Intervertebral disc degeneration (IVDD) is a significant contributor to low back pain and is associated with oxidative stress-induced pyroptosis of nucleus pulposus (NP) cell. Citrulline, a non-essential amino acid integral to the urea cycle and nitric oxide synthesis, plays an essential role in maintaining intracellular redox balance. This study aimed to investigate the protective effects of citrulline on oxidative stress-damaged human NP cells and its underlying molecular mechanism related to cellular pyroptosis. Primary human NP cells were isolated from non-degenerated intervertebral disc tissues of donors with lumbar fractures, and oxidative stress along with pyroptosis was induced using TBHP. TBHP exposure significantly induced oxidative stress and pyroptosis in NP cells, as evidenced by increased expression of NLRP3, ASC, cleaved caspase-1 and cleaved GSDMD, along with heightened ROS levels and augmented secretion of IL-1β and IL-18 in the supernatant. Notably, citrulline treatment effectively reversed these effects in a dose-dependent manner. Mechanistically, citrulline sustains intracellular redox homeostasis through the SLC7A2/eNOS signaling axis, a process correlated with suppressed NLRP3 inflammasome assembly in NP cells. Knockdown of either SLC7A2 or eNOS abolished the protective effects of citrulline. And upregulation of SLC7A2-eNOS axis enhanced the anti-oxidative and anti-pyroptotic effects of citrulline. Herein, Citrulline alleviates oxidative stress-induced pyroptosis in human NP cells by inhibiting the assembly of the NLRP3 inflammasome via the SLC7A2/eNOS signaling pathway, which suggests a novel potential therapeutic and nutritional intervention strategy for IVDD.

BACKGROUND: The weight-adjusted waist index (WWI) is a novel obesity index that is calculated as the waist circumference (WC) divided by the square root of body weight (kg). Previous studies have revealed that higher body mass index (BMI) and WC increase the risk of low back pain (LBP). However, no research explores the relationship between WWI and LBP. METHODS: Data utilized in this cross-sectional study were drawn from the National Health and Nutrition Examination Survey. Three logistic regression models were used to evaluate the association between WWI and LBP. Stratified analysis was applied to assess the stability of the results. Receiver-operating characteristic (ROC) curves were employed to visually assess and compare the predictive effectiveness of WWI, BMI, WC, and weight on LBP. RESULTS: A significant positive correlation was observed between WWI and LBP, model 1 (odds ratio [OR] = 1.222,95% confidence interval (95% CI) [1.164, 1.283], P < 0.0001), model 2 (OR = 1.187, 95% CI [1.118, 1.261], P< 0.0001), and model 3 (OR = 1.129, 95% CI [1.056, 1.207], P< 0.001). Relative to the Q1, Q3 (model 1 (OR = 1.241, 95% CI [1.114, 1.382], P < 0.001), model 2 (OR = 1.192, 95% CI1.310], P = 0.047)) and Q4 (model 1 (OR = 1.524, 95% CI [1.341, 1.733], P< 0.0001), model 2 (OR = 1.422,95% CI [1.233, 1.640], P< 0.0001), model 3 (OR = 1.333, 95% CI [1.149, 1.547], P < 0.001)) all showed a significant positive correlation between them. The area under the receiver-operating characteristic curve (AUC) for WWI is 0.5447536, the AUC for BMI is 0.5466724, and the AUC for WC and weight is 0.5501341 and 0.5376615, respectively. CONCLUSIONS: This cross-sectional study revealed a significant positive association between WWI and LBP, but WWI did not show better predictive efficacy than BMI and WC.

