Intervertebral disc(ID)degeneration(IDD)is one of the main causes of chronic low back pain,and degenerative lesions are usually caused by an imbalance between catabolic and anabolic processes in the ID.The environment...Intervertebral disc(ID)degeneration(IDD)is one of the main causes of chronic low back pain,and degenerative lesions are usually caused by an imbalance between catabolic and anabolic processes in the ID.The environment in which the ID is located is harsh,with almost no vascular distribution within the disc,and the nutrient supply relies mainly on the diffusion of oxygen and nutrients from the blood vessels located under the endplate.The stability of its internal environment also plays an important role in preventing IDD.The main feature of disc degeneration is a decrease in the number of cells.Mesenchymal stem cells have been used in the treatment of disc lesions due to their ability to differentiate into nucleus pulposus cells in a nonspecific anti-inflammatory manner.The main purpose is to promote their regeneration.The current aim of stem cell therapy is to replace the aged and metamorphosed cells in the ID and to increase the content of the extracellular matrix.The treatment of disc degeneration with stem cells has achieved good efficacy,and the current challenge is how to improve this efficacy.Here,we reviewed current treatments for disc degeneration and summarize studies on stem cell vesicles,enhancement of therapeutic effects when stem cells are mixed with related substances,and improvements in the efficacy of stem cell therapy by adjuvants under adverse conditions.We reviewed the new approaches and ideas for stem cell treatment of disc degeneration in order to contribute to the development of new therapeutic approaches to meet current challenges.展开更多
Intervertebral disc(IVD)degenerative diseases are a common problem in the world,and they cause substantial social and economic burdens for people.The current methods for treating IVD degenerative diseases mainly inclu...Intervertebral disc(IVD)degenerative diseases are a common problem in the world,and they cause substantial social and economic burdens for people.The current methods for treating IVD degenerative diseases mainly include surgery and conservative treatment,which cannot fundamentally restore the normal structure of the disc.With continuous research on the mechanism of degeneration and the development of regenerative medicine,rapid progress has been made in the field of regenerative medicine regarding the use of stem cell-derived exosomes,which are active biological substances used in intercellular communication,because they show a strong effect in promoting tissue regeneration.The study of exosomes in the field of IVD degeneration has just begun,and many surprising achievements have been made.This paper mainly reviews the biological characteristics of exosomes and highlights the current status of exosomes in the field of IVD degeneration,as well as future developments regarding exosomes.展开更多
Karacoline is a compound found in the plant Aconitum kusnezoffii Reichb.Although Aconitum kusnezoffii Reichb is widely used for the treatment of pain,very few studies have been carried out on the use of karacoline due...Karacoline is a compound found in the plant Aconitum kusnezoffii Reichb.Although Aconitum kusnezoffii Reichb is widely used for the treatment of pain,very few studies have been carried out on the use of karacoline due to its potential toxicity.In this study,we selected key matrix metalloproteinases(MMPs),collagen II,and aggrecan as targets due to their association with intervertebral disc degeneration(IDD).Using these targets,we then used network pharmacology to predict a series of molecules that might exert therapeutic effects on IDD.Of these molecules,karacoline was predicted to have the best effect.Tumor necrosis factor(TNF)-a is known to promote the degeneration of the extracellular matrix in IDD.We therefore applied different concentrations of karacoline(0,1.25,or 12.88 mM)along with 100 ng/mL TNF-a to rat nucleus pulposus cells and found that karacoline reduced the expression of MMP-14 in IDD by inhibiting the nuclear factor(NF)-κB pathway,while collagen II and aggrecan expression was increased.This suggested that extracellular matrix degradation was inhibited by karacoline(P<0.05).Our data therefore reveal a new clinical application of karacoline and provide support for the use of network pharmacology in predicting novel drugs.展开更多
ObjectiveTo investigate the gene expression changes in normal and degeneration lumbar intervertebral disc in humans, providing information for clinical. MethodsThe PCR products of 4096 human genes were spotted onto a ...ObjectiveTo investigate the gene expression changes in normal and degeneration lumbar intervertebral disc in humans, providing information for clinical. MethodsThe PCR products of 4096 human genes were spotted onto a kind of chemical-material-coated-glass slides. The total RNAs were isolated from the tissues. Both the mRNAs from the degeneration and normal lumbar intervertebral disc in humans were reversely transcribed to the cDNAs, which used as the hybridization probes with the incorporations of fluorescent dUTP. The mixed probes were then hybridized to the cDNA microarray. After high-stringent washing, the cDNA microarray was scanned for the fluorescent signals and analyzed with computer image analysis. ResultsAmong the 4096 targets, there were 706 genes whose expression levels differed between the degeneration and normal lumbar intervertebral disc in all cases, comprising 298 up-regulated and 358 down-regulated ones. ConclusionDNA microarray technology is an effective technique in screening for differently expressed genes between the degeneration and normal lumbar intervertebral disc. Cell apoptosis plays an important role in the process of lumbar intervertebral disc degeneration.展开更多
BACKGROUND Intervertebral disc degeneration(IVDD)is the leading cause of lower back pain.Disc degeneration is characterized by reduced cellularity and decreased production of extracellular matrix(ECM).Mesenchymal stem...BACKGROUND Intervertebral disc degeneration(IVDD)is the leading cause of lower back pain.Disc degeneration is characterized by reduced cellularity and decreased production of extracellular matrix(ECM).Mesenchymal stem cells(MSCs)have been envisioned as a promising treatment for degenerative illnesses.Cell-based therapy using ECM-producing chondrogenic derivatives of MSCs has the potential to restore the functionality of the intervertebral disc(IVD).AIM To investigate the potential of chondrogenic transcription factors to promote differentiation of human umbilical cord MSCs into chondrocytes,and to assess their therapeutic potential in IVD regeneration.METHODS MSCs were isolated and characterized morphologically and immunologically by the expression of specific markers.MSCs were then transfected with Sox-9 and Six-1 transcription factors to direct differentiation and were assessed for chondrogenic lineage based on the expression of specific markers.These differentiated MSCs were implanted in the rat model of IVDD.The regenerative potential of transplanted cells was investigated using histochemical and molecular analyses of IVDs.RESULTS Isolated cells showed fibroblast-like morphology and expressed CD105,CD90,CD73,CD29,and Vimentin but not CD45 antigens.Overexpression of Sox-9 and Six-1 greatly enhanced the gene expression of transforming growth factor beta-1 gene,BMP,Sox-9,Six-1,and Aggrecan,and protein expression of Sox-9 and Six-1.The implanted cells integrated,survived,and homed in the degenerated intervertebral disc.Histological grading showed that the transfected MSCs regenerated the IVD and restored normal architecture.CONCLUSION Genetically modified MSCs accelerate cartilage regeneration,providing a unique opportunity and impetus for stem cell-based therapeutic approach for degenerative disc diseases.展开更多
