Nonsurgical therapy for lumbar spinal stenosis caused by ligamentum flavum hypertrophy: A review.

Lumbar spinal stenosis (LSS) can cause a range of cauda equina symptoms, including lower back and leg pain, numbness, and intermittent claudication. This disease affects approximately 103 million people worldwide, particularly the elderly, and can seriously compromise their health and well-being. Ligamentum flavum hypertrophy (LFH) is one of the main contributing factors to this disease. Surgical treatment is currently recommended for LSS caused by LFH. For patients who do not meet the criteria for surgery, symptom relief can be achieved by using oral nonsteroidal anti-inflammatory drugs (NSAIDs) and epidural steroid injections. Exercise therapy and needle knife can also help to reduce the effects of mechanical stress. However, the effectiveness of these methods varies, and targeting the delay in LF hypertrophy is challenging. Therefore, further research and development of new drugs is necessary to address this issue. Several new drugs, including cyclopamine and N-acetyl-l-cysteine, are currently undergoing testing and may serve as new treatments for LSS caused by LFH.

For better or worse: crosstalk of parvovirus and host DNA damage response.

Parvoviruses are a group of non-enveloped DNA viruses that have a broad spectrum of natural infections, making them important in public health. NS1 is the largest and most complex non-structural protein in the parvovirus genome, which is indispensable in the life cycle of parvovirus and is closely related to viral replication, induction of host cell apoptosis, cycle arrest, DNA damage response (DDR), and other processes. Parvovirus activates and utilizes the DDR pathway to promote viral replication through NS1, thereby increasing pathogenicity to the host cells. Here, we review the latest progress of parvovirus in regulating host cell DDR during the parvovirus lifecycle and discuss the potential of cellular consequences of regulating the DDR pathway, targeting to provide the theoretical basis for further elucidation of the pathogenesis of parvovirus and development of new antiviral drugs.

Transforaminal endoscopic lumbar discectomy using a 45° puncture angle and foraminotomy versus traditional THESYS for L5/S1 lumbar disc herniation: a prospective randomized controlled trial.

PURPOSE: Prospective comparison of the efficacy and safety of transforaminal endoscopic lumbar discectomy (TELD) with a 45° puncture angle versus traditional Thomas Hoogland endoscopy spine systems (THESYS) for the surgical treatment of L5/S1 lumbar disc herniation (LDH). METHODS: Consecutive patients with L5/S1 LDH who underwent TELD were randomized (1:1) assigned to the 45° TELD group and the THESYS group. Clinical outcomes were assessed at pre-operation, 1-day and 3/6-months post-operation till final follow-up. Surgical-related parameters, visual analogue scale (VAS) score, oswestry disability index (ODI), and modified MacNab criteria, and surgical complications were recorded and analysed. RESULTS: All patients were followed up for at least 24 months. Compared to the THESYS group, the 45° TELD group had a shorter operative time (P < 0.001) and intraoperative radiation time (P < 0.001) and a smaller VAS score for back pain (P < 0.001) and leg pain intraoperatively (P < 0.001). The VAS and ODI in the 45° TELD group were significantly better than those in the THESYS group within 3 months postoperatively. However, from 3 months on, both groups showed comparable VAS and ODI. There was no significant difference between the two groups of modified MacNab criteria. There were two cases of residual disc and two cases of recurrence that required reoperation in the THESYS group. CONCLUSION: For L5/S1 LDH, the 45° TELD technique was superior to traditional THESYS in terms of surgery-related parameters and faster improvement of VAS and ODI, with a lower complication rate.

Aptamer Technology and Its Applications in Bone Diseases.

Aptamers are single-stranded nucleic acids (DNA, short RNA, or other artificial molecules) produced by the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) technology, which can be tightly and specifically combined with desired targets. As a comparable alternative to antibodies, aptamers have many advantages over traditional antibodies such as a strong chemical stability and rapid bulk production. In addition, aptamers can bind targets in various ways, and are not limited like the antigen-antibody combination. Studies have shown that aptamers have tremendous potential to diagnose and treat clinical diseases. However, only a few aptamer-based drugs have been used because of limitations of the aptamers and SELEX technology. To promote the development and applications of aptamers, we present a review of the methods optimizing the SELEX technology and modifying aptamers to boost the selection success rate and improve aptamer characteristics. In addition, we review the application of aptamers to treat bone diseases.

