Background: Osteoarthritis (OA) is a multifactorial disease, including inflammation, autophagy and senescence. Published work has indicated that empagliflozin (EMP) exhibits robust anti-inflammatory and anti-senescence effects, while its role in autophagy appears paradoxical. Here, we aim to identify the chondroprotective effect of EMP on OA. Methods: An OA model was established both in vitro, by stimulating primary chondrocytes (isolated from C57BL/6J mice) with IL-1β, and in vivo, by performing (Destabilized medial meniscus) DMM surgery on C57BL/6J mice. (Western blot) WB and (quantitative real-time polymerase chain reaction) qRT-PCR analysis were employed to detect the gene expression. (Immunofluorescence) IF staining was employed to detect the expression and location of target protein. SA-β-gal staining was employed to evaluate cellular senescence. Autophagic flux was assessed using a GFP-RFP-LC3 adenoviral vector. Network pharmacology was applied to identify potential pathways for experimental validation. The effects of EMP in vivo were evaluated by μ-CT, histological and (Immunohistochemistry) IHC staining. Results: EMP promoted anabolism, inhibited the inflammatory response and catabolism in IL-1β stimulated chondrocytes. EMP enhanced autophagic activity and attenuated senescent phenotype in vitro. Mechanistically, EMP regulated the PI3K/Akt/mTOR and AMPK pathways. The chondroprotective effects of EMP were reversed by (3-methyladenine) 3-MA. EMP also ameliorated OA-related phenotype in DMM models. Compared with (Kartogenin) KGN, EMP showed more pronounced suppression of inflammatory and catabolic markers, while both compounds similarly promoted anabolic marker expression. Conclusions: These in vitro and in vivo data collectively indicates that EMP can alleviate OA both in IL-1β stimulated chondrocytes and DMM induced models. Beyond its established role in diabetes management, EMP is evaluated in the context of OA, emerging as a novel and promising therapeutic agent for OA.

Background:Renal fibrosis is a common pathological outcome of chronic kidney disease and is characterized by persistent profibrotic signaling and impaired cellular homeostasis. Genkwanin (GAK), a natural flavonoid compound, has shown anti-inflammatory and antioxidant activities in several disease models. However, its role in renal fibrosis remains unclear. Materials and methods:We investigated the antifibrotic effects of GAK in a TGF-β1-induced HK-2 cell model and a unilateral ureteral obstruction (UUO) mouse model. EMT- and fibrosis-related changes were assessed by RT-qPCR, Western blotting, immunofluorescence, and histological staining. The involvement of TGF-β1/SMAD2 and β-catenin signaling was examined using pharmacological modulators. Autophagic flux was evaluated by tandem mCherry-GFP-LC3 analysis, transmission electron microscopy, and autophagy-related protein expression. TFEB inhibition was used to further assess the role of lysosome-autophagy regulation. Results:GAK significantly attenuated TGF-β1-induced EMT and extracellular matrix accumulation in HK-2 cells and reduced renal fibrotic injury in UUO mice. Mechanistically, GAK decreased p-SMAD2 expression and limited β-catenin nuclear redistribution, indicating suppression of both TGF-β1/SMAD2 and β-catenin signaling. In addition, GAK improved autophagic flux and increased TFEB expression. Inhibition of TFEB partially weakened the protective effects of GAK on fibrosis-related and autophagy-related changes, suggesting that TFEB-mediated lysosome-autophagy function contributes to its antifibrotic action. Conclusion:In conclusion, GAK alleviates renal fibrosis in vitro and in vivo, at least in part, by suppressing TGF-β1/SMAD2 and β-catenin signaling and by restoring TFEB-associated autophagic flux.