The nervous system plays a pivotal regulatory role in the maintenance of bone homeostasis, and the protective effects of dopamine and its receptors on bone metabolism are emerging. Despite these protective roles, the functional contribution of dopaminergic signaling, particularly through specific receptor subtypes, remains unexplored in glucocorticoid (GC)-associated osteonecrosis of the femoral head (ONFH) pathogenesis. Here, the dopamine D1 receptor (DRD1), a G protein-coupled receptor with few identified bone-related functions, is identified as a positive regulator of GC-induced apoptosis. The dopamine levels in the serum of GC-associated ONFH patients are significantly lower than those in the normal population. The protein and gene expression levels of DRD1 and the number of DRD1-positive cells are abnormally elevated in the pathological state of GC-associated ONFH, and DRD1 is expressed in osteoblasts. Overexpression of DRD1 attenuates GC-induced osteogenic inhibition and apoptosis in vivo and in vitro. Mechanistically, overexpression of DRD1 elevates cAMP levels, activates downstream protein kinase A, and inhibits GC-induced endoplasmic reticulum stress and apoptosis through the ATF3/CHOP signaling pathway, thus improving bone homeostasis. Importantly, Madopar, an FDA-approved dopaminergic agent, inhibits GC-induced osteoblastic apoptosis and ONFH via DRD1. Collectively, this study not only deciphers a previously unrecognized DRD1-mediated neuro-osteogenic axis but also repurposes an FDA-approved drug (Madopar) for precision ONFH management.

BackgroundInsulin resistance is one of the major pathophysiological features of type 2 diabetes mellitus. Studies have revealed the association between type 2 diabetes mellitus and low back pain. However, few studies explored the relationship between insulin resistance and low back pain directly. Therefore, this study selected HOMA-IR, TyG, TyG-BMI, TyG-WC, and TyG-WtHR as indicators of insulin resistance to comprehensively investigate the association between insulin resistance and low back pain.MethodsThe data for this cross-sectional study were from NHANES. Multivariate logistic regression was used to assess the association of insulin resistance with low back pain, and the stability of the results was evaluated by stratified analysis.ResultsA total of 6,126 adult participants were included in the study, including 3,657 non-LBP participants and 2,469 LBP patients. All of these five indices showed significant association with low back pain after full adjustment for all covariates (Model 3), HOMA-IR [OR = 1.052, 95% CI (1.018, 1.087), p = 0.003], TyG [OR = 1.431, 95% CI (1.013, 2.021), p = 0.042], TyG-BMI [OR = 1.003, 95% CI (1.002, 1.005), p < 0.0001], TyG-WC [OR = 1.001, 95% CI (1.001, 1.002), p < 0.0001], TyG-WtHR [OR = 1.268, 95% CI (1.155, 1.393), p < 0.0001]. The relationship between insulin resistance and low back pain is stable in most stratified populations (p-interaction >0.05).ConclusionInsulin resistance is associated with an increased risk of low back pain. The HOMA-IR, TyG, TyG-WC, TyG-BMI, and TyG-WtHR all showed a stable correlation with low back pain. TyG-BMI, TyG-WC, and TyG-WtHR are more stable in their associations with low back pain than TyG alone.

Estimated glucose disposal rate (eGDR) is a novel insulin resistance (IR) assessment surrogate. Although it has shown promising potential in other metabolic disease studies, no research has yet explored its relationship with osteoarthritis (OA). Therefore, this study aims to investigate the association between eGDR and OA in a cross-sectional observational cohort. Data utilized in this cross-sectional study were drawn from the National Health and Nutrition Examination Survey (NHANES). Logistic regression models were used to evaluate the association between eGDR and OA, stratified analysis was applied to assess the stability of the results. A total of 19,040 participants were included in the study, including 2,001 OA patients and 17,039 non-OA participants with an age distribution ranging from 20 to 85 years. The fully adjusted logistic regression model shows that eGDR were less likely associated with OA compared to those with non-OA (OR = 0.879, 95

BackgroundOsteoarthritis (OA) is a common chronic disease among the elderly, causing pain, functional limitations, and a decline in quality of life. Diabetes mellitus (DM), a prevalent metabolic disorder, has been proven to have an association with OA. However, the specific impact of DM on the physical function of OA patients remains lack of in-depth exploration. This study aims to investigate whether OA patients with DM (DMOA) experience more severe physical function limitations.MethodThe study utilized National Health and Nutrition Examination Survey (NHANES) data from 1999-2018. Logistic regression models were used to analyze the association between DMOA and physical function limitations. Stratified analysis was applied to assess the stability of these results.ResultsDMOA patients exhibited significantly worse physical function compared to those OA patiants who do not complicated with DM (non-DMOA), especially in high-intensity and frequent joint use activities like walking long distances (OR = 1.870, 95%CI[1.243,2.814], P = 0.003), crouching (OR = 1.417, 95%CI[1.116, 1.799], P = 0.005), and standing for long periods (OR = 1.423,95%CI[1.141,1.774], P = 0.002). Even after adjusting for demographics, socioeconomic and health factors, the association between DMOA and physical function impairment remained significant.ConclusionThis study revealed that the DMOA population has worse physical function than non-DMOA population, especially in high-intensity and frequent joint use activities. Managing DM in OA patients is crucial to improve their physical function and overall quality of life. The impact of DM should be considered in the selection of therapeutic agents and care for OA.