Exosomes Derived from Runx2-Overexpressing BMSCs Enhance Cartilage Tissue Regeneration and Prevent Osteoarthritis of the Knee in a Rabbit Model.

Objectives: Osteoarthritis is the leading disease of joints worldwide. Osteoarthritis may be treated by exosomes derived from Runx2-overexpressed bone marrow mesenchymal stem cells (R-BMSCs-Exos). R-BMSCs-Exos would promote the proliferation, migration, and phenotypic maintenance of articular chondrocytes. Methods: BMSCs were transfected with and without Runx2. Exosomes derived from BMSCs and R-BMSCs (BMSCs-Exos and R-BMSCs-Exos) were isolated and identified. Proliferation, migration, and phenotypic maintenance were determined in vitro and compared between groups. The mechanism for activation of Yes-associated protein (YAP) was investigated using small interfering RNA (siRNA). The exosomes' preventive role was determined in vivo using Masson trichrome and immunohistochemical staining. Results: R-BMSCs-Exos enhance the proliferation, migration, and phenotypic maintenance of articular chondrocytes based on the YAP being activated. R-BMSCs-Exos prevent knee osteoarthritis as studied in vivo through a rabbit model. Conclusions: Findings emphasize the efficacy of R-BMSCs-Exos in preventing osteoarthritis. Potential source of exosomes is sorted out for the advantages and shortcomings. The exosomes are then modified based on the molecular mechanisms to address their limitations. Such exosomes derived from modified cells have the role in future therapeutics.

MiR-206 regulates the Th17/Treg ratio during osteoarthritis.

BACKGROUND: The present study aimed to determine the functional role of miR-206 in T helper 17 (Th17)/regulatory T (Treg) cell differentiation during the development of osteoarthritis (OA). METHODS: Patients with OA and healthy controls were recruited for investigating the association between miR-206 and Th17/Treg ratio. Transfection experiments were conducted in CD4+ T cells to verify the mechanism of miR-206 on the balance of Treg/Th17. OA model was constructed to detect the clinical score, histopathological changes and Treg/Th17 ratio. OA model was induced in rats to verify the effect of miR-206 inhibition on Th17/Treg immunoregulation. RESULTS: High expression of miR-206 was positively correlated with peripheral Th17/Treg imbalance in patients with OA. The interactions between miR-206 and the 3' untranslated regions (3'-UTR) of suppressor of cytokine signaling-3 (SOCS3) and fork head transcriptional factor 3 (Foxp3) were confirmed by luciferase reporter assays. MiR-206 disturbed the Th17/Treg balance by targeting SOCS3 and Foxp3. In vivo assay demonstrated that antagomiR directed against miR-206 restored Th17/Treg balance during the development of OA. CONCLUSION: MiR-206 contributed to the progression of OA by modulating Th17/Treg imbalance, suggesting that miR-206 inhibition might be a promising therapeutic strategy for the treatment of OA.

BMP2 induces hMSC osteogenesis and matrix remodeling.

With increasing age, the microenvironment in the bone marrow is altered, leading to a decrease in bone marrow mesenchymal stem cell (BMSC) differentiation, which reduces the number of bone cells and weakens osteogenic capacity, resulting in osteoporosis (OP). The clinical manifestations of OP include bone loss, bone microstructural destruction and altered bone quality. Bone morphogenetic protein 2 (BMP2) serves an important role in inducing the osteogenic differentiation of mesenchymal stem cells (MSCs). Regulating the bone marrow matrix microenvironment and promoting osteogenic differentiation of BMSCs is of significance for both the prevention and treatment of OP. In the present study, isobaric tags for relative and absolute quantification (iTRAQ) high­throughput proteomics technology was combined with bioinformatics analysis to screen 249 differentially expressed proteins in human MSCs overexpressing BMP2, of which 173 were upregulated and 76 proteins were downregulated. The proteins were also involved in signaling pathways associated with extracellular matrix organization, osteoblast differentiation, ossification, bone development, chondrocyte differentiation and bone morphogenesis. By carefully screening the proteins, N­cadherin (CDH2), a protein with osteogenic differentiation potential, was verified by perturbations in the background of BMP2 overexpression. The role of CDH3 in the osteogenic differentiation of MSCs was confirmed by the regulation of several cognate osteogenic markers, suggesting CDH2 as a promising candidate in the field of osteogenesis.