BACKGROUND:Osteoarthritis (OA) is a degenerative joint disorder for which no effective disease-modifying treatments currently exist. Chondrocyte senescence is recognized as a major contributor to OA progression. Daucosterol (DAU), a naturally derived phytosterol with anti-inflammatory and antioxidant effects, has not been investigated for its therapeutic effects in OA. METHODS:Murine chondrocytes stimulated with interleukin-1β (IL-1β) were treated with DAU in vitro. Senescence, matrix metabolism, inflammation, and mitochondrial function were assessed. Network pharmacology and pathway inhibition were used for mechanistic studies. In vivo, the efficacy of DAU was assessed using a mouse destabilized medial meniscus (DMM) model. RESULTS:DAU inhibited IL-1β-induced senescence, inflammation, and matrix degradation in chondrocytes, and simultaneously enhanced extracellular matrix (ECM) production. Mechanistically, DAU selectively inhibited the c-Jun N-terminal kinase (JNK) pathway. This JNK inhibition was crucial, as the JNK inhibitor SP600125 phenocopied DAU's effects. Furthermore, DAU restored mitochondrial membrane potential, reduced reactive oxygen species (ROS) production, and activated the NRF2 antioxidant pathway. In the mouse DMM models, intra-articular DAU administration alleviated cartilage degradation and reduced senescence marker P16 expression. CONCLUSIONS:This work characterizes DAU as a new senomorphic agent that alleviates OA development by selectively suppressing JNK signaling, thereby restoring mitochondrial function and mitigating cellular senescence. Overall, DAU may provide a novel therapeutic strategy for OA treatment.

Osteosarcoma represents the most prevalent primary malignant bone tumor in adolescents and young adults, with limited improvement in survival outcomes observed over recent decades. The development of personalized therapies remains challenging due to substantial molecular heterogeneity and the absence of robust prognostic models. In this study, we developed a machine learning-based consensus prognostic signature (MLPS) by integrating multi-cohort transcriptomic datasets and applying ten distinct machine learning algorithms. The resulting MLPS, comprising 11 prognostic genes, reliably stratified patients into high- and low-risk groups with significantly different survival outcomes and outperformed existing models (C-index = 0.862). The application of functional enrichment analyses revealed immune activation and inflammatory signaling in the low-risk group, consistent with a "hot tumor" phenotype. In contrast, the high-risk group exhibited upregulation of proliferative oncogenic pathways. Of particular significance is the observation that MLPS was able to suggest differential responses to chemotherapy and immunotherapy, thereby under-scoring its clinical utility. Single-cell analysis revealed that LGR4 expression is largely confined to malignant cell clusters. In vitro LGR4 knockdown significantly reduced osteosarcoma cell proliferation, migration, and PI3K-AKT-mTOR pathway activity, confirming its oncogenic role. These findings demonstrate the value of MLPS as a robust tool for prognostic assessment and individualized therapeutic decision-making in osteosarcoma.

BACKGROUND:Osteoarthritis (OA) is a chronic degenerative disorder marked by progressive degradation of articular cartilage. Inflammation and impairment of autophagy are crucial in OA pathogenesis, leading to chondrocyte dysfunction and disease progression. The therapeutic potential of CORM-3, a carbon monoxide-releasing molecule with anti-inflammatory and autophagy-enhancing properties, remains unexplored in OA. METHODS:Chondrocytes were treated with interleukin-1β (IL-1β) to establish an inflammatory model in vitro. The impact of CORM-3 on chondrocyte inflammation, extracellular matrix (ECM) metabolism, and autophagy activity was assessed by RT-qPCR, Western blot, immunofluorescence, and autophagy flow assay. OA was induced in mice to investigate CORM-3's therapeutic potential in vivo through surgical destabilization of the medial meniscus (DMM). RESULTS:CORM-3 significantly inhibited the inflammation of chondrocytes and the imbalance of extracellular matrix (ECM) metabolism induced by IL-1β, thereby exerting a chondroprotective effect in vitro. Mechanistically, CORM-3 effectively inhibited the mitogen-activated protein kinase (MAPK) and mTOR signaling pathways. Further, CORM-3 exerted a similar chondroprotective effect with MAPK-IN-1, a MAPK pathway inhibitor, and rapamycin, a specific mTOR inhibitor. Additionally, CORM-3 also restored the impairment of autophagy. Furthermore, 3-Methyladenine (3-MA), an autophagy inhibitor, reversed CORM-3's chondroprotective effect. In vivo, treatment with CORM-3 inhibited cartilage OA-like lesions to mitigate OA progression. CONCLUSION:This study identifies that CORM-3 inhibits inflammation, maintains ECM metabolism homeostasis, and restores impaired autophagy via inhibiting the MAPK and mTOR pathways, thereby protecting chondrocytes. In vivo, CORM-3 treatment significantly alleviates OA progression, suggesting its therapeutic potential for OA.

