Combination of stem cells and nerve guide conduit for the treatment of peripheral nerve injury: A meta-analysis.

INTRODUCTION/AIMS: Many small-sized, single-center preclinical studies have investigated the benefits of introducing stem cells into the interior of nerve conduit. The aims of this meta-analysis are to review and contrast the effects of various types of stem cells in in vivo models used to reconstruct peripheral nerve injuries (PNIs) and to assess the reliability and stability of the available evidence. METHODS: A systematic search was conducted using Cochrane Library, Embase, PubMed, and Web of Science to identify studies conducted from January 1, 2000, to September 21, 2022, and investigate stem cell therapy in peripheral nerve reconstruction animal models. Studies that met the relevant criteria were deemed eligible for this meta-analysis. RESULTS: Fifty-five preclinical studies with a total of 1234 animals were incorporated. Stem cells demonstrated a positive impact on peripheral nerve regeneration at different follow-up times in the forest plots of five outcome indicators: compound muscle action potential (CMAP) amplitude, latency, muscle mass ratio, nerve conduction velocity, and sciatic functional index (SFI). In most comparisons, stem cell groups showed substantial differences compared with the control groups. The superior performance of adipose-derived stem cells (ADSCs) in terms of SFI, CMAP amplitude, and latency (p < .001) was identified. DISCUSSION: The findings consistently demonstrated a favorable outcome in the reconstruction process when utilizing different groups of stem cells, as opposed to control groups where stem cells were not employed.

Patient characteristics and procedural variables are associated with length of stay and hospital cost among unilateral primary total hip arthroplasty patients: a single-center retrospective cohort study.

BACKGROUND: Total hip arthroplasty (THA) is a successful treatment for many hip diseases. Length of stay (LOS) and hospital cost are crucial parameters to quantify the medical efficacy and quality of unilateral primary THA patients. Clinical variables associated with LOS and hospital costs haven't been investigated thoroughly. METHODS: The present study retrospectively explored the contributors of LOS and hospital costs among a total of 452 unilateral primary THA patients from January 2019 to January 2020. All patients received conventional in-house rehabilitation services within our institute prior to discharge. Outcome parameters included LOS and hospital cost while clinical variables included patient characteristics and procedural variables. Multivariable linear regression analysis was performed to assess the association between outcome parameters and clinical variables by controlling confounding factors. Moreover, we analyzed patients in two groups according to their diagnosis with femur neck fracture (FNF) (confine THA) or non-FNF (elective THA) separately. RESULTS: Among all 452 eligible participants (266 females and 186 males; age 57.05 ± 15.99 year-old), 145 (32.08%) patients diagnosed with FNF and 307 (67.92%) diagnosed with non-FNF were analyzed separately. Multivariable linear regression analysis revealed that clinical variables including surgery duration, transfusion, and comorbidity (stroke) among the elective THA patients while the approach and comorbidities (stoke, diabetes mellitus, coronary heart disease) among the confine THA patients were associated with a prolonged LOS (P < 0.05). Variables including the American Society of Anesthesiologists classification (ASA), duration, blood loss, and transfusion among the elective THA while the approach, duration, blood loss, transfusion, catheter, and comorbidities (stoke and coronary heart disease) among the confine THA were associated with higher hospital cost (P < 0.05). The results revealed that variables were associated with LOS and hospital cost at different degrees among both elective and confine THA. CONCLUSIONS: Specific clinical variables of the patient characteristics and procedural variables are associated the LOS and hospital cost, which may be different between the elective and confine THA patients. The findings may indicate that evaluation and identification of detailed perioperative factors are beneficial in managing perioperative preparation, adjusting patients' anticipation, decreasing LOS, and reducing hospital cost.

The structure of exopolyphosphatase (PPX) from Porphyromonas gingivalis in complex with substrate analogs and magnesium ions reveals the basis for polyphosphate processivity.

