outgrowth of cartilage formed at the margins of the affected joint through endochondral ossification-like processes, and is one of the most common radiographic features of osteoarthritis (OA) that has been used to define the stage of disease. Osteophyte has been regarded to adapt the joint to the altered biomechanics of OA patients, limits joint movement and represent a source of joint pain, however, the mechanism of osteophyte formation, the morphology characteristics and biomechanical properties of osteophyte cells are remained unclear. In the present study, we isolated osteophyte cells and chondrocytes from late-stage OA patients who underwent total knee replacement surgeries, by applying Atomic Force Microscopy (AFM), we identified osteophyte cells were in irregular shape with dendrites, shrunk cell body, smooth surface and high elastic modulus (23.3 ± 5.4 kPa) when compared with chondrocytes (6.5 ± 1.8 kPa). In addition, osteophyte cells showed higher proliferation ability and colony formation capacity than chondrocytes. Mechanistically, we identified YAP1, the core transcriptional factor of Hippo signaling pathway, was highly expressed in osteophyte cell both at protein and RNA levels. Inactivation of Hippo/YAP1 signaling pathway by Verteporfin is sufficient to inhibit osteophyte cell proliferation in vitro and attenuate osteophyte formation in vivo. In conclusion, the morphology characteristic and biomechanical property of osteophyte cells at single cell level are quite different from chondrocytes, although we could not exclude other regulatory mechanisms, our findings suggested that Hippo/YAP1 is of great importance for osteophyte formation.

Cancer-Specific Survival after Limb Salvage versus Amputation in Children and Adolescents with Osteosarcoma: A Population-Based Analysis with Propensity Score Matching.

Background: The study aims to identify whether osteosarcoma patients of children and young adults will benefit from a survival profit from the choice of the operation method. Methods: The National Cancer Institute SEER database from 2000 to 2018 was selected for a retrospective analysis of 1630 children and young adults with a primary diagnosis of osteosarcoma, 1222 who underwent limb-preserving surgery, and 408 who underwent amputation. Confounders were controlled for by propensity score matching (PSM), cancer-specific survival (CSS) was analyzed using the Kaplan-Meier method, and univariate and multivariate Cox regression was used to analyze the factors influencing the prognosis of children and young osteosarcoma patients after surgery. A nomogram plot predicted 1-, 3-, and 5- survival rate in osteosarcoma. The model's accuracy was validated by the area under the ROC and calibration curves. Results: After PSM, multifactor Cox regression analysis found AJCC Stage III-IV (CSS : HR = 5.26, 95% CI 1.95-14.18, p=0. 001; HR = 5.54, 95% CI 2.56-12.01, p < 0. 001. Limb salvage surgery (CSS : HR = 0.58, 95% CI 0.44-0.77, p < 0. 001) has independent impact factors for CSS prognosis. The survival curve before and after PSM showed that patients with osteosarcoma of children and young adults who underwent limb salvage surgery had a survival benefit compared with those who underwent amputation surgery. Gender, chemotherapy, histology, primary tumor site, stage, and surgical modality were modeled in a total of six variables in the nomogram. The model exhibited good predictive performance. The AUC were 0.823, 0.74, and 0.757 for training set at 1, 3, and 5 years, respectively. The AUC of validation set 0.666, 0.722, and 0.699 at 1, 3, and 5 years, respectively. The model also predicted CSS with good fidelity for both datasets. This model was significantly superior to the 8th edition of the AJCC TNM staging system, with a better net benefit in predicting CSS in children and young adults with osteosarcoma. Conclusion: Limb salvage surgery is an option for children and young adults with osteosarcoma and cancer-specific survival rates can be improved by receiving limb salvage surgery.

Silencing of IRF7 ameliorates osteoarthritis by inhibiting chondrocyte pyroptosis via targeting FGF21.

Osteoarthritis (OA) is the most common joint disease which can lead to serious disability. Interferon regulatory factor 7 (IRF7) is a member of the interferon regulatory factor family. This study aimed to explore the function and potential mechanism of IRF7 in OA. Our results found that IRF7 was increased in LPS-stimulated C28/I2 chondrocytes and in OA mice established with medial menisco-tibial ligament (MMTL) transection. IRF7 silencing enhanced cell viability, reduced IL-18 and IL-1ß levels and suppressed cell apoptosis. IRF7 knockdown decreased ROS and LDH levels, and inhibited pyroptosis in LPS-treated chondrocytes. IRF7 negatively regulated FGF21 expression. FGF21 overexpression alleviated pyroptosis in LPS-stimulated chondrocytes. Knockdown of IRF7 improved OA injury in mice. In conclusion, our study demonstrates that silencing of IRF7 alleviates OA by inhibiting chondrocyte pyroptosis via upregulation of FGF21.

Researching the application of virtual reality in medical education: one-year follow-up of a randomized trial.