Interleukin 6 receptor (IL6R) inhibitors are effective drugs as therapy for rheumatoid arthritis (RA). However, few studies on IL6R inhibition for relieving chronic low back pain (CLBP) have been conducted. These existing studies are plagued by issues such as small sample sizes and inconsistent inclusion criteria. With advances in genomics, more and more evidence is revealing the role of heritability in the etiology of disease, and Mendelian randomization (MR) analyses are being used more broadly to infer causation. MR analysis was used in the present study to investigate the effect of IL6R inhibitors on CLBP. IL6R single nucleotide polymorphisms (SNPs) from Europe were selected from online databases. C-reactive protein (CRP) levels were utilized as an exposure factor, RA was employed as a positive control, and two CLBP-related genome-wide association studies (GAWS) data were used as primary outcomes for drug-targeted MR analyses for examining causality between IL6R inhibitors and CLBP. In addition, repeated analyses were also performed using different GWAS data related to exposure to test the stability of the results. IL6R inhibitors significantly reduced the risk of CLBP, ukb-a-346 (OR: 0.9564, 95

BackgroundAutoimmune diseases (ADs) are a category of conditions characterized by misrecognition of autologous tissues and organs by the immune system, leading to severe impairment of patients’ health and quality of life. Increasing evidence suggests a connection between fluctuations in plasma metabolites and ADs. However, the existence of a causal relationship behind these associations remains uncertain.MethodsApplying the two-sample mendelian randomization (MR) method, the reciprocal causality between plasma metabolites and ADs was analyzed. We took the intersection of two metabolite genome-wide association study (GWAS) datasets for GWAS-meta and obtained 1,009 metabolites’ GWAS data using METAL software. We accessed GWAS summary statistics for 5 common ADs, inflammatory bowel disease (IBD), multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) from published GWAS data. MR analyses were performed in discovery and replication stage simultaneously. Meanwhile, the reverse MR analysis was conducted to investigate the possibility of reverse causal association. Furthermore, a series of sensitivity analyses were conducted to validate the robustness of the results. These statistical analyses were conducted using R software. Finally, the web version of MetaboAnalyst 5.0. was applied to analyze metabolic pathways. Ultimately, we conducted ELISA assays on plasma samples from patients to validate the results.Results4 metabolites were identified to have causal relationships with IBD, 2 metabolites with MS, 13 metabolites with RA, and 4 metabolites with T1D. In the reverse MR analysis, we recognized causality between SLE and 22 metabolites, IBD and 4 metabolites, RA and 22 metabolites, and T1D and 37 metabolites. Additionally, 4 significant metabolic pathways were identified in RA by metabolic pathway analysis in the forward MR analysis. Correspondingly, in the reverse, 11 significant metabolic pathways in RA, 8 in SLE, and 4 in T1D were obtained using identical approaches. Furthermore, the protective role of glutamate was confirmed through ELISA assays.ConclusionsOur research established a reciprocal causality between plasma metabolites and ADs. Furthermore, diverse metabolic pathways correlated with ADs were uncovered. Novel insights into the prediction and diagnosis were provided, as well as new targets for precise treatment of these conditions were discovered.