The enzymes exopolyphosphatase/guanosine pentaphosphate phosphohydrolase (PPX/GppA) play important roles in the bacterial stringent response. PPX degrades inorganic polyphosphate (polyP), a polymer composed of a few to hundreds of phosphate residues supporting cell survival in the stationary phase. The crystal structure of PPX from Porphyromonas gingivalis (PgPPX) in complex with catalytic magnesium ions and several sulfate ions was solved. PgPPX contained two domains and represented a "closed" configuration. Four sulfate ions forming a linear dispersed chain were observed in the aqueduct of the PPX dimer, which the long polyP chain most likely occupied. The side chain of R255 stretched into the cavity where polyP could be located, obstructing the entrance of larger substrates such as NTP and NDP. This study provided the first view into the structure of the PPX/GppA homolog in complex with magnesium ions and substrate analogs and explained how PgPPX implemented its functionality.

Limited aerenchyma reduces oxygen diffusion and methane emission in paddy.

Greenhouse gasses (GHG) emission from the agricultural lands is a serious threat to the environment. Plants such as rice (Oryza sativa L.) that are cultivated in submerged conditions (paddy field) contribute up to 19% of CH4 emission from agricultural lands. Such plants have evolved lysigenous aerenchyma in their root system which facilitates the exchange of O2 and GHG between aerial parts of plant and rhizosphere. Currently, the regulation of GHG and O2 via aerenchyma formation is poorly understood in plants, especially in rice. Here, a reverse genetic approach was employed to reduce the aerenchyma formation by analyzing two mutants i.e., oslsd1.1-m12 and oslsd1.1-m51 generated by Tos17 and T-DNA insertion. The wild-type (WT) and the mutants were grown in paddy (flooded), non-paddy and hydroponic system to assess phenotypic traits including O2 diffusion, GHG emission and aerenchyma formation. The mutants exhibited significant reductions in several morphophysiological traits including 20-60% aerenchyma formation at various distances from the root apex, 25% root development, 50% diffusion of O2 and 27-36% emission of methane (CH4) as compared to WT. The differential effects of the oslsd1.1 mutants in aerenchyma-mediated CH4 mitigation were also evident in the diversity of (pmoA, mcrA) methanotrophs in the rhizosphere. Our results indicate the novel pathway in which reduced aerenchyma in rice is responsible for the mitigation of CH4, diffusion of O2 and the root growth in rice. Limited aerenchyma mediated approach to mitigate GHG specially CH4 mitigation in agriculture is helpful technique for sustainable development.

Interleukin-6 promotes migration and extracellular matrix synthesis in retinal pigment epithelial cells.

Proliferative vitreoretinopathy (PVR) is the most common cause of surgical failure in the rhegmatogenous retinal detachment (RD) treatment. Retinal pigment epithelial (RPE) cell proliferation, migration, and the synthesis of extracellular matrix (ECM) are intrinsic to the formation of a PVR membrane. High level of interleukin-6 (IL-6) has been found in the vitreous of PVR patients, while the role of IL-6 in RPE cells remaining further characterized. In the present study, we evaluated the potential regulatory effects of IL-6 on cell migration, ECM components, and transforming growth factor ß2 (TGF-ß2) expression in RPE cells. Furthermore, cell counting kit-8 (CCK­8) assay was used to investigate cell proliferation activity. We found that IL-6 promoted fibronectin (Fn) and type I collagen (COL-1), TGF-ß2 expression in RPE cells, also stimulate RPE cell migration effectively. Moreover, the induction of IL-6 activated the Janus kinase/signal transducers and activators of transcription (JAK/STAT3) and the nuclear factor kappa-B (NF-κB) signaling pathways significantly. Simultaneously, both JAK/STAT3 and NF-κB pathways inhibitors, WP1066 and BAY11-7082, alleviated IL-6-induced biological effects, respectively. However, it was noted that IL-6 had little effect on α-smooth muscle actin (α-SMA) expression. Collectively, our results reveal that IL-6 promotes RPE cell migration and ECM synthesis via activating JAK/STAT3 and NF-κB signaling pathways, which may play a crucial role in PVR formation.