Overexpressing Runx2 of BMSCs Improves the Repairment of knee Cartilage Defects.

BACKGROUND: Recruitment of gene modifying bone marrow mesenchymal stem cells (BMSCs) has been considered an alternative to single-cell injection in articular cartilage repair. PURPOSE: This study aimed to investigate whether the effect of runt-related transcription factor 2(Runx2) overexpression bone marrow mesenchymal stem cells in vivo could improve the quality of repaired tissue of a knee cartilage defect in a rabbit model. METHODS: Thirty-two New Zealand rabbits were randomly divided into four groups. The blank group (Con) did not receive anything, the model group (Mo) was administered saline, the simple stem cell group (MSCs) received MSCs injection, and the Runx2 transfection group (R-MSCs) received Runx2 overexpression MSCs injection. After adapting to the environment for a week, a 5 mm diameter cylindrical osteochondral defect was created in the center of the medial femoral condyle. Cell and saline injections were performed in the first and third weeks after surgery. The cartilage repair was evaluated by macroscopically and microscopically at 4 and 8 weeks. RESULTS: Macroscopically, defects were filled and surfaces were smoother in the MSCs groups than in the Mo group at 4th week. Microscopically, the R-MSCs group showed coloration similar to surrounding normal articular cartilage tissue at 8 weeks in masson trichrome staining. The COL-II, SOX9, and Aggrecan mRNA expressions of MSCs were enhanced at 4 weeks compared with R-MSCs, then the expression reduced at 8 weeks, but was still higher than Mo group level (P<0.05). The western blot examination revealed that the COL-IIand SOX9 expression of MSCs was higher than R-MSCs at 4 weeks, then the expression reduced at 8 weeks, but was still higher than the Mo level (P<0.05). The IL-1ß content in the joint fluid also revealed that cartilage repair with R-MSCs was better than that with MSCs at 8 weeks (P<0.05). CONCLUSION: The R-MSCs group showed cellular morphology and arrangement similar to surrounding normal articular cartilage tissue, and Runx2 overexpression of MSCs resulted in overall superior cartilage repair as compared with MSCs at 8 weeks.

Epigenetic Modulation on Tau Phosphorylation in Alzheimer's Disease.

Tau hyperphosphorylation is a typical pathological change in Alzheimer's disease (AD) and is involved in the early onset and progression of AD. Epigenetic modification refers to heritable alterations in gene expression that are not caused by direct changes in the DNA sequence of the gene. Epigenetic modifications, such as noncoding RNA regulation, DNA methylation, and histone modification, can directly or indirectly affect the regulation of tau phosphorylation, thereby participating in AD development and progression. This review summarizes the current research progress on the mechanisms of epigenetic modification associated with tau phosphorylation.

Mechanism of Action of Icariin in Bone Marrow Mesenchymal Stem Cells.

Osteoporosis, femoral head necrosis, and congenital bone defects are orthopedic disorders characterized by reduced bone generation and insufficient bone mass. Bone regenerative therapy primarily relies on the bone marrow mesenchymal stem cells (BMSCs) and their ability to differentiate osteogenically. Icariin (ICA) is the active ingredient of Herba epimedii, a common herb used in traditional Chinese medicine (TCM) formulations, and can effectively enhance BMSC proliferation and osteogenesis. However, the underlying mechanism of ICA action in BMSCs is not completely clear. In this review, we provide an overview of the studies on the role and mechanism of action of ICA in BMSCs, to provide greater insights into its potential clinical use in bone regeneration.

ß­ecdysterone protects against apoptosis by promoting autophagy in nucleus pulposus cells and ameliorates disc degeneration.

