Isthmin-1 promotes growth and progression of colorectal cancer through the interaction with EGFR and YBX-1.

While previous studies have indicated the involvement of Isthmin 1 (ISM1), a secreted protein, in cancer development, the precise mechanisms have remained elusive. In this study, we unveiled that ISM1 is significantly overexpressed in both the blood and tissue samples of colorectal cancer (CRC) patients, correlating with their poor prognosis. Functional experiments demonstrated that enforced ISM1 expression significantly enhances CRC proliferation, migration, invasion and tumor growth. Notably, our investigation reveals an interaction of ISM1 with epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase (RTK) family of CRC cells. The binding of ISM1 triggered EGFR activation and initiate downstream signaling pathways. Meanwhile, intracellular ISM1 interacted with Y-box binding protein 1 (YBX1), enhancing its transcriptional regulation on EGFR. Furthermore, our research uncovered the regulation of ISM1 expression by the hypoxia-inducible transcription factor HIF-1α in CRC cells. Mechanistically, we identified HIF-1α as a direct regulator of ISM1, binding to a hypoxia response element on its promoter. This novel mechanism illuminated potential therapeutic targets, offering insights into restraining HIF-1α/ISM1/EGFR-driven CRC progression and metastasis.

Amphiphilic Rhodamine Fluorescent Probes Combined with Basal Imaging for Fine Structures of the Cell Membrane.

Confocal fluorescence imaging of fine structures of the cell membrane is important for understanding their biofunctions but is often neglected due to the lack of an effective method. Herein, we develop new amphiphilic rhodamine fluorescent probe RMGs in combination with basal imaging for this purpose. The probes show high signal-to-noise ratio and brightness and low internalization rate, making them suitable for imaging the fine substructures of the cell membrane. Using the representative probe RMG3, we not only observed the cell pseudopodia and intercellular nanotubes but also monitored the formation of migrasomes in real time. More importantly, in-depth imaging studies on more cell lines revealed for the first time that hepatocellular carcinoma cells secreted much more adherent extracellular vesicles than other cell lines, which might serve as a potential indicator of liver cells. We believe that RMGs may be useful for investigating the fine structures of the cell membrane.

Comparing perioperative outcomes between regional anesthesia and general anesthesia in patients undergoing hip fracture surgery: a systematic review and meta-analysis.

PURPOSE: Nearly all patients with hip fractures undergo surgical treatment. The use of different anesthesia techniques during surgery may influence the clinical outcomes. The optimal anesthetic technique for patients undergoing hip fracture surgery is still controversial. We performed this updated systematic review and meta-analysis to compare clinical outcomes of patients undergoing hip fracture surgery with different anesthesia techniques. SOURCE: Articles published from 2000 to May 2023 were included from MEDLINE, Embase, Web of Science, and the Cochrane Library. We included randomized controlled trials and observational studies comparing general anesthesia (GA) with regional anesthesia (RA) for the outcomes of 30-day mortality, 90-day mortality, in-hospital mortality, perioperative complications, length of hospital stay, and length of surgery in patients undergoing hip fracture surgery. Subgroup analyses were performed for the outcomes based on study design (randomized controlled trials or observational studies). We used a random-effects model for all analyses. PRINCIPAL FINDINGS: In this meta-analysis, we included 12 randomized controlled trials. There was no difference in postoperative 30-day mortality between the two groups (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.44 to 1.74; I2 = 0%). The incidence of intraoperative hypotension was lower in patients who received RA vs GA (OR, 0.52; 95% CI, 0.38 to 0.72; I2 = 0%). No significant differences were observed in 90-day mortality, in-hospital mortality, postoperative delirium, pneumonia, myocardial infarction, venous thromboembolism, length of surgery, and length of hospital stay. CONCLUSION: In this updated systematic review and meta-analysis, RA did not reduce postoperative 30-day mortality in hip fracture surgery patients compared to GA. Fewer patients receiving RA had intraoperative hypotension than those receiving GA did. Apart from intraoperative hypotension, the data showed no differences in complications between the two anesthetic techniques. STUDY REGISTRATION: PROSPERO (CRD42023411854); registered 7 April 2023.