Interleukin-2 induces extracellular matrix synthesis and TGF-ß2 expression in retinal pigment epithelial cells.

Macular fibrosis is a vital obstacle of vision acuity improvement of age-related macular degeneration patients. This study was to investigate the effects of interleukin 2 (IL-2) on epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) synthesis and transforming growth factor ß2 (TGF-ß2) expression in retinal pigment epithelial (RPE) cells. 10 µg/L IL-2 was used to induce fibrosis in RPE cells for various times. Western blot was used to detect the EMT marker α-smooth muscle actin (α-SMA), ECM markers fibronectin (Fn) and type 1 collagen (COL-1), TGF-ß2, and the activation of the JAK/STAT3 and NF-κB signaling pathway. Furthermore, JAK/STAT3 and NF-κB signaling pathways were specifically blocked by WP1066 or BAY11-7082, respectively, and the expression of α-SMA, COL-1, Fn and TGF-ß2 protein were detected. Wound healing and Transwell assays were used to measure cell migration ability of IL-2 with or without WP1066 or BAY11-7082. After induction of IL-2, the expressions of Fn, COL-1, TGF-ß2 protein were significantly increased, and this effect was correlated with IL-2 treatment duration, while α-SMA protein expression did not change significantly. Both WP1066 and BAY11-7082 could effectively downregulate the expression of Fn, COL-1 and TGF-ß2 induced by IL-2. What's more, both NF-κB and JAK/STAT3 inhibitors could suppress the activation of the other signaling pathway. Additionally, JAK/STAT3 inhibitor WP1066 and NF-κB inhibitor BAY 11-7082 could obviously decrease RPE cells migration capability induced by IL-2. IL-2 promotes cell migration, ECM synthesis and TGF-ß2 expression in RPE cells via JAK/STAT3 and NF-κB signaling pathways, which may play an important role in proliferative vitreoretinopathy.

Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2.

Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC50 = 27 nM). Then we carried out structure-based drug design and synthesized a series of compounds with an aminopyridine scaffold. Finally, compound 12k and 12l were identified as the promising inhibitors of JAK2, which exhibited high inhibitory activity (IC50 = 6 nM and 3 nM, respectively) and selectivity for JAK2 over JAK1 and JAK3, and showed potent antiproliferative activities toward HEL human erythroleukemia cells. Moreover, 12k suppressed symptoms of the collagen-induced arthritis (CIA) model in rats.

Structural Optimization and Structure-Activity Relationship of 4-Thiazolidinone Derivatives as Novel Inhibitors of Human Dihydroorotate Dehydrogenase.

Human dihydroorotate dehydrogenase (hDHODH), one of the attractive targets for the development of immunosuppressive drugs, is also a potential target of anticancer drugs and anti-leukemic drugs. The development of promising hDHODH inhibitors is in high demand. Based on the unique binding mode of our previous reported 4-thiazolidinone derivatives, via molecular docking method, three new series 4-thiazolidinone derivatives were designed and synthesized as hDHODH inhibitors. The preliminary structure-activity relationship was investigated. Compound 9 of biphenyl series and compound 37 of amide series displayed IC50 values of 1.32 µM and 1.45 µM, respectively. This research will provide valuable reference for the research of new structures of hDHODH inhibitors.

[Design, synthesis and structure-activity relationship studies of human dihydroorotate dehydrogenase inhibitors].

In this study, 1-(3-(4-chlorophenyl)-5-methylthio-1H-1,2,4-triazol-1-yl)-butan-1-one discovered previously in our lab was selected as a inhibitor of human dihydroorotate dehydrogenase ( HsDHODH) for structural optimization. The co-crystal of HsDHODH with the hit was obtained and analyzed for guiding the subsequent structural optimization. As a result, a series of novel triazole derivatives were designed and synthesized as potent HsDHODH inhibitors. Among them, compound (3-(4-chlorophenyl)-5-ethylthio-1H- 1,2,4-triazol-1-yl)-furan-2-yl-methanone displayed high potency in the inhibition of HsDHODH with an IC50 value of 1.50 µmol·L−1. Meanwhile, the structure-activity relationships were analyzed based on the biological data and the co-crystal structure. These results provide a valuable reference for optimization of 1H-1,2,4- triazole derivatives as HsDHODH inhibitors in the future.