Osteoarthritis (OA) is a degenerative joint disorder characterized by chronic inflammation, impaired lubrication, and progressive cartilage degradation. To address these multifaceted pathologies, we developed a multifunctional nanoparticle, termed HPQ@K, based on hyaluronic acid (HA), for co-delivery of quercetin (QUT) - a compound with anti-inflammatory, antioxidant, and hyaluronidase properties - and kartogenin (KGN), which induces chondroautophagy and cartilage regeneration. QUT was conjugated to HA through reactive oxygen species (ROS)- and pH-sensitive boronate ester linkages, leading to self-assembled micelles that encapsulate KGN and enable stimulus-responsive drug release under inflammatory OA conditions. HPQ@K retains the innate lubricity and biocompatibility of HA, while exhibiting enhanced resistance to enzymatic degradation, thereby prolonging its joint residence time. Its nanospheric structure ensures uniform articular coverage and combines hydration lubrication with a "ball-bearing" effect to achieve superlubricity. In murine chondrocytes, OA models, and human cartilage tissues, HPQ@K enhanced drug bioavailability and enabled spatiotemporally controlled release, mitigating oxidative stress, restoring mitochondrial function, promoting autophagy, and reducing cellular senescence. Furthermore, it significantly lowered friction coefficients and protected cartilage from mechanical damage. Collectively, HPQ@K constitutes an all-in-one nanotherapeutic platform that concurrently targets inflammation, restores joint lubrication, and facilitates cartilage repair, offering a comprehensive triple-therapy strategy for advanced OA.

BACKGROUND:Osteoarthritis is a chronic degenerative joint disease marked by chondrocyte senescence and extracellular matrix degradation. Vaccarin, a flavonoid with anti-inflammatory and antioxidant properties, has not been previously investigated for its therapeutic potential in osteoarthritis. PURPOSE:To evaluate the therapeutic potential of Vaccarin in osteoarthritis and elucidate its underlying mechanisms. DESIGN AND METHOD:This study utilized in vitro chondrocyte cultures and RNA sequencing to identify relevant pathways, followed by validation at the genetic, protein, and metabolic levels using multiple approaches. Additionally, the therapeutic effects of Vaccarin were assessed in vivo using a destabilization of the medial meniscus (DMM)-induced osteoarthritis mouse model and human cartilage samples from osteoarthritis patients. RESULTS:Vaccarin effectively ameliorated osteoarthritis both in vivo and in vitro. Transcriptomic sequencing indicated a significant downregulation of serum amyloid A2 (SAA2) expression following Vaccarin treatment. Multi-omics analysis, validated by human specimens, indicated that SAA2 is minimally secreted in healthy articular cartilage but serves as a crucial osteoarthritis biomarker in Asian populations. Mechanistically, Vaccarin inhibits c-Jun N-terminal kinase (JNK) phosphorylation, thereby reducing SAA2 expression and mitigating chondrocyte inflammation and senescence. Notably, inflammatory conditions upregulate SAA2 expression in chondrocytes via the JNK pathway. Elevated SAA2 levels contribute to mitochondrial dysfunction in chondrocytes, leading to increased reactive oxygen species (ROS) production and exacerbating osteoarthritis progression. CONCLUSION:This study identifies SAA2 as a potential therapeutic target for osteoarthritis and suggests that Vaccarin presents a promising treatment avenue.

