Abnormal metabolism in melanocytes participates in the activation of dendritic cell in halo nevus.

A comprehensive analysis of spatial transcriptomics was carried out to better understand the progress of halo nevus. We found that halo nevus was characterized by overactive immune responses, triggered by chemokines and dendritic cells (DCs), T cells, and macrophages. Consequently, we observed abnormal cell death, such as apoptosis and disulfidptosis in halo nevus, some were closely related to immunity. Interestingly, we identified aberrant metabolites such as uridine diphosphate glucose (UDP-G) within the halo nevus. UDP-G, accompanied by the infiltration of DCs and T cells, exhibited correlations with certain forms of cell death. Subsequent experiments confirmed that UDP-G was increased in vitiligo serum and could activate DCs. We also confirmed that oxidative response is an inducer of UDP-G. In summary, the immune response in halo nevus, including DC activation, was accompanied by abnormal cell death and metabolites. Especially, melanocyte-derived UDP-G may play a crucial role in DC activation.

Brain-derived extracellular vesicles: Potential diagnostic biomarkers for central nervous system diseases.

Extracellular vesicles (EVs) are membrane-enclosed nanovesicles secreted by cells into the extracellular space and contain functional biomolecules, e.g. signaling receptors, bioactive lipids, nucleic acids, and proteins, which can serve as biomarkers. Neurons and glial cells secrete EVs, contributing to various physiological and pathological aspects of brain diseases. EVs confer their role in the bidirectional crosstalk between the central nervous system (CNS) and the periphery owing to their distinctive ability to cross the unique blood-brain barrier (BBB). Thus, EVs in the blood, cerebrospinal fluid (CSF), and urine can be intriguing biomarkers, enabling the minimally invasive diagnosis of CNS diseases. Although there has been an enormous interest in evaluating EVs as promising biomarkers, the lack of ultra-sensitive approaches for isolating and detecting brain-derived EVs (BDEVs) has hindered the development of efficient biomarkers. This review presents the recent salient findings of exosomal biomarkers, focusing on brain disorders. We summarize highly sensitive sensors for EV detection and state-of-the-art methods for single EV detection. Finally, the prospect of developing advanced EV analysis approaches for the non-invasive diagnosis of brain diseases is presented.

Over-expression of microRNA-145 Elevating Autophagy Activities via Downregulating FRS2 Expression.

OBJECTIVES: Osteoarthritis (OA) is one of the most common chronic and progressive joint diseases characterized by cartilage degeneration and chondrocyte death. In this study, we aimed to identify the modulation effect of miR-145 on chondrocytes' autophagy during the development of OA. BACKGROUND: Osteoarthritis (OA) is one of the most prevalent types of chronic and progressive joint disorder with the symptoms of joint pain and stiffness, and it leads to disability at the end stage. In recent years, microRNA-145 (miR-145) has been found to activate autophagy in various cell types, including mesenchymal stem cells, cardiomyocytes, and osteosarcoma cells. However, it is unknown whether miR-145 regulates the progression of OA by influencing chondrocyte autophagy. METHODS: Before investigating the regulatory effect of miR-145 on the autophagic activity of chondrocytes, the expression of miR-145 in human joint samples was analyzed. The targeting relationship between miR-145 and FRS2 was detected by dual luciferase assay. The effect of FRS2 and miR-145 on the autophagic activity of chondrocytes was observed by bidirectional expression of FRS2 and miR-145. RESULTS: The miR-145 expression and LC3-II/LC3-I ratio were significantly decreased and the SQSTM1 expression was increased in OA patients. The miR-145 overexpression in C20A4 cells increased LC3-II/LC3-I ratio, decreased SQSTM1 expression, and was positively correlated with autophagic activity. Under oxidative stress, miR-145 overexpression significantly improved chondrocyte viability through autophagy stimulation. FRS2 is a potential target of miR-145 via a binding sequence within its 3' UTR. FRS2 acts as the downstream mediator of miR-145 to suppress autophagy through activating PI3K/Akt/mTOR pathways. CONCLUSION: The miR-145 acts as a protective factor against chondrocytes by regulating miRFRS2- autophagy axis. The decrease of miR-145 in articular synovial fluid may turn out to be an important marker for early diagnosis of OA, and modulation of miR-145 may represent a promising therapeutic strategy for OA.

