Paucatalinone A from Paulownia Catalpifolia Gong Tong Elicits mitochondrial-mediated cancer cell death to combat osteosarcoma.

As the global cancer burden escalates, the search for alternative therapies becomes increasingly vital. Natural products, particularly plant-derived compounds, have emerged as promising alternatives to conventional cancer treatments due to their diverse bioactivities and favorable biosafety profiles. Here, we investigate Paucatalinone A, a newly discovered geranylated flavanone derived from the fruit of Paulownia Catalpifolia Gong Tong, notable for its significant anti-cancer properties. We revealed the capability of Paucatalinone A to induce apoptosis in osteosarcoma cells and deciphered its underlying mechanisms. Our findings demonstrate that Paucatalinone A substantially augments apoptosis, inhibits cell proliferation, and demonstrates a pronounced anti-tumor effect in a murine model of osteosarcoma. Mechanistically, Paucatalinone A disrupts calcium homeostasis and exacerbates intracellular reactive oxygen species accumulation, leading to mitochondrial impairment, cytoskeletal collapse, and caspase-dependent apoptotic cell death. This study underscores the potential of Paucatalinone A in initiating apoptosis in cancer cells and highlights the therapeutic efficacy of plant-derived agents in treating osteosarcoma, offering a viable approach for managing other intractable cancers.

A novel injectable hydrogel prepared from phenylboronic acid modified gelatin and oxidized-dextran for bone tissue engineering.

Complicated fractures have always been challenging in orthopaedics. Designing a multifunctional biomaterial that can contribute to the treatment of fractures using a simple operation remains challenging. Here, we developed a trinity hydrogel system consisting of hydrogel prepared from phenylboronic acid modified gelatin and oxidized-dextran, lithium and cobalt co-doped mesoporous bioactive glass nanoparticles (MBGNs), and irisin. This hydrogel material exhibits considerable injectability, fat-to-shape, and self-healing characteristics. In addition, compared to hydrogel prepared from gelatin and oxidized-dextran, the hydrogel material presented a noticeable enhancement in compression stress and adhesion strength towards porcine bone fragments, which enables it more effectively splice bone fragments during surgery. Based on the various interactions between irisin and the hydrogel network, the system exhibited a clear sustained release of irisin. Based on the results of in vitro cell tests, the hydrogel material showed good cytocompatibility. And it also considerably enhanced the in vitro pro-osteogenic and pro-angiogenic capacities of bone marrow mesenchymal stromal cells (BMSCs) and human umbilical vein endothelial cells (HUVECs). In vivo experimental results indicated that this hydrogel considerably improved the repair of cranial defects in rats. The current study provides a feasible strategy for the treatment of bone fractures and stimulation of fracture healing.

Association of Depressive Symptom Trajectory With Physical Activity Collected by mHealth Devices in the Electronic Framingham Heart Study: Cohort Study.

BACKGROUND: Few studies have examined the association between depressive symptom trajectories and physical activity collected by mobile health (mHealth) devices. OBJECTIVE: We aimed to investigate if antecedent depressive symptom trajectories predict subsequent physical activity among participants in the electronic Framingham Heart Study (eFHS). METHODS: We performed group-based multi-trajectory modeling to construct depressive symptom trajectory groups using both depressive symptoms (Center for Epidemiological Studies-Depression [CES-D] scores) and antidepressant medication use in eFHS participants who attended 3 Framingham Heart Study research exams over 14 years. At the third exam, eFHS participants were instructed to use a smartphone app for submitting physical activity index (PAI) surveys. In addition, they were provided with a study smartwatch to track their daily step counts. We performed linear mixed models to examine the association between depressive symptom trajectories and physical activity including app-based PAI and smartwatch-collected step counts over a 1-year follow-up adjusting for age, sex, wear hour, BMI, smoking status, and other health variables. RESULTS: We identified 3 depressive symptom trajectory groups from 722 eFHS participants (mean age 53, SD 8.5 years; n=432, 60% women). The low symptom group (n=570; mean follow-up 287, SD 109 days) consisted of participants with consistently low CES-D scores, and a small proportion reported antidepressant use. The moderate symptom group (n=71; mean follow-up 280, SD 118 days) included participants with intermediate CES-D scores, who showed the highest and increasing likelihood of reporting antidepressant use across 3 exams. The high symptom group (n=81; mean follow-up 252, SD 116 days) comprised participants with the highest CES-D scores, and the proportion of antidepressant use fell between the other 2 groups. Compared to the low symptom group, the high symptom group had decreased PAI (mean difference -1.09, 95% CI -2.16 to -0.01) and the moderate symptom group walked fewer daily steps (823 fewer, 95% CI -1421 to -226) during the 1-year follow-up. CONCLUSIONS: Antecedent depressive symptoms or antidepressant medication use was associated with lower subsequent physical activity collected by mHealth devices in eFHS. Future investigation of interventions to improve mood including via mHealth technologies to help promote people's daily physical activity is needed.