Background:The anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) are important structures to maintain knee stability. The present study aimed to further enrich understandings of the morphology of the cruciate ligaments and explore the relationship between the diameter of ACL and PCL. Method:This study collected valid MRI samples of 50 male and 50 female normal right knee joints and measured the diameter of each point of the ACL and PCL through the 3D Slicer. Results:The diameter of the ACL in the sagittal MRI of the normal right knee joint was significantly different from the diameter of each point of the PCL. The average diameter of each point of the ACL was larger than the diameter of the corresponding point of the PCL. Males and females had statistical differences in their PCL origin point, PCL midpoint, ACL origin point, ACL midpoint, and ACL insertion point diameters under sagittal MRI examination. The average diameter of males was greater than the average diameter of females at the above corresponding sites. In sagittal MRI scans of the normal right knee joint, we observed that only the origin point of the PCL exhibited a moderate correlation with the midpoint and insertion point of the ACL in terms of their respective diameters. Conclusion:The correlation between diameters of normal ACL and PCL in knee joint MRI was moderate and may help clinicians determine appropriate graft for cruciate ligament reconstruction surgery quickly for severe cruciate ligament injuries.

Intervertebral disc degeneration (IVDD) is a progressive degenerative disease influenced by various factors. Genkwanin, a known anti-inflammatory flavonoid, has not been explored for its potential in IVDD management. This study aims to investigate the effects and mechanisms of genkwanin on IVDD. In vitro, cell experiments revealed that genkwanin dose-dependently inhibited Interleukin-1β-induced expression levels of inflammatory factors (Interleukin-6, inducible nitric oxide synthase, cyclooxygenase-2) and degradation metabolic protein (matrix metalloproteinase-13). Concurrently, genkwanin upregulated the expression of synthetic metabolism genes (type II collagen, aggrecan). Moreover, genkwanin effectively reduced the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin, mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) pathways. Transcriptome sequencing analysis identified integrin α2 (ITGA2) as a potential target of genkwanin, and silencing ITGA2 reversed the activation of PI3K/AKT pathway induced by Interleukin-1β. Furthermore, genkwanin alleviated Interleukin-1β-induced senescence and apoptosis in nucleus pulposus cells. In vivo animal experiments demonstrated that genkwanin mitigated the progression of IVDD in the rat model through imaging and histological examinations. In conclusion, This study suggest that genkwanin inhibits inflammation in nucleus pulposus cells, promotes extracellular matrix remodeling, suppresses cellular senescence and apoptosis, through the ITGA2/PI3K/AKT, NF-κB and MAPK signaling pathways. These findings indicate that genkwanin may be a promising therapeutic candidate for IVDD.

A 54-year-old male patient presented with a mass on the posterior aspect of the right thigh, first noticed 9 months ago without any apparent cause. The mass had significantly enlarged over the past 2 months, accompanied by numbness in the dorsum of the right foot and right calf. The patient had no significant past medical history.

This study focuses on the role of topoisomerases (TOPs) in sarcomas (SARCs), highlighting TOPs' influence on sarcoma prognosis through mRNA expression, genetic mutations, immune infiltration, and DNA methylation analysis using transcriptase sequencing and other techniques. The findings indicate that TOP gene mutations correlate with increased inflammation, immune cell infiltration, DNA repair abnormalities, and mitochondrial fusion genes alterations, all of which negatively affect sarcoma prognosis. Abnormal TOP expression may independently affect sarcoma patients' survival. Cutting-edge genomic tools such as Oncomine, gene expression profiling interactive analysis (GEPIA), and cBio Cancer Genomics Portal (cBioPortal) are utilized to explore the TOP gene family (TOP1/1MT/2A/2B/3A/3B) in soft-tissue sarcomas (STSs). This in-depth analysis reveals a notable upregulation of TOP mRNA in STS patients arcoss various SARC subtypes, French Federation Nationale des Centres de Lutte Contre le Cancer classification (FNCLCC) grades, and specific molecular profiles correlating with poorer clinical outcomes. Furthermore, this investigation identifies distinct patterns of immune cell infiltration, genetic mutations, and somatic copy number variations linked to TOP genes that inversely affect patient survival rates. These findings underscore the diagnostic and therapeutic relevance of the TOP gene suite in STSs.