Bone metastases caused by breast cancer pose a major challenge to the successful treatment of breast cancer patients. Many researchers have suggested that herbal medicines are extremely effective at preventing and treating cancer-associated osteolysis. Previous studies have revealed that Morusin (MOR) is cytotoxic to many cancer cells ex vivo. Nevertheless, how MOR contributes to osteolysis induced by breast cancer is still unknown, and the potential mechanism of action against osteolysis is worthy of further study. The protective effect and molecular mechanism of MOR in inhibiting breast cancer cell-induced osteolysis were verified by experiments and network pharmacology. Cell function was assessed by cell proliferation, osteoclast (OC) formation, bone resorption, and phalloidin staining. Tumour growth was examined by micro-CT scanning in vivo. To identify potential MOR treatments, the active ingredient-target pathway of breast cancer was screened using network pharmacology and molecular docking approaches. This study is the first to report that MOR can prevent osteolysis induced by breast cancer cells. Specifically, our results revealed that MOR inhibits RANKL-induced osteoclastogenesis and restrains the proliferation, invasion and migration of MDA-MB-231 breast cells through restraining the PI3K/AKT/MTOR signalling pathway. Notably, MOR prevented bone loss caused by breast cancer cell-induced osteolysis in vivo, indicating that MOR inhibited the development of OCs and the resorption of bone, which are essential for cancer cell-associated bone distraction. This study showed that MOR treatment inhibited osteolysis induced by breast cancer in vivo. MOR inhibited OC differentiation and bone resorption ex vivo and in vivo and might be a potential drug candidate for treating breast cancer-induced osteolysis.

OBJECTIVE:This meta-analysis aims to refine the understanding of the optimal choice between different cage shapes in transforaminal lumbar interbody fusion (TLIF) by systematically comparing perioperative data, radiological outcomes, clinical results, and complications associated with banana-shaped and straight bullet cages.METHODS:A meticulous literature search encompassing PubMed, Embase, Scopus, Web of Science, China Knowledge Network, and Wanfang Data was executed up to October 5, 2023. Inclusion criteria focused on studies comparing banana-shaped and straight bullet cages in TLIF. The quality of included studies was assessed using appropriate tools such as the Newcastle-Ottawa Scale (NOS) for nonrandomized studies. Rigorous evaluations were performed for radiographic outcomes, including disc height (DH), segmental lordosis (SL), lumbar lordosis (LL), subsidence, and fusion rates. Clinical outcomes were meticulously evaluated using visual analogue scale (VAS), Oswestry Disability Index (ODI), and complications.RESULTS:The analysis incorporated 7 studies, involving 573 patients (297 with banana-shaped cages, 276 with straight cages), all with NOS ratings exceeding 5 stars. No statistically significant differences were observed in operative time, blood loss, or hospitalization between the 2 cage shapes. Banana-shaped cages exhibited greater changes in DH (p = 0.001), SL (p = 0.02), and LL (p = 0.01). Despite statistically higher changes in ODI for straight cages (26.33, p < 0.0001), the actual value remained similar to banana-shaped cages (26.15). Both cage types demonstrated similar efficacy in VAS, complication rates, subsidence, and fusion rates.CONCLUSION:Although banana-shaped cages can excel in restoring DH, SL, and LL, straight bullet cages can provide comparable functional improvements, pain relief, and complication rates.

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent an effective strategy for reducing cardiovascular disease risk. Yet, PCSK9’s impact on osteoporosis remains unclear. Hence, we employed Mendelian randomization (MR) analysis for examining PCSK9 inhibitor effects on osteoporosis. Methods Single nucleotide polymorphisms (SNPs) for 3-hydroxy-3-methylglutaryl cofactor A reductase (HMGCR) and PCSK9 were gathered from available online databases for European pedigrees. Four osteoporosis-related genome-wide association studies (GWAS) data served as the main outcomes, and coronary artery disease (CAD) as a positive control for drug-targeted MR analyses. The results of MR analyses examined by sensitivity analyses were incorporated into a meta-analysis for examining causality between PCSK9 and HMGCR inhibitors and osteoporosis. Results The meta-analysis involving a total of 1,263,102 subjects, showed that PCSK9 inhibitors can increase osteoporosis risk (P < 0.05, I2, 39%). However, HMGCR inhibitors are not associated with osteoporosis risk. Additionally, a replication of the analysis was conducted with another exposure-related GWAS dataset, which led to similar conclusions. Conclusion PCSK9 inhibitors increase osteoporosis risk. However, HMGCR inhibitors are unremarkably linked to osteoporosis.