Self-assembled coating with a metal-polyphenolic network for intraocular lens modification to prevent posterior capsule opacification.

Posterior capsule opacification (PCO) is a main complication after cataract surgery and intraocular lens (IOLs) implantation and is attributed to residual lens epithelial cells (LECs) migrating to the IOL surface and posterior capsules. IOL surface modification has been a newly-developing research filed in recent years; however, the applicability and economical acquisition of modified materials remain unsolved. In this study, we first applied a metal-polyphenolic network coating with a self-assembly technique on the IOL surface by using tannic acid (TA) combined with AlCl3, which are easily acquire and applying on the IOL surface to solve the IOL transmittance affair. Using wound healing and Transwell assay to verify AZD0364 inhibits cell migration (P< 0.05), the lipopolysaccharide-induced macrophage inflammation model to verify pterostilbene (PTE) inhibits the inflammatory reaction (P< 0.01). By optimizes its self-assembly coating parameters and calculating its drug release kinetics, we successfully loaded these two drugs on the coating, named TA (AZD0364/PTE) IOL. Its surface morphology characteristics were analyzed by scanning electron microscope, x-ray photoelectron spectrometer and water contact angle. The optical performance was carefully investigated by optical instruments and equipment (n= 3). Thein vitroresults showed that TA (AZD0364/PTE) IOL can significantly inhibit cell adhesion and acute inflammation (n= 3,P< 0.0001). Importantly, afterin vivoimplantation for 28 d with eight rabbits PCO models in two groups, the TA (AZD0364/PTE) IOL group maintained clear refracting media and decreased the inflammatory reaction compared with the original IOL group (P< 0.05). This study provides a new applicable and economical strategy for preventing PCO and offers a reference for the next generation of IOLs that benefit cataract patients.

Anoikis resistance regulates immune infiltration and drug sensitivity in clear-cell renal cell carcinoma: insights from multi omics, single cell analysis and in vitro experiment.

Background: Anoikis is a form of programmed cell death essential for preventing cancer metastasis. In some solid cancer, anoikis resistance can facilitate tumor progression. However, this phenomenon is underexplored in clear-cell renal cell carcinoma (ccRCC). Methods: Using SVM machine learning, we identified core anoikis-related genes (ARGs) from ccRCC patient transcriptomic data. A LASSO Cox regression model stratified patients into risk groups, informing a prognostic model. GSVA and ssGSEA assessed immune infiltration, and single-cell analysis examined ARG expression across immune cells. Quantitative PCR and immunohistochemistry validated ARG expression differences between immune therapy responders and non-responders in ccRCC. Results: ARGs such as CCND1, CDKN3, PLK1, and BID were key in predicting ccRCC outcomes, linking higher risk with increased Treg infiltration and reduced M1 macrophage presence, indicating an immunosuppressive environment facilitated by anoikis resistance. Single-cell insights showed ARG enrichment in Tregs and dendritic cells, affecting immune checkpoints. Immunohistochemical analysis reveals that ARGs protein expression is markedly elevated in ccRCC tissues responsive to immunotherapy. Conclusion: This study establishes a novel anoikis resistance gene signature that predicts survival and immunotherapy response in ccRCC, suggesting that manipulating the immune environment through these ARGs could improve therapeutic strategies and prognostication in ccRCC.

SAMD4A serves as a negative prognostic marker for gastric cancer patients.

