pH-Responsive Mesoporous Silica Nanoparticles Loaded with Naringin for Targeted Osteoclast Inhibition and Bone Regeneration.

Background: It is well-established that osteoclast activity is significantly influenced by fluctuations in intracellular pH. Consequently, a pH-sensitive gated nano-drug delivery system represents a promising therapeutic approach to mitigate osteoclast overactivity. Our prior research indicated that naringin, a natural flavonoid, effectively mitigates osteoclast activity. However, naringin showed low oral availability and short half-life, which hinders its clinical application. We developed a drug delivery system wherein chitosan, as gatekeepers, coats mesoporous silica nanoparticles loaded with naringin (CS@MSNs-Naringin). However, the inhibitory effects of CS@MSNs-Naringin on osteoclasts and the underlying mechanisms remain unclear, warranting further research. Methods: First, we synthesized CS@MSNs-Naringin and conducted a comprehensive characterization. We also measured drug release rates in a pH gradient solution and verified its biosafety. Subsequently, we investigated the impact of CS@MSNs-Naringin on osteoclasts induced by bone marrow-derived macrophages, focusing on differentiation and bone resorption activity while exploring potential mechanisms. Finally, we established a rat model of bilateral critical-sized calvarial bone defects, in which CS@MSNs-Naringin was dispersed in GelMA hydrogel to achieve in situ drug delivery. We observed the ability of CS@MSNs-Naringin to promote bone regeneration and inhibit osteoclast activity in vivo. Results: CS@MSNs-Naringin exhibited high uniformity and dispersity, low cytotoxicity (concentration≤120 µg/mL), and significant pH sensitivity. In vitro, compared to Naringin and MSNs-Naringin, CS@MSNs-Naringin more effectively inhibited the formation and bone resorption activity of osteoclasts. This effect was accompanied by decreased phosphorylation of key factors in the NF-κB and MAPK signaling pathways, increased apoptosis levels, and a subsequent reduction in the production of osteoclast-specific genes and proteins. In vivo, CS@MSNs-Naringin outperformed Naringin and MSNs-Naringin, promoting new bone formation while inhibiting osteoclast activity to a greater extent. Conclusion: Our research suggested that CS@MSNs-Naringin exhibited the strikingly ability to anti-osteoclasts in vitro and in vivo, moreover promoted bone regeneration in the calvarial bone defect.

Magnesium status modulating the effect of serum vitamin D levels on retinopathy: National Health and Nutrition Examination Survey 2005 to 2008.

Aim: Magnesium levels may influence the effect of vitamin D levels on the body. This study aimed to assess the combined effect of magnesium status as reflected by magnesium depletion score (MDS) and vitamin D status on the risk of retinopathy. Methods: This cross-sectional study included participants aged 40 years and older with complete information on vitamin D, MDS, and retinopathy assessment from the 2005-2008 National Health and Nutrition Examination Survey (NHANES). Logistic regression analysis was utilized to analyze the relationship of MDS and vitamin D with retinopathy and expressed as odds ratio (OR) and 95% confidence interval (CI). Results: Of these 4,953 participants included, 602 (9.53%) participants had retinopathy. Serum vitamin D levels ≤30 nmol/L (vs. >30 nmol/L) (OR = 1.38, 95%CI: 1.05-1.81) and MDS >2 points (vs. ≤2 points) (OR = 1.47, 95%CI: 1.01-2.16) were associated with higher odds of retinopathy. There was an interaction between MDS and vitamin D on the increased odds of retinopathy (OR = 2.29, 95%CI: 1.12-4.68, P interaction = 0.025). In different MDS groups, serum vitamin D levels ≤30 nmol/L increased the odds of retinopathy only in the MDS >2 group (OR = 2.90, 95%CI: 1.16-7.24), but not in the MDS ≤2 group (p = 0.293). Subgroups analyses demonstrated that the interaction between MDS and serum vitamin D on retinopathy was observed in males (OR = 6.88, 95%CI: 1.41-33.66, P interaction = 0.019), people with diabetes (OR = 3.43, 95%CI: 1.78-6.63, P interaction < 0.001), and people with body mass index (BMI) ≥25 kg/m2 (OR = 2.46, 95%CI: 1.11-5.44, P interaction = 0.028). Conclusion: Magnesium plays a moderating role in the relationship between serum vitamin D and retinopathy. The protective effect of vitamin D against retinopathy was primarily present among those with inadequate magnesium levels.

