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Background Bisphenol A (BPA) levels are high in women with polycystic ovary syndrome (PCOS). The mechanism by which BPA induces abnormal glucose metabolism in PCOS patients is largely unknown. Methods Serum and urine samples were collected from women with and without PCOS (control) at the reproductive medicine center with informed consent. Non-PCOS patients who received in vitro fertilization were recruited for collection of ovarian follicular fluid and granular cells. Wild-type C57BL/6 and AhR −/− mice were used to verify the effects of BPA on PCOS. Real-time PCR, western blotting, and ELISA were conducted to analyze the function of BPA. Chip-qPCR verified the role of AhR in GLUT4 transcription. Flow cytometry was performed to determine glucose uptake. Results A positive correlation was observed between BPA concentration and serum BPA levels in PCOS patients. BPA aggravated the changes in PCOS with abnormal glucose metabolism, impaired fertility, and increased body fat. Mechanistically, we showed that BPA activated AhR and led to decreased glucose transport via GLUT4 downregulation in ovarian granular cells. Therefore, the use of inhibitors or knockout of AhR could effectively rescue BPA-induced metabolic disorders in PCOS mice. Conclusions Our results revealed that BPA suppressed GLUT4 expression and induced abnormal glucose metabolism by activating AhR, causing insulin resistance, and is thus a potential contributor to the development of PCOS. Therefore, AhR could be a potential new therapeutic target for PCOS. Dp7QWqxpppdxU99YCnw6gz Video Abstract

Objective Chronic Kidney Disease (CKD) frequently leads to Mineral Bone Disorder (MBD), which significantly affects patient quality of life due to bone fragility and metabolic disturbances. This study investigates the role of Casein Kinase 2 (CK2) and Ubiquitin-Specific Protease 7 (USP7) in modulating Runt-related Transcription Factor 2 (RUNX2)-driven osteogenesis in a CKD-MBD mouse model. Methods A CKD-MBD mouse model was established using 5/6 nephrectomy. Bioinformatic analysis of CKD-related datasets identified RUNX2 and USP7 as key genes implicated in bone metabolism. In vivo and in vitro experiments were conducted to assess the effects of CK2-mediated phosphorylation and USP7-induced deubiquitination on RUNX2 stability and function. Histomorphometry, Enzyme-Linked Immunosorbent Assay (ELISA), and micro-CT analyses were performed to evaluate bone density, strength, and metabolic markers. Results RUNX2 and USP7 were significantly downregulated in CKD-MBD mice. Silencing RUNX2 impaired osteoblast differentiation, reduced bone density, and increased bone turnover, while CK2 overexpression restored RUNX2 activity by phosphorylation, recruiting USP7 to stabilize RUNX2. Enhanced osteoblast differentiation and improved bone metabolism were observed in CKD-MBD mice upon CK2 activation. Conclusion CK2 activation promotes RUNX2 phosphorylation and stabilization by USP7, leading to improved osteogenesis and bone metabolism in CKD-MBD. Targeting the CK2/USP7/RUNX2 axis presents a potential therapeutic strategy for managing CKD-related bone disorders.

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.

Targeting angiogenesis has been considered a promising treatment for a large number of malignancies, including osteosarcoma. Bevacizumab (Bev) is an anti-vascular endothelial growth factor being used for this purpose. We herein investigate the therapeutic potential of Bev in angiogenesis during osteosarcoma and the related mechanisms. Bioinformatics were performed for identification of osteosarcoma-related microarray dataset to collect related lncRNA and miRNA, with MIAT and miR-613 obtained. The predicted binding site between miR-613 and GPR158 3′UTR region was further confirmed by luciferase assay. Then, their effects combined with treatment with Bev on osteosarcoma cells were explored by the gain- and loss-of-function. After extraction from osteosarcoma patients’ serum (serum-EVs) and identification, EVs were co-cultured with osteosarcoma cells, the biological behaviors of which were detected by CCK-8 assay and microtubule formation in vitro. A mouse tumor xenograft model was used to determine the effect of Bev on tumor angiogenesis in vivo. Bev inhibited osteosarcoma cell proliferation and angiogenesis in vivo and in vitro. Besides, serum-EVs could transfer MIAT (EV-MIAT) into osteosarcoma cells, where it is competitively bound to miR-613 to elevate GPR158, thus promoting osteosarcoma cell proliferation and angiogenesis. Furthermore, Bev arrested osteosarcoma cell proliferation and angiogenesis by inhibiting EV-MIAT and inducing miR-613-mediated GPR158 inhibition. In conclusion, the Bev-mediated MIAT/miR-613/GPR158 regulatory feedback revealed a new molecular mechanism in the pathogenesis of osteosarcoma angiogenesis.