Enhancement of the therapeutic efficacy of mesenchymal stem cell-derived exosomes in osteoarthritis.

Osteoarthritis (OA), a common joint disorder with articular cartilage degradation as the main pathological change, is the major source of pain and disability worldwide. Despite current treatments, the overall treatment outcome is unsatisfactory. Thus, patients with severe OA often require joint replacement surgery. In recent years, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic option for preclinical and clinical palliation of OA. MSC-derived exosomes (MSC-Exos) carrying bioactive molecules of the parental cells, including non-coding RNAs (ncRNAs) and proteins, have demonstrated a significant impact on the modulation of various physiological behaviors of cells in the joint cavity, making them promising candidates for cell-free therapy for OA. This review provides a comprehensive overview of the biosynthesis and composition of MSC-Exos and their mechanisms of action in OA. We also discussed the potential of MSC-Exos as a therapeutic tool for modulating intercellular communication in OA. Additionally, we explored bioengineering approaches to enhance MSC-Exos' therapeutic potential, which may help to overcome challenges and achieve clinically meaningful OA therapies.

Research progress in the mechanism and treatment of osteosarcoma.

ABSTRACT: Osteosarcoma (OS) is the most common primary malignant bone tumor that more commonly occurs in children and adolescents. The most commonly used treatment for OS is surgery combined with chemotherapy, but the treatment outcomes are typically unsatisfactory. High rates of metastasis and post-treatment recurrence rates are major challenges in the treatment of OS. This underlines the need for studying the in-depth characterization of the pathogenetic mechanisms of OS and development of more effective therapeutic modalities. Previous studies have demonstrated the important role of the bone microenvironment and the regulation of signaling pathways in the occurrence and development of OS. In this review, we discussed the available evidence pertaining to the mechanisms of OS development and identified therapeutic targets for OS. We also summarized the available treatment modalities for OS and identified future priorities for therapeutics research.

Harnessing knee joint resident mesenchymal stem cells in cartilage tissue engineering.

Osteoarthritis (OA) is a widespread clinical disease characterized by cartilage degeneration in middle-aged and elderly people. Currently, there is no effective treatment for OA apart from total joint replacement in advanced stages. Mesenchymal stem cells (MSCs) are a type of adult stem cell with diverse differentiation capabilities and immunomodulatory potentials. MSCs are known to effectively regulate the cartilage microenvironment, promote cartilage regeneration, and alleviate OA symptoms. As a result, they are promising sources of cells for OA therapy. Recent studies have revealed the presence of resident MSCs in synovial fluid, synovial membrane, and articular cartilage, which can be collected as knee joint-derived MSCs (KJD-MSC). Several preclinical and clinical studies have demonstrated that KJD-MSCs have great potential for OA treatment, whether applied alone, in combination with biomaterials, or as exocrine MSCs. In this article, we will review the characteristics of MSCs in the joints, including their cytological characteristics, such as proliferation, cartilage differentiation, and immunomodulatory abilities, as well as the biological function of MSC exosomes. We will also discuss the use of tissue engineering in OA treatment and introduce the concept of a new generation of stem cell-based tissue engineering therapy, including the use of engineering, gene therapy, and gene editing techniques to create KJD-MSCs or KJD-MSC derivative exosomes with improved functionality and targeted delivery. These advances aim to maximize the efficiency of cartilage tissue engineering and provide new strategies to overcome the bottleneck of OA therapy. STATEMENT OF SIGNIFICANCE: This research will provide new insights into the medicinal benefit of Joint resident Mesenchymal Stem Cells (MSCs), specifically on its cartilage tissue engineering ability. Through this review, the community will further realize promoting joint resident mesenchymal stem cells, especially cartilage progenitor/MSC-like progenitor cells (CPSC), as a preventive measure against osteoarthritis and cartilage injury. People and medical institutions may also consider cartilage derived MSC as an alternative approach against cartilage degeneration. Moreover, the discussion presented in this study will convey valuable information for future research that will explore the medicinal benefits of cartilage derived MSC.