BACKGROUND: Compared with traditional tendon repair teaching methods, using a virtual reality (VR) simulator to teach tendon suturing can significantly improve medical students' exercise time, operation flow and operation knowledge. At present, the purpose of this study is to explore the long-term influence of VR simulator teaching on the practice performance of medical students. METHOD: This is a one-year long-term follow-up study of a randomized controlled study. A total of 117 participants who completed the initial study were invited to participate in the follow-up study. Participants in the VR group and the control group were required to complete a questionnaire developed by the authors and the teachers in the teaching and research department and to provide their surgical internship scores and Objective Structure Clinical Examination(OSCE) graduation scores. RESULTS: Of the 117 invitees, 108 completed the follow-up. The answers to the questions about career choice and study habits were more positive in the VR group than in the control group (p < 0.05). The total score for clinical practice in the VR group was better than that in the control group, and the difference was statistically significant (p < 0.05). In the OSCE examination, the scores for physical examination, suturing and knotting and image reading were higher in the VR group than in the control group, and the difference was statistically significant (p < 0.05). CONCLUSION: The results of the one-year long-term follow-up indicated that compared with medical students experiencing the traditional teaching mode, those experiencing the VR teaching mode had more determined career pursuit and active willingness to learn, better evaluations from teachers in the process of surgical clinical practice, and better scores in physical examination, suturing and knotting and image reading in the OSCE examination. In the study of nonlinear dynamics to cultivate a good learning model for medical students, the VR teaching model is expected to become an effective and stable initial sensitive element. TRIAL REGISTRATION: Chinese Clinical Trial Registry(25/05/2021, ChiCTR2100046648); http://www.chictr.org.cn/hvshowproject.aspx?id=90180 .

Triclocarban triggers osteoarthritis via DNMT1-mediated epigenetic modification and suppression of COL2A in cartilage tissues.

Triclocarban (TCC) is a widely used environmental endocrine-disrupting chemical (EDC). Articular injury of EDCs has been reported; however, whether and how TCCs damage the joint have not yet been determined. Herein, we revealed that exposure to TCC caused osteoarthritis (OA) within the zebrafish anal fin. Mechanistically, TCC stimulates the expression of DNMT1 and initiates DNA hypermethylation of the type II collagen coding gene, which further suppresses the expression of type II collagen and other extracellular matrices. This further results in decreased cartilage tissue and narrowing of the intraarticular space, which is typical of the pathogenesis of OA. The regulation of OA occurrence by TCC is conserved between zebrafish cartilage tissue and human chondrocytes. Our findings clarified the hazard and potential mechanisms of TCC towards articular health and highlighted DNMT1 as a potential therapeutic target for OA caused by TCC.

Construction and validation of web-based nomograms for detecting and prognosticating in prostate adenocarcinoma with bone metastasis.

Bone metastasis (BM) is one of the most common sites of metastasis in prostate adenocarcinoma (PA). PA with BM can significantly diminish patients' quality of life and result in a poor prognosis. The objective of this study was to establish two web-based nomograms to estimate the risk and prognosis of BM in PA patients. From the Surveillance, Epidemiology, and End Results (SEER) database, data on 308,332 patients diagnosed with PA were retrieved retrospectively. Logistic and Cox regression, respectively, were used to determine independent risk and prognostic factors. Then, We constructed two web-based nomograms and the results were validated by receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA) , and the Kaplan-Meier analyses. The independent risk factors for BM in PA patients included race, PSA, ISUP, T stage, N stage, brain, liver, lung metastasis, surgery, radiation and chemotherapy. The independent prognostic predictors for overall survival (OS) were age, marital status, PSA, ISUP and liver metastasis. Both nomograms could effectively predict risk and prognosis of BM in PA patients according to the results of ROC curves, calibration, and DCA in the training and validation sets. And the Kaplan-Meier analysis illustrated that the prognostic nomogram could significantly distinguish the population with different survival risks. We successfully constructed the two web-based nomograms for predicting the incidence of BM and the prognosis of PA patients with BM, which may assist clinicians in optimizing the establishment of individualized treatment programs and enhancing patients' prognoses.

Single-Cell RNA Sequencing Reveals Transcriptional Changes in the Cartilage of Subchondral Insufficiency Fracture of the Knee.