Phosphatidylinositol 3-kinase (PI3K) is frequently hyperactivated in cancer, playing pivotal roles in the pathophysiology of both malignant and immune cells. The impact of PI3K inhibitors on the tumor microenvironment (TME) within lung cancer remains largely unknown. In this study, we explored the regulatory effects of GNE-493, an innovative dual inhibitor of PI3K and mammalian target of rapamycin (mTOR), on the TME of lung cancer. First, through the analysis of The Cancer Genome Atlas-lung squamous cell carcinoma (LUSC) cohort, we found PIK3CA to be related to CD8 T cells, which may affect the overall survival rate of patients by affecting CD8 function. We herein demonstrated that GNE-493 can significantly inhibit tumor cell proliferation and promote cell apoptosis while increasing the expression of the immunogenic death-related molecules CRT and HSP70 using in vitro cell proliferation and apoptosis experiments on the murine KP lung cancer cell line and human A549 lung cancer cell line. Next, through the establishment of an orthotopic tumor model in vivo, it was found that after GNE-493 intervention, the infiltration of CD4+ and CD8+ T cells in mouse lung tumor was significantly increased, and the expression of CRT in tumors could be induced to increase. To explore the mechanisms underlying PI3K inhibition-induced changes in the TME, the gene expression differences of T cells in the control group versus GNE-493-treated KP tumors were analyzed by RNA-seq, and the main effector pathway of anti -tumor immunity was identified. The IFN/TNF family molecules were significantly upregulated after GNE-493 treatment. In summary, our findings indicate that GNE-493 promotes immunogenic cell death in lung cancer cells, and elucidates its regulatory impact on molecules associated with the adaptive immune response. Our study provides novel insights into how PI3K/mTOR inhibitors exert their activity by modulating the tumor-immune interaction.

The cure rate for patients with osteosarcoma (OS) has stagnated over the past few decades. Penfluridol, a first-generation antipsychotic, has demonstrated to prevent lung and esophageal malignancies from proliferation and metastasis. However, the effect of penfluridol on OS and its underlying molecular mechanism remains unclear. This study revealed that penfluridol effectively inhibited cell proliferation and migration, and induced G2/M phase arrest in OS cells. In addition, penfluridol treatment was found to increased reactive oxygen species (ROS) levels in OS cells. Combined with the RNA-Seq results, the anti-OS effect of penfluridol was hypothesized to be attributed to the induction of ferroptosis. Western blot results showed that penfluridol promoted intracellular Fe2+ concentration, membrane lipid peroxidation, and decreased intracellular GSH level to induce ferroptosis. Further studies showed that p62/Keap1/Nrf2 signaling pathway was implicated in penfluridol-induced ferroptosis in OS cells. Overexpression of p62 effectively reversed penfluridol-induced ferroptosis. In vivo, penfluridol effectively inhibited proliferation and prolonged survival in xenograft tumor model. Therefore, penfluridol is a promising drug targeting OS in the future.

Previous studies have demonstrated a relationship between prevalence of Osteoarthritis (OA) and insulin resistance (IR). The correlation between IR surrogates indices and gold standard tool for IR evaluation (Hyperinsulinemic-euglycemic clamp (HIEC)) have been well demonstrated. However, few studies evaluated the relationship between IR surrogates and OA. The aim of this study is to investigate the potential associations between different IR surrogates (the homeostatic model assessment of insulin resistance (HOMA-IR) index, the triglyceride glucose (TyG) index, the triglyceride glucose with body mass (TyG-BMI) index, the triglyceride glucose with waist circumference (TyG-WC) index, and the triglyceride glucose with the ratio of waist circumference divided by height (TyG-WtHR) index) and OA. This study used data from the National Health and Nutrition Examination Survey (NHANES). Multivariate logistic regression analysis was used to assess the associations of different IR surrogates with OA. After adjusting for covariates, TyG-BMI index (OR = 1.006, 95