Clinical studies have found that patients withcervical degenerative disease are usually accompanied by dizziness.Anterior cervical surgery can eliminate not only chronic neck pain,cervical radiculopathy or myelopathy,...Clinical studies have found that patients withcervical degenerative disease are usually accompanied by dizziness.Anterior cervical surgery can eliminate not only chronic neck pain,cervical radiculopathy or myelopathy,but also dizziness.Immunohistochemical studies show that a large number of mechanoreceptors,especially Ruffini corpuscles,are present in degenerated cervical discs.The available evidence suggests a key role of Ruffini corpuscles in the pathogenesis of dizziness caused by cervical degenerative disease(i.e.cervical discogenic dizziness).Disc degeneration is characterized by an elevation of inflammatory cytokines,which stimulates the mechanoreceptors in degenerated discs and results in peripheral sensitization.Abnormal cervical proprioceptive inputs from the mechanoreceptors are transmitted to the central nervous system,resulting in sensory mismatches with vestibular and visual information and leads to dizziness.In addition,neck pain caused by cervical disc degeneration can play a key role in cervical discogenic dizziness by increasing the sensitivity of muscle spindles.Like cervical discogenic pain,the diagnosis of cervical discogenic dizziness can be challenging and can be made only after other potential causes of dizziness have been ruled out.Conservative treatment is effective for the majority of patients.Existing basic and clinical studies have shown that cervical intervertebral disc degeneration can lead to dizziness.展开更多
<strong>Objective:</strong> To describe the relationship between autophagy and apoptosis and the possible signaling pathways involved in degenerative lumbar intervertebral disc. <strong>Summary of Ba...<strong>Objective:</strong> To describe the relationship between autophagy and apoptosis and the possible signaling pathways involved in degenerative lumbar intervertebral disc. <strong>Summary of Background Data:</strong> Autophagy and apoptosis are regulatory cellular mechanisms that determine many pathologies, including degenerative intervertebral disc disease. The interactions between these events in the damage or protection of intervertebral disc cells and in cellular homeostasis remain controversial. <strong>Methods:</strong> The sample size was twenty patients who underwent lumbar spine surgery for symptomatic disc herniation or spondylolisthesis. Intervertebral discs were classified by magnetic resonance as Pfirrmann grade IV and grade V. Six patients were operated on two levels, resulting in twenty-six intervertebral discs that were submitted to immunohistochemistry to verify the protein expression of autophagy and apoptosis markers. <strong>Results: </strong>The autophagic markers had greater protein expression in the human intervertebral disc (Pfirrmann Grades IV and V). Under these conditions, autophagy and apoptosis showed a negative correlation. Regarding apoptosis, caspase 8 presented the highest protein expression, which allows inferring the preference for the extrinsic pathway in cell death. <strong>Conclusions: </strong>Autophagy had the greatest protein expression negative profile compared to apoptosis. Caspase 8 had the highest protein expression in apoptosis.展开更多
BACKGROUND Conventional plain X-ray images of rats,the most common animals used as degeneration models,exhibit unclear vertebral structure and blurry intervertebral disc spaces due to their small size,slender vertebra...BACKGROUND Conventional plain X-ray images of rats,the most common animals used as degeneration models,exhibit unclear vertebral structure and blurry intervertebral disc spaces due to their small size,slender vertebral bodies.AIM To apply molybdenum target X-ray photography in the evaluation of caudal intervertebral disc(IVD)degeneration in rat models.METHODS Two types of rat caudal IVD degeneration models(needle-punctured model and endplate-destructed model)were established,and their effectiveness was verified using nuclear magnetic resonance imaging.Molybdenum target inspection and routine plain X-ray were then performed on these models.Additionally,four observers were assigned to measure the intervertebral height of degenerated segments on molybdenum target plain X-ray images and routine plain X-ray images,respectively.The degeneration was evaluated and statistical analysis was subsequently conducted.RESULTS Nine rats in the needle-punctured model and 10 rats in the endplate-destructed model were effective.Compared with routine plain X-ray images,molybdenum target plain X-ray images showed higher clarity,stronger contrast,as well as clearer and more accurate structural development.The McNemar test confirmed that the difference was statistically significant(P=0.031).In the two models,the reliability of the intervertebral height measured by the four observers on routine plain X-ray images was poor(ICC<0.4),while the data obtained from the molybdenum target plain X-ray images were more reliable.CONCLUSIONMolybdenum target inspection can obtain clearer images and display fine calcification in the imaging evaluation of caudal IVD degeneration in rats,thus ensuring a more accurate evaluation of degeneration.展开更多
<strong>Objective:</strong> To characterize the association between DNA damage and Intervertebral disc degeneration (IDD). <strong>Summary of</strong> <strong>Background Data:</strong&...<strong>Objective:</strong> To characterize the association between DNA damage and Intervertebral disc degeneration (IDD). <strong>Summary of</strong> <strong>Background Data:</strong> IDD is the main disorder causing low back pain and is the most promising target for intervention. Many factors can contribute to the etiology, such as genetics, environment and lifestyle, but it is not yet fully understood. DNA damage can influence this process and needs to be studied, as well as the agents that can determine these damages. <strong>Methods:</strong> A systematic literature search of PubMed, Web of Science and Scopus was performed to identify studies related to DNA damage to the intervertebral disc. <strong>Results:</strong> After screening 61 records, 7 articles were included according to the selection criteria. All studies showed some relation between DNA damage and IDD. However, DNA damage was always considered a secondary issue to be investigated. <strong>Conclusions:</strong> Many factors can influence DNA damage induced by different genotoxic agents on the degenerative cascade of IVD. However, the correlation between IDD severity and DNA damage, as well as the factual role of DNA damage in disc degeneration could not be defined.展开更多
Objectives： To develop a rabbit model of intervertebral disc degeneration that more exactly simulates the pathological changes of human intervertebral disc degeneration. Methods： Twelve New Zealand white rabbits wer...Objectives： To develop a rabbit model of intervertebral disc degeneration that more exactly simulates the pathological changes of human intervertebral disc degeneration. Methods： Twelve New Zealand white rabbits were utilized to establish three different disc injury models according to the following protocol; group A： anulus punctures were done with a 18-gauge needle at L2-L3 and L5-L6; Group B： intradiscal injection of interleukin-1 IL-1β with a 23-gauge needle at L3-L4; and Group C： intradiscal injection of phosphate buffer saline（PBS） with a 23-gauge needle at L4-LS. The L1-L2 level was used as a control. Rabbits were killed after 24 weeks. The intervertebral disc height was measured by lateral plain radiographs. After the radiographic measurements were obtained, the intervertebral discs were removed and analyzed for DNA, sulfated glycosaminoglycan（s-GAG） and water contents of nucleus pulposus. Results： The intervertebral disc height, s-GAG, and water contents in anulus needle punctures were significantly decreased in Group A, but the DNA content in the nucleus pulposus was significantly increased when compared to the control. The significant decrease of disc height and water contents were demonstrated, only the s-GAG and DNA contents did not show a significant difference in Group B when compared to the control. The significant decrease of disc height, s-GAG, water, and DNA contents did not show in Group C when compared to the control. Conclusion： The 18-gauge puncture models produced the most consistent disc degeneration in the rabbit lumbar spine.展开更多