This review critically evaluates advancements in multifunctional hydrogels, particularly focusing on their applications in osteoarthritis (OA) therapy. As research evolves from traditional natural materials, there is a significant shift towards synthetic and composite hydrogels, known for their superior mechanical properties and enhanced biodegradability. This review spotlights novel applications such as injectable hydrogels, microneedle technology, and responsive hydrogels, which have revolutionized OA treatment through targeted and efficient therapeutic delivery. Moreover, it discusses innovative hydrogel materials, including protein-based and superlubricating hydrogels, for their potential to reduce joint friction and inflammation. The integration of bioactive compounds within hydrogels to augment therapeutic efficacy is also examined. Furthermore, the review anticipates continued technological advancements and a deeper understanding of hydrogel-based OA therapies. It emphasizes the potential of hydrogels to provide tailored, minimally invasive treatments, thus highlighting their critical role in advancing the dynamic field of biomaterial science for OA management.

Cancer-associated muscle wasting is a widespread syndrome in people with cancer and is characterized by weight loss and muscle atrophy, leading to increased morbidity and mortality. However, the tumor-derived factors that affect the development of muscle wasting and the mechanism by which they act remain unknown. To address this knowledge gap, we aimed to delineate differences in tumor molecular characteristics (especially secretion characteristics) between patients with and without sarcopenia across 10 tumor types from The Cancer Genome Atlas (TCGA). We integrated radiological characteristics from CT scans of TCGA cancer patients, which allowed us to calculate skeletal muscle area (SMA) to confirm sarcopenia. We combined TCGA and GTEx (The Genotype-Tissue Expression) data to analyze upregulated secretory genes in 10 tumor types compared with normal tissues. Upregulated secretory genes in the tumor microenvironment and their relation to SMA were analyzed to identify potential muscle wasting biomarkers (560 samples). Meanwhile, their predictive values for patient survival was validated in 3530 samples in 10 tumor types. A total of 560 participants with transcriptomic data and SMA were included. Among those, 136 participants (24.28%) were defined as having sarcopenia based on SMA. Enrichment analysis for upregulated secretory genes in cancers revealed that pathways associated with muscle wasting were strongly enriched in tumor types with a higher prevalence of sarcopenia. A series of SMA-associated secretory protein-coding genes were identified in cancers, which showed distinct gene expression profiles according to tumor type, and could be used to predict prognosis in cancers (p value ≤ 0.002). Unfortunately, those genes were different and rarely overlapped across tumor types. Tumor secretome characteristics were closely related to sarcopenia. Highly expressed secretory mediators in the tumor microenvironment were associated with SMA and could affect the overall survival of cancer patients, which may provide a valuable starting point for the further understanding of the molecular basis of muscle wasting in cancers. More importantly, tumor-derived pro-sarcopenic factors differ across tumor types and genders, which implies that mechanisms of cancer-associated muscle wasting are complex and diverse across tumors, and may require individualized treatment approaches.