INTRODUCTION: The incidence and mortality of gastric cancer remain high in the world. We aim to explore the role of SAMD4A in gastric cancer. METHODS: The expression of SAMD4A was up-regulated in gastric adenocarcinoma and the expression level of SAMD4A in gastric adenocarcinoma and adjacent normal tissues was verified by RT-qPCR. Immunohistochemical showed that SAMD4A was mainly located in the cytoplasm. RESULT: The result showed that the expression of SAMD4A was positively correlated with the depth of invasion, the number of lymph node metastasis, and the clinical stage in patients with gastric adenocarcinoma. Survival analysis of GEPIA database showed that the overall survival of gastric adenocarcinoma patients with positive SAMD4A expression was lower than that of the negative group. Gastric cancer cell lines with knockdown of the SAMD4A gene were used to observe the differences in cell proliferation, invasion, and migration abilities between the knockdown group and the control group. The results showed that the proliferation, invasion, and migration abilities of the SAMD4A knockdown group were both weakened compared with the control group. This study is the first to find that the expression level of SAMD4A in gastric cancer is higher than that in the adjacent group and is associated with poor prognosis of patients. SAMD4A promotes the proliferation, invasion, and migration of gastric adenocarcinoma cells. CONCLUSION: This indicates that SAMD4A plays an important role in the occurrence and development of gastric cancer, and is expected to be an effective indicator for the diagnosis and evaluation of the prognosis of gastric cancer.

Role of reactive oxygen species in epithelial-mesenchymal transition and apoptosis of human lens epithelial cells.

AIM: To investigate the role of reactive oxygen species (ROS) in epithelial-mesenchymal transition (EMT) and apoptosis of human lens epithelial cells (HLECs). METHODS: Flow cytometry was used to assess ROS production after transforming growth factor ß2 (TGF-ß2) induction. Apoptosis of HLECs after H2O2 and TGF-ß2 interference with or without ROS scavenger N-acetylcysteine (NAC) were assessed by flow cytometry. The corresponding protein expression levels of the EMT marker α-smooth muscle actin (α-SMA), the extracellular matrix (ECM), marker fibronectin (Fn), and apoptosis-associated proteins were detected by using Western blotting in the presence of an ROS scavenger (NAC). Wound-healing and Transwell assays were used to assess the migration capability of HLECs. RESULTS: TGF-ß2 stimulates ROS production within 8h in HLECs. Additionally, TGF-ß2 induced HLECs cell apoptosis, EMT/ECM synthesis protein markers expression, and pro-apoptotic proteins production; nonetheless, NAC treatment prevented these responses. Similarly, TGF-ß2 promoted HLECs cell migration, whereas NAC inhibited cell migration. We further determined that although ROS initiated apoptosis, it only induced the accumulation of the EMT marker α-SMA protein, but not COL-1 or Fn. CONCLUSION: ROS contribute to TGF-ß2-induced EMT/ECM synthesis and cell apoptosis of HLECs; however, ROS alone are not sufficient for EMT/ECM synthesis.

LncRNA XLOC_015548 affects the proliferation and differentiation of myoblasts via the MAPK signaling pathway.

In recent years, an increasing number of studies have reported that long non-coding RNAs (lncRNAs) play essential regulatory roles in myogenic differentiation. In this study, a specific LncRNA XLOC_015548 (Lnc000280) was identified. However, little research has explored its mechanism of action by constructing XLOC_015548 gene editing cell models. In this study, relevant sequences were obtained according to the RNA-seq results. Subsequently, XLOC_015548 knockdown and over-expression lentiviral vectors were constructed, and the C2C12 myoblast cell line was transfected to prepare the XLOC_015548 gene-edited myoblast model. The in vitro analysis revealed that over-expression of XLOC_015548 significantly promoted the proliferation and differentiation of myoblasts and the formation of myotubes, whereas the opposite result was obtained in the knockdown group. XLOC_015548 regulated myogenic differentiation and affected the expression of myogenic differentiation regulators such as Myod, myogenin, and MyHC. Regarding the signaling pathway, we found that XLOC_015548 correlated with the phosphorylation level of MAPK/MEK/ERK pathway proteins. And the degree of phosphorylation was positively correlated with the protein expression of myogenic differentiation regulators. In conclusion, a new gene-edited myoblast model was constructed based on the lncRNA regulator XLOC_015548. The in vitro cell experiments verified that XLOC_015548 had regulatory effects on muscle growth and myoblast differentiation. These findings provide a laboratory foundation for the clinical application of lncRNAs as regulatory factors in the treatment of disuse muscle atrophy.