ZIF-8-Encapsulated Pexidartinib Delivery via Targeted Peptide-Modified M1 Macrophages Attenuates MDSC-Mediated Immunosuppression in Osteosarcoma.

Adoptive cellular therapy is a promising strategy for cancer treatment. However, the effectiveness of this therapy is limited by its intricate and immunosuppressive tumor microenvironment. In this study, a targeted therapeutic strategy for macrophage loading of drugs is presented to enhance anti-tumor efficacy of macrophages. K7M2-target peptide (KTP) is used to modify macrophages to enhance their affinity for tumors. Pexidartinib-loaded ZIF-8 nanoparticles (P@ZIF-8) are loaded into macrophages to synergistically alleviate the immunosuppressive tumor microenvironment synergistically. Thus, the M1 macrophages decorated with KTP carried P@ZIF-8 and are named P@ZIF/M1-KTP. The tumor volumes in the P@ZIF/M1-KTP group are significantly smaller than those in the other groups, indicating that P@ZIF/M1-KTP exhibited enhanced anti-tumor efficacy. Mechanistically, an increased ratio of CD4+ T cells and a decreased ratio of MDSCs in the tumor tissues after treatment with P@ZIF/M1-KTP indicated that it can alleviate the immunosuppressive tumor microenvironment. RNA-seq further confirms the enhanced immune cell function. Consequently, P@ZIF/M1-KTP has great potential as a novel adoptive cellular therapeutic strategy for tumors.

Intestinal Flora Imbalance Induced by Antibiotic Use in Rats.

Aim: This study aims to explore the effect of different doses of antibiotics on rats in order to observe alterations in their fecal microbiota, inflammatory changes in the colonic mucosa and four types of inflammatory markers in blood serum. Methods: Our methodology involved separating 84 female Sprague Dawley rats into groups A-G, with each group consisting of 12 rats. We collected the rat feces for analysis, using a distinct medium for bacterial cultivation and counting colonies under a microscope. On the 11th and 15th days of the experiment, half of the rats from each group were euthanized and 5 mL of abdominal aortic blood and colon tissues were collected. Inflammations changes of colon were observed and assessed by pathological Hematoxylin Eosin (HE) staining. Enzyme-linked immune sorbent assay (ELISA) was adopted for detecting C-reactive protein (CRP), IL-6, IL1-ß and TNF-α. Results: Our findings revealed that the initial average weight of the rats did not differ between groups (p>0.05); but significant differences were observed between stool samples, water intake, food intake and weight (p=0.009, <0.001, 0.016 and 0.04, respectively) within two hours after the experiment. Additionally, there were notable differences among the groups in nine tested microbiota before and after weighting methods (all p<0.001). There were no difference in nine microbiota at day 1 (all p>0.05); at day 4 A/B (p=0.044), A/D (p<0.001), A/E (p=0.029); at day 8, all p<0.01, at day 11, only A/F exist significant difference (p<0.001); at day 14 only A/D has difference (p=0.045). Inflammation changes of colon were observed between groups A-G at days 11 and 15. Significant differences between all groups can be observed for CRP, IL-6, IL1-ß and TNF-α (p<0.001). Conclusion: This study suggests that antibiotics administration can disrupt the balance of bacteria in the rat gut ecosystem, resulting in an inflammatory response in their bloodstream and inducing inflammation changes of colon.

Investigating the synergy of Shikonin and Valproic acid in inducing apoptosis of osteosarcoma cells via ROS-mediated EGR1 expression.