ObjectiveInterleukin-6 (IL-6) is a multiple-effect cell factor implicated in the etiopathogenesis of several rheumatologic disorders. The blockade of the IL-6 pathway via IL6R inhibitors effectively treats these disorders. However, the clinical significance of the IL6R blockade for ankylosing spondylitis (AS) therapy remains controversial. With advances in genomics, increasing evidence has revealed the role of heritability in the etiology of disease, and Mendelian randomization (MR) analyses are being used more broadly to infer causation. Therefore, this MR study aims to evaluate the potential therapeutic utility of IL6R-targeted approaches in AS.MethodsThe C-reactive protein (CRP) level was used as an exposure factor, and rheumatoid arthritis (RA) was used as a positive control. As-related genome-wide association study (GWAS) data were used as the primary outcome of drug-targeted MR analyses to test the relation between IL6R blockers and AS. Inverse variance weighting (IVW) is the primary analytical approach. Various sensitivity tests were performed to check the robustness and trustworthiness of the causality estimation, including consistency, heterogeneity, and pleiotropy analyses. In addition, repeated analysis was conducted using different GWAS data related to exposures and outcomes to examine the results for stability.ResultsAccording to the IVW results, IL6R inhibitors significantly reduced the risk of AS in ukb-b-18194 (OR: 0.995, 95% CI 0.993–0.996, P = 5.12 × 10−08) and ukb-a-88 (OR: 0.994, 95% CI 0.993–0.996, P = 6.25 × 10−15). Moreover, repeated analyses were performed using different exposure-related GWAS data, yielding similar results, ukb-b-18194 (OR: 0.995, 95% CI 0.993–0.997, P = 1.25 × 10−06) and ukb-a-88 (OR: 0.995, 95% CI 0.994–0.997, P = 7.81 × 10−09). Heterogeneity analyses and pleiotropy analyses indicated no significant heterogeneity or pleiotropy.ConclusionThis MR analysis result further validates that the IL-6 pathway may contribute to the pathogenesis of AS and that the inhibition of IL6R reduces the risk of AS. These findings may guide future studies and provide more favorable drug treatment options for people at high risk of AS.

Abstract Background Osteoporosis and frailty are two common features in the elderly population. Despite many review articles mentioning the association between osteoporosis and frailty, there is a lack of original research directly investigating their relationship. Therefore, this study was conducted to examine the correlation between osteoporosis and frailty. Methods We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES), using logistic regression analysis to assess the association of osteoporosis with the frailty index. In addition, we further explored the causal relationship between them using Mendelian randomization (MR) study. Results In the cross-sectional study, 19,091 non-frailty participants and 5878 frailty participants were included in this study. We observed a significant positive association between osteoporosis and frailty after adjusting for demographic characteristics, body mass index (BMI), smoking, and alcohol use (OR = 1.454, 95% CI [1.142,1.851], P = 0.003). Moreover, the MR study showed a bidirectional causal relationship between osteoporosis and frailty. When osteoporosis was used as an exposure factor, the frailty pooled OR value calculated utilizing the inverse variance weighted (IVW) method was 2.81 (95% CI [1.69, 4.68], P = 6.82 × 10− 5). When frailty was used as an exposure factor, the OR value calculated using the IVW method was 1.01 (95% CI [1.00,1.01], P = 3.65 × 10− 7). Conclusions Osteoporosis was positively correlated with frailty, and the results remained robust after adjusting for covariates. Further, MR studies have shown a bidirectional causal relationship between osteoporosis and frailty.

BackgroundWhile intervertebral disc degeneration (IVDD) is crucial in numerous spinally related illnesses and is common among the elderly, the complete understanding of its pathogenic mechanisms is still an area of ongoing study. In recent years, it has revealed that liposomes are crucial in the initiation and progression of IVDD. However, their intrinsic mediators and related mechanisms remain unclear. With the development of genomics, an increasing amount of data points to the contribution of genetics in the etiology of disease. Accordingly, this study explored the causality between liposomes and IVDD by Mendelian randomization (MR) analysis and deeply investigated the intermediary roles of undetected metabolites.MethodsAccording to MR analysis, 179 liposomes and 1400 metabolites were evaluated for their causal association with IVDD. Single nucleotide polymorphisms (SNPs) are strongly associated with the concentrations of liposomes and metabolites. Consequently, they were employed as instrumental variables (IVs) to deduce if they constituted risk elements or protective elements for IVDD. Furthermore, mediation analysis was conducted to pinpoint possible metabolic mediators that link liposomes to IVDD. The inverse variance weighting (IVW) was the main analytical technique. Various confidence tests in the causality estimates were performed, including consistency, heterogeneity, pleiotropy, and sensitivity analyses. Inverse MR analysis was also utilized to estimate potential reverse causality.ResultsMR analysis identified 13 liposomes and 79 metabolites markedly relevant to IVDD. Moreover, the mediation analysis was carried out by choosing the liposome, specifically the triacylglycerol (48:2) levels, which were found to be most notably associated with an increased risk of IVDD. In all, three metabolite-associated mediators were identified (3-methylcytidine levels, inosine 5’-monophosphate (IMP) to phosphate ratio, and adenosine 5’-diphosphate (ADP) to glycine ratio).ConclusionThe analysis’s findings suggested possible causal connections between liposomes, metabolites, and IVDD, which could act as both forecast and prognosis clinical indicators, thereby aiding in the exploration of the pathogenesis behind IVDD.

