ABSTRACT
BACKGROUND: Evident adolescent idiopathic scoliosis (AIS) incurs high treatment costs, low quality of life, and many complications. Early screening of AIS is essential to avoid progressing to an evident stage. However, there is no valid serum biomarker for AIS for early screening. METHODS: Antibody-based array is a large-scale study of proteins, which is expected to reveal a serum protein signature as biomarker for AIS. There are two segments of the research, including biomarkers screening and validation. In the biomarkers screening group, a total of 16 volunteers participated in this study, and we carried out differentially expressed proteins screening via protein array assay between No-AIS group and the AIS group, through which GeneSet enrichment analysis was performed. In the validation group with a total of 62 volunteers, the differentially expressed proteins from screening group were verified by Enzyme-Linked immunosorbent assay (ELISA), and then multiple regression analysis. RESULTS: In our study, there were twenty-nine differentially expressed proteins in AIS, through Protein array assay and GeneSet enrichment analysis in the biomarkers screening group. Then the expression of FAP, CD23 and B2M decreased as the degree of AIS increased via ELISA in validation group (FAP, p < 0.0001; CD23, p = 0.0002; B2M, p < 0.0001). Further, the results of multiple regression analysis showed that FAP, CD23 are linked to Cobb angle, whereas B2M were excluded because of multicollinearity. CONCLUSIONS: Altogether, we found that serum protein FAP and CD23 are intimately related to AIS, suggesting FAP and CD23 are expected to serve as the serum biomarkers, which significantly facilitate frequent longitudinal monitoring as to keep track of disease progression and tailor treatment accordingly.
Subject(s)
Quality of Life , Scoliosis , Humans , Adolescent , Scoliosis/diagnosis , Antibodies , Blood Proteins , BiomarkersABSTRACT
Vascularized osteogenesis is essential for successful bone regeneration, yet its realization during large size bone defect healing remains challenging due to the difficulty to couple multiple biological processes. Herein, harnessing the intrinsic angiogenic potential of vascular derived extracellular matrix (vECM) and its specific affinity to growth factors, a vECM/GelMA based hybrid hydrogel delivery system is constructed to achieve optimized bone morphogenetic protein-2 (BMP-2) therapeutic index and provide intrinsic angiogenic induction during bone healing. The incorporation of vECM not only effectively regulates BMP-2 kinetics to match the bone healing timeframe, but also promotes angiogenesis both in vitro and in vivo. In vivo results also show that vECM-mediated BMP-2 release remarkably enhances vascularized bone formation for critical size bone defects. In particular, blood vessel ingrowth stained with CD31 marker in the defect area is substantially encouraged over the course of healing, suggesting incorporation of vECM served roles in both angiogenesis and osteogenesis. Thus, the authors' study exemplifies that affinity of growth factor towards ECM may be a promising strategy to be leveraged to develop sophisticated delivery systems endowed with desirable properties for regenerative medicine applications.
Subject(s)
Bone Morphogenetic Protein 2 , Bone Regeneration , Bone Morphogenetic Protein 2/pharmacology , Extracellular Matrix , Hydrogels , OsteogenesisABSTRACT
Target therapy for highly heterogeneous cancers represents a major clinical challenge due to the lack of recurrent therapeutic targets identified in these tumors. Herein, the authors report a tumor-customized targeting photothermal therapy (PTT) strategy for highly heterogeneous cancers, by which 2D supramolecular self-assembled nanodiscs are modified with tumor-specific binding peptides identified by phage display techniques. Taking osteosarcoma (OS) as a model heterogeneous cancer, an OS targeting peptide (OTP) is first selected after biopanning and is demonstrated to successfully bind to this heterogeneous cancer cells/tissues. Successful conjugation of OTP to heptamethine cyanine (Cy7)-based 2D nanodiscs Cy7-TCF (2-dicyanomethylene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran,TCF) enables the 2D nanodiscs to specifically target the heterogeneous tumor. Notably, a single dose injection of this targeted nanodisc (T-ND) not only effectively induces enhanced photothermal tumor ablation under near-infrared light, but also exhibits sevenfold increase of tumor retention time (more than 24 days) compared to generic nanomedicine. Thus, the authors' findings suggest that the combination of phage display-based affinity peptides selection and 2D supramolecular nanodiscs leads to the development of a platform technology for highly heterogeneous cancers precise therapy, offering specific tumor targeting, ultralong tumor retention, and precise PTT.