HNF4A Negatively Regulated Posterior Capsular Opacification via Transcriptional Inhibition of MMP2.

PURPOSE: Posterior capsular opacification is the most common complication after cataract surgery. Abnormal proliferation, migration, epithelial-mesenchymal transition, and extracellular matrix synthesis of residual lens epithelial cells are considered to be the main pathogenic mechanisms. Hepatocyte nuclear factor 4α has been reported to regulate epithelial-mesenchymal transition in different tumors. Our objective was to investigate the role and mechanism of hepatocyte nuclear factor 4α in posterior capsular opacification. METHODS: Hepatocyte nuclear factor 4α expression was tested in posterior capsular opacification rat lens capsules and cell models. Hepatocyte nuclear factor 4α was knocked down using small hairpin RNA. Cell viability was measured by Cell Counting Kit-8 assay. Cell migration ability was evaluated by wound healing and Transwell assays. Epithelial-mesenchymal transition markers were detected by Western blotting. Transcriptome sequencing was used to screen for downstream effectors of hepatocyte nuclear factor 4α. Chromatin immunoprecipitation and a dual luciferase reporter assay were used to determine the binding of hepatocyte nuclear factor 4α to the MMP2 promoter region. RESULTS: Hepatocyte nuclear factor 4α was downregulated in posterior capsular opacification tissue and cell models. In vitro studies showed that hepatocyte nuclear factor 4α deletion facilitated cell proliferation, migration, and epithelial-mesenchymal transition protein marker expression in lens epithelial cells. Hepatocyte nuclear factor 4α knockdown promoted epithelial-mesenchymal transition and migration of lens epithelial cells via MMP2. Mechanistically, hepatocyte nuclear factor 4α decreased MMP2 expression by binding to the MMP2 promoter region. Hepatocyte nuclear factor 4α deletion also promoted epithelial-mesenchymal transition in rat lens capsules. CONCLUSIONS: We demonstrated that hepatocyte nuclear factor 4α inhibited epithelial-mesenchymal transition of lens epithelial cells by directly binding to the MMP2 promoter region and inhibiting the expression of MMP2, thus leading to retardation of posterior capsular opacification formation and development, suggesting that hepatocyte nuclear factor 4α is a potential therapeutic target for posterior capsular opacification.

Crosstalk between ferroptosis and chondrocytes in osteoarthritis: a systematic review of in vivo and in vitro studies.

Purpose: Recent scientific reports have revealed a close association between ferroptosis and the occurrence and development of osteoarthritis (OA). Nevertheless, the precise mechanisms by which ferroptosis influences OA and how to hobble OA progression by inhibiting chondrocyte ferroptosis have not yet been fully elucidated. This study aims to conduct a comprehensive systematic review (SR) to address these gaps. Methods: Following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020, we conducted a comprehensive search of the Embase, Ovid, ProQuest, PubMed, Scopus, the Cochrane Library, and Web of Science databases to identify relevant studies that investigate the association between ferroptosis and chondrocytes in OA. Our search included studies published from the inception of these databases until January 31st, 2023. Only studies that met the predetermined quality criteria were included in this SR. Results: In this comprehensive SR, a total of 21 studies that met the specified criteria were considered suitable and included in the current updated synthesis. The mechanisms underlying chondrocyte ferroptosis and its association with OA progression involve various biological phenomena, including mitochondrial dysfunction, dysregulated iron metabolism, oxidative stress, and crucial signaling pathways. Conclusion: Ferroptosis in chondrocytes has opened an entirely new chapter for the investigation of OA, and targeted regulation of it is springing up as an attractive and promising therapeutic tactic for OA. Systematic review registration: https://inplasy.com/inplasy-2023-3-0044/, identifier INPLASY202330044.