BACKGROUND: Osteosarcoma is the most prevalent malignant bone tumour with a poor prognosis. Shikonin (SHK) is derived from the traditional Chinese medicine Lithospermum that has been extensively studied for its notable anti-tumour effects, including for osteosarcoma. However, its application has certain limitations. Valproic acid (VPA) is a histone deacetylase inhibitor (HDACI) that has recently been employed as an adjunctive therapeutic agent that allows chromatin to assume a more relaxed state, thereby enhancing anti-tumour efficacy. PURPOSE: This study was aimed to investigate the synergistic anti-tumour efficacy of SHK in combination with VPA and elucidate its underlying mechanism. METHODS/STUDY DESIGN: CCK-8 assays were utilized to calculate the combination index. Additional assays, including colony formation, acridine orange/ethidium bromide double fluorescent staining, and flow cytometry, were employed to evaluate the effects on osteosarcoma cells. Wound healing and transwell assays were utilized to assess cell mobility. RNA sequencing, PCR, and Western blot analyses were conducted to uncover the underlying mechanism. Rescue experiments were performed to validate the mechanism of apoptotic induction. The impact of SHK and VPA combination treatment on primary osteosarcoma cells was also assessed. Finally, in vivo experiments were conducted to validate its anti-tumour effects and mechanism. RESULTS: The combination of SHK and VPA synergistically inhibited the proliferation and migration of osteosarcoma cells in vitro and induced apoptosis in these cells. Through a comprehensive analysis involving RNA sequencing, PCR, Western blot, and rescue experiments, we have substantiated our hypothesis that the combination of SHK and VPA induced apoptosis via the ROS-EGR1-Bax axis. Importantly, our in vivo experiments corroborated these findings, demonstrating the potential of the SHK and VPA combination as a promising therapeutic approach for osteosarcoma. CONCLUSION: The combination of SHK and VPA exerted an anti-tumour effect by inducing apoptosis through the ROS-EGR1-Bax pathway. Repurposing the old drug VPA demonstrated its effectiveness as an adjunctive therapeutic agent for SHK, enhancing its anti-tumour efficacy and revealing its potential value. Furthermore, our study expanded the application of natural compounds in the anti-tumour field and overcame some of their limitations through combination therapy. Finally, we enhanced the understanding of the mechanistic pathways linking reactive oxygen species (ROS) accumulation and apoptosis in osteosarcoma cells. Additionally, we elucidated the role of EGR1 in osteosarcoma cells, offering novel strategies and concepts for the treatment of osteosarcoma.

Biomimetic Intrafibrillar Mineralization of Native Tendon for Soft-Hard Interface Integration by Infiltration of Amorphous Calcium Phosphate Precursors.

Soft and hard tissues possess distinct biological properties. Integrating the soft-hard interface is difficult due to the inherent non-osteogenesis of soft tissue, especially of anterior cruciate ligament and rotator cuff reconstruction. This property makes it difficult for tendons to be mineralized and integrated with bone in vivo. To overcome this challenge, a biomimetic mineralization strategy is employed to engineer mineralized tendons. The strategy involved infiltrating amorphous calcium phosphate precursors into collagen fibrils, resulting in hydroxyapatite deposition along the c-axis. The mineralized tendon presented characteristics similar to bone tissue and induced osteogenic differentiation of mesenchymal stem cells. Additionally, the interface between the newly formed bone and tendon is serrated, suggesting a superb integration between the two tissues. This strategy allows for biomineralization of tendon collagen and replicating the hallmarks of the bone matrix and extracellular niche, including nanostructure and inherent osteoinductive properties, ultimately facilitating the integration of soft and hard tissues.

Umbilical cord mesenchymal stem cells relieve osteoarthritis in rats through immunoregulation and inhibition of chondrocyte apoptosis.

This study aims to investigate the effectiveness of umbilical cord mesenchymal stem cells (UCMSCs) in treating osteoarthritis (OA). Sprague-Dawley rats were used in in vivo experiments and divided into four groups: normal, OA model, saline, and UCMSC-treated groups (n = 6). An OA model was established by injecting iodoacetic acid into the joint cavity. The results indicate that UCMSC transplantation significantly reduced joint surface and articular cartilage damage, and the levels of IL-1ß, TNF-α, and MMP13 in the joint fluid were significantly reduced after UCMSC treatment. In vitro experiments showed that co-culturing UCMSCs and chondrocytes promoted the expression of aggrecan, COL2, SOX9, and BCL-2; downregulated the expression of BAX and BAD in chondrocytes; and promoted the expression of IL-10 and TGF-ß1 in UCMSCs. Additionally, the supernatant of UCMSCs inhibited the expression of IL-1ß and TNF-α in the articular cavity and promoted the expression of COL2 and aggrecan in vivo. These effects were impaired when IL-10 and TGF-ß1 were removed. Collectively, UCMSC transplantation appears to improve joint pathology, reduce inflammatory factors, and decrease chondrocyte apoptosis, likely through the involvement of IL-10 and TGF-ß1, thus providing a potential therapeutic option for patients with OA.

Strategy insight: Mechanical properties of biomaterials' influence on hydrogel-mesenchymal stromal cell combination for osteoarthritis therapy.