Subject(s)
Nanoparticles , Neoplasms , Cell Line, Tumor , Humans , Infrared Rays , Nanomedicine , Nanoparticles/chemistry , Neoplasms/drug therapy , Phototherapy , Photothermal TherapyABSTRACT
Iodine has been known as an effective disinfectant with broad-spectrum antimicrobial potency yet without drug resistance risk when used in clinic. However, the exploration of iodine for antibacterial therapy in orthopedics remains sparse due to its volatile nature and poor solubility. Herein, leveraging the superior absorption capability of metal-organic frameworks (MOFs) and their inherent photocatalytic properties, iodine-loaded MOF surface is presented to realize responsive iodine release along with intracellular reactive oxygen species(ROS) oxidation under near-infrared (NIR) exposure to achieve synergistic antibacterial effect. Iodine is successfully loaded using vapor deposition process onto zeolitic imidazolate framework-8(ZIF-8), which is immobilized onto micro arc oxidized titanium via a hydrothermal approach. The combination of NIR-triggered iodine release and ZIF-8 mediated ROS oxidative stress substantially augments the antibacterial efficacy of this approach both in vitro and in vivo. Furthermore, this composite coating also supported osteogenic differentiation of bone marrow stromal cells, as well as improved osseointegration of coated implants using an intramedullary rat model, suggesting improvement of antibacterial efficacy does not impair osteogenic potential of the implants. Altogether, immobilization of iodine via MOF on orthopedic implants with synergistic antibacterial effect can be a promising strategy to combat bacterial infections.
Subject(s)
Anti-Infective Agents , Iodine , Metal-Organic Frameworks , Orthopedics , Animals , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/pharmacology , Iodine/pharmacology , Metal-Organic Frameworks/pharmacology , Osteogenesis , Rats , Titanium/pharmacologyABSTRACT
OBJECTIVE: To elucidate the role of LRRK2 in intervertebral disc degeneration (IDD) as well as its mitophagy regulation mechanism. METHODS: The expression of LRRK2 in human degenerative nucleus pulposus tissues as well as in oxidative stress-induced rat nucleus pulposus cells (NPCs) was detected by western blot. LRRK2 was knocked down in NPCs by lentivirus (LV)-shLRRK2 transfection; apoptosis and mitophagy were assessed by western blot, TUNEL assay, immunofluorescence staining and mitophagy detection assay in LRRK2-deficient NPCs under oxidative stress. After knockdown of Parkin in NPCs with siRNA transfection, apoptosis and mitophagy were further assessed. In puncture-induced rat IDD model, X-ray, MRI, hematoxylin-eosin (HE) and Safranin O-Fast green (SO) staining were performed to evaluate the therapeutic effects of LV-shLRRK2 on IDD. RESULTS: We found that the expression of LRRK2 was increased in degenerative NPCs both in vivo and in vitro. LRRK2 deficiency significantly suppressed oxidative stress-induced mitochondria-dependent apoptosis in NPCs; meanwhile, mitophagy was promoted. However, these effects were abolished by the mitophagy inhibitor, suggesting the effect of LRRK2 on apoptosis in NPCs is mitophagy-dependent. Furthermore, Parkin knockdown study showed that LRRK2 deficiency activated mitophagy by recruiting Parkin. In vivo study demonstrated that LRRK2 inhibition ameliorated IDD in rats. CONCLUSIONS: The results revealed that LRRK2 is involved in the pathogenesis of IDD, while knockdown of LRRK2 inhibits oxidative stress-induced apoptosis through mitophagy. Thus, inhibition of LRRK2 may be a promising therapeutic strategy for IDD.