Teriparatide ameliorates articular cartilage degradation and aberrant subchondral bone remodeling in DMM mice.

Objective: Knee osteoarthritis (KOA) is a highly prevalent musculoskeletal disorder characterized by degeneration of cartilage and abnormal remodeling of subchondral bone (SCB). Teriparatide (PTH (1-34)) is an effective anabolic drug for osteoporosis (OP) and regulates osteoprotegerin (OPG)/receptor activator of nuclear factor ligand (RANKL)/RANK signaling, which also has a therapeutic effect on KOA by ameliorating cartilage degradation and inhibiting aberrant remodeling of SCB. However, the mechanisms of PTH (1-34) in treating KOA are still uncertain and remain to be explored. Therefore, we compared the effect of PTH (1-34) on the post-traumatic KOA mouse model to explore the potential therapeutic effect and mechanisms. Methods: In vivo study, eight-week-old male mice including wild-type (WT) (n â€‹= â€‹54) and OPG-/- (n â€‹= â€‹54) were investigated and compared. Post-traumatic KOA model was created by destabilization of medial meniscus (DMM). WT mice were randomly assigned into three groups: the sham group (WT-sham; n â€‹= â€‹18), the DMM group (WT-DMM; n â€‹= â€‹18), and the PTH (1-34)-treated group (WT-DMM â€‹+ â€‹PTH (1-34); n â€‹= â€‹18). Similarly, the OPG-/- mice were randomly allocated into three groups as well. The designed mice were executed at the 4th, 8th, and 12th weeks to evaluate KOA progression. To further explore the chondro-protective of PTH (1-34), the ATDC5 chondrocytes were stimulated with different concentrations of PTH (1-34) in vitro. Results: Compared with the WT-sham mice, significant wear of cartilage in terms of reduced cartilage thickness and glycosaminoglycan (GAG) loss was detected in the WT-DMM mice. PTH (1-34) exhibited cartilage-protective by alleviating wear, retaining the thickness and GAG contents. Moreover, the deterioration of the SCB was alleviated and the expression of PTH1R/OPG/RANKL/RANK were found to increase after PTH (1-34) treatment. Among the OPG-/- mice, the cartilage of the DMM mice displayed typical KOA change with higher OARSI score and thinner cartilage. The damage of the cartilage was alleviated but the abnormal remodeling of SCB didn't show any response to the PTH (1-34) treatment. Compared with the WT-DMM mice, the OPG-/--DMM mice caught more aggressive KOA with thinner cartilage, sever cartilage damage, and more abnormal remodeling of SCB. Moreover, both the damaged cartilage from the WT-DMM mice and the OPG-/--DMM mice were alleviated but only the deterioration of SCB in WT-DMM mice was alleviated after the administration of PTH (1-34). In vitro study, PTH (1-34) could promote the viability of chondrocytes, enhance the synthesis of extracellular matrix (ECM) (AGC, COLII, and SOX9) at the mRNA and protein level, but inhibit the secretion of inflammatory cytokines (TNF-α and IL-6). Conclusion: Both wear of the cartilage was alleviated and aberrant remodeling of the SCB was inhibited in the WT mice, but only the cartilage-protective effect was observed in the OPG-/- mice. PTH (1-34) exhibited chondro-protective effect by decelerating cartilage degeneration in vivo as well as by promoting the proliferation and enhancing ECM synthesis of chondrocytes in vitro. The current investigation implied that the rescue of the disturbed SCB is dependent on the regulation of OPG while the chondro-protective effect is independent of modulation of OPG, which provides proof for the treatment of KOA. The translational potential of this article: Systemic administration of PTH (1-34) could exert a therapeutic effect on both cartilage and SCB in different mechanisms to alleviate KOA progression, which might be a novel therapy for KOA.

Magnesium Ions Promote In Vitro Rat Bone Marrow Stromal Cell Angiogenesis Through Notch Signaling.

