Effects of human umbilical cord mesenchymal stem cell-derived exosomes in the rat osteoarthritis models.

Mesenchymal stem cells (MSCs) offer great potential for treatment of osteoarthritis (OA) by promoting articular cartilage regeneration via paracrine secretion of exosomes; however, the underlying mechanisms are not fully understood. This study aimed to explore the therapeutic effects of exosomes secreted by human umbilical cord-derived MSCs (hUC-MSCs) in rat models of OA and reveal the underlying mechanisms. UC-MSCs and UC-MSC-exosomes were prepared and identified by transmission electron microscopy and flow cytometry. IL-1ß-induced OA chondrocytes and the operation and collagenase-induced OA rat models were established. The results of micro-computed tomography, histology, and immunohistochemistry showed that UC-MSC-exosomes promoted cartilage regeneration in OA rats. ELISA results showed that the levels of synovial fluid cytokines, TNF-α, IL-1ß, and IL-6, were lower in exosome therapy group than control group in both OA rat models. Exosome treatment significantly downregulated the expression of MMP-13 and ADAMTS-5 in chondrocytes stimulated by IL-1ß, and upregulated collagen II expression. These findings suggest that hUC-MSC-exosomes offer a promising option for the therapy for OA.

Ecofriendly Protocol for ipso-Bromination of Arylboronic Acids.

We report a novel and environmentally friendly method for the ipso-bromination of arylboronic acids by exploiting the oxone/KBr system. We discovered that CuBr can catalyze the reaction and increase the yield from 63 to 97%. We believe that CuBr might catalyze the in situ generation of HOBr from oxone/KBr. The mild reaction condition permits tolerance of a diverse array of functional groups with exclusive regio- and chemoselectivity and allows low-cost large-scale reaction without explosion risk.

BiBr3 -Mediated Intramolecular Aza-Prins Cyclization of Aza-Achmatowicz Rearrangement Products: Asymmetric Total Synthesis of Suaveoline and Sarpagine Alkaloids.

An intramolecular aza-Prins cyclization of aza-Achmatowicz rearrangement products was developed in which bismuth tribromide (BiBr3 ) plays a dual role as an efficient Lewis acid and source of the bromide nucleophile. This approach enables the facile construction of highly functionalized 9-azabicyclo[3.3.1]nonanes (9-ABNs), which are valuable synthetic building blocks and a powerful platform for the synthesis of a variety of alkaloid natural products and drug molecules. Suitable substrates for the aza-Prins cyclization include 1,1-disubstituted alkenes, 1,2-disubstituted alkenes, alkynes, and allenes, with good to excellent yields observed. Finally, we showcase the application of this new approach to the enantioselective total synthesis of six indole alkaloids: (-)-suaveoline (1), (-)-norsuaveoline (2), (-)-macrophylline (3), (+)-normacusine B (4), (+)-Na -methyl-16-epipericyclivine (5) and (+)-affinisine (6) in a total of 9-14 steps. This study significantly expands the synthetic utility of the aza-Achmatowicz rearrangement, and the strategy (aza-Achmatowicz/aza-Prins) is expected to be applicable to the total synthesis of other members of the big family of macroline and sarpagine indole alkaloids.

Marine Alkaloid Lepadins E and H Induce Ferroptosis for Cancer Chemotherapy.

Induction of ferroptosis emerges as an effective method for cancer treatment. With massive efforts to elucidate the ferroptosis mechanism, the development of new ferroptosis inducers proceeds rather slowly, with only a few small molecules identified. Herein, we report our discovery of marine alkaloid lepadins E and H as a new class of ferroptosis inducers. Our in vitro studies show that lepadins E and H exhibit significant cytotoxicity, promote p53 expression, increase ROS production and lipid peroxides, reduce SLC7A11 and GPX4 levels, and upregulate ACSL4 expression, all of which consistently support induction of ferroptosis through the classical p53-SLC7A11-GPX4 pathway. Our animal model study of lepadin H confirms its in vivo antitumor efficacy with negligible toxicity to normal organs. This work elucidates the mode of action of lepadins (E and H) and verifies their in vivo efficacy as a new class of ferroptosis inducers for anticancer therapy with translational potential.

Mechanism of Exosomal LncRNA PART1 in Esophageal Cancer Angiogenesis by Targeting miR-302a-3p/CDC25A Axis.