Degenerative disc disease is the most common cause of low back pain. Intervertebral disc abnormalities are commonly evaluated by magnetic resonance imaging (MRI), and Pfirrmann’s system involves the use of T2-weighte...Degenerative disc disease is the most common cause of low back pain. Intervertebral disc abnormalities are commonly evaluated by magnetic resonance imaging (MRI), and Pfirrmann’s system involves the use of T2-weighted images (T2WI) to classify disc degeneration. However, as this classification is based on visual evaluation, it is not possible to quantify degeneration using this method. The present study was performed to establish an MRI-based intervertebral disc classification system using diffusional kurtosis imaging (DKI), to quantify intervertebral disc water content according to the Pfirrmann classification. Sagittal mean diffusional kurtosis (MK) mapping was performed for the L3/4, L4/5, and L5/S1 intervertebral discs in 32 patients (15 female, 17 male;age range, 24 - 82 years;mean age, 57.7 years). The degree of disc degeneration was assessed in the midsagittal section on T2WI according to the Pfirrmann classification (grade I - V). The relationships between MK values, which are correlated with intervertebral disc composition changes, and grade of degeneration determined using the Pfirrmann classification were analyzed. The MK values tended to decrease with increasing grade of degeneration, and differed significantly between grades I and IV, but not between grade IV and V (P < 0.05, Mann-Whitney U test). DKI is an effective means of detecting the early stages of disc degeneration. Therefore, DKI may be a useful diagnostic tool for quantitative assessment of intervertebral disc degeneration.展开更多
The lumbar spine,an important part of the body’s motor mechanism,is more susceptible to damage as it bears most of the body’s load.Age can cause clinical manifestations such as neurological impairment,back and leg p...The lumbar spine,an important part of the body’s motor mechanism,is more susceptible to damage as it bears most of the body’s load.Age can cause clinical manifestations such as neurological impairment,back and leg pain in the lumbar spine.External forces result in nucleus pulposus out,destruction of the intervertebral disc fibrous ring,and gradual aging and damage.Lumbar degenerative change is a common middle-aged and old-aged disease,and its clinical symptoms on the initial stage are not obvious,but it becomes more and more serious as they get older.Patients with severe lumbar degenerative changes will appear symptoms such as urinary and fecal incontinence,lower extremity numbness,back pain,and sexual dysfunction.The main reason for back pain and leg pain is the degenerative changes in the lumbar intervertebral discs,at the same time which also leads to patients’lumbar instability.This study focuses on the correlation analysis of intervertebral disc degeneration with HTRA1 and HAPLN1 gene polymorphisms.展开更多
Sustained and intense inflammation is the pathological basis for intervertebral disc degeneration(IVDD).Effective antagonism or reduction of local inflammatory factors may help regulate the IVDD microenvironment and r...Sustained and intense inflammation is the pathological basis for intervertebral disc degeneration(IVDD).Effective antagonism or reduction of local inflammatory factors may help regulate the IVDD microenvironment and reshape the extracellular matrix of the disc.This study reports an immunomodulatory hydrogel microsphere system combining cell membrane-coated mimic technology and surface chemical modification methods by grafting neutrophil membrane-coated polylactic-glycolic acid copolymer nanoparticles loaded with transforming growth factor-beta 1(TGF-β1)(T-NNPs)onto the surface of methacrylic acid gelatin anhydride microspheres(GM)via amide bonds.The nanoparticle-microsphere complex(GM@T-NNPs)sustained the long-term release of T-NNPs with excellent cell-like functions,effectively bound to pro-inflammatory cytokines,and improved the release kinetics of TGF-β1,maintaining a 36 day-acting release.GM@T-NNPs significantly inhibited lipopolysaccharide-induced inflammation in nucleus pulposus cells in vitro,downregulated the expression of inflammatory factors and matrix metalloproteinase,and upregulated the expression of collagen-II and aggrecan.GM@T-NNPs effectively restored intervertebral disc height and significantly improved the structure and biomechanical function of the nucleus pulposus in a rat IVDD model.The integration of biomimetic technology and nano-drug delivery systems expands the application of biomimetic cell membrane-coated materials and provides a new treatment strategy for IVDD.展开更多
Oxidative stress and aging lead to progressive senescence of nucleus pulposus(NP)cells,resulting in intervertebral disc(IVD)degeneration(IVDD).In some cases,degenerative IVD can further cause low back pain(LBP).Severa...Oxidative stress and aging lead to progressive senescence of nucleus pulposus(NP)cells,resulting in intervertebral disc(IVD)degeneration(IVDD).In some cases,degenerative IVD can further cause low back pain(LBP).Several studies have confirmed that delaying and rejuvenating the senescence of NP cells can attenuate IVDD.However,the relatively closed tissue structure of IVDs presents challenges for the local application of anti-senescence drugs.Here,we prepared an anti-senescence hydrogel by conjugating phenylboronic acid-modified gelatin methacryloyl(GP)with quercetin to alleviate IVDD by removing senescent NP cells.The hydrogel exhibited injectability,biodegradability,prominent biocompatibility and responsive release of quercetin under pathological conditions.In vitro experiments demonstrated that the hydrogel could reduce the expression of senescence markers and restore the metabolic balance in senescent NP cells.In vivo studies validated that a single injection of the hydrogel in situ could maintain IVD tissue structure and alleviate sensitivity to noxious mechanical force in the rat models,indicating a potential therapeutic approach for ameliorating IVDD and LBP.This approach helps prevent potential systemic toxicity associated with systemic administration and reduces the morbidity resulting from repeated injections of free drugs into the IVD,providing a new strategy for IVDD treatment.展开更多
Intervertebral disc degeneration(IVDD)can be caused by aging,injury,and genetic factors.The pathological changes associated with IVDD include the excessive accumulation of reactive oxygen species(ROS),cellular pyropto...Intervertebral disc degeneration(IVDD)can be caused by aging,injury,and genetic factors.The pathological changes associated with IVDD include the excessive accumulation of reactive oxygen species(ROS),cellular pyroptosis,and extracellular matrix(ECM)degradation.There are currently no approved specific molecular therapies for IVDD.In this study,we developed a multifunctional and microenvironment-responsive metal-phenolic network release platform,termed TMP@Alg-PBA/PVA,which could treat(IL-1β)-induced IVDD.The metal-phenolic network(TA-Mn-PVP,TMP)released from this platform targeted mitochondria to efficiently scavenge ROS and reduce ECM degradation.Pyroptosis was suppressed through the inhibition of the IL-17/ERK signaling pathway.These findings demonstrate the versatility of the platform.And in a rat model of IVDD,TMP@Alg-PBA/PVA exhibited excellent therapeutic effects by reducing the progression of the disease.TMP@Alg-PBA/PVA,therefore,presents clinical potential for the treatment of IVDD.展开更多