Osteosarcoma is a prevalent kind of primary bone malignancy. Trifluoperazine, as an antipsychotic drug, has anti-tumor activity against a variety of cancers. Nevertheless, the impact of trifluoperazine on osteosarcoma is unclear. Our investigation aimed to explore the mechanism of trifluoperazine's effect on osteosarcoma. We found that trifluoperazine inhibited 143B and U2-OS osteosarcoma cell proliferation in a method based on the dose. Furthermore, it was shown that trifluoperazine induced the accumulation of reactive oxygen species (ROS) to cause mitochondrial damage and induced mitophagy in osteosarcoma cells. Finally, combined with RNA-seq results, we first demonstrated the AMPK/mTOR/ULK1 signaling pathway as a potential mechanism of trifluoperazine-mediated mitophagy in osteosarcoma cells and can be suppressed by AMPK inhibitor Compound C.

BACKGROUND:Although intervertebral disc degeneration (IVDD) is a critical factor in many spine-related diseases and has an extremely high prevalence in the aging population, the potential pathogenesis remains to be clarified entirely. Immune cells have been found to perform an essential function during the onset and progression of IVDD in recent years. Therefore, we explored the association between immune cell characteristics and IVDD through Mendelian randomization (MR) analysis and further delved into the mediating role of potential metabolites. METHODS:Based on the MR analysis, the association of 731 immune cell phenotypes and 1400 metabolites on IVDD were assessed. Single nucleotide polymorphisms were closely associated the expression levels of immune cell characteristics and the concentrations of metabolites and have been used as instrumental variables for deducing them as risk factors or protective factors for IVDD. In addition, mediation analyses have been performed to identify potential metabolite mediators between immune cell characteristics and IVDD. RESULTS:MR analysis identified 27 immune cell phenotypes and 79 metabolites significantly associated with IVDD. In addition, mediation analysis was performed by selecting the immune cell phenotype that most significantly increased the risk of IVDD - CD86 on monocytes. A total of 4 metabolite-mediated mediation relationships were revealed (3 b-hydroxy-5-cholenoic acid, X-22509, N-acetyl-L-glutamine, and N2-acetyl, N6, N6-dimethyllysine). CONCLUSIONS:The findings of this analysis identified underlying association between immune cell phenotypes, metabolite, and IVDD that may serve as predictive and prognostic clinical biomarkers and benefit IVDD pathogenesis research.

BackgroundSpinal meningioma is a common intraspinal tumor, which mainly occurs in the thoracic spine. Ossified meningioma (OSM) is an extremely rare histological variant. Our article reports a rare patient with dorsal complete OSM and reviews this subject.Case presentationA 68-year-old woman presented with a one-year history of progressive weakness in both lower limbs with gait disturbance. Physical examination revealed hypoesthesia with a sensory level below T10. Babinski and pathological signs on both sides were weakly positive. Magnetic resonance imaging (MRI) showed a mass at the T10 to T11 level causing severe compression of the spinal cord. Computed tomography (CT) showed complete ossification of the mass. 18F-Fluoro-deoxy-glucose positron emission tomography CT (18F-FDG PET/CT) scan combined with MRI revealed that the mass was an intradural extramedullary high-density ossified nodule. The patient underwent a gross total resection of the mass and pathologic examination indicated that the mass was a meningioma with diffused psammomatous bodies.ConclusionWe identified a rare case of dorsal complete OSM occurring in a 68-year-old woman. After complete surgical resection, although there were complications such as cerebral fluid leakage and fever, the patient finally recovered with a satisfactory result.