Subject(s)
Apoptosis/genetics , Intervertebral Disc Degeneration/genetics , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics , Mitophagy/genetics , Nucleus Pulposus/metabolism , Ubiquitin-Protein Ligases/metabolism , Adult , Aged , Animals , Disease Models, Animal , Female , Gene Knockdown Techniques , Humans , Intervertebral Disc Degeneration/metabolism , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Male , Middle Aged , Nucleus Pulposus/cytology , Oxidative Stress/genetics , RatsABSTRACT
Exosome therapy is a promising therapeutic approach for intervertebral disc degeneration (IVDD) and achieves its therapeutic effects by regulating metabolic disorders, the microenvironment and cell homeostasis with the sustained release of microRNAs, proteins, and transcription factors. However, the rapid clearance and disruption of exosomes are the two major challenges for the application of exosome therapy in IVDD. Herein, a thermosensitive acellular extracellular matrix (ECM) hydrogel coupled with adipose-derived mesenchymal stem cell (ADSC) exosomes (dECM@exo) that inherits the superior properties of nucleus pulposus tissue and ADSCs was fabricated to ameliorate IVDD. This thermosensitive dECM@exo hydrogel system can provide not only in situ gelation to replenish ECM leakage in nucleus pulposus cells (NPCs) but also an environment for the growth of NPCs. In addition, sustained release of ADSC-derived exosomes from this system regulates matrix synthesis and degradation by regulating matrix metalloproteinases (MMPs) and inhibits pyroptosis by mitigating the inflammatory response in vitro. Animal results demonstrated that the dECM@exo hydrogel system maintained early IVD microenvironment homeostasis and ameliorated IVDD. This functional system can serve as a powerful platform for IVD drug delivery and biotherapy and an alternative therapy for IVDD.
Subject(s)
Exosomes/metabolism , Extracellular Matrix/drug effects , Hydrogels/pharmacology , Intervertebral Disc Degeneration/drug therapy , Pyroptosis , Animals , Humans , Intervertebral Disc Degeneration/metabolism , Intervertebral Disc Degeneration/pathology , Intervertebral Disc Degeneration/surgery , Male , Matrix Metalloproteinase 13/genetics , Mesenchymal Stem Cells , MicroRNAs/metabolism , Nucleus Pulposus/drug effects , Nucleus Pulposus/metabolism , Rats , Tissue EngineeringABSTRACT
Engineering approaches for growth factor delivery have been considerably advanced for tissue regeneration, yet most of them fail to provide a complex combination of signals emulating a natural healing cascade, which substantially limits their clinical successes. Herein, we aimed to emulate the natural bone healing cascades by coupling the processes of angiogenesis and osteogenesis with a hybrid dual growth factor delivery system to achieve vascularized bone formation. Basic fibroblast growth factor (bFGF) was loaded into methacrylate gelatin (GelMA) to mimic angiogenic signalling during the inflammation and soft callus phases of the bone healing process, while bone morphogenetic protein-2 (BMP-2) was bound onto mineral coated microparticles (MCM) to mimics osteogenic signalling in the hard callus and bone remodelling phases. An Initial high concentration of bFGF accompanied by a sustainable release of BMP-2 and inorganic ions was realized to orchestrate well-coupled osteogenic and angiogenic effects for bone regeneration. In vitro experiments indicated that the hybrid hydrogel markedly enhanced the formation of vasculature in human umbilical vein endothelial cells (HUVECs), as well as the osteogenic differentiation of mesenchymal stem cells (BMSCs). In vivo results confirmed the optimal osteogenic performance of our F/G-B/M hydrogel, which was primarily attributed to the FGF-induced vascularization. This research presents a facile and potent alternative for treating bone defects by emulating natural cascades of bone healing.
Subject(s)
Fibroblast Growth Factor 2 , Human Umbilical Vein Endothelial Cells/metabolism , Hydrogels , Neovascularization, Physiologic/drug effects , Osteogenesis/drug effects , Bone Regeneration/drug effects , Bone and Bones/blood supply , Bone and Bones/drug effects , Cells, Cultured , Fibroblast Growth Factor 2/chemistry , Fibroblast Growth Factor 2/pharmacology , Humans , Hydrogels/chemistry , Hydrogels/pharmacology , Methacrylates/chemistryABSTRACT
PURPOSE: No study so far has paid attention to strabismus-related spinal imbalance. This study aimed to determine the epidemiology of thoracic scoliosis in children and adolescents with strabismus and investigate the association of two diseases. METHODS AND DESIGN: A cross-sectional study. Study group consists of 1935 consecutive candidates for strabismus surgery (4-18 years); Control group consists of the age- and sex-matched patients with respiratory diseases. All subjects underwent a screening program based on chest plain radiographs using the Cobb method. Their demographic information, clinical variables and results of Cobb angle were recorded and analyzed. RESULTS: A significantly higher prevalence of thoracic scoliosis (289/1935, 14.94% versus 58/1935, 3.00%) was found in study group compared with control group. Among strabismic patients, the coronal thoracic scoliosis curve mainly distributed in right and in main thoracic (198/289) and in the curves 10°-19° (224/289); Age range 7-9 years (103/1935), female (179/1935) and concomitant exotropia patients (159/851) were more likely to have thoracic scoliosis. According to the logistic regression, thoracic scoliosis had no significant association with age, BMI, duration of illness and onset age (p > 0.05). However, gender, BCVA, type of strabismus and degree of strabismus showed a significant relationship with the prevalence of thoracic scoliosis (p < 0.05). CONCLUSIONS: With a pooled prevalence of 14.94%, strabismus patients showed a great higher risk of developing thoracic scoliosis. Screening for scoliosis in strabismus patients can be helpful to discover a high prevalence of potential coronal scoliosis. More attention should be paid to ophthalmological problems in patients with scoliosis. These slides can be retrieved under Electronic Supplementary Material.