Effect of different bone cement distributions in percutaneous kyphoplasty on clinical outcomes for osteoporotic vertebral compression fractures: A retrospective study.

Osteoporotic fractures and their complications are becoming increasingly harmful to the elderly. This study aimed to evaluate the clinical results of connected or unconnected bilateral cement after bilateral percutaneous kyphoplasty (PKP) in patients with osteoporotic vertebral compression fractures (OVCF). The clinical data of 217 patients with single-segment OVCF were retrospectively collected. Patients were allocated into 2 groups according to the bilateral bone cement in the vertebrae was connected or unconnected after surgery. The surgery-related indexes of the 2 groups were compared, including operation time; bone cement injection volume; contact situation between bone cement and the upper and lower endplates of the vertebral body; visual analogue scale (VAS) scores before surgery, 1 week and 1 year after surgery; Oswestry disability index (ODI) before surgery, 1 week and 1 year after surgery; local kyphosis angle (LKA) before surgery, 1 week and 1 year after surgery; postoperative vertebral body height at 1 week and 1 year after surgery; vertebral body height restoration rate (HRR) at 1 week and 1 year after surgery. The follow-up results of all patients were recorded. The postoperative VAS, ODI, vertebral body height, LKA and other indexes of the 2 groups were significantly improved compared with those before the operation (P < .05), and there was no significant difference between the 2 groups (P > .05). At the same time, there were no significant difference in vertebral body HRR and bone cement leakage rate between the 2 groups (P > .05). X-ray examination showed that 21 of 217 patients (21/217, 9.8%) had a refracture of the injured vertebral body, including 16 cases (16/121, 13.2%) in the unconnected group and 5 cases (5/96, 5.2%) in the connected group (P < .05). Adjacent vertebrae fractures occurred in 25 cases (25/217, 11.5%), while 19 cases (19/121, 15.7%) were in the unconnected group and 6 cases (6/96, 6.3%) were in the connected group (P < .05). PKP has a good therapeutic effect on OVCF no matter whether the bilateral bone cement is connected or not. However, if the bilateral cement inside the vertebra was connected, the risk of recollapse of the injured vertebrae and the new fracture of adjacent vertebrae could be reduced.

Addition of Tibial Tubercle Osteotomy to Combined MPFL Reconstruction and Lateral Retinacular Release not Recommended for Recurrent Patellar Dislocation in Patients with 15 to 20 mm TT-TG.