OBJECTIVE: LncRNA PART1 has been confirmed related to multiple cancer bioactivities mediated with vascular endothelial growth factor signaling. Nevertheless, the role of LncRNA PART1 in esophageal cancer induced angiogenesis remains unclear. The present work focused on assessing LncRNA PART1 effects on esophageal cancer-induced angiogenesis and exploring possible mechanisms. METHODS: Western blot and immunofluorescence were conducted for identifying EC9706 exosomes. MiR-302a-3p and LncRNA PART1 levels were assessed by real-time quantitative polymerase chain reaction. Cell Counting Kit-8, EdU, wound healing, transwell, and tubule information were adopted for detecting human umbilical vein endothelial cell viability, proliferation, migration, invasion, and tubule information, respectively. Starbase software and dual-luciferase reporter were conducted for predicting and judging the expression interrelation of LncRNA PART1 and its potential target-miR-302a-3p. The same methods were carried out for verifying the inhibiting influences of miR-302a-3p upregulation and its potential target-cell division cycle 25 A. RESULTS: LncRNA PART1 levels were upregulated and related to the overall survival of patients in esophageal cancer. EC9706-Exos accelerated human umbilical vein endothelial cell proliferation, migration, invasion, and tubule formation via LncRNA PART1. LncRNA PART1 served as a sponge of miR-302a-3p, then miR-302a-3p targeted cell division cycle 25 A, and EC9706-Exos accelerated human umbilical vein endothelial cell angiogenesis via LncRNA PART1/ miR-302a-3p/cell division cycle 25 A axis. CONCLUSION: EC9706-Exos accelerates human umbilical vein endothelial cell angiogenesis via LncRNA PART1/miR-302a-3p/ cell division cycle 25 A axis, indicating EC9706-Exos may act as a promoter of angiogenesis. Our research will contribute to clarify the mechanism of tumor angiogenesis.

Clinical Efficacy of Intra-Articular Injection with P-PRP Versus that of L-PRP in Treating Knee Cartilage Lesion: A Randomized Controlled Trial.

OBJECTIVE: Platelet-rich plasma（PRP), with different concentration of leukocytes, may lead to varying effects in the treatment of cartilage lesions. So far, current research has not shown enough evidence on this. To evaluate the clinical efficacy and safety of intra-articular injection with pure platelet-rich plasma (P-PRP) versus those of leukocyte platelet-rich plasma (L-PRP) in treating knee cartilage lesions, we conducted a double-blind, randomized controlled clinical trial with a larger sample and longer follow-up period. METHODS: From October 2019 to October 2020, 95 patients were invited to participate in our study, and 60 (63.2%) were randomized to P-PRP (n = 30) or L-PRP (n = 30) groups. Patients from the two groups were treated with knee intra-articular injections of P-PRP or L-PRP. Visual analog scale (VAS) and Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores were assessed using an unpaired t-test for independent samples preoperatively and at 6 weeks, 12 weeks, 6 months, and 12 months after intervention. RESULTS: We followed up 27 cases in the P-PRP group and 26 cases in the L-PRP group. No significant differences in VAS and WOMAC scores were found between the two groups before the intervention (p > 0.05). The WOMAC Pain and VAS-Motions scores of the P-PRP group were significantly lower than those of the L-PRP group at 6 weeks after the intervention (p < 0.05). While the long-term clinical efficacy of both injections was similar and weakened after 12 months, more adverse events were found in the L-PRP group. CONCLUSIONS: The short-term results demonstrate a positive effect in reducing pain and improving function in patients with knee cartilage lesions in the two groups. While the P-PRP injection showed better clinical efficacy in the early phase of postoperative rehabilitation and resulted in fewer adverse events, long-term follow-up showed similar and weakened efficacy after 12 months. TRIAL REGISTRATION: ChiCTR1900026365. Registered on October 3, 2019, http://www.chictr.org.cn/showproj.aspx?proj=43911.

Two Green Protocols for Halogenative Semipinacol Rearrangement.

Semipinacol rearrangement is a special type of Wagner-Meerwein rearrangement that involves carbocation 1,2-rearrangement to provide carbonyl compounds with an α-quaternary carbon center. It has been strategically used for natural product synthesis and construction of highly congested quaternary carbons. Herein, we report a safe and green protocol that uses oxone/halide and Fenton bromide to achieve halogenative semipinacol rearrangement. The key feature of this method is the green in situ generation of reactive halogenating species from oxidation of halide with oxone or H2O2, which produces a nontoxic byproduct (potassium sulfate or water). Easy operation (insensitive to air and moisture) at room temperature without using special equipment adds additional advantage over previous methods.