Subject(s)
Scoliosis , Spinal Fusion , Strabismus , Adolescent , Child , China/epidemiology , Cross-Sectional Studies , Female , Humans , Male , Prevalence , Scoliosis/diagnostic imaging , Scoliosis/epidemiology , Scoliosis/surgery , Strabismus/epidemiology , Strabismus/surgery , Thoracic Vertebrae/diagnostic imaging , Thoracic Vertebrae/surgery , Treatment OutcomeABSTRACT
Intervertebral disc degeneration (IDD) is a complicated disease in patients. The pathogenesis of IDD encompasses cellular oxidative stress, mitochondrion dysfunction and apoptosis. Melatonin eliminates oxygen free radicals, regulates mitochondrial homoeostasis and function, stimulates mitophagy and protects against cellular apoptosis. Therefore, we hypothesize that melatonin has beneficial effect on IDD by mitophagy stimulation and inhibition of apoptosis. The effects of melatonin on IDD were investigated in vitro and in vivo. For the former, melatonin diminished cellular apoptosis caused by tert-butyl hydroperoxide in nucleus pulposus (NP) cells. Mitophagy, as well as its upstream regulator Parkin, was activated by melatonin in both a dose and time-dependent manner. Mitophagy inhibition by cyclosporine A (CsA) partially eliminated the protective effects of melatonin against NP cell apoptosis, suggesting that mitophagy is involved in the protective effect of melatonin on IDD. In addition, melatonin was demonstrated to preserve the extracellular matrix (ECM) content of Collagen II, Aggrecan and Sox-9, while inhibiting the expression of matrix degeneration enzymes, including MMP-13 and ADAMTS-5. In vivo, our results demonstrated that melatonin treatment ameliorated IDD in a puncture-induced rat model. To conclude, our results suggested that melatonin protected NP cells against apoptosis via mitophagy induction and ameliorated disc degeneration, providing the potential therapy for IDD.
Subject(s)
Apoptosis/drug effects , Intervertebral Disc Degeneration/prevention & control , Melatonin/pharmacology , Mitophagy/drug effects , Animals , Antioxidants/pharmacology , Cells, Cultured , Intervertebral Disc Degeneration/genetics , Intervertebral Disc Degeneration/metabolism , Male , Microscopy, Electron, Transmission , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondria/ultrastructure , Nucleus Pulposus/drug effects , Nucleus Pulposus/metabolism , Nucleus Pulposus/pathology , RNA Interference , Rats, Sprague-Dawley , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolismABSTRACT
Melatonin is reportedly associated with intervertebral disc degeneration (IDD). Endplate cartilage is vitally important to intervertebral discs in physiological and pathological conditions. However, the effects and mechanism of melatonin on endplate chondrocytes (EPCs) are still unclear. Herein, we studied the effects of melatonin on EPC apoptosis and calcification and elucidated the underlying mechanism. Our study revealed that melatonin treatment decreases the incidence of apoptosis and inhibits EPC calcification in a dose-dependent manner. We also found that melatonin upregulates Sirt1 expression and activity and promotes autophagy in EPCs. Autophagy inhibition by 3-methyladenine reversed the protective effect of melatonin on apoptosis and calcification, while the Sirt1 inhibitor EX-527 suppressed melatonin-induced autophagy and the protective effects of melatonin against apoptosis and calcification, indicating that the beneficial effects of melatonin in EPCs are mediated through the Sirt1-autophagy pathway. Furthermore, melatonin may ameliorate IDD in vivo in rats. Collectively, this study revealed that melatonin reduces EPC apoptosis and calcification and that the underlying mechanism may be related to Sirt1-autophagy pathway regulation, which may help us better understand the association between melatonin and IDD.