Low back pain(LBP)is a common disease that imposes a huge social and economic burden on people.Intervertebral disc(IVD)degeneration(IVDD)is often considered to be the leading cause of LBP and further aggravate and cau...Low back pain(LBP)is a common disease that imposes a huge social and economic burden on people.Intervertebral disc(IVD)degeneration(IVDD)is often considered to be the leading cause of LBP and further aggravate and cause serious spinal problems.The established treatment strategy for IVDD consists of physiotherapy,pain medication by drug therapy,and,if necessary,surgery,but none of them can be treated from the etiology;that is,it cannot fundamentally reverse IVD and reconstruct the mechanical function of the spine.With the development of nanotechnology and regenerative medicine,nano-drug delivery systems(NDDSs)have improved treatment results because of their good biodegradability,biocompatibility,precise targeted specific drug delivery,prolonged drug release time,and enhanced drug efficacy,and various new NDDSs for drugs,proteins,cells,and genes have brought light and hope for the treatment of IVDD.This review summarizes the research progress of NDDSs in the treatment of IVDD and provides prospects for using NDDSs to address the challenges of IVDD.We hope that the ideas generated in this review will provide insight into the precise treatment of IVDD.展开更多
Stem cell transplantation has been proved a promising therapeutic instrument in intervertebral disc degeneration(IVDD).However,the elevation of oxidative stress in the degenerated region impairs the efficiency of mese...Stem cell transplantation has been proved a promising therapeutic instrument in intervertebral disc degeneration(IVDD).However,the elevation of oxidative stress in the degenerated region impairs the efficiency of mesenchymal stem cells(BMSCs)transplantation treatment via exaggeration of mitochondrial ROS and promotion of BMSCs apoptosis.Herein,we applied an emulsion-confined assembly method to encapsulate Coenzyme Q10(Co-Q10),a promising hydrophobic antioxidant which targets mitochondria ROS,into the lecithin micelles,which renders the insoluble Co-Q10 dispersible in water as stable colloids.These micelles are injectable,which displayed efficient ability to facilitate Co-Q10 to get into BMSCs in vitro,and exhibited prolonged release of Co-Q10 in intervertebral disc tissue of animal models.Compared to mere use of Co-Q10,the Co-Q10 loaded micelle possessed better bioactivities,which elevated the viability,restored mitochondrial structure as well as function,and enhanced production of ECM components in rat BMSCs.Moreover,it is demonstrated that the injection of this micelle with BMSCs retained disc height and alleviated IVDD in a rat needle puncture model.Therefore,these Co-Q10 loaded micelles play a protective role in cell survival and differentiation through antagonizing mitochondrial ROS,and might be a potential therapeutic agent for IVDD.展开更多
Intervertebral disc degeneration(IVDD)is a leading cause of low back pain.The strategy of using functional materials to deliver nucleic acids provides a powerful tool for ameliorating IVDD.However,the immunogenicity o...Intervertebral disc degeneration(IVDD)is a leading cause of low back pain.The strategy of using functional materials to deliver nucleic acids provides a powerful tool for ameliorating IVDD.However,the immunogenicity of nucleic acid vectors and the poor mechanical properties of functional materials greatly limit their effects.Herein,antagomir-204-3p(AM)shows low immunogenicity and effectively inhibits the apoptosis of nucleus pulposus cells.Moreover,a high-strength biohydrogel based on zinc-oxidized sodium alginate-gelatin(ZOG)is designed as a multifunctional nucleic acid delivery platform.ZOG loaded with AM(ZOGA)exhibits great hygroscopicity,antibacterial activity,biocompatibility,and biodegradability.Moreover,ZOGA can be cross-linked with nucleus pulposus tissue to form a high-strength collagen network that improves the mechanical properties of the intervertebral disc(IVD).In addition,ZOGA provides an advantageous microenvironment for genetic expression in which AM can play an efficient role in maintaining the metabolic balance of the extracellular matrix.The results of the radiological and histological analyses demonstrate that ZOGA restores the height of the IVD,retains moisture in the IVD,and maintains the tissue structure.The ZOGA platform shows the sustained release of nucleic acids and has the potential for application to ameliorate IVDD,opening a path for future studies related to IVD.展开更多
Inflammation,abnormal cholesterol metabolism,and macrophage infiltration are involved in the destruction of the extracellular matrix of the nucleus pulposus(NP),culminating in intervertebral disc degeneration(IDD).Whe...Inflammation,abnormal cholesterol metabolism,and macrophage infiltration are involved in the destruction of the extracellular matrix of the nucleus pulposus(NP),culminating in intervertebral disc degeneration(IDD).Whether nimbolide(Nim),a natural extract,can alleviate IDD is unclear.In this study,we demonstrated that Nim promotes cholesterol efflux and inhibits the activation of the nuclear factor kappa B(NF-κB)and mitogen-activated protein kinase(MAPK)signaling pathways by activating sirtuin 1(SIRT1)in nucleus pulposus cells(NPCs)during inflammation.Thus,Nim balanced matrix anabolism and catabolism of NPCs.However,the inhibition of SIRT1 significantly attenuated the effects of Nim.We also found that Nim promoted the expression of SIRT1 in RAW 264.7,which enhanced the proportion of M2 macrophages by facilitating cholesterol homeostasis reprogramming and impeded M1-like macrophages polarization by blocking the activation of inflammatory signaling.Based on these results,Nim can improve the microenvironment and facilitate matrix metabolism equilibrium in NPCs.Furthermore,in vivo treatment with Nim delayed IDD progression by boosting SIRT1 expression,modulating macrophage polarization and preserving the extracellular matrix.In conclusion,Nim may represent a novel therapeutic strategy for treating IDD.展开更多
Stem cell-based transplantation is a promising therapeutic approach for intervertebral disc degeneration(IDD).Current limitations of stem cells include with their insufficient cell source,poor proliferation capacity,l...Stem cell-based transplantation is a promising therapeutic approach for intervertebral disc degeneration(IDD).Current limitations of stem cells include with their insufficient cell source,poor proliferation capacity,low nucleus pulposus(NP)-specific differentiation potential,and inability to avoid pyroptosis caused by the acidic IDD microenvironment after transplantation.To address these challenges,embryo-derived long-term expandable nucleus pulposus progenitor cells(NPPCs)and esterase-responsive ibuprofen nano-micelles(PEG-PIB)were prepared for synergistic transplantation.In this study,we propose a biomaterial pre-modification cell strategy;the PEG-PIB were endocytosed to pre-modify the NPPCs with adaptability in harsh IDD microenvironment through inhibiting pyroptosis.The results indicated that the PEG-PIB pre-modified NPPCs exhibited inhibition of pyroptosis in vitro;their further synergistic transplantation yielded effective functional recovery,histological regeneration,and inhibition of pyroptosis during IDD regeneration.Herein,we offer a novel biomaterial pre-modification cell strategy for synergistic transplantation with promising therapeutic effects in IDD regeneration.展开更多
基金National Natural Science Foundation of China,No.82202766Natural Science Foundation of Hubei Province of China,No.2022CFB686+1 种基金Science Foundation of Union Hospital,No.2021xhyn102Scientific Research Training Program for Young Talents in Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,China.