Intervertebral disc degeneration (IVDD) is a progressive degenerative disease influenced by various factors. Genkwanin, a known anti-inflammatory flavonoid, has not been explored for its potential in IVDD management. This study aims to investigate the effects and mechanisms of genkwanin on IVDD. In vitro, cell experiments revealed that genkwanin dose-dependently inhibited Interleukin-1 beta-induced expression levels of inflammatory factors (Interleukin-6, inducible nitric oxide synthase, cyclooxygenase-2) and degradation metabolic protein (matrix metalloproteinase-13). Concurrently, genkwanin upregulated the expression of synthetic metabolism genes (type II collagen, aggrecan). Moreover, genkwanin effectively reduced the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin, mitogen-activated protein kinase (MAPK), and nuclear factor-kappa B (NF-kappa B) pathways. Transcriptome sequencing analysis identified integrin alpha 2 (ITGA2) as a potential target of genkwanin, and silencing ITGA2 reversed the activation of PI3K/AKT pathway induced by Interleukin-1 beta. Furthermore, genkwanin alleviated Interleukin-1 beta-induced senescence and apoptosis in nucleus pulposus cells. In vivo animal experiments demonstrated that genkwanin mitigated the progression of IVDD in the rat model through imaging and histological examinations. In conclusion, This study suggest that genkwanin inhibits inflammation in nucleus pulposus cells, promotes extracellular matrix remodeling, suppresses cellular senescence and apoptosis, through the ITGA2/PI3K/AKT, NF-kappa B and MAPK signaling pathways. These findings indicate that genkwanin may be a promising therapeutic candidate for IVDD.

BACKGROUND:Accumulating evidence indicates that intervertebral disc degeneration (IDD) is associated with diabetes mellitus (DM), while the underlying mechanisms still remain elusive. Herein, the current study sought to explore the potential molecular mechanism of IDD in diabetic rats based on transcriptome sequencing data.METHODS:Streptozotocin (STZ)-induced diabetes mellitus type 1 (T1DM) rats were used to obtain the nucleus pulposus tissues for transcriptome sequencing. Next, differentially expressed genes (DEGs) in transcriptome sequencing data and GSE34000 microarray dataset were obtained and intersected to acquire the candidate genes. Moreover, GO and KEGG enrichment analyses were performed to analyze the cellular functions and molecular signaling pathways primarily regulated by candidate DEGs.RESULTS:A total of 35 key genes involved in IDD of T1DM rats were mainly enriched in the extracellular matrix (ECM) and cytokine adhesion binding-related pathways. NLRP3 inflammasome activation promoted the pyroptosis of nucleus pulposus cells (NPCs). Besides, BMP7 could affect the IDD of T1DM rats by regulating the inflammatory responses. Additionally, NPCs were isolated from STZ-induced T1DM rats to illustrate the effects of BMP7 on IDD of T1DM rats using the ectopic expression method. Both in vitro and in vivo experiments validated that BMP7 alleviated IDD of T1DM rats by inhibiting NLRP3 inflammasome activation and pyroptosis of NPCs.CONCLUSION:Collectively, our findings provided novel mechanistic insights for understanding of the role of BMP7 in IDD of T1DM, and further highlighted BMP7 as a potential therapeutic target for preventing IDD in T1DM.