Subject(s)
Calcinosis/drug therapy , Chondrocytes/drug effects , Melatonin/pharmacology , Sirtuin 1/metabolism , Animals , Apoptosis/drug effects , Autophagy/drug effects , Autophagy/physiology , Calcinosis/metabolism , Calcinosis/pathology , Carbazoles/pharmacology , Cells, Cultured , Chondrocytes/pathology , Disease Models, Animal , Female , Intervertebral Disc Degeneration/chemically induced , Intervertebral Disc Degeneration/drug therapy , Intervertebral Disc Degeneration/pathology , Male , Oxidative Stress/drug effects , Protective Agents/pharmacology , Rats, Sprague-Dawley , Sirtuin 1/antagonists & inhibitors , tert-Butylhydroperoxide/toxicityABSTRACT
Attenuating oxidative stress-induced damage and promoting endothelial progenitor cell (EPC) differentiation are critical for ischaemic injuries. We suggested monotropein (Mtp), a bioactive constituent used in traditional Chinese medicine, can inhibit oxidative stress-induced mitochondrial dysfunction and stimulate bone marrow-derived EPC (BM-EPC) differentiation. Results showed Mtp significantly elevated migration and tube formation of BM-EPCs and prevented tert-butyl hydroperoxide (TBHP)-induced programmed cell death through apoptosis and autophagy by reducing intracellular reactive oxygen species release and restoring mitochondrial membrane potential, which may be mediated viamTOR/p70S6K/4EBP1 and AMPK phosphorylation. Moreover, Mtp accelerated wound healing in rats, as indicated by reduced healing times, decreased macrophage infiltration and increased blood vessel formation. In summary, Mtp promoted mobilization and differentiation of BM-EPCs and protected against apoptosis and autophagy by suppressing the AMPK/mTOR pathway, improving wound healing in vivo. This study revealed that Mtp is a potential therapeutic for endothelial injury-related wounds.
Subject(s)
Angiogenesis Inducing Agents/pharmacology , Antioxidants/pharmacology , Endothelial Progenitor Cells/drug effects , Iridoids/pharmacology , Surgical Wound/drug therapy , Wound Healing/drug effects , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Animals , Apoptosis/drug effects , Apoptosis/genetics , Autophagy/drug effects , Autophagy/genetics , Bone Marrow Cells/cytology , Bone Marrow Cells/drug effects , Bone Marrow Cells/metabolism , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Movement/drug effects , Cell Proliferation/drug effects , Endothelial Progenitor Cells/cytology , Endothelial Progenitor Cells/metabolism , Gene Expression Regulation/drug effects , Intracellular Signaling Peptides and Proteins , Male , Neovascularization, Physiologic/drug effects , Oxidative Stress/drug effects , Phosphoproteins/genetics , Phosphoproteins/metabolism , Primary Cell Culture , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Signal Transduction , Surgical Wound/genetics , Surgical Wound/metabolism , Surgical Wound/pathology , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , tert-Butylhydroperoxide/antagonists & inhibitors , tert-Butylhydroperoxide/pharmacologyABSTRACT
Intervertebral disc degeneration (IVDD) is one of the major causes of low back pain. Polydatin (PD) has been shown to exert multiple pharmacological effects on different diseases; here, we test the therapeutic potential of PD for IVDD. In in-vitro experiments, we confirmed PD is nontoxic to nucleus pulposus cells (NPCs) under the concentration of 400 µmol/L. Furthermore, PD was able to decrease the level of senescence in TNF-α-treated NPCs, as indicated by ß-gal staining as well as senescence markers p53 and p16 expression. In the aspect of extracellular matrix (ECM), PD not only reduced metalloproteinase 3 (MMP-3), metalloproteinase 13 (MMP-13) and a disintegrin-like and metalloproteinase thrombospondin type 1 motif 4 (ADAMTS-4) expression, but also increased aggrecan and collagen II levels. Mitochondrion is closely related to cellular senescence and ECM homeostasis; mechanistically, we found PD may rescue TNF-α-induced mitochondrial dysfunction, and it may also promote Nrf2 expression and activity. Silencing Nrf2 partly abolished the protective effects of PD on mitochondrial homeostasis, senescence and ECM homeostasis in TNF-α-treated NPCs. Correspondingly, PD ameliorated IVDD in rat model by promoting Nrf2 activity, preserving ECM and inhibiting senescence in nucleus pulposus cells. To sum up, our study suggests that PD exerts protective effects in NPCs against IVDD and reveals the underlying mechanism of PD on Nrf2 activation in NPCs.