Bone defects are often caused by trauma or surgery and can lead to delayed healing or even bone nonunion, thereby resulting in impaired function of the damaged site. Magnesium ions and related metallic materials play a crucial role in repairing bone defects, but the mechanism remains unclear. In this study, we induced the angiogenic differentiation of bone marrow stromal cells (BMSCs) with different concentrations of magnesium ions. The mechanism was investigated using γ-secretase inhibitor (DAPT) at different time points (7 and 14 days). Angiogenesis, differentiation, migration, and chemotaxis were detected using the tube formation assay, wound-healing assay, and Transwell assay. Besides, we analyzed mRNA expression and the angiogenesis-related protein levels of genes by RT-qPCR and western blot. We discovered that compared with other concentrations, the 5 mM magnesium ion concentration was more conducive to forming tubes. Additionally, hypoxia-inducible factor 1 alpha (Hif-1α) and endothelial nitric oxide (eNOS) expression both increased (p < 0.05). After 7 and 14 days of induction, 5 mM magnesium ion group tube formation, migration, and chemotaxis were enhanced, and the expression of Notch pathway genes increased. Moreover, expression of the Notch target genes hairy and enhancer of split 1 (Hes1) and Hes5 (hairy and enhancer of split 5), as well as the angiogenesis-related genes Hif-1α and eNOS, were enhanced (p < 0.05). However, these trends did not occur when DAPT was applied. This indicates that 5 mM magnesium ion is the optimal concentration for promoting the angiogenesis and differentiation of BMSCs in vitro. By activating the Notch signaling pathway, magnesium ions up-regulate the downstream genes Hes1 and Hes5 and the angiogenesis-related genes Hif-1α and eNOS, thereby promoting the angiogenesis differentiation of BMSCs. Additionally, magnesium ion-induced differentiation enhances the migration and chemotaxis of BMSCs. Thus, we can conclude that magnesium ions and related metallic materials promote angiogenesis to repair bone defects. This provides the rationale for developing artificial magnesium-containing bone materials through tissue engineering.

Corrigendum to 'Teriparatide ameliorates articular cartilage degradation and aberrant subchondral bone remodeling in DMM mice' [J. Orthop. Transl.] 38 (2023) 241-255].

[This corrects the article DOI: 10.1016/j.jot.2022.10.015.].

The E3 Ligase RNF157 Inhibits Lens Epithelial Cell Apoptosis by Negatively Regulating p53 in Age-Related Cataracts.

Purpose: Age-related cataract (ARC) is a major cause of vision impairment worldwide. The E3 ubiquitin ligase RING finger protein 157 (RNF157) is involved in regulating cell survival and downregulated in human cataractous lens samples. However, the function of RNF157 in cataracts remains unclear. This study aimed to determine the role of RNF157 in ARC. Methods: Real-time polymerase chain reaction (PCR) and Western blotting were used to analyze the expression of RNF157 in clinical lens capsules, rat cataract models, and oxidative stress cell models. Western blot analysis and flow cytometry were used to evaluate cell apoptosis. Co-IP assay, protein stability assay, and ubiquitination assay were used to detect the interaction between RNF157 and its substrate p53. Results: The expression of RNF157 was downregulated in human cataract samples, UVB-induced rat cataract model, and H2O2-treated human lens epithelial cells (LECs). Ectopic expression of RNF157 protected LECs from H2O2-induced apoptosis. In contrast, knockdown of RNF157 enhanced oxidative stress-induced apoptotic cell death. Moreover, silence of RNF157 in the rat ex vivo lens model exacerbated lens opacity. Mechanistically, RNF157 causes ubiquitination and degradation of the tumor antigen p53. Overexpression of p53 eliminated the antiapoptotic effects of RNF157, whereas p53 knockdown rescued RNF157 silencing-induced cell death. Conclusions: Our findings revealed that reduced RNF157 expression promoted LEC apoptosis by upregulating p53 in cataracts, suggesting that the regulation of RNF157 expression may serve as a potential therapeutic strategy for cataracts.