文摘Intervertebral disc(ID)degeneration(IDD)is one of the main causes of chronic low back pain,and degenerative lesions are usually caused by an imbalance between catabolic and anabolic processes in the ID.The environment in which the ID is located is harsh,with almost no vascular distribution within the disc,and the nutrient supply relies mainly on the diffusion of oxygen and nutrients from the blood vessels located under the endplate.The stability of its internal environment also plays an important role in preventing IDD.The main feature of disc degeneration is a decrease in the number of cells.Mesenchymal stem cells have been used in the treatment of disc lesions due to their ability to differentiate into nucleus pulposus cells in a nonspecific anti-inflammatory manner.The main purpose is to promote their regeneration.The current aim of stem cell therapy is to replace the aged and metamorphosed cells in the ID and to increase the content of the extracellular matrix.The treatment of disc degeneration with stem cells has achieved good efficacy,and the current challenge is how to improve this efficacy.Here,we reviewed current treatments for disc degeneration and summarize studies on stem cell vesicles,enhancement of therapeutic effects when stem cells are mixed with related substances,and improvements in the efficacy of stem cell therapy by adjuvants under adverse conditions.We reviewed the new approaches and ideas for stem cell treatment of disc degeneration in order to contribute to the development of new therapeutic approaches to meet current challenges.
文摘Intervertebral disc(IVD)degenerative diseases are a common problem in the world,and they cause substantial social and economic burdens for people.The current methods for treating IVD degenerative diseases mainly include surgery and conservative treatment,which cannot fundamentally restore the normal structure of the disc.With continuous research on the mechanism of degeneration and the development of regenerative medicine,rapid progress has been made in the field of regenerative medicine regarding the use of stem cell-derived exosomes,which are active biological substances used in intercellular communication,because they show a strong effect in promoting tissue regeneration.The study of exosomes in the field of IVD degeneration has just begun,and many surprising achievements have been made.This paper mainly reviews the biological characteristics of exosomes and highlights the current status of exosomes in the field of IVD degeneration,as well as future developments regarding exosomes.
文摘Karacoline is a compound found in the plant Aconitum kusnezoffii Reichb.Although Aconitum kusnezoffii Reichb is widely used for the treatment of pain,very few studies have been carried out on the use of karacoline due to its potential toxicity.In this study,we selected key matrix metalloproteinases(MMPs),collagen II,and aggrecan as targets due to their association with intervertebral disc degeneration(IDD).Using these targets,we then used network pharmacology to predict a series of molecules that might exert therapeutic effects on IDD.Of these molecules,karacoline was predicted to have the best effect.Tumor necrosis factor(TNF)-a is known to promote the degeneration of the extracellular matrix in IDD.We therefore applied different concentrations of karacoline(0,1.25,or 12.88 mM)along with 100 ng/mL TNF-a to rat nucleus pulposus cells and found that karacoline reduced the expression of MMP-14 in IDD by inhibiting the nuclear factor(NF)-κB pathway,while collagen II and aggrecan expression was increased.This suggested that extracellular matrix degradation was inhibited by karacoline(P<0.05).Our data therefore reveal a new clinical application of karacoline and provide support for the use of network pharmacology in predicting novel drugs.
文摘ObjectiveTo investigate the gene expression changes in normal and degeneration lumbar intervertebral disc in humans, providing information for clinical. MethodsThe PCR products of 4096 human genes were spotted onto a kind of chemical-material-coated-glass slides. The total RNAs were isolated from the tissues. Both the mRNAs from the degeneration and normal lumbar intervertebral disc in humans were reversely transcribed to the cDNAs, which used as the hybridization probes with the incorporations of fluorescent dUTP. The mixed probes were then hybridized to the cDNA microarray. After high-stringent washing, the cDNA microarray was scanned for the fluorescent signals and analyzed with computer image analysis. ResultsAmong the 4096 targets, there were 706 genes whose expression levels differed between the degeneration and normal lumbar intervertebral disc in all cases, comprising 298 up-regulated and 358 down-regulated ones. ConclusionDNA microarray technology is an effective technique in screening for differently expressed genes between the degeneration and normal lumbar intervertebral disc. Cell apoptosis plays an important role in the process of lumbar intervertebral disc degeneration.
基金Supported by Higher Education Commission Pakistan,No. 7083
文摘BACKGROUND Intervertebral disc degeneration(IVDD)is the leading cause of lower back pain.Disc degeneration is characterized by reduced cellularity and decreased production of extracellular matrix(ECM).Mesenchymal stem cells(MSCs)have been envisioned as a promising treatment for degenerative illnesses.Cell-based therapy using ECM-producing chondrogenic derivatives of MSCs has the potential to restore the functionality of the intervertebral disc(IVD).AIM To investigate the potential of chondrogenic transcription factors to promote differentiation of human umbilical cord MSCs into chondrocytes,and to assess their therapeutic potential in IVD regeneration.METHODS MSCs were isolated and characterized morphologically and immunologically by the expression of specific markers.MSCs were then transfected with Sox-9 and Six-1 transcription factors to direct differentiation and were assessed for chondrogenic lineage based on the expression of specific markers.These differentiated MSCs were implanted in the rat model of IVDD.The regenerative potential of transplanted cells was investigated using histochemical and molecular analyses of IVDs.RESULTS Isolated cells showed fibroblast-like morphology and expressed CD105,CD90,CD73,CD29,and Vimentin but not CD45 antigens.Overexpression of Sox-9 and Six-1 greatly enhanced the gene expression of transforming growth factor beta-1 gene,BMP,Sox-9,Six-1,and Aggrecan,and protein expression of Sox-9 and Six-1.The implanted cells integrated,survived,and homed in the degenerated intervertebral disc.Histological grading showed that the transfected MSCs regenerated the IVD and restored normal architecture.CONCLUSION Genetically modified MSCs accelerate cartilage regeneration,providing a unique opportunity and impetus for stem cell-based therapeutic approach for degenerative disc diseases.
文摘Clinical studies have found that patients withcervical degenerative disease are usually accompanied by dizziness.Anterior cervical surgery can eliminate not only chronic neck pain,cervical radiculopathy or myelopathy,but also dizziness.Immunohistochemical studies show that a large number of mechanoreceptors,especially Ruffini corpuscles,are present in degenerated cervical discs.The available evidence suggests a key role of Ruffini corpuscles in the pathogenesis of dizziness caused by cervical degenerative disease(i.e.cervical discogenic dizziness).Disc degeneration is characterized by an elevation of inflammatory cytokines,which stimulates the mechanoreceptors in degenerated discs and results in peripheral sensitization.Abnormal cervical proprioceptive inputs from the mechanoreceptors are transmitted to the central nervous system,resulting in sensory mismatches with vestibular and visual information and leads to dizziness.In addition,neck pain caused by cervical disc degeneration can play a key role in cervical discogenic dizziness by increasing the sensitivity of muscle spindles.Like cervical discogenic pain,the diagnosis of cervical discogenic dizziness can be challenging and can be made only after other potential causes of dizziness have been ruled out.Conservative treatment is effective for the majority of patients.Existing basic and clinical studies have shown that cervical intervertebral disc degeneration can lead to dizziness.