Femoral prosthesis fracture after hip arthroplasty revision: A Case Report and Review of Literature.

RATIONALE: A solution revision prosthesis has a multilayer microporous Porocoat coating, and the availability of multiple stem body sizes ensures that the prosthesis is adapted to each patient's anatomical structure so that there a firm attachment with the bone cortex in the middle of the femur. Therefore, the Solution prosthesis is one of the most commonly used and most effective prostheses in total hip arthroplasty worldwide. PATIENT CONCERNS: We reported a case of a 54-year-old female patient with periprosthetic femoral fractures after hip arthroplasty. DIAGNOSIS: The case was identified as type B2 prosthesis loosening according to the Vancouver classification. INTERVENTIONS: We performed revision surgery on her using the Solution prosthesis. Seven months after the surgery, the patient developed a mid-femoral prosthesis fracture for no apparent reason. We performed a second revision surgery of the hip joint and allogeneic bone plate fixation. OUTCOMES: The patient was satisfied with the treatment. LESSONS: For patients with type B2 prosthesis loosening and prosthesis fracture, hip arthroplasty revision and an allogeneic bone plate could be used to ensure more stable support.

Influence of lower-limb mechanical axis on the curative effect of medial high tibial osteotomy for knee osteoarthritis.

PURPOSE: To investigate the effect of the ratio of the medial tibial plateau width to the total tibial plateau width on the therapeutic efficacy of high tibial osteotomy (HTO) on the medial side for the treatment of knee osteoarthritis. METHODS: In this study, we retrospectively analyzed information of 278 patients who underwent medial HTO for knee osteoarthritis with varus deformity. The Tinetti Gait and Balance Assessment Tool, the Visual Analog Scale (VAS), and the Knee Society Scoring System (KSS) were used to comprehensively evaluate the function of the knee joint after HTO. RESULTS: After adjusting for potential confounding factors (i.e., age, gender, body mass index/BMI, and surgical site), the Tinetti assessment score was optimized when the degree of correction was 53.67%, with the ß-value on the left and right sides of the inflection point of 0.49 (confidence interval, CI: 0.20, 0.78, P = 0.0009) and- 0.26 (95% CI: - 0.30, - 0.22, P < 0.0001), respectively. The KSS score was optimized when the degree of correction was 55.45%, with the ß-value on the left and right sides of the inflection point of 2.77 (95% CI: 1.64, 3.90, P < 0.0001) and - 1.18 (95% CI: - 1.46, - 0.91, P < 0.0001), respectively. The VAS score was the lowest when the degree of correction was 55.00%, with the ß-value on the left and right sides of the inflection point of - 0.16 (95% CI: - 0.29, - 0.03, P = 0.0146) and 0.08 (95% CI: 0.05, 0.10, P < 0.0001), respectively. Stratified analysis showed that the BMI affected the Tinetti assessment score (ß = - 0.14, 95% CI: - 0.24, - 0.04, P = 0.0071). According to the smooth-curve fitting results, when the BMI was > 28, the Tinetti assessment score showed a negative trend. CONCLUSION: The degree of lower-limb mechanical axis correction correlated with the functional status of the knee joint after MOW HTO. When the ratio of the medial tibial plateau width to the total tibial plateau width was approximately 55%, the post-MOW HTO outcomes were optimized and the patients experienced the highest satisfaction. In addition, very high BMI was not conducive for the postoperative recovery of the knee joint function. LEVEL OF EVIDENCE: III Case-control study/Retrospective comparative study.

Comparison of topical and intravenous Tranexamic acid for high tibial osteotomy: A retrospective study.