Objective:To investigate the clinical value of thromboelastogram in early diagnosis of deep vein thrombosis (DVT) in patients undergoing free flap surgery of lower extremity.Methods:A retrospective study was conducted to analyze the 192 patients undergoing surgical repair of soft tissue defects at lower extremity with free anterolateral femoral flap at Department of Orthopaedics, Tongji Hospital from January 2018 to June 2022. There were 117 males and 75 females, with an age of (45.6±12.7) years and an area of skin defects ranging from 5 cm × 3 cm to 18 cm × 9 cm. The patients were divided into 2 groups according to whether DVT occurred on the first day after surgery. In the DVT group of 22 patients, there were 14 males and 8 females, with an age of (47.7±14.3) years; in the DVT-free group of 170 patients, there were 103 males and 67 females, with an age of (45.3±12.5) years. The 2 groups were compared in terms of reaction time, coagulation time, maximum amplitude and coagulation angle in the thromboelastogram. Diagram of receiver operating characteristic (ROC) curves was used to evaluate the predictive value of thromboelastography in assessing the risk of DVT after surgery.Results:The 2 groups were comparable because there was no significant difference in the baseline information or operation time between them ( P>0.05). The reaction time [(5.21±0.85) min] and coagulation time [(1.12±0.30) min] in the DVT group were significantly shorter than those in the DVT-free group [(6.48±0.06) min and (1.60±0.03) min], and the maximum amplitude [(71.45±1.17) mm] and coagulation angle [69.54° (64.59°, 76.64°) ] in the DVT group were significantly larger than those in the DVT-free group [(66.63±0.40) mm and 64.92°(54.11°, 74.21°)] (all P<0.05). The optimal cut-off points in the ROC diagram were 5.46 min at reaction time, 1.52 min at coagulation time, 72.31 mm at maximum amplitude and 59.89° at coagulation angle. The sensitivity and specificity of detecting DVT on the first day after surgery were 80.7% and 71.6%, respectively, according to the combination of the best cut-off points in the ROC diagram and all the indexes in the thromboelastogram. Conclusion:Thromboelastogram is of a great value for the diagnosis of lower extremity DVT, and of a positive significance for the prevention of serious complications after surgery in patients undergoing free flap surgery of lower extremity.

Osteoarthritis (OA) is a chronic progressive articular illness which commonly affects older‑aged adults, presenting with cartilage inflammation and degradation. Rutaecarpine (RUT) has been shown to exert promising anti‑inflammatory effects; however, the efficacy of RUT in the treatment of OA is debatable. The present study investigated the potential of RUT in alleviating OA in a mouse model. Treatment with RUT inhibited the inflammatory response and extracellular matrix degradation by suppressing process regulators in interleukin (IL)‑1β‑stimulated chondrocytes. Moreover, treatment with RUT in vitro upregulated the gene expression of anabolic agents, such as collagen type II, aggrecan and SRY‑box transcription factor 9, indicating that RUT contributed to cartilage repair. Additionally, flow cytometric assays, and the measurement of β‑galactosidase levels, autophagic flux and related protein expression revealed that RUT effectively attenuated IL‑1β‑induced chondrocyte apoptosis, senescence and autophagy impairment. In addition, bioinformatics analysis and in vitro experiments demonstrated that RUT protected cartilage by mediating the phosphoinositide‑3‑kinase (PI3K)/Akt/nuclear factor‑κB (NF‑κB) and mitogen‑activated protein kinase (MAPK) pathways. The ameliorative effects of RUT on IL‑1β‑stimulated chondrocytes were abrogated when siRNA was used to knock down integrin αVβ3. Furthermore, the results of immunohistochemical analysis and microcomputed tomography confirmed the in vivo therapeutic effects of RUT in mice with OA. On the whole, the present study demonstrates that RUT attenuates the inflammatory response and cartilage degradation in mice with OA by suppressing the activation of the PI3K/AKT/NF‑κB and MAPK pathways. Integrin αVβ3 may play a pivotal role in these effects.

目的 分析低级别软骨肉瘤和内生软骨瘤患者的临床特征及术前各项检查指标的结果,及其在两者鉴别中的作用.方法 收集2015年1月至2020年12月在华中科技大学同济医学院附属同济医院行手术治疗的105例内生软骨瘤和42例低级别软骨肉瘤患者的临床资料.通过Spearman相关性检验和ROC曲线分析术前的临床及检查指标与术后肿瘤性质的相关性,并分析其鉴别诊断能力,多因素Logistic回归分析明确与肿瘤性质相关的危险因素并构建No-mogram预测模型.结果 低级别软骨肉瘤组的患者年龄、肿瘤大小、中性粒与淋巴细胞比值(NLR)及碱性磷酸酶(ALP)明显高于内生软骨瘤组,而淋巴细胞与单核细胞比值(LMR)及白蛋白与球蛋白比值(AGR)则明显更低.肿瘤大小和NLR值与低级别软骨肉瘤的诊断呈正相关,而LMR值与其呈负相关;这3个因素与肿瘤性质间的Spearman相关系数的绝对值均大于0.4且AUC值均大于0.7.肿瘤大小、NLR及LMR值鉴别两种肿瘤的最佳截断值分别为6.3 cm、1.6和4.3.Nomogram模型对于鉴别内生软骨瘤和低级别软骨肉瘤有较好的效能,该模型的ROC曲线下面积为0.96.结论 对于诊断不明确的软骨源性肿瘤,患者的临床特征及术前检查指标可能有助于低级别软骨肉瘤和内生软骨瘤的鉴别.