Subject(s)
Glucosides/pharmacology , Intervertebral Disc Degeneration/drug therapy , Low Back Pain/drug therapy , NF-E2-Related Factor 2/genetics , Stilbenes/pharmacology , ADAMTS4 Protein/genetics , Aggrecans/genetics , Animals , Cells, Cultured , Cellular Senescence/drug effects , Collagen/genetics , Disease Models, Animal , Extracellular Matrix/drug effects , Extracellular Matrix/genetics , Humans , Intervertebral Disc/drug effects , Intervertebral Disc/pathology , Intervertebral Disc Degeneration/genetics , Intervertebral Disc Degeneration/pathology , Low Back Pain/genetics , Low Back Pain/pathology , Matrix Metalloproteinase 13/genetics , Matrix Metalloproteinase 3/genetics , Nucleus Pulposus/drug effects , Nucleus Pulposus/pathology , Rats , Tumor Necrosis Factor-alpha/geneticsABSTRACT
Spinal cord injury (SCI) is a severe neurological disease; however, few drugs have been proved to treat SCI effectively. Neuroinflammation is the major pathogenesis of SCI secondary injury and considered to be the therapeutic target of SCI. Salidroside (Sal) has been reported to exert anti-inflammatory effects in airway, adipose and myocardial tissue; however, the role of Sal in SCI therapeutics has not been clarified. In this study, we showed that Sal could improve the functional recovery of spinal cord in rats as revealed by increased BBB locomotor rating scale, angle of incline, and decreased cavity of spinal cord injury and apoptosis of neurons in vivo. Immunofluorescence double staining of microglia marker and M1/M2 marker demonstrated that Sal could suppress M1 microglia polarization and activate M2 microglia polarization in vivo. To verify how Sal exerts its effects on microglia polarization and neuron protection, we performed the mechanism study in vitro in microglia cell line BV-2 and neuron cell line PC12. The results showed that Sal prevents apoptosis of PC12 cells in coculture with LPS-induced M1 BV-2 microglia, also the inflammatory secretion phenotype of M1 BV-2 microglia was suppressed by Sal, and further studies demonstrated that autophagic flux regulation through AMPK/mTOR pathway was involved in Sal regulated microglia polarization after SCI. Overall, our study illustrated that Sal could promote spinal cord injury functional recovery in rats, and the mechanism may relate to its microglia polarization modulation through AMPK-/mTOR-mediated autophagic flux stimulation.
Subject(s)
Cell Polarity/drug effects , Glucosides/therapeutic use , Inflammation/drug therapy , Microglia/pathology , Neurons/pathology , Phenols/therapeutic use , Recovery of Function , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/physiopathology , Adenylate Kinase/metabolism , Animals , Apoptosis/drug effects , Autophagy/drug effects , Cell Line , Female , Glucosides/pharmacology , Inflammation/complications , Inflammation Mediators/metabolism , Lipopolysaccharides , Macrophages/drug effects , Macrophages/metabolism , Macrophages/pathology , Mice , Microglia/drug effects , Mitochondria/drug effects , Mitochondria/metabolism , Models, Biological , Motor Activity/drug effects , Neurons/drug effects , Neurons/metabolism , Phenols/pharmacology , Rats, Sprague-Dawley , Recovery of Function/drug effects , Signal Transduction/drug effects , Spinal Cord Injuries/complications , Spinal Cord Injuries/pathology , TOR Serine-Threonine Kinases/metabolismABSTRACT
Wound therapy remains a clinical challenge due to the complexity of healing pathology and high demand of achieving functional and aesthetically satisfactory scars. Newly formed blood vessels are essential for tissue repair since they can support cells at the wound site with nutrition and oxygen. In this study, we investigated the effects of Asperosaponin VI (ASA VI) isolated from a traditional Chinese medicine, the root of Dipsacus asper Wall, in promoting angiogenesis, as well as its function in wound therapeutics. Treatment of human umbilical vein endothelial cells (HUVECs) with ASA VI (20-80 µg/mL) dose-dependently promoted the proliferation, migration and enhanced their angiogenic ability in vitro, which were associated with the up-regulated HIF-1α/VEGF signaling. Full-thickness cutaneous wound model rats were injected with ASA VI (20 mg·kg-1·d-1, iv) for 21 d. Administration of ASA VI significantly promoted the cutaneous wound healing, and more blood vessels were observed in the regenerated tissue. Due to rapid vascularization, the cellular proliferation status, granulation tissue formation, collagen matrix deposition and remodeling processes were all accelerated, resulting in efficient wound healing. In summary, ASA VI promotes angiogenesis of HUVECs in vitro via up-regulating the HIF-1α/VEGF pathway, and efficiently enhances the vascularization in regenerated tissue and facilitates wound healing in vivo. The results reveal that ASA VI is a potential therapeutic for vessel injury-related wounds.