Surgery is the primary treatment for recurrent patellar dislocation. However, there is still a lack of consensus regarding the choice of combined surgical methods due to the complexity of the anatomical factors. This study aimed to investigate the efficacy and radiological changes in medial patellofemoral ligament reconstruction (MPFLR) and lateral retinacular release (LRR) with and without tibial tubercle osteotomy (TTO) for recurrent patellar dislocation in patients with a tibial tubercle-trochlear groove (TT-TG) distance of 15 to 20 mm. Fifty-four patients were enrolled in this retrospective study between 2010 and 2014. The average patient age was 21.6 ± 5.0 years. All patients underwent MPFLR and LRR, and in 18 patients, these procedures were combined with TTO. Patients were evaluated preoperatively and postoperatively for patellar lateral shift, patellar tilt angle, TT-TG distance, Q-angle, Caton-Deschamps index (CDI), Kujala, and Lysholm scores. The minimally clinical important difference was used to compare clinical outcomes between two groups. In the mean follow-up of 82.6 ± 15.9 months, functional scores improved significantly in both groups (p < 0.01). There were no significant differences in postoperative function scores between the two groups (Kujala, p = 0.25, mean difference = 1.5, 95% confidence interval [CI]: -1.4-4.4; Lysholm, p = 0.76, mean difference = -0.6, 95% CI: -5.9-4.7). Additionally, TTO significantly decreased Q-angle (23.6 ± 2.4 vs. 17.4 ± 2.9, p < 0.01), TT-TG (17.1 ± 1.5 vs. 10.4 ± 1.8, p < 0.01), and CDI (1.18 ± 0.12 vs. 1.08 ± 0.07, p < 0.01). Combined MPFLR and LRR with and without TTO are both effective techniques for recurrent patellar dislocation. Additional osteotomy can correct patellar alta and tibial tubercle lateralization. However, given that there were no significant differences in postoperative functional scores or recurrence rate between groups, we may not recommend TTO in addition to MPFLR and LRR in patients with TT-TG of 15 to 20 mm. Long-term and prospective cohort studies are required to assess further outcomes.

Diet Quality Scores Are Positively Associated with Whole Blood-Derived Mitochondrial DNA Copy Number in the Framingham Heart Study.

BACKGROUND: The association between diet quality and mitochondrial DNA copy number (mtDNA-CN) remains to be examined. OBJECTIVES: We aimed to study the relation between diet quality and mtDNA-CN. METHODS: We analyzed data from 2931 Framingham Heart Study (FHS) participants (mean age of 57 y, 55% females). Whole-genome sequencing was used to calculate mtDNA-CN from whole-blood samples. We examined the cross-sectional associations between 3 diet quality scores, the Dietary Approaches to Stop Hypertension (DASH) score, the Alternative Healthy Eating Index (AHEI), and the Mediterranean diet score (MDS), and mtDNA-CN. Linear mixed models were used to account for maternal lineage. RESULTS: We observed that a higher DASH score was positively associated with mtDNA-CN after adjusting for sex, age, energy intake, smoking status, alcohol intake, and physical activity level. A 1-SD increase in the DASH score was associated with a 0.042-SD greater mtDNA-CN (95% CI: 0.007, 0.077; P = 0.02). Similarly, for each SD increase in AHEI and MDS, the mtDNA-CN SD increased by 0.056 (95% CI: 0.019, 0.092; P = 0.003) and 0.047 (95% CI: 0.01, 0.083; P = 0.01), respectively. Diet quality scores were associated with neutrophil and lymphocyte counts but not platelet counts, e.g., for a 1-SD increase in the DASH, neutrophils decreased by 0.8% (95% CI: 0.5%, 1.1%; P = 4.1 × 10-6), lymphocytes increased by 0.7% (95% CI: 0.4%, 1%, P = 1.2 × 10-5), and there was no significant change in platelet number (0.1 × 1000/µL; 95% CI: -1.6, 1.9; P = 0.89). Further adjustment for neutrophil, lymphocyte, and platelet counts and the associations between diet quality scores and mtDNA-CN were completely attenuated to nonsignificant (P = 0.95, 0.54, and 0.91, respectively). CONCLUSIONS: We observed that higher diet quality is associated with a greater whole-blood derived mtDNA-CN in middle-aged to older adult FHS participants, and that blood cell composition, particularly neutrophil counts, attenuated the association between diet quality and mtDNA-CN.

TRIM3 Negatively Regulates Autophagy Through Promoting Degradation of Beclin1 in Ewing Sarcoma Cells.