Asymptomatic Hyperuricemia Is Associated with Achilles Tendon Rupture through Disrupting the Normal Functions of Tendon Stem/Progenitor Cells.

Hyperuricemia is a metabolic disorder that is essential to the development of inflammatory gout, with increasing prevalence over recent years. Emerging clinical findings has evidenced remarkable tendon damage in individuals with longstanding asymptomatic hyperuricemia, yet the impact of hyperuricemia on tendon homeostasis and associated repercussions is largely unknown. Here, we investigated whether asymptomatic hyperuricemia was associated with spontaneous ruptures in the Achilles tendon and the pathological effect of hyperuricemia on the tendon stem/progenitor cells (TSPCs). Significantly higher serum uric acid (SUA) levels were found in 648 closed Achilles tendon rupture (ATR) patients comparing to those in 12559 healthy volunteers. In vitro study demonstrated that uric acid (UA) dose dependently reduced rat Achilles TSPC viability, decreased the expressions of tendon collagens, and deformed their structural organization while significantly increased the transcript levels of matrix degradative enzymes and proinflammatory factors. Consistently, marked disruptions in Achilles tendon tissue structural and functional integrity were found in a rat model of hyperuricemia, together with enhanced immune cell infiltration. Transcriptome analysis revealed a significant elevation in genes involved in metabolic stress and tissue degeneration in TSPCs challenged by hyperuricemia. Specifically, reduced activity of the AKT-mTOR pathway with enhanced autophagic signaling was confirmed. Our findings indicate that asymptomatic hyperuricemia may be a predisposition of ATR by impeding the normal functions of TSPCs. This information may provide theoretical and experimental basis for exploring the early prevention and care of ATR.

Corrigendum: Disulfiram suppressed peritendinous fibrosis through inhibiting macrophage accumulation and its pro-inflammatory properties in tendon bone healing.

[This corrects the article DOI: 10.3389/fbioe.2022.823933.].

Identification of diagnostic mRNA biomarkers in whole blood for ankylosing spondylitis using WGCNA and machine learning feature selection.

Ankylosing spondylitis (AS) is a common inflammatory spondyloarthritis affecting the spine and sacroiliac joint that finally results in sclerosis of the axial skeleton. Aside from human leukocyte antigen B27, transcriptomic biomarkers in blood for AS diagnosis still remain unknown. Hence, this study aimed to investigate credible AS-specific mRNA biomarkers from the whole blood of AS patients by analyzing an mRNA expression profile (GSE73754) downloaded Gene Expression Omnibus, which includes AS and healthy control blood samples. Weighted gene co-expression network analysis was performed and revealed three mRNA modules associated with AS. By performing gene set enrichment analysis, the functional annotations of these modules revealed immune biological processes that occur in AS. Several feature mRNAs were identified by analyzing the hubs of the protein-protein interaction network, which was based on the intersection between differentially expressed mRNAs and mRNA modules. A machine learning-based feature selection method, SVM-RFE, was used to further screen out 13 key feature mRNAs. After verifying by qPCR, IL17RA, Sqstm1, Picalm, Eif4e, Srrt, Lrrfip1, Synj1 and Cxcr6 were found to be significant for AS diagnosis. Among them, Cxcr6, IL17RA and Lrrfip1 were correlated with severity of AS symptoms. In conclusion, our findings provide a framework for identifying the key mRNAs in whole blood of AS that is conducive for the development of novel diagnostic markers for AS.

Culture of Mesenchymal Stem Cells Derived From the Infrapatellar Fat Pad Without Enzyme and Preliminary Study on the Repair of Articular Cartilage Defects in Rabbits.