Osteoarthritis (OA) is a kind of degenerative joint disease usually found in older adults and those who have received meniscal surgery, bringing great suffering to a number of patients worldwide. One of the major pathological features of OA is retrograde changes in the articular cartilage. Mesenchymal stromal cells (MSCs) can differentiate into chondrocytes and promote cartilage regeneration, thus having great potential for the treatment of osteoarthritis. However, improving the therapeutic effect of MSCs in the joint cavity is still an open problem. Hydrogel made of different biomaterials has been recognized as an ideal carrier for MSCs in recent years. This review focuses on the influence of the mechanical properties of hydrogels on the efficacy of MSCs in OA treatment and compares artificial materials with articular cartilage, hoping to provide a reference for further development of modified hydrogels to improve the therapeutic effect of MSCs.

Newly compiled Tai Chi (Bafa Wubu) promotes lower extremity exercise: a preliminary cross sectional study.

Background: Tai Chi (Bafa Wubu) is a new type of simplified Tai Chi widely practiced by Tai Chi enthusiasts that has developed and perfected simplified Tai Chi movement and enriched Tai Chi practice methods. When practicing, Tai Chi athletes and enthusiasts can choose the Bafa Wubu movements to practice according to their physical conditions. The purpose of this article is to discuss the mechanism by which Bafa Wubu promotes lower extremity exercise from the perspective of exercise biomechanics. Objectives: This article aims to explore the scientific training methods and technical characteristics of Bafa Wubu, and its contribution to comprehensive exercise of the lower extremities, by analyzing the biomechanical characteristics of the lower extremities of participants who practice Bafa Wubu at different levels and by comparing their ground reaction force, lower limb joints, and muscles during Bafa Wubu. Methods: A total of 16 male participants were recruited and divided into an amateur group (N = 8) and a professional group (N = 8). The data were collected by a BTS 3D infrared-based motion capture system, and Kistler 3D force plate. The lower extremity joint forces and muscle strength were calculated by anybody simulation software with inverse dynamics. Results: During elbowing and leaning sideways with steps sideways (ELS), the ground reaction force of the professional group was significantly higher than that of the amateur group in the sagittal, vertical, and frontal axes (P < 0.01). While stepping forward, backward, and sideways, the professional group's joints loading at the hip, knee, and ankle was always higher in the vertical direction (P < 0.01). Furthermore, during warding off with steps forward (WOF), laying with steps forward (LF), and rolling back with steps backward (RBB), hip joint loading increased in the med-lat direction. During actions with steps backward and sideways, the professional group's ankle flexion/extension torque and hip abduction/rotation torque were significantly larger than those of the amateur group (P < 0.01). Different actions in Bafa Wubu activate muscles to different degrees, whereas the iliacus is mainly responsible for stabilizing postures when practitioners perform standing knee lifting motions. Conclusions: Professional groups who have been practicing Tai Chi (Bafa Wubu) for a long time have higher ground reaction force, and the force on the three joints of the lower extremities is different for various movements, which has positive significance for exercising the joints of the lower extremities. In addition, various motions activate muscles of different types at different levels. For amateurs to practice different movements to stimulate the muscles, targeted areas of practice promote the lower extremity muscles' synergistic force. In summary, the muscles and joints of the lower extremity can obtain comprehensive and balanced exercise through Bafa Wubu.

Silencing eL31 suppresses the progression of colorectal cancer via targeting DEPDC1.

BACKGROUND: Colorectal cancer (CRC) is one of the most commonly diagnosed human malignancies. Ribosomal protein L31 (RPL31, aka eL31) is a component of the 60S large ribosomal subunit, and its expression pattern and functional role in CRC have not been reported. METHODS: Herein, we identified that eL31 protein level was dramatically increased in CRC tissues through using IHC analysis. More notably, elevated eL31 was associated with larger tumor size and shorter overall survival. Besides, we evaluated the effects of eL31 depletion on CRC cell phenotypes in vitro. RESULTS: The data indicated that eL31 knockdown restricted CRC cell proliferation, migration and colony formation whilst enhancing cell apoptosis. Importantly, eL31 was also essential for CRC tumor growth in vivo, as demonstrated by impaired tumor growth markers and reduced Ki67 levels in xenografts from eL31-depleted cells. In addition, our evidence indicated that DEP domain containing 1 (DEPDC1) was a potential downstream target of eL31 in regulating CRC. Consistently, DEPDC1 depletion restrained CRC cell proliferation and migration, as well as facilitated cell apoptosis. More interestingly, DEPDC1 depletion could reverse the promotion effects of eL31 elevation on CRC cells. CONCLUSIONS: Identification of eL31's function in CRC may pave the way for future development of more specific and more effective targeted therapy strategies against CRC.