RéSUMé: OBJECTIF: Presque toutes les personnes ayant subi une fracture de la hanche se font opérer. L'utilisation de différentes techniques d'anesthésie pendant la chirurgie peut influencer les issues cliniques. La technique d'anesthésie optimale pour la patientèle bénéficiant de chirurgie de fracture de la hanche est encore controversée. Nous avons réalisé cette mise à jour par revue systématique et méta-analyse pour comparer les issues cliniques des personnes bénéficiant d'une chirurgie de fracture de la hanche avec différentes techniques d'anesthésie. SOURCES: Les articles publiés de 2000 à mai 2023 ont été inclus à partir des bases de données MEDLINE, Embase, Web of Science et Cochrane Library. Nous avons inclus des études randomisées contrôlées et des études observationnelles comparant l'anesthésie générale (AG) à l'anesthésie régionale (AR) pour les issues de mortalité à 30 jours, de mortalité à 90 jours, de mortalité intrahospitalière, de complications périopératoires, de durée de séjour à l'hôpital et de durée de la chirurgie pour les personnes bénéficiant d'une chirurgie de fracture de la hanche. Des analyses de sous-groupes ont été réalisées pour les issues en fonction de la méthodologie utilisée (étude randomisée contrôlée ou étude observationnelle). Un modèle à effets aléatoires a été utilisé pour toutes les analyses. CONSTATATIONS PRINCIPALES: Dans cette méta-analyse, nous avons inclus 12 études randomisées contrôlées. Il n'y avait pas de différence dans la mortalité postopératoire à 30 jours entre les deux groupes (rapport de cotes [RC], 0,88; intervalle de confiance à 95 % [IC], 0,44 à 1,74; I2 = 0 %). L'incidence d'hypotension peropératoire était plus faible chez les patient·es ayant reçu une AR vs une AG (RC, 0,52; IC 95 %, 0,38 à 0,72; I2 = 0 %). Aucune différence significative n'a été observée dans les issues de mortalité à 90 jours, de mortalité intrahospitalière, de delirium postopératoire, de pneumonie, d'infarctus du myocarde, de thromboembolie veineuse, de durée de la chirurgie, et de durée du séjour à l'hôpital. CONCLUSION: Dans cette revue systématique avec méta-analyse, l'anesthésie régionale n'a pas réduit la mortalité postopératoire à 30 jours chez les personnes ayant bénéficié d'une chirurgie de fracture de la hanche par rapport à l'anesthésie générale. Une proportion moindre de patient·es ayant reçu une AR présentaient une hypotension peropératoire par rapport aux personnes ayant reçu une AG. En dehors de l'hypotension peropératoire, les données n'ont montré aucune différence dans les complications entre les deux techniques anesthésiques. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42023411854); enregistrée le 7 avril 2023.

Klebsiella aerogenes exacerbates colon tumorigenesis in the AOM/DSS-induced C57BL/6J mouse.

Klebsiella aerogenes (K. aerogenes, KA) is a gram-negative opportunistic pathogen from the Klebsiella species and the Enterobacteriaceae family. However, the impact of K. aerogenes on colorectal cancer (CRC) remains uncertain. A colitis-associated tumorigenesis animal model was established by administering azoxymethane (AOM) and dextran sulfate sodium (DSS) to C57BL/6J mice. The concentration of K. aerogenes gavage in mice was 109 cfu. The study measured the following parameters: tumor formation (number and size), intestinal permeability (MUC2, ZO-1, and Occludin), colonic inflammation (TNF-α, IL-1ß, IL-6, and IL-10), proliferation and the fluctuation of the intestinal flora. Under the AOM/DSS-treated setting, K. aerogenes colonization worsened colitis by exacerbating intestinal inflammatory reaction and destroying the mucosal barrier. The intervention markedly augmented the quantity and dimensions of neoplasm in the AOM/DSS mice, stimulated cellular growth, and impeded cellular programmed cell death. In addition, K. aerogenes exacerbated the imbalance of the intestinal microbiota by elevating the abundance of Pseudomonas, Erysipelatoclostridium, Turicibacter, Rikenella, and Muribaculum and leading to a reduction in the abundance of Odoribacter, Alloprevotella, Roseburia, and Lachnospiraceae_NK4A136_group. The presence of K. aerogenes in AOM/DSS-treated mice promoted tumorigenesis, worsened intestinal inflammation, disrupted the intestinal barrier, and caused disturbance to the gut microbiota.