文摘<strong>Objective:</strong> To describe the relationship between autophagy and apoptosis and the possible signaling pathways involved in degenerative lumbar intervertebral disc. <strong>Summary of Background Data:</strong> Autophagy and apoptosis are regulatory cellular mechanisms that determine many pathologies, including degenerative intervertebral disc disease. The interactions between these events in the damage or protection of intervertebral disc cells and in cellular homeostasis remain controversial. <strong>Methods:</strong> The sample size was twenty patients who underwent lumbar spine surgery for symptomatic disc herniation or spondylolisthesis. Intervertebral discs were classified by magnetic resonance as Pfirrmann grade IV and grade V. Six patients were operated on two levels, resulting in twenty-six intervertebral discs that were submitted to immunohistochemistry to verify the protein expression of autophagy and apoptosis markers. <strong>Results: </strong>The autophagic markers had greater protein expression in the human intervertebral disc (Pfirrmann Grades IV and V). Under these conditions, autophagy and apoptosis showed a negative correlation. Regarding apoptosis, caspase 8 presented the highest protein expression, which allows inferring the preference for the extrinsic pathway in cell death. <strong>Conclusions: </strong>Autophagy had the greatest protein expression negative profile compared to apoptosis. Caspase 8 had the highest protein expression in apoptosis.
基金Supported by the National Key Research and Development Program of China,No.2017YFA0105404。
文摘BACKGROUND Conventional plain X-ray images of rats,the most common animals used as degeneration models,exhibit unclear vertebral structure and blurry intervertebral disc spaces due to their small size,slender vertebral bodies.AIM To apply molybdenum target X-ray photography in the evaluation of caudal intervertebral disc(IVD)degeneration in rat models.METHODS Two types of rat caudal IVD degeneration models(needle-punctured model and endplate-destructed model)were established,and their effectiveness was verified using nuclear magnetic resonance imaging.Molybdenum target inspection and routine plain X-ray were then performed on these models.Additionally,four observers were assigned to measure the intervertebral height of degenerated segments on molybdenum target plain X-ray images and routine plain X-ray images,respectively.The degeneration was evaluated and statistical analysis was subsequently conducted.RESULTS Nine rats in the needle-punctured model and 10 rats in the endplate-destructed model were effective.Compared with routine plain X-ray images,molybdenum target plain X-ray images showed higher clarity,stronger contrast,as well as clearer and more accurate structural development.The McNemar test confirmed that the difference was statistically significant(P=0.031).In the two models,the reliability of the intervertebral height measured by the four observers on routine plain X-ray images was poor(ICC<0.4),while the data obtained from the molybdenum target plain X-ray images were more reliable.CONCLUSIONMolybdenum target inspection can obtain clearer images and display fine calcification in the imaging evaluation of caudal IVD degeneration in rats,thus ensuring a more accurate evaluation of degeneration.
文摘<strong>Objective:</strong> To characterize the association between DNA damage and Intervertebral disc degeneration (IDD). <strong>Summary of</strong> <strong>Background Data:</strong> IDD is the main disorder causing low back pain and is the most promising target for intervention. Many factors can contribute to the etiology, such as genetics, environment and lifestyle, but it is not yet fully understood. DNA damage can influence this process and needs to be studied, as well as the agents that can determine these damages. <strong>Methods:</strong> A systematic literature search of PubMed, Web of Science and Scopus was performed to identify studies related to DNA damage to the intervertebral disc. <strong>Results:</strong> After screening 61 records, 7 articles were included according to the selection criteria. All studies showed some relation between DNA damage and IDD. However, DNA damage was always considered a secondary issue to be investigated. <strong>Conclusions:</strong> Many factors can influence DNA damage induced by different genotoxic agents on the degenerative cascade of IVD. However, the correlation between IDD severity and DNA damage, as well as the factual role of DNA damage in disc degeneration could not be defined.
基金National Natural Science Foundation ofChina(30400163)
文摘Objectives： To develop a rabbit model of intervertebral disc degeneration that more exactly simulates the pathological changes of human intervertebral disc degeneration. Methods： Twelve New Zealand white rabbits were utilized to establish three different disc injury models according to the following protocol; group A： anulus punctures were done with a 18-gauge needle at L2-L3 and L5-L6; Group B： intradiscal injection of interleukin-1 IL-1β with a 23-gauge needle at L3-L4; and Group C： intradiscal injection of phosphate buffer saline（PBS） with a 23-gauge needle at L4-LS. The L1-L2 level was used as a control. Rabbits were killed after 24 weeks. The intervertebral disc height was measured by lateral plain radiographs. After the radiographic measurements were obtained, the intervertebral discs were removed and analyzed for DNA, sulfated glycosaminoglycan（s-GAG） and water contents of nucleus pulposus. Results： The intervertebral disc height, s-GAG, and water contents in anulus needle punctures were significantly decreased in Group A, but the DNA content in the nucleus pulposus was significantly increased when compared to the control. The significant decrease of disc height and water contents were demonstrated, only the s-GAG and DNA contents did not show a significant difference in Group B when compared to the control. The significant decrease of disc height, s-GAG, water, and DNA contents did not show in Group C when compared to the control. Conclusion： The 18-gauge puncture models produced the most consistent disc degeneration in the rabbit lumbar spine.
文摘Degenerative disc disease is the most common cause of low back pain. Intervertebral disc abnormalities are commonly evaluated by magnetic resonance imaging (MRI), and Pfirrmann’s system involves the use of T2-weighted images (T2WI) to classify disc degeneration. However, as this classification is based on visual evaluation, it is not possible to quantify degeneration using this method. The present study was performed to establish an MRI-based intervertebral disc classification system using diffusional kurtosis imaging (DKI), to quantify intervertebral disc water content according to the Pfirrmann classification. Sagittal mean diffusional kurtosis (MK) mapping was performed for the L3/4, L4/5, and L5/S1 intervertebral discs in 32 patients (15 female, 17 male;age range, 24 - 82 years;mean age, 57.7 years). The degree of disc degeneration was assessed in the midsagittal section on T2WI according to the Pfirrmann classification (grade I - V). The relationships between MK values, which are correlated with intervertebral disc composition changes, and grade of degeneration determined using the Pfirrmann classification were analyzed. The MK values tended to decrease with increasing grade of degeneration, and differed significantly between grades I and IV, but not between grade IV and V (P < 0.05, Mann-Whitney U test). DKI is an effective means of detecting the early stages of disc degeneration. Therefore, DKI may be a useful diagnostic tool for quantitative assessment of intervertebral disc degeneration.