Purpose: Subchondral insufficiency fracture of the knee (SIFK) is a common cause of knee joint pain that mainly afflicts the elderly. Until now, how a sudden insufficiency fracture of subchondral bone affects the transcriptomic profiles of cartilage in SIFK and OA patients are largely unknown. Methods: Single-cell RNA sequencing (scRNA-seq) was used to identify various cell subsets and evaluate transcriptomic differences in cartilage of SIFK and OA patients. In addition, the above findings were confirmed by histological evaluation and immunohistochemical (IHC) staining. Results: We found that the transcriptomic profiles of cartilage in the SIFK patient was completely different from those of normal and OA patients. Accordingly, several novel cell clusters with activation of hypoxia and endochondral ossification signaling were identified in the SIFK cartilage. Chondrocyte trajectories analysis and IHC staining revealed that transcription factors including TCF4 were found to be highly up-regulated during the occurrence of SIFK, which might drive the reactive formation of cartilage and fibrous tissue and the activation of endochondral ossification. Conclusion: This is the first report to elucidate the transcriptomic alterations and distinct cell type subpopulations in the cartilage of SIFK and OA by the use of scRNA-seq, which provides a new insight in the understanding of the initiation and progression of SIFK.

An antibacterial hemostatic AuNPs@corn stalk/chitin composite sponge with shape recovery for promoting wound healing.

The development of shape-memory sponge dressings with functions, such as hemostasis, antibacterial activity, and wound healing, is of great significance in clinical applications. Herein, a novel AuNPs@corn stalk/chitin composite sponge (CCAu) was fabricated by crosslinking the chitin matrix with corn stalk-embedded gold nanoparticles (AuNPs). The addition of AuNPs@corn stalk gave the porous chitin sponge shape-recovery ability with improved softness, porosity, and water absorption. Correspondingly, the composite sponge showed better hemostatic effects than commercial PVF sponges. The photothermal effect of AuNPs endowed the composite sponge with excellent antibacterial activity. In addition, the wound treated with composite sponge containing antioxidant AuNPs exhibited a significantly faster wound healing rate (reaching 41.6 % on day 3) than the CH (33.2 %) and control (12.6 %) group through promoting cell migration, angiogenesis and collagen deposition. Therefore, the multifunctional composite sponge with great biocompatibility in this work provides a potential strategy for wound healing.

Effects of 6-Hydroxykaempferol: A Potential Natural Product for Amelioration of Tendon Impairment.

Tendon impairment is a common injury associated with impairment of range of motion and pain. Currently, evidence has confirmed that natural herbs contribute to orthopedics and have shown excellent results in the clinical management of tendon impairment. Shujin Huoxue tablet (SHT) and its complex prescriptions are regularly used in tendon rupture therapy with positive results. This study aimed to discover the potential molecules that promote tendon healing. The Chinese traditional medicine system pharmacological database analysis platform (TCMSP) is the primary resource. The Traditional Chinese Medicine Integrated Database and Encyclopedia of Traditional Chinese Medicine database were used as secondary databases. The GeneCards database was used to search for reported tendinopathy-related genes by keywords. Functions of the targeted genes were analyzed using Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes. Protein-protein interaction information was extracted from the STRING database. Docking study, MTT assay, quantitative real-time PCR, and migration assays were performed to obtain a better understanding of the herbs according to cell function to test the basic pharmacological action in vitro. A total of 104 disease nodes, 496 target gene nodes, 35 ingredient nodes, and one drug node were extracted. According to the TCMSP database, 6-hydroxykaempferol, which reportedly promotes the proliferation of microvascular endothelial cells, is a molecule found in SHT. We found that it promoted the proliferation and migration of tendon fibroblasts and elevated tendon repair-related gene expression. Purified 6-hydroxykaempferol promoted the proliferation and migration of tendon fibroblasts and increased their mRNA expression in tendon proliferation.

Versatile Nano-PROTAC-Induced Epigenetic Reader Degradation for Efficient Lung Cancer Therapy.

Recent evidence has indicated that overexpression of the epigenetic reader bromodomain-containing protein 4 (BRD4) contributes to a poor prognosis of lung cancers, and the suppression of its expression promotes cell apoptosis and leads to tumor shrinkage. Proteolysis targeting chimera (PROTAC) has recently emerged as a promising therapeutic strategy with the capability to precisely degrade targeted proteins. Herein, a novel style of versatile nano-PROTAC (CREATE (CRV-LLC membrane/DS-PLGA/dBET6)) is developed, which is constructed by using a pH/GSH (glutathione)-responsive polymer (disulfide bond-linked poly(lactic-co-glycolic acid), DS-PLGA) to load BRD4-targeted PROTAC (dBET6), followed by the camouflage with engineered lung cancer cell membranes with dual targeting capability. Notably, CREATE remarkably confers simultaneous targeting ability to lung cancer cells and tumor-associated macrophages (TAMs). The pH/GSH-responsive design improves the release of dBET6 payload from nanoparticles to induce pronounced apoptosis of both cells, which synergistically inhibits tumor growth in both subcutaneous and orthotopic tumor-bearing mouse model. Furthermore, the efficient tumor inhibition is due to the direct elimination of lung cancer cells and TAMs, which remodels the tumor microenvironment. Taken together, the results elucidate the construction of a versatile nano-PROTAC enables to eliminate both lung cancer cells and TAMs, which opens a new avenue for efficient lung cancer therapy via PROTAC.