Preoperative Decreased Hounsfield Unit Values of Cervical Vertebrae and the Relative Cross-Sectional Area of Flexion/Extension Paraspinal Muscles Are Novel Risk Factors for the Loss of Cervical Lordosis after Open-Door Laminoplasty.

Open-door laminoplasty is widely used for patients with cervical spondylotic myelopathy (CSM). However, the loss of cervical lordosis (LCL) seems to be unavoidable in the long-term follow-up after surgery, which may affect the clinical outcomes. The risk factors for this complication are still unclear. In this study, patients who underwent open-door laminoplasty between April 2016 and June 2021 were enrolled. Cervical X-rays were obtained to measure the C2-7 Cobb angle, C2-7 sagittal vertical axis (SVA), T1 slope (T1S) and ranges of motion (ROM). Cervical computed tomography (CT) scans and magnetic resonance imaging (MRI) were collected to evaluate the cervical Hounsfield unit values (HU) and the relative cross-sectional area (RCSA) of paraspinal muscles, respectively. A total of 42 patients were included and the average follow-up period was 24.9 months. Among the patients, 24 cases (57.1%) had a LCL of more than 5° at a 1-year follow-up and were labeled as members of the LCL group. The follow-up JOA scores were significantly lower in the LCL group (13.9 ± 0.6 vs. 14.4 ± 0.8, p = 0.021) and the mean JOA recovery rate was negatively correlated with LCL (r = -0.409, p = 0.007). In addition, LCL was positively correlated to the preoperative T1S, flexion ROM, flexion/extension ROM and the RCSA of flexion/extension muscles, while it was negatively correlated to extension ROM and the HU value of cervical vertebrae. Furthermore, multiple linear regression showed that preoperative T1S, mean HU value of cervical vertebrae, flexion/extension ROM and the flexion/extension RCSA were independent risk factors for LCL. Spine surgeons should consider these parameters before performing open-door laminoplasty.

Cytotoxic Isopentenyl Phloroglucinol Compounds from Garcinia xanthochymus Using LC-MS-Based Metabolomics.

Many unique chemical metabolites with significant antitumor activities have been isolated from Garcinia species and have become a leading hotspot of antitumor research in recent years. The aim of this study was to identify bioactive compounds from different plant parts (leaf, branch, stem bark, fruit, and seed) of G. xanthochymus through combining LC-MS-based metabolomics with cytotoxicity assays. As a result, 70% methanol seed extract exerted significant cytotoxic effects on five human cancer cell types (HL-60, A549, SMMC-7721, MDA-MB-231, and SW480). LC-MS-based metabolomics analysis was used, including principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA), in order to identify 12 potential markers from seed extract that may relate to bioactivity. LC-MS guidance isolated the markers to obtain three compounds and identified new isopentenyl phloroglucinols (1-3, named garxanthochin A-C), using spectroscopic methods. Among them, garxanthochin B (2) demonstrated moderate inhibitory activities against five human cancer cell types, with IC50 values of 14.71~24.43 µM. These findings indicate that G. xanthochymus seed has significant cytotoxic activity against cancer cells and garxanthochin B has potential applications in the development of antitumor-led natural compounds.

YTHDF1 Enhances Chondrogenic Differentiation by Activating the Wnt/ß-Catenin Signaling Pathway.