Objective: The aim of the study was to evaluate the advantages of without enzyme isolating patellar fat pad-derived mesenchymal stem cells (IPFP-SCs) and the feasibility of cartilage repair. Methods: The IPFP-SCs were isolated using the without enzyme method and compared with the IPFP-SCs obtained by the traditional enzyme digestion method in terms of cell proliferation ability, characterization, and differentiation ability, and the differences in chondrogenic induction and differentiation between the two groups were compared. Twenty-four New Zealand rabbits were randomly divided into four groups (n = 6). After the articular cartilage defects were modeled, different preparations were injected into the joint cavity. The rabbits in the group A were injected with the mixture of IPFP-SCs and pure PRP (P-PRP), separated using the without enzyme method, while those in the group B were injected with the mixture of IPFP-SCs and P-PRP separated with the digestion method, while those in the group C were injected with SVF separated using the without enzyme method, and those in the group D were injected with normal saline. At 6 weeks and 12 weeks after operation, the cartilage repair of rabbit joint specimens was observed and evaluated by gross observation and histological staining, and the effects of different IPFP-SCs application forms in repairing cartilage defects were compared. Results: The time required to obtain IPFP-SCs by enzyme-free isolation was significantly less than that by enzyme digestion, while the acquisition rate of primary cells was significantly lower than that by enzyme digestion. After culture and amplification, the two IPFP-SCs from different sources did not show significant differences in cell proliferation, cell phenotype, and differentiation ability. In animal experiments, groups A and B had the best effect on the repair of cartilage defects, and there was no significant difference between the two groups. The repair effect in group C was weaker than that in the former two groups, but it was relatively better than that in group D. Conclusion: It is more time-saving to obtain IPFP-SCs by the without enzyme method than by enzymatic digestion, and there is no significant difference in cell identification and differentiation potential between the two methods. However, the rate of obtaining primary cells was significantly lower than that with the enzyme digestion method. IPFP-SCs showed good repair effect in the rabbit animal cartilage defect model, providing ideas and reference for the clinical application of stem cells in repairing articular cartilage.

Disulfiram Suppressed Peritendinous Fibrosis Through Inhibiting Macrophage Accumulation and Its Pro-inflammatory Properties in Tendon Bone Healing.

The communication between macrophages and tendon cells plays a critical role in regulating the tendon-healing process. However, the potential mechanisms through which macrophages can control peritendinous fibrosis are unknown. Our data showed a strong pro-inflammatory phenotype of macrophages after a mouse tendon-bone injury. Moreover, by using a small-molecule compound library, we identified an aldehyde dehydrogenase inhibitor, disulfiram (DSF), which can significantly promote the transition of macrophage from M1 to M2 phenotype and decrease macrophage pro-inflammatory phenotype. Mechanistically, DSF targets gasdermin D (GSDMD) to attenuate macrophage cell pyroptosis, interleukin-1ß, and high mobility group box 1 protein release. These pro-inflammatory cytokines and damage-associated molecular patterns are essential for regulating tenocyte and fibroblast proliferation, migration, and fibrotic activity. Deficiency or inhibition of GSDMD significantly suppressed peritendinous fibrosis formation around the injured tendon and was accompanied by increased regenerated bone and fibrocartilage compared with the wild-type littermates. Collectively, these findings reveal a novel pathway of GSDMD-dependent macrophage cell pyroptosis in remodeling fibrogenesis in tendon-bone injury. Thus, GSDMD may represent a potential therapeutic target in tendon-bone healing.

Identification and development of the novel 7-genes diagnostic signature by integrating multi cohorts based on osteoarthritis.

BACKGROUND: A chronic progressive degenerative joint disease, such as osteoarthritis (OA) is positively related to age. The medical economy is facing a major burden, because of the high disability rate seen in patients with OA. Therefore, to prevent and treat OA, exploring the diagnostic biomarkers of OA will be of great significance. METHODS: Differentially expressed genes (DEGs) were obtained from the Gene Expression Omnibus database using the RobustRankAggreg R package, and a protein-protein interaction network was constructed. The module was obtained from Cytoscape, and the four algorithms of degree, MNC, closeness, and MCC in CytoHubba were used to identify the hub genes. A diagnostic model was constructed using Support Vector Machines (SVM), and the ability of the model to predict was evaluated by other cohorts. RESULTS: From normal and OA samples, 136 DEGs were identified, out of which 45 were downregulated in the normal group and 91 were upregulated in the OA group. These genes were associated with the extracellular matrix-receptor interactions, the PI3K-Akt signaling pathway, and the protein digestion and absorption pathway, as per a functional enrichment analysis. Finally, we identified the 7 hub genes (COL6A3, COL1A2, COL1A1, MMP2, COL3A1, POST, and FN1). These genes have important roles and are widely involved in the immune response, apoptosis, inflammation, and bone development. These 7 genes were used to construct a diagnostic model by SVM, and it performed well in different cohorts. Additionally, we verified the methylation expression of these hub genes. CONCLUSIONS: The 7-genes signature can be used for the diagnosis of OA and can provide new ideas in the clinical decision-making for patients with OA.