Subject(s)
Hypoxia-Inducible Factor 1, alpha Subunit/physiology , Neovascularization, Physiologic/physiology , Saponins/pharmacology , Vascular Endothelial Growth Factor A/physiology , Wound Healing/drug effects , Animals , Cell Movement/physiology , Cell Proliferation/physiology , Cells, Cultured , Dose-Response Relationship, Drug , Drugs, Chinese Herbal/pharmacology , Humans , Rats , Signal Transduction/drug effects , Up-Regulation/drug effectsABSTRACT
Many microRNAs (miRNAs) have been identified as being involved in diabetes; however, the question of which ones may be the most promising therapeutical targets still needs more investigation. This study aims to understand the overall development tendency and identify a specific miRNA molecule to attenuate diabetes. We developed a combined analysis method based on bibliometrics and bioinformatics to visualize research institutions, authors, cited references, and keywords to identify a promising target for diabetes. Our data showed that diabetes-related miRNA is receiving continuously increasing attention, with a large number of publications, indicating that this is still a hot topic in diabetes research. Scientists from different institutions are collaborating closely in this field. miR-21, miR-146a, miR-155, and miR-34a are frequently mentioned as high-frequency keywords in the related references. Moreover, among all the above miRNAs, bioinformatics analysis further strengthens the argument that miR-21 is the top significantly upregulated molecule in diabetes patients and plays an important role in the pathogenesis of diabetes. Our study may provide a way to identify targets and promote the clinical translation of miRNA-related therapeutical strategies for diabetes, which could also indicate present and future directions for research in this area.
ABSTRACT
Deep tissue infection is a common clinical issue and therapeutic difficulty caused by the disruption of the host antibacterial immune function, resulting in treatment failure and infection relapse. Intracellular pathogens are refractory to elimination and can manipulate host cell biology even after appropriate treatment, resulting in a locoregional immunosuppressive state that leads to an inadequate response to conventional anti-infective therapies. Here, a novel antibacterial strategy involving autogenous immunity using a biomimetic nanoparticle (NP)-based regulating system is reported to induce in situ collaborative innate-adaptive immune responses. It is observed that a macrophage membrane coating facilitates NP enrichment at the infection site, followed by active NP accumulation in macrophages in a mannose-dependent manner. These NP-armed macrophages exhibit considerably improved innate capabilities, including more efficient intracellular ROS generation and pro-inflammatory factor secretion, M1 phenotype promotion, and effective eradication of invasive bacteria. Furthermore, the reprogrammed macrophages direct T cell activation at infectious sites, resulting in a robust adaptive antimicrobial immune response to ultimately achieve bacterial clearance and prevent infection relapse. Overall, these results provide a conceptual framework for a novel macrophage-based strategy for infection treatment via the regulation of autogenous immunity.