Increasing cell apoptosis is one of the major causes of intervertebral disc degeneration (IDD). ß-ecdysterone has been demonstrated to protect PC12 cells against neurotoxicity. A previous study revealed that ß­ecdysterone may be involved in the regulation of autophagy in osteoblasts. Therefore, we hypothesized that ß­ecdysterone may possess therapeutic effects on IDD via autophagy stimulation. The effect of ß­ecdysterone on IDD was explored by in vitro experiments. The results demonstrated that ß­ecdysterone attenuated the apoptosis induced by tert­butyl hydroperoxide via promoting autophagy in nucleus pulposus cells. Beclin­1, an indispensable protein for the stimulation of autophagy, is upregulated and stabilized by ß­ecdysterone in a dose­ and time­dependent manner in nucleus pulposus cells. Inhibition of autophagy with 3­methyladenine partially abrogated the protective function of ß­ecdysterone against apoptosis of nucleus pulposus cells, indicating that autophagy participated in the protective effect of ß­ecdysterone on IDD. Additionally, ß­ecdysterone promoted the expression of anabolic genes while inhibiting the expression of catabolic genes in nucleus pulposus cells. Collectively, the present study demonstrated that ß­ecdysterone may protect nucleus pulposus cells against apoptosis by autophagy stimulation and ameliorate disc degeneration, which indicates that ß­ecdysterone may be a potential therapeutic agent for IDD.

Mechanisms of Zuogui Pill in Treating Osteoporosis: Perspective from Bone Marrow Mesenchymal Stem Cells.

The current treatment strategies for osteoporosis (OP) involve promoting osteogenic differentiation and inhibiting adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). According to a theory of traditional Chinese medicine (TCM), the kidneys contain an "essence" that regulate bone metabolism and generate marrow. Kidney disorders are therefore considered to be a major cause of OP as per the principles of TCM, which recommends kidney-tonifying treatments for OP. The Zuogui pill (ZGP) is a classic kidney-tonifying medication that effectively improves OP symptoms. Studies have shown that ZGP can promote the osteogenic differentiation of BMSCs, providing scientific evidence for the TCM theory linking kidneys with bone metabolism. In this review, we have provided an overview of recent studies that examined the underlying mechanisms of ZGP mediated regulation of BMSC osteogenic and adipogenic differentiation.

[Panlongqi tablet (Chinese characters) combined with lumbar facet joint release for the treatment of lumbar spinal stenosis of Fengshi Bizu (Chinese characters)].

OBJECTIVE: To investigate the clinical efficacy of Panlongqi tablet (Chinese characters) combined with lumbar facet joint release for lumbar spinal stenosis of type Fengshi Bizu (Chinese characters). METHODS: Since February 2012 to February 2013, 120 patients with lumbar spinal stenosis of Fengshi Bizu (Chinese characters) syndrome were retrospectively studied. According to different treatment methods, 120 patients with lumbar spinal stenosis were divided into Panlongqi tablet (Chinese characters)group and control groups, respectively. In Panlongqi tablet (Chinese characters)group, 60 patients were treated by Panlongqi tablet (Chinese characters) combined with lumbar facet joints release solution including 26 males and 34 females with an average age of (60.40±3.36) years old ranging from 46 to 65 ; the course of the disease was 2 to 15 years (averaged 7.6 years). In control group the other 60 patients were treated with lumbar facet joint release including 24 males and 36 females with an average age of (61.20±2.47) years old ranging from 48 to 63; the course was 3 to 14 years (averaged 6.9 years). The clinical effect of patients were evaluated by JOA and ODI score before treatment, at 4 weeks and 3 months after treatment. RESULTS: All patients were followed up for 4 to 7 months (means 5.6 months). After 3 months,7 cases in control group recurrenced symptoms,only 1 case in Panlongqi tablet (Chinese characters) group recurrenced. At 4 weeks and 3 months of follow-up, ODI score and JOA score of Panlongqi tablet group were much better than those of the control group. CONCLUSION: For lumbar spinal stenosis of type Fengshi Bizu (Chinese characters),which were treated with lumbar facet joint release with Panlongqi tablet(Chinese characters), supplemented by back muscle exercise, in relieving waist and low back pain symptoms and improving functional status of lower lumbar spine, can obtain satisfactory clinical outcome, is a good method of conservative treatment for such diseases.