Identification and development of a novel 5-gene diagnostic model based on immune infiltration analysis of osteoarthritis.

BACKGROUND: Osteoarthritis (OA), which is due to the progressive loss and degeneration of articular cartilage, is the leading cause of disability worldwide. Therefore, it is of great significance to explore OA biomarkers for the prevention, diagnosis, and treatment of OA. METHODS AND MATERIALS: The GSE129147, GSE57218, GSE51588, GSE117999, and GSE98918 datasets with normal and OA samples were downloaded from the Gene Expression Omnibus (GEO) database. The GSE117999 and GSE98918 datasets were integrated, and immune infiltration was evaluated. The differentially expressed genes (DEGs) were analyzed using the limma package in R, and weighted gene co-expression network analysis (WGCNA) was used to explore the co-expression genes and co-expression modules. The co-expression module genes were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and hub genes were identified by the degree, MNC, closeness, and MCC algorithms. The hub genes were used to construct a diagnostic model based on support vector machines. RESULTS: The Immune Score in the OA samples was significantly higher than in the normal samples, and a total of 2313 DEGs were identified. Through WGCNA, we found that the yellow module was significantly positively correlated with the OA samples and Immune Score and negatively correlated with the normal samples. The 142 DEGs of the yellow module were related to biological processes such as regulation of inflammatory response, positive regulation of inflammatory response, blood vessel morphogenesis, endothelial cell migration, and humoral immune response. The intersections of the genes obtained by the 4 algorithms resulted in 5 final hub genes, and the diagnostic model constructed with these 5 genes showed good performance in the training and validation cohorts. CONCLUSIONS: The 5-gene diagnostic model can be used to diagnose OA and guide clinical decision-making.

Early Efficacy of Type I Collagen-Based Matrix-Assisted Autologous Chondrocyte Transplantation for the Treatment of Articular Cartilage Lesions.

Background: Articular cartilage is a complex structure that allows for low frictional gliding and effective shock absorption. Various sports injuries and inflammatory conditions can lead to lesions in the articular cartilage, which has limited regenerative potential. Type I collagen combined with autologous chondrocytes in a three-dimensional culture were used to induce the regeneration of single-layer autologous expanded chondrocytes without chondrogenic differentiation. Purpose: To assess the clinical, radiological, and histological changes following collagen-based autologous chondrocyte transplantation (MACT) for chondral knee lesions. Methods: The study prospectively enrolled 20 patients with symptomatic knee chondral lesions (mean size lesion was 2.41 ± 0.43 cm2, range: 2.0-3.4 cm2) in the lateral femoral condyle and femoral groove who underwent type I collagen-based MACT between July 2017 and July 2019. knee injury and osteoarthritis outcome score (KOOS) was assessed before the procedure, and periodic clinical follow-up was conducted every 3 months for a maximum of 12 months following the procedure and at 1-year intervals thereafter. Magnetic resonance imaging (MRI) T2 mapping of repaired cartilage was also used for the quantitative analysis of regeneration. In one patient, second-look arthroscopy was performed to assess cartilage regeneration characteristics, and a portion of regenerated cartilage was harvested for histological evaluation 12 months after implantation. Results: At pre-operation and at three, six, 12, and 24 months after the operation, KOOS pain, symptoms, daily life activities, sports and recreation, as well as the quality of life were significantly improved between every two time points. Hematoxylin and eosin (HE) staining indicated that the newly formed cartilage was comprised of naive chondrocytes. Safranin O-fast (S-O) green staining of the regenerated tissue revealed fibroblast-like cells surrounded by glycosaminoglycans. Immunohistochemistry (IHC) analysis indicated that collagen type II was uniformly distributed at the deep zone of articular cartilage and type I collagen mainly depositing in the superficial cartilage layer. The T2 values for repaired tissue gradually decreased, eventually approaching near-average values. Conclusion: The present study demonstrated that type I collagen-based MACT is a clinically effective treatment for improving functionality and pain levels. Histological evidence confirmed hyaline cartilage induction and showed that repaired cartilage tended to emerge from the deep to the superficial layer. The quantitative MRI T2 mapping test indicated that there still was a difference between the transplanted cartilage and the surrounding hyaline cartilage. Taken together, the current method represents an efficient approach for the restoration of knee cartilage lesions.

Decellularized extracellular matrix loaded with IPFP-SC for repairing rabbit osteochondral defects.