Cartilage is derived from the chondrogenic differentiation of stem cells, for which the regulatory mechanism has not been fully elucidated. N6-methyladenosine (m6A) messenger RNA (mRNA) methylation is the most common posttranscriptional modification in eukaryotic mRNAs and is mediated by m6A regulators. However, whether m6A regulators play roles in chondrogenic differentiation is unknown. Herein, we aim to determine the role of a main m6A reader protein, YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), in chondrogenic differentiation regulation. Western blotting (WB) assays found that the expression of YTHDF1 increased during chondrogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). The results of quantitative polymerase chain reaction, WB, immunohistochemistry, and Alcian blue staining revealed that overexpression of YTHDF1 increased cartilage matrix synthesis and the expression of chondrogenic markers when hBMSCs, ATDC5 cells, or C3H10T1/2 cells were induced to undergo chondrogenesis. Conversely, chondrogenesis was clearly inhibited when YTHDF1 was knocked down in hBMSCs, ATDC5 cells, or C3H10T1/2 cells. Further RNA sequencing and molecular biology experiments found that YTHDF1 activated the Wnt/ß-catenin signaling pathway during chondrogenic differentiation. Finally, the effects of overexpression and knockdown of YTHDF1 on chondrogenic differentiation were reversed by inhibiting or activating ß-catenin activity. Therefore, we demonstrated that YTDHF1 promoted chondrogenic differentiation through activation of the Wnt/ß-catenin signaling pathway.

Correlation analysis of surgical outcomes and spino-pelvic parameters in patients with degenerative lumbar scoliosis.

Objectives: The study aims to analyze factors that affect the postoperative health-related quality of life (HRQOL) of degenerative lumbar scoliosis (DLS) patients and explore the appropriate pelvic incidence minus lumbar lordosis (PI-LL) value for Chinese DLS patients. Methods: DLS patients who met the inclusion and exclusion criteria were included in this study. General information, spino-pelvic parameters, and HRQOL were collected. Correlation analysis was used to explore the spino-pelvic parameters that affect the postoperative HRQOL. Thresholds of each parameter were obtained using the receiver operating characteristic (ROC) curve. Regardless of the effect of age, DLS patients were classified into three groups according to the SRS-Schwab classification: group 0 means PI-LL < 10°, group+means PI-LL = 10-20°, and group ++ means PI-LL > 20°. Postoperative HRQOL was analyzed using variance methods. The ROC curve was used to measure the appropriate PI-LL threshold. When considering the effect of age, the patients with Oswestry Disability Index (ODI) < 75% percentile were considered to have a satisfactory clinical outcome, which was drawn to an equation between PI-LL, age, and PI by multiple linear regression equation. Results: A total of 71 patients were included. Compared with the control group, there were significant differences in both postoperative ODI and Scoliosis Research Society 22 (SRS-22) scores when the postoperative Cobb angle ≤11°, postoperative lumbar lordosis index (LLI) > 0.8, postoperative sagittal vertical axis (SVA) ≤ 5 cm, postoperative T1 pelvic angle (TPA) ≤ 16° and postoperative global tilt (GT) ≤ 22°, respectively. Regardless of the effect of age, there was a statistical difference in postoperative HRQOL between group 0 and group ++. The PI-LL threshold derived from the ROC curve was 14.4°. Compared with the PI-LL > 14° group, the PI-LL ≤ 14° group achieved a lower postoperative ODI score and a higher postoperative SRS-22 score. Considering the influence of age, the equation for ideal PI-LL was PI-LL = 0.52age + 0.38PI-39.4 (R = 0.509, p = 0.001). Conclusions: PI-LL was an important parameter that affects the postoperative HRQOL of DLS patients. Sufficient LL should be restored during the operation (LL ≥ PI-14°). The appropriate PI-LL value was affected by age. Smaller LL needed to be restored as the age increased.

Identifying the key genes regulating mesenchymal stem cells chondrogenic differentiation: an in vitro study.

BACKGROUND: Mesenchymal stem cells (MSCs) possess the potential to differentiate into chondrocytes, which makes them an ideal source for healing cartilage defects. Here, we seek to identify the essential genes participating in MSCs chondrogenesis. METHODS: Human MSCs were induced for chondrogenesis for 7, 14, and 21 days using a high-density micromass culture system, and RNA was extracted for RNA-seq. RESULTS: A total of 6247 differentially expressed genes (DEGs) were identified on day 7, and 85 DEGs were identified on day 14. However, no significant DEGs was identified on day 21. The top 30 DEGs at day 7, including COL9A3, COL10A1, and CILP2, are closely related to extracellular matrix organization. While the top 30 DEGs at day 14 revealed that inflammation-related genes were enriched, including CXCL8, TLR2, and CCL20. We also conducted protein-protein interaction (PPI) networks analysis using the search tool for the retrieval of interacting genes (STRING) database and identified key hub genes, including CXCL8, TLR2, CCL20, and MMP3. The transcriptional factors were also analyzed, identifying the top 5 TFs: LEF1, FOXO1, RORA, BHLHE41, and SOX5. We demonstrated one particular TF, RORA, in promoting early MSCs chondrogenesis. CONCLUSIONS: Taken together, our results suggested that these DEGs may have a complex effect on MSCs chondrogenesis both synergistically and solitarily.