BACKGROUND AND AIM: Ewing sarcoma (ES) is an aggressive neoplasm predominantly occurring in adolescents and has a poor prognosis when metastasized. In the current study, we were aiming to investigate the function of TRIM3 in autophagy in ES cells. METHODS: The expression of TRIM3 in Ewing sarcoma tissues and normal tissues was examined by quantitative PCR and western blot. The effect of TRIM3 on autophagy was detected by western blot and immunofluorescence assay. Target of TRIM3 was examined by western blot, immunoprecipitation and ubiquitination assay. RESULTS: We found the expression of TRIM3 was significantly up-regulated in Ewing sarcoma tissues compared with normal tissues, and this phenomenon was regulated by EWS-FLI1 expression. Furthermore, we observed that overexpression of TRIM3 markedly and consistently inhibited autophagy in ES cells, and autophagy was enhanced in TRIM3-silenced ES cells. Finally, we found in ES cells, TRIM3 could directly interact with Beclin1, and improved its K48-linked polyubiquitinaion, leading to the degradation of Beclin1 and then regulated autophagy. CONCLUSION: In the present research, for the first time we revealed that TRIM3 negatively regulates autophagy through promoting degradation of Beclin1 in Ewing sarcoma cells, and these findings may provide ideas for ES research.

Interleukin-37 (IL-37) Suppresses Pertussis Toxin-Induced Inflammatory Myopathy in a Rat Model.

BACKGROUND Recent data have demonstrated the potential immunosuppressive roles of interleukin-37 (IL-37) in several diseases, but whether it is involved in the pathogenesis of inflammatory myopathy has not been elucidated. MATERIAL AND METHODS An experimental autoimmune myositis (EAM) model was built by subcutaneous injections of pertussis toxin (PTX) and purified rabbit myosin (10mg/kg) emulsified with an equal volume of conventional complete Freund's adjuvant (CFA) in a Lewis model. Autoimmune myositis Lewis model rats were divided into 3 groups: group A rats (control group) were injected with CFA in saline weekly; group B (IL-37 group) rats were injected with saline with IL-37 and CFA in saline weekly; and group C (IL-37 + SIS3 group) rats were injected with IL-37, CFA, and SIS3. ELISA was also used to assess the expressions of TNF-α, IL-6, IL-1ß, TGF-ß1, and CK. HE staining was performed to assess pathological changes in lung and muscle tissues. RESULTS The expressions of TNF-α, IL-6, IL-1ß, TGF-ß1, and CK significantly increased in autoimmune myositis Lewis model rats. After IL-37 treatment, the expression of TNF-α, IL-6, IL-1ß, TGF-ß1, and CK was significantly reduced, as were the inflammatory responses of lung and muscle. However, SIS3 reduced the effects of IL-37 on the autoimmune myositis Lewis model rats. CONCLUSIONS These findings indicate that IL-37 protects against inflammatory response via regulating Smad3 in autoimmune myositis Lewis model rats.

EWS-FLI1 positively regulates autophagy by increasing ATG4B expression in Ewing sarcoma cells.

Ewing sarcoma (ES) is the most common malignant bone tumor in children and young adults. It is characterized by chromosomal translocations fusing the EWS gene with an ETS oncogene, most frequently FLI1. In the present study, the authors aimed to investigate the function of EWS-FLI1 in autophagy in ES cells, and identified that EWS-FLI1 positively regulates autophagy in ES cells. ATG4B expression was observed markedly upregulated by EWS-FLI1 overexpression, and silencing of ATG4B dramatically inhibits autophagy in ES cells. Furthermore, apoptosis was inhibited in ATG4B overexpressed ES cells, and ATG4B-potentiated autophagy is required for ES cells survival. Taken together, the authors demonstrated the role of EWS-FLI1 and ATG4B in autophagy in ES cells, and suggested EWS-FLI1 and ATG4B as potential therapeutic targets for ES.

Effects of Unilateral Tourniquet Used in Patients Undergoing Simultaneous Bilateral Total Knee Arthroplasty.