BACKGROUND: Tissue engineering is widely applied to treat osteochondral damage in osteoarthritis (OA). However, the superposition of seed cells, material scaffolds, inducing factors, and microenvironmental factors limit their practical application. We intended to develop a novel tissue engineering method for improving the repairment of osteochondral damage and to discuss its effect on repairing osteochondral defects. METHODS: The combined decellularization methods of physics, chemistry and enzymes were used to decellularize rabbit rib cartilage and articular cartilage, and rabbit decellularizated osteochondral composite scaffolds were prepared. The structure and organization of the scaffolds were analyzed. We extracted and identified infrapatellar fat pad stem cells (IPFP-SCs) from healthy rabbits and OA rabbit, which were different in viability, migration, osteogenic and chondrogenic differentiation. Finally, a variety of decellularizated bone cartilage composite scaffolds were loaded with rabbit IPFP-SC for in vitro and in vivo studies. RESULTS: The decellularization effect was strong, and the organic ingredients were lost. The layered scaffold showed lower density, greater porosity, larger pore size and water absorption than the whole scaffold, but the mechanical properties of the two scaffolds were low. IPFP-SCs were successfully extracted, and the migration and cartilage ability of IPFP-SCs in OA group were weak. The decellularized scaffold showed a high biocompatibility. The structure and composition of osteochondral promoted osteogenic differentiation and chondrogenic differentiation of IPFP-SCs. Moreover, the decellularized extracellular matrix loaded with IPFP-SC had the strongest repairing effect. CONCLUSION: The decellularized extracellular matrix loaded with IPFP-SC showed a better repair effect on rabbit osteochondral defects.

Effect of qingfeixuanxie decoction on clinical symptoms, pulmonary function, and inflammatory reaction in patients with COPD in acute exacerbation.

OBJECTIVE: To study the effect of self-prepared Qingfeixuanxie Decoction on the clinical symptoms, lung function and inflammatory response of patients with chronic obstructive pulmonary disease (COPD) in the acute exacerbation stage (AECOPD). METHODS: A total of 96 AECOPD patients were equally randomized into a control group and an observation group. Fourteen days after treatment, the clinical efficacy of the two groups was evaluated, and the clinical symptom scores, lung function, blood gas indicators, serum inflammatory response marker levels, the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), the sleep quality score and quality of life score between the two groups before and after treatment were compared. RESULTS: The total effective rate of the observation group was 91.67%, which was significantly higher than 72.92% of the control group (P<0.05); after treatment, the two groups obtained apparent mitigation in terms of the clinical symptoms, forced expiratory volume in the first second (FEV1), FEV1/forced vital capacity (FVC), partial pressure of carbon dioxide (PaCO2), partial pressure of blood oxygen (PaO2), arterial oxygen saturation (SaO2), and serum interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) expression levels compared to those before treatment (P<0.05), with better performance in the observation group than the control group (P<0.05). The SAS and SDS scores of the two groups of patients after treatment and 1 month after treatment showed a notable decrease (P<0.01). Patients in the observation group were recorded with higher sleep quality scores, shorter time to fall asleep, and longer sleep time than those in the control group. Higher scores of working conditions, life functions, and physical strength on the CCQQ scale than the control group were also observed in the observation group (P<0.05). CONCLUSION: Qingfeixuanxie Decoction can improve the clinical efficacy of patients with AECOPD, further mitigate the clinical symptoms and the lung functions of patients, and inhibit inflammatory reactions.

Comparison between Intra-Articular Injection of Infrapatellar Fat Pad (IPFP) Cell Concentrates and IPFP-Mesenchymal Stem Cells (MSCs) for Cartilage Defect Repair of the Knee Joint in Rabbits.

Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic method in regenerative medicine. Our previous research adopted a simple nonenzymatic strategy for the preparation of a new type of ready-to-use infrapatellar fat pad (IPFP) cell concentrates. The aim of this study was to compare the therapeutic efficacy of intra-articular (IA) injection of autologous IPFP cell concentrates and allogeneic IPFP-MSCs obtained from these concentrates in a rabbit articular cartilage defect model. IPFP-MSCs sprouting from the IPFP cell concentrates were characterized via flow cytometry as well as based on their potential for differentiation into adipocytes, osteoblasts, and chondrocytes. In the rabbit model, cartilage defects were created on the trochlear groove, followed by treatment with IPFP cell concentrates, IPFP-MSCs, or normal saline IA injection. Distal femur samples were evaluated at 6 and 12 weeks posttreatment via macroscopic observation and histological assessment based on the International Cartilage Repair Society (ICRS) macroscopic scoring system as well as the ICRS visual histological assessment scale. The macroscopic score and histological score were significantly higher in the IPFP-MSC group compared to the IPFP cell concentrate group at 12 weeks. Further, both treatment groups had higher scores compared to the normal saline group. In comparison to the latter, the groups treated with IPFP-MSCs and IPFP cell concentrates showed considerably better cartilage regeneration. Overall, IPFP-MSCs represent an effective therapeutic strategy for stimulating articular cartilage regeneration. Further, due to the simple, cost-effective, nonenzymatic, and safe preparation process, IPFP cell concentrates may represent an effective alternative to stem cell-based therapy in the clinic.

Mechanical Overloading Induced-Activation of mTOR Signaling in Tendon Stem/Progenitor Cells Contributes to Tendinopathy Development.

Despite the importance of mechanical loading in tendon homeostasis and pathophysiology, the molecular responses involved in the mechanotransduction in tendon cells remain unclear. In this study, we found that in vitro mechanical loading activated the mammalian target of rapamycin (mTOR) in rat patellar tendon stem/progenitor cells (TSCs) in a stretching magnitude-dependent manner. Application of rapamycin, a specific inhibitor of mTOR, attenuated the phosphorylation of S6 and 4E-BP1 and as such, largely inhibited the mechanical activation of mTOR. Moreover, rapamycin significantly decreased the proliferation and non-tenocyte differentiation of PTSCs as indicated by the reduced expression levels of LPL, PPARγ, SOX-9, collagen II, Runx-2, and osteocalcin genes. In the animal studies, mice subjected to intensive treadmill running (ITR) developed tendon degeneration, as evidenced by the formation of round-shaped cells, accumulation of proteoglycans, and expression of SOX-9 and collagen II proteins. However, daily injections of rapamycin in ITR mice reduced all these tendon degenerative changes. Collectively, these findings suggest that mechanical loading activates the mTOR signaling in TSCs, and rapamycin may be used to prevent tendinopathy development by blocking non-tenocyte differentiation due to mechanical over-activation of mTOR in TSCs.

Efficacy and Safety of Denosumab in Osteoporosis or Low Bone Mineral Density Postmenopausal Women.

Denosumab, a human monoclonal antibody, acts against the receptor activator of nuclear factor-κB ligand and is a promising antiresorptive agent in patients with osteoporosis. This study aimed to update the efficacy and safety of denosumab vs. placebo in osteoporosis or low bone mineral density (BMD) postmenopausal women. PubMed, Embase, Cochrane library, and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) reporting the efficacy and safety data of denosumab vs. placebo in osteoporosis or low BMD postmenopausal women. A random-effects model was used to calculate pooled weight mean differences (WMDs) or relative risks (RRs) with corresponding 95% confidence intervals (CIs) for treatment effectiveness of denosumab vs. placebo. Eleven RCTs including 12,013 postmenopausal women with osteoporosis or low BMD were preferred for the final meta-analysis. The summary results indicated that the percentage change of BMD in the denosumab group was greater than that of BMD in placebo at 1/3 radius (WMD: 3.43; 95%CI: 3.24-3.62; p < 0.001), femoral neck (WMD: 3.05; 95%CI: 1.78-4.33; p < 0.001), lumbar spine (WMD: 6.25; 95%CI: 4.59-7.92; p < 0.001), total hip (WMD: 4.36; 95%CI: 4.07-4.66; p < 0.001), trochanter (WMD: 6.00; 95%CI: 5.95-6.05; p < 0.001), and total body (WMD: 3.20; 95%CI: 2.03-4.38; p < 0.001). Moreover, denosumab therapy significantly reduced the risk of clinical fractures (RR: 0.57; 95%CI: 0.51-0.63; p < 0.001), nonvertebral fracture (RR: 0.83; 95%CI: 0.70-0.97; p = 0.018), vertebral fracture (RR: 0.32; 95%CI: 0.25-0.40; p < 0.001), and hip fracture (RR: 0.61; 95%CI: 0.37-0.98; p = 0.042). Finally, denosumab did not cause excess risks of adverse events. These findings suggested that postmenopausal women receiving denosumab had increased BMDs and reduced fractures at various sites without inducing any adverse events.