Evaluating bone quality and asymmetrical aplasia of the thoracic vertebral body in Lenke 1A adolescent idiopathic scoliosis using hounsfield units.

Study Design: Retrospective analysis. Objective: To evaluate bone quality and investigate asymmetrical development of the thoracic vertebral body in adolescent idiopathic scoliosis (AIS) based on Hounsfield unit (HU) measurements obtained from computed-tomography (CT) scans. Summary of Background Data: HU value demonstrated higher reliability and accuracy than the traditional method, indicating that they could be used to individually evaluate and effectively assess the bone quality of every vertebra in the CT films. Methods: Total 30 AIS patients classified as Lenke Type 1A and 30 paired controls were included in this study. Regions of interest for HU value were measured on three horizontal images of the thoracic vertebrae. HU measurements of the whole vertebral body in each vertebra were obtained. Using HU value, we separately measured the concave and convex sides of each vertebral body in patients' group, as well as within the left and right sides in controls. Results: In controls, the mean HU value of T1-T12 thoracic vertebral bodies was 240.03 ± 39.77, with no statistical differences among different levels. As for AIS patients, in the structural curve, the apical region had a significantly lower HU compared with the other regions, and asymmetrical change was found between the concave and convex sides, most significantly in the apical region. In the non-structural curve, the average HU value was 254.99 ± 44.48, and no significant difference was found either among the different levels of vertebrae or between the concave and convex sides. Conclusions: Abnormal and asymmetrical changes in bone quality of the thoracic vertebral body in patients with Lenke 1A AIS were indicated. Low bone quality in the convex side of the structural curve indicated stronger internal fixation in surgery to correct the deformity.

Establishment and large-scale validation of a three-dimensional tumor model on an array chip for anticancer drug evaluation.

Two-dimensional (2D) tumor model has always poorly predicted drug response of animal model due to the lack of recapitulation of tumor microenvironment. Establishing a biomimetic, controllable, and cost-effective three-dimensional (3D) model and large-scale validation of its in vivo predictivity has shown promise in bridging the gap between the 2D tumor model and animal model. Here, we established a matrigel-based 3D micro-tumor model on an array chip for large-scale anticancer drug evaluation. Compared with the 2D tumor model, the 3D tumor model on the chip showed spheroid morphology, slower proliferation kinetics, and comparable reproducibility. Next, the results of the chemotherapeutic evaluation from 18 drugs against 27 cancer cell lines showed 17.6% of drug resistance on the 3D tumor model. Moreover, the evaluation results of targeted drugs showed expected sensitivity and higher specificity on the 3D tumor model compared with the 2D model. Finally, the evaluation results on the 3D tumor model were more consistent with the in vivo cell-derived xenograft model, and excluded 95% false-positive results from the 2D model. Overall, the matrigel-based 3D micro-tumor model on the array chip provides a promising tool to accelerate anticancer drug discovery.

Irisin enhances chondrogenic differentiation of human mesenchymal stem cells via Rap1/PI3K/AKT axis.