OBJECTIVE: To assess the benefits of use of a tourniquet in one limb in patients undergoing simultaneous bilateral total knee arthroplasty (TKA). METHODS: A prospective randomized trial was designed to evaluate the outcomes of unilateral tourniquet use during simultaneous bilateral TKA. A total of 52 (36 women and 16 men) patients with osteoarthritis who underwent simultaneous bilateral primary TKA between January 2010 and January 2015 were assigned randomly to tourniquet (TG) or non-tourniquet (NG) groups prior to surgery. Operating time, pain score, range of motion, first active straight-leg raise time, swelling, wound healing, deep vein thrombosis, and Knee Society score were observed. RESULTS: Mean operating time in the TG group was shorter than that in the NG group (P < 0.05). Postoperative pain was measured by a visual analog scale (VAS) and straight-leg raise time, which was lower and shorter in limbs operated without the use of a tourniquet (P < 0.05). In addition, this group had less postoperative swelling and lower incidence of wound complications in the early postoperative period (P < 0.05). There was no significant difference in the range of motion (ROM), deep venous thrombosis incidence, and Knee Society scores between the two groups. CONCLUSIONS: Tourniquet use in bilateral TKA can reduce intraoperative time but was associated with a higher incidence of wound complications and larger postoperative knee swelling.

NFATc1 phosphorylation by DYRK1A increases its protein stability.

NFATs are transcription factors involved in immune activation and tumor progression. Previous reports showed that DYRK1A suppressed NFATc2 transcriptional activity through phosphorylation. Nonetheless, our results showed that DYRK1A increased NFATc1/αA protein level and subsequent transcriptional activity. DYRK1A phosphorylation of NFATc1/αA at S261, S278, S403 and S409 interfered with NFATc1 ubiquitination and ubiquitin-proteasome degradation. Our results imply that DYRK1A is a positive kinase in regulation of NFATc1.

Core decompression or quadratus femoris muscle pedicle bone grafting for nontraumatic osteonecrosis of the femoral head: A randomized control study.

BACKGROUND: The traditional management for osteonecrosis of the femoral head (ONFH) includes core decompression (CD) and quadratus femoris muscle pedicle bone graft (QF-MPBG). The aim of this study was to investigate the effects of CD and QF-MPBG on the patients with nontraumatic ONFH in an early stage. MATERIALS AND METHODS: 39 patients (47 hips) with ONFH in an early stage (Ficat Stage I or II) were randomly divided into two groups according to random number table method. One group was treated with CD and cancellous bone grafting. Another group was treated QF-MPBG with cancellous bone grafting. The hip function was evaluated using Harris hip score (HHS). The repair of the femoral head was estimated through X-ray, computed tomography (CT), or magnetic resonance imaging (MRI). The surgical time and intraoperative blood loss was calculated. RESULTS: All patients were followed for an average 2.5 years (range from 1.5 to 4 years). Two hips in CD group progressed into stage 3 and three hips in QF-MPBG group processed into stage 3. No patient accepted the THA at the last followup. The HHSs significantly increased in both groups after surgery (P < 0.05). No statistical differences were found between CD and QF-MPBG groups in postoperative HHSs at last followup (P > 0.05). X-ray and CT showed that the femoral head did not progress to collapse after operation in both groups. In addition, MRI showed that the edema signals decreased. However, the surgical time was longer in QF-MPBG group than that in CD group (P < 0.05). The intraoperative blood loss was more in QF-MPBG than that in CD group (P < 0.05). CONCLUSION: The CD with bone graft could relieve hip pain, improve hip function with much lesser surgical trauma compared to QF-MPBG. Hence, the CD with bone graft should be generally used for the treatment of patients with an early stage (Ficat Stage I or II) ONFH.

Improved repair of bone defects with prevascularized tissue-engineered bones constructed in a perfusion bioreactor.

Vascularization of tissue-engineered bones is critical to achieving satisfactory repair of bone defects. The authors investigated the use of prevascularized tissue-engineered bone for repairing bone defects. The new bone was greater in the prevascularized group than in the non-vascularized group, indicating that prevascularized tissue-engineered bone improves the repair of bone defects. [Orthopedics. 2014; 37(10):685-690.].

Tissue-engineered bone constructed in a bioreactor for repairing critical-sized bone defects in sheep.