Subject(s)
Immunity, Innate , Macrophages , Humans , Macrophages/metabolism , Anti-Bacterial Agents/metabolism , Adaptive Immunity , RecurrenceABSTRACT
Bone is a common organ for solid tumor metastasis. Malignant bone tumor becomes insensitive to systemic therapy after colonization, followed by poor prognosis and high relapse rate. Immune and bone cells in situ constitute a unique immune microenvironment, which plays a crucial role in the context of bone metastasis. This review firstly focuses on lymphatic cells in bone metastatic cancer, including their function in tumor dissemination, invasion, growth and possible cytotoxicity-induced eradication. Subsequently, we examine myeloid cells, namely macrophages, myeloid-derived suppressor cells, dendritic cells, and megakaryocytes, evaluating their interaction with cytotoxic T lymphocytes and contribution to bone metastasis. As important components of skeletal tissue, osteoclasts and osteoblasts derived from bone marrow stromal cells, engaging in 'vicious cycle' accelerate osteolytic bone metastasis. We also explain the concept tumor dormancy and investigate underlying role of immune microenvironment on it. Additionally, a thorough review of emerging treatments for bone metastatic malignancy in clinical research, especially immunotherapy, is presented, indicating current challenges and opportunities in research and development of bone metastasis therapies.
Subject(s)
Bone Neoplasms , Tumor Microenvironment , Humans , Neoplasm Recurrence, Local , Bone and Bones/pathology , Bone Neoplasms/pathology , MacrophagesABSTRACT
Focused on the key areas of energy, buildings, industry, and transportation, with 2020 as the base year and 2035 as the target year, we respectively designed the baseline scenario, policy scenario, and enhanced scenario, calculated the emission reduction potential of air pollutants and CO2 of Beijing, and constructed an assessment method of co-control effect gradation index to evaluate the co-control effect of air pollutants and CO2 in the policy scenario and enhanced scenario. The results showed that in the policy scenario and enhanced scenario, the reduction rates of air pollutants emissions will reach 11%-75% and 12%-94%, respectively, and reduction rates of CO2 emissions will reach 41% and 52%, respectively, compared with those from the baseline scenario. Optimizing vehicle structure had the largest contribution to the emission reduction of NOx, VOCs, and CO2, and the emission reduction rates will reach 74%, 80%, and 31% in the policy scenario and 68%, 74%, and 22% in the enhanced scenario, respectively. Replacing coal-fired with clean energy in rural areas had the largest contribution to the emission reduction of SO2; the emission reduction rates will reach 47% and 35% in the policy scenario and enhanced scenario, respectively. Improving the green level of new buildings had the largest contribution to the emission reduction of PM10; the emission reduction rates will reach 79% and 74% in the policy scenario and enhanced scenario, respectively. Optimizing travel structure and promoting green development of digital infrastructure had the best co-control effect. The co-control effect of replacing coal-fired with clean energy in rural areas, optimizing vehicle structure, and promoting green upgrading of the manufacturing industry will be improved to a better status in the enhanced scenario. More attention should be paid to improving the proportion of green trips, implementing the promotion of new energy vehicles, and the green transportation of goods to reduce emissions in the field of transportation. At the same time, with the continuous improvement in electrification level in the end energy consumption structure, the proportion of green electricity should be increased by expanding local renewable energy power production and increasing external green electricity transmission capacity, to enhance the co-control effect of pollution and carbon reduction.
ABSTRACT
Purpose: We retrospectively study twenty-nine surgical cases of aggressive vertebral hemangiomas (AVHs) with neurological deficits and extradural compression to determine the optimal surgical treatment strategy for AVHs at a single institution. Methods: Patients with AVHs with neurological deficits who underwent partial tumor resection plus decompression with or without vertebroplasty (VP), and radiotherapy between 2010 and 2021 were included in this study. Clinical characteristics, surgical outcomes, and follow-up data of the patients were reviewed retrospectively. Results: Twenty-nine AVH cases with neurological deficits and spinal instability were included in this study and treated surgically. The mean operation time of patients with decompression surgery plus VP (Groupe A) was 215.9 (120-265 min), shorter than that of decompression surgery without VP (Group B) 240.2 (120-320 min). Intraoperative blood loss was 273.3 (100-550 mL) in group A and 635.3 (200-1600 mL) in group B. In addition, a significant reduction in blood loss was observed in group A compared to the group B (p=0.0001). All patients experienced immediate pain relief and improvement in their neurological symptoms. Neurological function was assessed by the Frankel score, ASIA score, and the visual analogue scale (VAS) pain score decreased from 7.4 (4-9) to 1.3 (0-3). Of twenty-nine patients in this study, only 7% (2/29 patients) showed signs of recurrence. Conclusion: Decompression plus VP achieve good tumor control and decrease surgical complication. Preoperative vascular embolization and VP can reduce intraoperative bleeding in the treatment of AVH surgery. Moreover, postoperative radiotherapy seems to be a good technique to prevent tumor recurrence.