BACKGROUND: Human mesenchymal stem cells (hMSCs) have been proven to have inherent chondrogenic differentiation potential, which appears to be used in cartilage regeneration. Increasing evidence suggests that irisin enhances osteoblast differentiation of MSCs, but little is known about its potential on chondrogenic differentiation. METHODS: In the study, we investigated the effects of irisin on chondrogenic differentiation of hMSCs using a high-density pellet culture system. The cartilage pellets were evaluated by morphology, and the metabolism of cartilage matrix was detected by qPCR, western blot and immunohistochemistry. Next, RNA-seq was performed to explore the underlying mechanism. Furthermore, using the transduction of plasmid, miRNAs mimics and inhibitor, the activation of Rap1/PI3K/AKT axis, the expression level of SIPA1L2, and the functional verification of miR-125b-5p were detected on day 7 of chondrogenic differentiation of hMSCs. RESULTS: Compared with the controls, we found that irisin treatment could significantly enhance the chondrogenic differentiation of hMSCs, enlarge the induced-cartilage tissue and up-regulate the expression levels of cartilage markers. RNA-seq indicated that irisin activated the Rap1 and PI3K/AKT signaling pathway, and the lower expression level of SIPA1L2 and the higher expression level of miR-125b-5p were found in irisin-treated group. Further, we found that irisin treatment could up-regulate the expression level of miR-125b-5p, targeting SIPA1L2 and consequently activating the Rap1/PI3K/AKT axis on the process of chondrogenic differentiation of hMSCs. CONCLUSIONS: Collectively, our study reveals that irisin can enhance chondrogenic differentiation of hMSCs via the Rap1/PI3K/AKT pathway, suggesting that irisin possesses prospects in cartilage regeneration.

Consecutive Kummell's Disease Combined with Parkinson's Disease and Experienced Internal Fixation Failure: A Case Report and Literature Review.

BACKGROUND: The continuous occurrence of Kummell's disease is extremely rare in clinical practice, and its treatment is difficult. The study aimed to present a rare case of consecutive Kummell's disease combined with Parkinson's disease (PD) and experienced internal fixation failure. CASE PRESENTATION: A 69-year-old female patient had a history of PD for 10 years, and was treated by posterior decompression, fixation, and fusion because of Kummell's disease of T12 with neurological damage. The patient's back pain and lower limb pain were significantly improved after surgery. Twenty-two months later, the patient was rehospitalized for Kummell's disease of L4 with neuropathic pain of left lower extremity. She received almost identical surgical procedures as T12 lesion, and the difference was no L4 vertebroplasty preformed due to the fact that the L4 vertebrae collapse was not obvious, the intravertebral vacuum cleft (IVC) range was small, and the pedicle screw fixation strength was high. The pain symptoms were significantly relieved after operation. Unfortunately, there was a complication of internal fixation failure that occurred a month later, and a revision operation was carried out. CONCLUSION: Osteoporosis combined with PD may lead patients to become prone to consecutive Kummell's disease, and patients are prone to experience failure of internal fixation. Bone cement filling of vertebral IVC and effective support of anterior vertebral column are very important procedures to ensure the clinical efficacy of treating Kummell's disease.

Comparison of anterior or posterior approach in surgical treatment of thoracic and lumbar tuberculosis: a retrospective case-control study.

BACKGROUND: With the widespread use of the posterior surgery, more and more surgeons chose posterior surgery to treat thoracic and lumbar tuberculosis. But others still believed that the anterior surgery is more conducive to eradicating the lesions, and easier to place larger bone pieces for bone graft fusion. We compared the clinical and radiological outcomes of anterior and posterior surgical approaches and presented our views. METHODS: This study included 52 thoracic and lumbar tuberculosis patients at Sun Yat-sen Memorial Hospital from January 2010 to June 2018. All cases underwent radical debridement, nerve decompression, intervertebral bone graft fusion and internal fixation. Cases were divided into anterior group (24 cases) and posterior group (28 cases). Statistical analysis was used to compare the clinical effectiveness, radiological outcomes, complications and other related information. RESULTS: Patients in the anterior group and the posterior group were followed up for an average of 27.4 and 22.3 months, respectively. There were no statistically significant differences between groups in the preoperative, postoperative and last follow-up VAS score, ASIA grade and Cobb angle of local kyphosis. Moreover, there were no statistically significant differences in the improvement of neurological function, loss of kyphotic correction, total incidence of complications, operative time, intraoperative blood loss and hospital stay between the two groups (P > 0.05). But there was greater correction of kyphosis, earlier bone fusion, lower incidence of poor wound healing, less interference with the normal spine and less internal fixation consumables and medical cost in the anterior group (P < 0.05). CONCLUSIONS: Both anterior and posterior approaches are feasible for thoracic and lumbar tuberculosis. While for thoracic and lumbar tuberculosis patients with a single lesion limited in the anterior and middle columns of the spine without severe kyphosis, the anterior approach surgery may have greater advantages in kyphosis correction, bone fusion, wound healing, protection of the normal spine, and medical consumables and cost.