ABSTRACT: High tibial osteotomy (HTO) is a promising surgery that can treat osteoarthritis of the medial septum of the knee. However, the extensive release of soft tissue and the osteotomy gap may produce intraoperative and postoperative bone bleeding. Tranexamic acid (TXA) is an effective blood management strategy, as it competitively inhibits the activation process of plasminogen and prevents fibrinolytic enzymes from degrading fibrin. Therefore, we compared the operative bone bleeding of patients who underwent HTO who received either intravenous (IV) or topical TXA in this research.The medical records of a total of 191 patients (including 72 who received IV TXA, 64 who received topical TXA and 55 control patients) who received open-wedge HTO were retrospectively reviewed from January 2016 to August 2019. There were no obvious demographic differences between the groups. Here, we used independent parameters to assess the efficacy of topical and IV TXA in reducing blood loss.Compared with the IV TXA group, patients receiving topical TXA therapy had greater blood loss (622 ±â€Š231 ml versus 451 ±â€Š231 ml, mean difference 171 mL [95% CI, 87-254]; p < 0.001). The hemoglobin concentration of the IV TXA group was obviously higher than that of the topical medication group. No patients had thromboembolic complications during the entire study period.In our study, it seemed that either IV or topical use of TXA might reduce blood loss after open-wedge HTO, and the blood loss and amount of drainage in the IV TXA group showed huge decreases compared to those in the topical group.

Arbutin suppresses osteosarcoma progression via miR-338-3p/MTHFD1L and inactivation of the AKT/mTOR pathway.

Arbutin, a glycoside extracted from the plant Arctostaphylos uva-ursi, has been previously reported to possess antioxidant, anti-inflammatory and anticancer effects. Here, we investigated whether arbutin affects the proliferation of the cells of the osteosarcoma (OS) cell lines MG-63 and SW1353. Arbutin suppressed OS cell viability in a dose- and time-dependent manner, as shown by Cell Counting Kit-8 assay. Furthermore, arbutin exposure decreased the protein levels of MTHFD1L, CCND1 and phosphorylated-protein kinase B (AKT)/phosphorylated-mammalian target of rapamycin (mTOR). Potential upstream miRNAs of MTHFD1L were predicted using TargetScan, PICTAR5, miRanda and miRWalk. We performed luciferase activity assays to show that miR-338-3p directly targets and negatively regulates the expression of MTHFD1L. Knockdown of miR-338-3p promoted cell invasion, migration and proliferation in arbutin-treated OS cells via MTHFD1L. In summary, our data suggest that arbutin inhibits OS cell proliferation, migration and invasion via miR-338-3p/MTHFD1L and by inactivating the AKT/mTOR pathway.

MTHFD1L as a folate cycle enzyme correlates with prognostic outcome and its knockdown impairs cell invasive behaviors in osteosarcoma via mediating the AKT/mTOR pathway.

Osteosarcoma (OS) is the most frequent primary malignancy initially in bone with multiple genomic aberrations. Methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) is linked with the progression of diverse tumors. However, its function in OS is not understood completely. The expression pattern and prognostic significance of MTHFD1L in OS tissues were analyzed based on GEO database. The expression level of MTHFD1L in OS cell lines was explored by qRT-PCR. The cell proliferation, colony formation ability, invasion as well as migration in OS cells after MTHFD1L knockdown were determined using cell counting kit 8 (CCK-8) assay, colony formation and transwell methods. GSEA analysis was performed to predict the underlying mechanisms of MTHFD1L in OS development. Furthermore, the western blot was utilized to study the influence of MTHFD1L on AKT/mTOR pathway. Our results indicated that MTHFD1L expression was significantly up-regulated in OS tissues and cells compared with normal tissues and cells. High expression of MTHFD1L could lead to poor prognosis of OS patients. Cell proliferation, colony formation ability, migration and invasion were blocked because of reduced MTHFD1L in vitro. Moreover, cell cycle and AKT/mTOR pathway were all associated with MTHFD1L expression. In conclusion, the findings revealed that MTHFD1L might promote the development of OS via mediating cell cycle and AKT/mTOR pathway, indicating that MTHFD1L might act as a promising therapeutic target for OS treatment.