基金This work was supported by the Project of the Department of Science and Technology in Shaanxi Province(2020JM-702).
文摘The lumbar spine,an important part of the body’s motor mechanism,is more susceptible to damage as it bears most of the body’s load.Age can cause clinical manifestations such as neurological impairment,back and leg pain in the lumbar spine.External forces result in nucleus pulposus out,destruction of the intervertebral disc fibrous ring,and gradual aging and damage.Lumbar degenerative change is a common middle-aged and old-aged disease,and its clinical symptoms on the initial stage are not obvious,but it becomes more and more serious as they get older.Patients with severe lumbar degenerative changes will appear symptoms such as urinary and fecal incontinence,lower extremity numbness,back pain,and sexual dysfunction.The main reason for back pain and leg pain is the degenerative changes in the lumbar intervertebral discs,at the same time which also leads to patients’lumbar instability.This study focuses on the correlation analysis of intervertebral disc degeneration with HTRA1 and HAPLN1 gene polymorphisms.
基金supported by the National Natural Science Foundation of China (82072438,82272501,81972078,82120108017,82102589,82372484,82302683)Natural Science Foundation of Jiangsu Province (BK20211504)+4 种基金Social Development Project of Jiangsu Province (BE2021646)Jiangsu Province"333 Project"talent project (2069999)Suzhou Gusu Health Talent Program (GSWS2020001,GSWS2021009,GSWS2021007)Jiangsu Innovative and Enterpreneurial Talent Program (JSSCBS20211570)Medical Health Science and Technology Innovation Program of Suzhou (SKY2022119).
文摘Sustained and intense inflammation is the pathological basis for intervertebral disc degeneration(IVDD).Effective antagonism or reduction of local inflammatory factors may help regulate the IVDD microenvironment and reshape the extracellular matrix of the disc.This study reports an immunomodulatory hydrogel microsphere system combining cell membrane-coated mimic technology and surface chemical modification methods by grafting neutrophil membrane-coated polylactic-glycolic acid copolymer nanoparticles loaded with transforming growth factor-beta 1(TGF-β1)(T-NNPs)onto the surface of methacrylic acid gelatin anhydride microspheres(GM)via amide bonds.The nanoparticle-microsphere complex(GM@T-NNPs)sustained the long-term release of T-NNPs with excellent cell-like functions,effectively bound to pro-inflammatory cytokines,and improved the release kinetics of TGF-β1,maintaining a 36 day-acting release.GM@T-NNPs significantly inhibited lipopolysaccharide-induced inflammation in nucleus pulposus cells in vitro,downregulated the expression of inflammatory factors and matrix metalloproteinase,and upregulated the expression of collagen-II and aggrecan.GM@T-NNPs effectively restored intervertebral disc height and significantly improved the structure and biomechanical function of the nucleus pulposus in a rat IVDD model.The integration of biomimetic technology and nano-drug delivery systems expands the application of biomimetic cell membrane-coated materials and provides a new treatment strategy for IVDD.
基金National Natural Science Foundation of China(82072490 and 21935011)Shenzhen Science and Technology Innovation Commission(KQTD20200820113012029)Guangdong Provincial Key Laboratory of Advanced Biomaterials(2022B1212010003).
文摘Oxidative stress and aging lead to progressive senescence of nucleus pulposus(NP)cells,resulting in intervertebral disc(IVD)degeneration(IVDD).In some cases,degenerative IVD can further cause low back pain(LBP).Several studies have confirmed that delaying and rejuvenating the senescence of NP cells can attenuate IVDD.However,the relatively closed tissue structure of IVDs presents challenges for the local application of anti-senescence drugs.Here,we prepared an anti-senescence hydrogel by conjugating phenylboronic acid-modified gelatin methacryloyl(GP)with quercetin to alleviate IVDD by removing senescent NP cells.The hydrogel exhibited injectability,biodegradability,prominent biocompatibility and responsive release of quercetin under pathological conditions.In vitro experiments demonstrated that the hydrogel could reduce the expression of senescence markers and restore the metabolic balance in senescent NP cells.In vivo studies validated that a single injection of the hydrogel in situ could maintain IVD tissue structure and alleviate sensitivity to noxious mechanical force in the rat models,indicating a potential therapeutic approach for ameliorating IVDD and LBP.This approach helps prevent potential systemic toxicity associated with systemic administration and reduces the morbidity resulting from repeated injections of free drugs into the IVD,providing a new strategy for IVDD treatment.
基金supported by the Key Projects of Hunan Provincial Science and Technology Department,China (2021RC4057)Key R&D Program of Hunan Provincial Science and Technology Department,China (2023SK2044)+1 种基金Natural Science Foundation of Hunan Province,China (2023JJ40906)Natural Science Foundation of Changsha,China (kq2208364).
文摘Intervertebral disc degeneration(IVDD)can be caused by aging,injury,and genetic factors.The pathological changes associated with IVDD include the excessive accumulation of reactive oxygen species(ROS),cellular pyroptosis,and extracellular matrix(ECM)degradation.There are currently no approved specific molecular therapies for IVDD.In this study,we developed a multifunctional and microenvironment-responsive metal-phenolic network release platform,termed TMP@Alg-PBA/PVA,which could treat(IL-1β)-induced IVDD.The metal-phenolic network(TA-Mn-PVP,TMP)released from this platform targeted mitochondria to efficiently scavenge ROS and reduce ECM degradation.Pyroptosis was suppressed through the inhibition of the IL-17/ERK signaling pathway.These findings demonstrate the versatility of the platform.And in a rat model of IVDD,TMP@Alg-PBA/PVA exhibited excellent therapeutic effects by reducing the progression of the disease.TMP@Alg-PBA/PVA,therefore,presents clinical potential for the treatment of IVDD.
基金This work was supported by the Natural Science Foundation of Gansu province(21JR7RA406)Cuiying Technology Innovation Project of Lanzhou University Second Hospital(CY2020-MS20)+1 种基金Zhanjun Ma is supported by a co-founding from the UCLouvain-China Scholarship Council(CSC)Jingjing Yang is supported by a grant from the CSC.
文摘Low back pain(LBP)is a common disease that imposes a huge social and economic burden on people.Intervertebral disc(IVD)degeneration(IVDD)is often considered to be the leading cause of LBP and further aggravate and cause serious spinal problems.The established treatment strategy for IVDD consists of physiotherapy,pain medication by drug therapy,and,if necessary,surgery,but none of them can be treated from the etiology;that is,it cannot fundamentally reverse IVD and reconstruct the mechanical function of the spine.With the development of nanotechnology and regenerative medicine,nano-drug delivery systems(NDDSs)have improved treatment results because of their good biodegradability,biocompatibility,precise targeted specific drug delivery,prolonged drug release time,and enhanced drug efficacy,and various new NDDSs for drugs,proteins,cells,and genes have brought light and hope for the treatment of IVDD.This review summarizes the research progress of NDDSs in the treatment of IVDD and provides prospects for using NDDSs to address the challenges of IVDD.We hope that the ideas generated in this review will provide insight into the precise treatment of IVDD.