PURPOSE: Repair of bone defects, particularly critical-sized bone defects, is a considerable challenge in orthopaedics. Tissue-engineered bones provide an effective approach. However, previous studies mainly focused on the repair of bone defects in small animals. For better clinical application, repairing critical-sized bone defects in large animals must be studied. This study investigated the effect of a tissue-engineered bone for repairing critical-sized bone defect in sheep. METHODS: A tissue-engineered bone was constructed by culturing bone marrow mesenchymal-stem-cell-derived osteoblast cells seeded in a porous ß-tricalcium phosphate ceramic (ß-TCP) scaffold in a perfusion bioreactor. A critical-sized bone defect in sheep was repaired with the tissue-engineered bone. At the eighth and 16th week after the implantation of the tissue-engineered bone, X-ray examination and histological analysis were performed to evaluate the defect. The bone defect with only the ß-TCP scaffold served as the control. RESULT: X-ray showed that the bone defect was successfully repaired 16 weeks after implantation of the tissue-engineered bone; histological sections showed that a sufficient volume of new bones formed in ß-TCP 16 weeks after implantation. Eight and 16 weeks after implantation, the volume of new bones that formed in the tissue-engineered bone group was more than that in the ß-TCP scaffold group (P < 0.05). CONCLUSION: Tissue-engineered bone improved osteogenesis in vivo and enhanced the ability to repair critical-sized bone defects in large animals.

[Effect of tourniquet on perioperative blood loss and short-term effectiveness in total knee arthroplasty].

OBJECTIVE: To investigate the effect of applying a tourniquet on perioperative blood loss and shortterm effectiveness in primary total knee arthroplasty (TKA). METHODS: A total of 94 patients (94 knees) with osteoarthritis underwent primary TKA between September 2010 and December 2011, whose data met the inclusion criteria and were retrospectively analyzed. A tourniquet was used in 51 cases (group A), no tourniquet in 43 cases (group B). There was no significant difference in gender, age, affected side, body mass index, preoperative hemoglobin (Hb) level, range of motion (ROM), visual analogue scale (VAS), Hospital for Special Surgery (HSS) score, Western Ontario and McMaster University Osteoarthritis Index (WOMAC) between 2 groups (P > 0.05). The data were compared between 2 groups, including hematocrit (Hct), Hb, hidden blood loss, dominant blood loss, theoretical total blood loss, the operation time, hospitalization days, increasing rate of circumference length above 10 cm of the knee, VAS score, ROM, HSS score, and WOMAC score. RESULTS: Four cases (7.84%) of group A and 1 case (2.33%) of group B received blood transfusions, showing no significant difference (Chi(2)=1.410, P=0.235). There was no significant difference in the Hb and Hct between 2 groups at 2 days after operation (P > 0.05). The dominant blood loss of group A was significantly less than that of group B (P < 0.05), while the hidden blood loss of group A was significantly more than that of group B (P < 0.05), but there was no significant difference in theoretical total blood loss between 2 groups (t=0.662, P=0.510). The operation time, hospitalization days, and VAS score at 3 days showed no significant difference between 2 groups (P > 0.05). The wound healed by first intention after operation without related complication. At 3 days after operation, the increasing rate of circumference length above 10 cm of the knee in group A was significantly higher than that of group B (t=9.435, P=0.000), but no significant difference at 7 days (t=0.462, P=0.645). At 3 and 5 days after operation, the ROM values in group B were significantly larger than those of group A (P < 0.05), but no significant difference at 7 days (t= -1.279, P=0.204). The patients were all followed up 12-18 months (mean, 14.3 months). There was no significant difference in the HSS score between 2 groups at 1 year after operation (t=0.952, P=0.344), but significant difference was found in the WOMAC score between 2 groups (t= -2.488, P=0.015). The X-ray films showed that the prosthesis was in good position, without loosening, subsidence, or osteolysis. CONCLUSION: Application of a tourniquet in TKA increases hidden blood loss, and there is no obvious advantage in reducing transfusion rate compared with the non-tourniquet group, so it is recommended to reduce the time and pressure of the tourniquet for patients with high-risk of thrombosis.