Objectives To evaluate the oncologic and functional results of scapular reconstruction after partial or total scapulectomy for chondrosarcoma. Materials and methods Twenty-one patients with chondrosarcoma who underwent partial or total scapulectomy between January 2005 and July 2019 were reviewed retrospectively. Results At a mean follow-up of 62.6 months (range, 13–123 months), four patients developed local recurrence, and three developed distant metastases, one of which developed both recurrence and metastasis. The overall survival rate of patients at 5 years was 84.6%, the disease-free survival rate was 69.3%, and the complication rate was 19% (4/21). The 1993 American Musculoskeletal Tumor Society (MSTS93) scores of patients in the partial scapulectomy group, total scapulectomy + humeral suspension group and prosthetic reconstruction group were 26.50 ± 1.38, 19.00 ± 2.58, and 21.38 ± 2.62, respectively. There was a statistically significant difference between the partial scapulectomy group and the total scapulectomy + humeral suspension or prosthetic reconstruction group ( P  = 0.006 and 0.0336, respectively). The range of motion of the shoulder joint for forward flexion was 80.83° ± 11.14°, 51.25° ± 21.36°, and 52.50° ± 11.02°, respectively. The p-values for the comparison between the partial scapulectomy group and the total scapulectomy + humeral suspension or prosthetic reconstruction group were 0.0493 and 0.0174, respectively. And the range of motion of abduction was 75.00° ± 10.49°, 32.50° ± 11.90°, 41.88° ± 11.63°, respectively. Patients in the partial scapulectomy group had significantly better postoperative shoulder abduction function than the total scapulectomy + humeral suspension or prosthetic reconstruction group ( P  = 0.0035 and 0.0304, respectively). There was no significant difference in MSTS93 scores and flexion and abduction function of the shoulder joint in the upper extremity after total scapulectomy with humeral suspension or prosthetic reconstruction ( P  > 0.05). Conclusions Surgical treatment of chondrosarcoma of the scapula can achieve a satisfactory prognosis and shoulder function. Total scapulectomy followed by prosthetic reconstruction or humeral suspension are both feasible treatments. Highlights Surgical treatment of chondrosarcoma of the scapula can achieve good oncologic and functional outcomes. Prosthetic reconstruction of the scapula after scapulectomy does not provide better functional results than humeral suspension, and both are feasible treatment modalities.

Purpose The paper holds the research purpose of confirming the long-term results of trans-scaphoid perilunate fracture dislocations (TSPFD) under the treatment of open reduction and internal fixation. Methods Anteroposterial-lateral radiographs of the patient's wrist were taken before and after surgery. We use a dorsal approach for all cases. Postoperative clinical and radiographic assessments were performed routinely. The scapholunate angle (SLA), estradiol angle (RLA), as well as lunotriquetral distance (LTD) assisted in the radiographic assessment. Clinical assessment was performed using the Krimmer score, modified Mayo wrist score (MWS), active flexion extension arc (FEA), radial deviation and ulnar deviation arc (RUDA) and grip strength. A visual analog scale (VAS) assisted in the pain evaluation, the VAS score ranges from 0 to 10. Results Twenty-two TSPFD patients due to the wrist trauma received operative treatment and we retrospectively analyzed the surgical results, together with evaluating their clinical and radiological follow-up. These patients held a mean age of 30 years old. Herzberg’s perilunate fracture-dislocation classification was taken into account to find that 19 males and 3 females suffered dorsal dislocation. The fellow-up time lasted 98.3 months on average. All cases obtained sufficient union after open reduction and internal fixation. The last follow-up found the median of grip strength was 20.00 (interquartile range, 20.00–21.25), which was 84.5% of the normal side. The modified Mayo wrist score evaluation scale considered 12 cases as excellent, and 10 good. The median of VAS and Krimmer scores at the final follow-up were 1.50 (interquartile range, 0.75–2.00) and 100.00 (interquartile range, 100.00–100.00), respectively, higher relative to the pre-operation ( P  < 0.001). No patients showed nerve damage preoperatively or postoperatively, or pin tract infection in any of the patient. Conclusions It is necessary to diagnose such complicated biomechanical damage in early stage and adopt the open reduction and stable fixation for treatment; appropriate treatment can contribute to a functionally adequate and anatomically integrated wrist.

Objective. It has been reported that bone marrow mesenchymal stem cells (BMSCs) are a potential source of autologous stem cells to support the nucleus pulposus (NP) regeneration in intervertebral disc degeneration (IDD). Herein, we aim to study the mechanism underlying the effects of BMSC-derived extracellular vesicles (BMSC-EVs) on nucleus pulposus cells (NPCs) in IDD. Methods. EVs were isolated from BMSCs. An IDD model was surgically established in C57BL/6J mice. NPCs were exposed to tBHP to establish an IDD cell model. RNA sequencing was performed to identify differentially expressed circRNAs in NP tissues harvested from mice with IDD. Interactions among circ_0050205, miR-665, and GPX4 were validated, and different interventions were used to study the roles of these molecules in NPC biological functions. Results. BMSC-EVs promoted NPC survival and inhibited NPC apoptosis and extracellular matrix (ECM) degradation. circ_0050205 expression was downregulated in the NP tissues of IDD mice, and BMSC-EVs facilitated NPC survival and suppressed ECM degradation in NPCs by transferring circ_0050205. circ_0050205 sponged miR-665 and upregulated GPX4 expression. BMSC-EVs expressing circ_0050205 promoted NPC survival-inhibited ECM degradation in NPCs and alleviated IDD in mice via the miR-665/GPX4 axis. Conclusion. In conclusion, BMSC-EVs promoted NPC survival-inhibited ECM degradation in NPCs and attenuated IDD progression via the circ_0050205/miR-665/GPX4 axis.