基金This work was supported by National Natural Science Foundation of China(Grant No.82072478 to Yunpeng Zhao)Shandong Provincial Natural Science Foundation(Grant No.ZR2020YQ54,ZR019MH05 to Yunpeng Zhao)+4 种基金National Natural Science Foundation of China(Grant No.81874022,82172483 to Xinyu Liu)National Natural Science Foundation of China(Grant No.81972128to Xuesong Zhang)Application of Clinical Features of Capital City of Science and Technology Commission China BEIJING Special subject(Z181100001718180 to Xuesong Zhang)National Nature Science Foundation(82102522 to Lianlei Wang)Shandong Natural Science Foundation(ZR202102210113 to Lianlei Wang)and Shandong Province Taishan Scholar Project.
文摘Stem cell transplantation has been proved a promising therapeutic instrument in intervertebral disc degeneration(IVDD).However,the elevation of oxidative stress in the degenerated region impairs the efficiency of mesenchymal stem cells(BMSCs)transplantation treatment via exaggeration of mitochondrial ROS and promotion of BMSCs apoptosis.Herein,we applied an emulsion-confined assembly method to encapsulate Coenzyme Q10(Co-Q10),a promising hydrophobic antioxidant which targets mitochondria ROS,into the lecithin micelles,which renders the insoluble Co-Q10 dispersible in water as stable colloids.These micelles are injectable,which displayed efficient ability to facilitate Co-Q10 to get into BMSCs in vitro,and exhibited prolonged release of Co-Q10 in intervertebral disc tissue of animal models.Compared to mere use of Co-Q10,the Co-Q10 loaded micelle possessed better bioactivities,which elevated the viability,restored mitochondrial structure as well as function,and enhanced production of ECM components in rat BMSCs.Moreover,it is demonstrated that the injection of this micelle with BMSCs retained disc height and alleviated IVDD in a rat needle puncture model.Therefore,these Co-Q10 loaded micelles play a protective role in cell survival and differentiation through antagonizing mitochondrial ROS,and might be a potential therapeutic agent for IVDD.
基金This work was supported by Zhejiang Provincial Natural Science Foundation of China(LGF21H060010)National Natural Science Foundation of China(82272555)+3 种基金Zhejiang Provincial Traditional Chinese Medicine Science and Technology Program(2020ZB146)Zhejiang Provincial Medical Technology Foundation of China(2022PY071)Wenzhou Major Scientific and Technological Innovation Project(ZY2022010)Wenzhou Public Welfare Science and Technology Project(WIUCASQD2019001).
文摘Intervertebral disc degeneration(IVDD)is a leading cause of low back pain.The strategy of using functional materials to deliver nucleic acids provides a powerful tool for ameliorating IVDD.However,the immunogenicity of nucleic acid vectors and the poor mechanical properties of functional materials greatly limit their effects.Herein,antagomir-204-3p(AM)shows low immunogenicity and effectively inhibits the apoptosis of nucleus pulposus cells.Moreover,a high-strength biohydrogel based on zinc-oxidized sodium alginate-gelatin(ZOG)is designed as a multifunctional nucleic acid delivery platform.ZOG loaded with AM(ZOGA)exhibits great hygroscopicity,antibacterial activity,biocompatibility,and biodegradability.Moreover,ZOGA can be cross-linked with nucleus pulposus tissue to form a high-strength collagen network that improves the mechanical properties of the intervertebral disc(IVD).In addition,ZOGA provides an advantageous microenvironment for genetic expression in which AM can play an efficient role in maintaining the metabolic balance of the extracellular matrix.The results of the radiological and histological analyses demonstrate that ZOGA restores the height of the IVD,retains moisture in the IVD,and maintains the tissue structure.The ZOGA platform shows the sustained release of nucleic acids and has the potential for application to ameliorate IVDD,opening a path for future studies related to IVD.
基金Center of Pharmaceutical Technology of Tsinghua University(Beijing,China)for the support of Schrodinger software and molecular dockingthe National Natural Science Foundation of China(grant numbers 91849114,82030068,and 82172506)。
文摘Inflammation,abnormal cholesterol metabolism,and macrophage infiltration are involved in the destruction of the extracellular matrix of the nucleus pulposus(NP),culminating in intervertebral disc degeneration(IDD).Whether nimbolide(Nim),a natural extract,can alleviate IDD is unclear.In this study,we demonstrated that Nim promotes cholesterol efflux and inhibits the activation of the nuclear factor kappa B(NF-κB)and mitogen-activated protein kinase(MAPK)signaling pathways by activating sirtuin 1(SIRT1)in nucleus pulposus cells(NPCs)during inflammation.Thus,Nim balanced matrix anabolism and catabolism of NPCs.However,the inhibition of SIRT1 significantly attenuated the effects of Nim.We also found that Nim promoted the expression of SIRT1 in RAW 264.7,which enhanced the proportion of M2 macrophages by facilitating cholesterol homeostasis reprogramming and impeded M1-like macrophages polarization by blocking the activation of inflammatory signaling.Based on these results,Nim can improve the microenvironment and facilitate matrix metabolism equilibrium in NPCs.Furthermore,in vivo treatment with Nim delayed IDD progression by boosting SIRT1 expression,modulating macrophage polarization and preserving the extracellular matrix.In conclusion,Nim may represent a novel therapeutic strategy for treating IDD.
基金Nature Science Foundation of Zhejiang Province(Y20H060063,LY19H060005,LQ18H060003,LZ22H090003)National Natural Science Foundation of China(NO.82072465,NO.81772379,NO.81972096,NO.82172457,NO.82002327)+1 种基金China Postdoctoral Science Foundation(2017M612011)Scientific Research Fund of Zhejiang Provincial Education Department(Y201941476).
文摘Stem cell-based transplantation is a promising therapeutic approach for intervertebral disc degeneration(IDD).Current limitations of stem cells include with their insufficient cell source,poor proliferation capacity,low nucleus pulposus(NP)-specific differentiation potential,and inability to avoid pyroptosis caused by the acidic IDD microenvironment after transplantation.To address these challenges,embryo-derived long-term expandable nucleus pulposus progenitor cells(NPPCs)and esterase-responsive ibuprofen nano-micelles(PEG-PIB)were prepared for synergistic transplantation.In this study,we propose a biomaterial pre-modification cell strategy;the PEG-PIB were endocytosed to pre-modify the NPPCs with adaptability in harsh IDD microenvironment through inhibiting pyroptosis.The results indicated that the PEG-PIB pre-modified NPPCs exhibited inhibition of pyroptosis in vitro;their further synergistic transplantation yielded effective functional recovery,histological regeneration,and inhibition of pyroptosis during IDD regeneration.Herein,we offer a novel biomaterial pre-modification cell strategy for synergistic transplantation with promising therapeutic effects in IDD regeneration.