The Neural Calcium Sensor1 (NCS1) is a crucial protein that binds to Ca2+ and is believed to play a role in regulating tumor invasion and cell proliferation. However, the role of NCS1 in immune infiltration and cancer prognosis is still unknown. Our study aimed to explore the expression profile, immune infiltration pattern, prognostic value, biological function, and potential compounds targeting NCS1 using public databases. High expression of NCS1 was detected by immune histochemical staining in LIHC (Liver hepatocellular carcinoma), BRCA (Breast invasive carcinoma), KIRC (Kidney renal clear cell carcinoma), and SKCM (Skin Cutaneous Melanoma). The expression of NCS1 in cancer was determined by TCGA (The Cancer Genome Atlas Program), GTEx (The Genotype-Tissue Expression), the Kaplan–Meier plotter, GEO (Gene Expression Omnibus), GEPIA2.0 (Gene Expression Profiling Interactive Analysis 2.0), HPA (The Human Protein Atlas), UALCAN, TIMER2.0, TISIDB, Metascape, Drugbank, chEMBL, and ICSDB databases. NCS1 has genomic mutations as well as aberrant DNA methylation in multiple cancers compared to normal tissues. Also, NCS1 was significantly different in the immune microenvironment, tumor mutational burden (TMB), microsatellite instability (MSI), and immune infiltrate-associated cells in different cancers, which could be used for the typing of immune and molecular subtypes of cancer and the presence of immune checkpoint resistance in several cancers. Univariate regression analysis, multivariate regression analysis, and gene enrichment analysis to construct prognostic models revealed that NCS1 is involved in immune regulation and can be used as a prognostic biomarker for SKCM, LIHC, BRCA, COAD, and KIRC. These results provide clues from a bioinformatic perspective and highlight the importance of NCS1 in a variety of cancers.

Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, is implicated in intervertebral disc degeneration (IDD). The current study explored the role of Fer-1 in IDD via the toll-like receptor 4 (TLR4)/NF-κB signaling pathway. IDD-related gene expression microarray GSE124272 and high-throughput sequencing data set GSE175710 were obtained through the Gene Expression Omnibus database. Differentially expressed genes in IDD were identified, followed by implementation of protein-protein interaction network analysis and receiver operating characteristic curve analysis. The main pathways in IDD were obtained through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional analyses, and target genes of Fer-1 were obtained through PubChem and PharmMapper websites. Finally, GPX4, FTH, and TLR4 expression was determined in a IDD rat model. Three key co-expression modules involved in IDD were obtained through Weighted Gene Co-Expression Network Analysis. Thirteen differentially expressed genes were found to be associated with IDD, and eight key genes (TLR4, BCL2A1, CXCL1, IL1R1, NAMPT, SOCS3, XCL1, and IRAK3) were found to affect IDD. These eight key genes had the diagnostic potential for IDD. The NF-κB signaling pathway was shown to play a predominant role in IDD development. Network pharmacologic analysis indicated a role of Fer-1 in suppressing ferroptosis and ameliorating IDD via the TLR4/NF-κB signaling pathway, which was verified by an in vivo animal experiment. The study showed that Fer-1 down-regulates TLR4 to inactivate NF-κB signaling pathway, suppressing ferroptosis and ultimately alleviating IDD in rats.