Melatonin reverses tumor necrosis factor-alpha-induced metabolic disturbance of human nucleus pulposus cells via MTNR1B/Gαi2/YAP signaling.

Background: Intervertebral disc degeneration (IDD), the main cause of low back pain, is closely related to the inflammatory microenvironment in the nucleus pulposus (NP). Tumor necrosis factor-α (TNF-α) plays an important role in inflammation-related metabolic disturbance of NP cells. Melatonin has been proven to regulate the metabolism of NP cells, but whether it can protect NP cells from TNF-α-induced damage is still unclear. Therefore, this study aims to investigate the role and specific mechanism of melatonin on regulating the metabolism of NP cells in the inflammatory microenvironment. Methods: Western blotting, RT-qPCR and immunohistochemistry were used to detect the expression of melatonin membrane receptors (MTNR1A/B) and TNF-α in human NP tissues. In vitro, human primary NP cells were treated with or without vehicle, TNF-α and melatonin. And the metabolic markers were also detected by western blotting and RT-qPCR. The activity of NF-κB signaling and Hippo/YAP signaling were assessed by western blotting and immunofluorescence. Membrane receptors inhibitors, pathway inhibitors, lentiviral infection, plasmids transfection and immunoprecipitation were used to explore the specific mechanism of melatonin. In vivo, the rat IDD model was constructed and melatonin was injected intraperitoneally to evaluate its therapeutical effect on IDD. Results: The upregulation of TNF-α and downregulation of melatonin membrane receptors (MTNR1A/B) were observed in degenerative NP tissues. Then we demonstrated that melatonin could alleviate the development of IDD in a rat model and reverse TNF-α-impaired metabolism of NP cells in vitro. Further investigation revealed that the protective effects of melatonin on NP cells mainly rely on MTNR1B, which subsequently activates Gαi2 protein. The activation of Gαi2 could upregulate the yes-associated protein (YAP) level, resulting in anabolic enhancement of NP cells. In addition, melatonin-mediated YAP upregulation increased the expression of IκBα and suppressed the TNF-α-induced activation of the NF-κB pathway, thereby inhibiting the catabolism of NP cells. Conclusions: Our results revealed that melatonin can reverse TNF-α-impaired metabolism of NP cells via the MTNR1B/Gαi2/YAP axis and suggested that melatonin can be used as a potential therapeutic drug in the treatment of IDD.

Corrigendum to "Melatonin Reverses the Loss of Stemness Induced by TNF-α in Human Bone Marrow Mesenchymal Stem Cells through Upregulation of YAP Expression".

[This corrects the article DOI: 10.1155/2019/6568394.].

Efficacy analysis of one-stage posterior-only surgical treatment for thoracic spinal tuberculosis in the T4-6 segments with minimum 5-year follow-up.

In recent years, with the in-depth research on spinal tuberculosis, posterior surgery alone has been praised highly by more and more surgeons due to the better correction of kyphosis, better maintenance of spinal physiological curvature, smaller surgical trauma and fewer surgical complications. However, there is currently lack of relevant reports about the efficacy of posterior surgery alone in the treatment of tuberculosis in the T4-6 segments. This study aimed to evaluate the clinical study efficacy and feasibility of one-stage posterior-only surgical treatment for thoracic spinal tuberculosis in the T4-6 segments. 67 patients with tuberculosis in T4-6 segments who underwent one-stage posterior-only surgery were included in this study. The clinical efficacy was evaluated using statistical analysis based on the data about erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Oswestry Dability Index (ODI) score, Visual Analogue Scale (VAS) score and Cobb angle before surgery, after surgery and at the last follow-up. All patients completed fusion during the follow-up period of 6-9 months. ESR and CRP were returned to normal for all patients at 6 months follow-up. In the meanwhile, among the 27 patients combined with neurological impairment, neurological functions of 22 cases (81.48%) recovered completely at the last follow-up (P < 0.05). Cobb angle of the kyphosis was improved from preoperative 34.8 ± 10.9° to postoperative 9.6 ± 2.8°, maintaining at 11.3 ± 3.2° at the last follow-up, The ODI and VAS scores were improved by 77.10% and 81.70%, respectively. This 5-year follow-up study shows that better clinical efficacy can be achieved for tuberculosis in T4-6 segments using one-stage posterior-only approach by costotransverse debridement in combination with bone graft and internal fixation. The posterior surgical method cannot only effectively accomplish debridement, obtain satisfactory clinical results, but also well correct kyphotic deformity and maintain it.