Methods Single-cell transcriptomics and high-throughput transcriptomics were used to screen factors significantly correlated with intervertebral disc degeneration (IDD). Expression changes of CFIm25 were determined via RT-qPCR and Western blot. NP cells were isolated from mouse intervertebral discs and induced to degrade with TNF-α and IL-1β. CFIm25 was knocked out using CRISPR-Cas9, and CFIm25 knockout and overexpressing nucleus pulposus (NP) cell lines were generated through lentiviral transfection. Proteoglycan expression, protein expression, inflammatory factor expression, cell viability, proliferation, migration, gene expression, and protein expression were analyzed using various assays (alcian blue staining, immunofluorescence, ELISA, CCK-8, EDU labeling, transwell migration, scratch assay, RT-qPCR, Western blot). The GelMA-HAMA hydrogel loaded with APET×2 polypeptide and sgRNA was designed, and its effects on NP regeneration were assessed through in vitro and mouse model experiments. The progression of IDD in mice was evaluated using X-ray, H&E staining, and Safranin O-Fast Green staining. Immunohistochemistry was performed to determine protein expression in NP tissue. Proteomic analysis combined with in vitro and in vivo experiments was conducted to elucidate the mechanisms of hydrogel action. Results CFIm25 was upregulated in IDD NP tissue and significantly correlated with disease progression. Inhibition of CFIm25 improved NP cell degeneration, enhanced cell proliferation, and migration. The hydrogel effectively knocked down CFIm25 expression, improved NP cell degeneration, promoted cell proliferation and migration, and mitigated IDD progression in a mouse model. The hydrogel inhibited inflammatory factor expression (IL-6, iNOS, IL-1β, TNF-α) by targeting the p38/NF-κB signaling pathway, increased collagen COLII and proteoglycan Aggrecan expression, and suppressed NP degeneration-related factors (COX-2, MMP-3). Conclusion The study highlighted the crucial role of CFIm25 in IDD and introduced a promising therapeutic strategy using a porous spherical GelMA-HAMA hydrogel loaded with APET×2 polypeptide and sgRNA. This innovative approach offers new possibilities for treating degenerated intervertebral discs. Graphical Abstract Molecular mechanism of GCA targeting CFIm25 in NP cells to promote regeneration of degenerated intervertebral disc NP

Osteosarcoma is a malignant bone tumor, with a high incidence worldwide. The involvement of long non-coding RNAs (lncRNAs) in cancers and their molecular association with the progression of osteosarcoma have been previously discussed. We conducted the present study to examine the effect of lncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) on osteosarcoma cell invasion and chemosensitivity to cisplatin (CDDP). After determination of the expression of Kcnq1 in osteosarcoma tissues and cells, the plasmids with overexpression or knockdown KCNQ1OT1 were introduced into the cells to aid the identification of cell proliferation, migration, invasion, chemosensitivity to CDDP, and apoptosis. Then, the interaction between KCNQ1OT1 and the Kcnq1/DNA methyltransferase 1 (DNMT1) axis was evaluated by measuring the level of Kcnq1 promoter region methylation and DNMT1 enrichment of the Kcnq1 promoter region. Low Kcnq1 expression and high KCNQ1OT1 expression were shown in osteosarcoma tissues and cells. Kcnq1 was negatively mediated by KCNQ1OT1 via DNMT1. The overexpression of Kcnq1 or knockdown of KCNQ1OT1 inhibited the proliferation, migration, and invasion, and it promoted the chemosensitivity to CDDP and apoptosis of MG-63 cells and its CDDP-resistant cell lines. Moreover, the same trend was observed in the cells following methylation inhibitor treatment. Collectively, knockdown of KCNQ1OT1 can inhibit the osteosarcoma progression through the Kcnq1/DNMT1 axis.

Determination of the postmortem interval (PMI) is crucial for investigating homicide. However, there are currently only limited methods available. Especially, once the PMI exceeds the duration of pre-adult development of the flies with the adult emergence, its determination is very approximate. Herein, we report the regular changes in hydrocarbon composition during the weathering process of the puparia in the field in Chrysomya megacephala (Fabricius) (Diptera: Calliphoridae), one of the common species of necrophagous flies. Correlation analysis showed that the relative abundance of nearly all of the branched alkanes and alkenes decreased significantly with the weathering time. Especially, for 9 of the peaks, over 88% of the variance in their abundance was explained by weathering time. Further analysis indicated that the regular changes caused mainly by the different weathering rates of various hydrocarbons. Additionally, the weathering rates were found to depend on the chemical structure and molecular weight of the hydrocarbons. These results indicate strongly that hydrocarbon analysis is a powerful tool for determining the weathering time of the necrophagous fly puparia, and is expected to markedly improve the determination of the late PMI.