Constructing intervertebral disc degeneration animal model: A review of current models.

Low back pain is one of the top disorders that leads to disability and affects disability-adjusted life years (DALY) globally. Intervertebral disc degeneration (IDD) and subsequent discogenic pain composed major causes of low back pain. Recent studies have identified several important risk factors contributing to IDD's development, such as inflammation, mechanical imbalance, and aging. Based on these etiology findings, three categories of animal models for inducing IDD are developed: the damage-induced model, the mechanical model, and the spontaneous model. These models are essential measures in studying the natural history of IDD and finding the possible therapeutic target against IDD. In this review, we will discuss the technical details of these models, the duration between model establishment, the occurrence of observable degeneration, and the potential in different study ranges. In promoting future research for IDD, each animal model should examine its concordance with natural IDD pathogenesis in humans. We hope this review can enhance the understanding and proper use of multiple animal models, which may attract more attention to this disease and contribute to translation research.

Calcium Binding Protein S100A16 Expedites Proliferation, Invasion and Epithelial-Mesenchymal Transition Process in Gastric Cancer.

Gastric cancer (GC) is one of the most common malignant tumors of the digestive system, listed as the second cause of cancer-related deaths worldwide. S100 Calcium Binding Protein A16 (S100A16) is an acidic calcium-binding protein associated with several types of tumor progression. However, the function of S100A16 in GC is still not very clear. In this study, we analyzed S100A16 expression with the GEPIA database and the UALCAN cancer database. Meanwhile, 100 clinical GC samples were used for the evaluation of its role in the prognostic analysis. We found that S100A16 is significantly upregulated in GC tissues and closely correlated with poor prognosis in GC patients. Functional studies reveal that S100A16 overexpression triggers GC cell proliferation and migration both in vivo and in vitro; by contrast, S100A16 knockdown restricts the speed of GC cell growth and mobility. Proteomic analysis results reveal a large S100A16 interactome, which includes ZO-2 (Zonula Occludens-2), a master regulator of cell-to-cell tight junctions. Mechanistic assay results indicate that excessive S100A16 instigates GC cell invasion, migration, and epithelial-mesenchymal transition (EMT) via ZO-2 inhibition, which arose from S100A16-mediated ZO-2 ubiquitination and degradation. Our results not only reveal that S100A16 is a promising candidate biomarker in GC early diagnosis and prediction of metastasis, but also establish the therapeutic importance of targeting S100A16 to prevent ZO-2 loss and suppress GC metastasis and progression.

Inhibition of nuclear receptor RORα attenuates cartilage damage in osteoarthritis by modulating IL-6/STAT3 pathway.

Osteoarthritis (OA) is characterized by cartilage destruction, chronic inflammation, and local pain. Evidence showed that retinoic acid receptor-related orphan receptor-α (RORα) is crucial in cartilage development and OA pathogenesis. Here, we investigated the role and molecular mechanism of RORα, an important member of the nuclear receptor family, in regulating the development of OA pathologic features. Investigation into clinical cartilage specimens showed that RORα expression level is positively correlated with the severity of OA and cartilage damage. In an in vivo OA model induced by anterior crucial ligament transaction, intra-articular injection of si-Rora adenovirus reversed the cartilage damage. The expression of cartilage matrix components type II collagen and aggrecan were elevated upon RORα blockade. RNA-seq data suggested that the IL-6/STAT3 pathway is significantly downregulated, manifesting the reduced expression level of both IL-6 and phosphorylated STAT3. RORα exerted its effect on IL-6/STAT3 signaling in two different ways, including interaction with STAT3 and IL-6 promoter. Taken together, our findings indicated the pivotal role of the RORα/IL-6/STAT3 axis in OA progression and confirmed that RORα blockade improved the matrix catabolism in OA chondrocytes. These results may provide a potential treatment target in OA therapy.