[Modified Chevron osteotomy in the treatment of moderate and severe hallux valgus].

OBJECTIVE: To investigate the method and clinical effect of modified Chevron osteotomy of the distal end of the first metatarsal in the treatment of moderate and severe hallux valgus. METHODS: From January 2015 to January 2019, 28 patients(30 feet) with moderate and severe hallux valgus were treated with modified Chevron osteotomy combined with lateral soft tissue release of the first metatarsophalangeal joint, including 2 males (2 feet) and 26 females (28 feet). The age ranged from 35 to 74 (57.3±9.3) years;10 feet on the left, 16 feet on the right, 2 cases on both sides(4 feet);the course of disease was 3 to 12 (9.32±3.89) years. The changes of hallux valgus angle(HVA), intermetatarsal angle(IMA) between the first and second metatarsals and distal metatarsal articular angle(DMAA) of the first metatarsal were measured and compared before and 6 months after operation. The American Orthopaedic Foot and Ankle Society(AOFAS) thumb joint scoring system was used to evaluate the curative effect. RESULTS: All 28 patients were followed up for 8 to 16 (11.28±3.42) months. The incision healed well in all patients, and there were no complications such as incision infection and metatarsal head necrosis. The healing time of osteotomy site was 6 to 10(7.12±1.34) weeks. Preoperative HVA, IMA, DMAA and AOFAS were (36.06±6.02) °, (21.78±4.16) °, (8.21±2.65) ° and (52.90±10.97) respectively, at six months after operation, they were (8.87±2.46) °, (11.66±2.84) °, (3.65±1.00) ° and (87.45±10.55) respectively, there was significant difference between preoperative and 6 months after operation(P<0.05). At 6 months after operation, AOFAS score was excellent in 20 feet, good in 7 feet and poor in 3 feet. Among the 3 patients with poor scores, 2 were excellent after revision, and 1 was significantly improved after using custom insoles. CONCLUSION: Modified Chevron can effectively correct HVA, IMA and DMAA and improve functional recovery. The modified Chevron osteotomy increases the moving distance and the contact of the osteotomy surface. It can be fixed with multiple screws, has strong correction ability, and can exercise early. It is one of the optional methods for the treatment of moderate and severe hallux valgus.

Establishment and evaluation of a specific antibiotic-induced inflammatory bowel disease model in rats.

Physical and chemical methods for generating rat models of enteritis have been established; however, antibiotic induction has rarely been used for this purpose. The present study aimed to establish and evaluate a rat model of inflammatory bowel disease (IBD) using antibiotics. A total of 84 Sprague-Dawley (SD) rats were divided into the following groups, according to the dosage and method of administration of the antibiotics: A, control; B, low-dose clindamycin; C, medium-dose clindamycin; D, high-dose clindamycin; E, low-dose clindamycin, ampicillin and streptomycin; F, medium-dose clindamycin, ampicillin and streptomycin; and G, high-dose clindamycin, ampicillin and streptomycin. Antibiotic administration was stopped on day 7; the modeling period covered days 1-7, and the recovery period covered days 8-15. Half of the animals were dissected on day 11, with the remaining animals dissected on day 15. Food and water intake, body weight and fecal weight were recorded. Intestinal flora was analyzed via microbial culture and quantitative PCR. The content of TNF-α, IL1-ß, IL-6 and C-reactive protein (CRP) was assessed in abdominal aorta blood. Colonic and rectal tissues were examined pathologically via hematoxylin-eosin staining to assess leukocyte infiltration and intestinal mucosal changes as indicators of inflammation. Rat weight, food intake, water intake and 2-h fecal weight were significantly different across the experimental groups (P = 0.040, P = 0.016, P<0.001 and P = 0.009, respectively). Microbial cultures revealed no significant differences between group A and B,C (P = 0.546,0.872) but significant differences betwenn group A and the other experimental groups (all P<0.001). Furthermore, significant differences in the levels of Bacteroides, Faecalibacterium prausnitzii and Dialister invisus on day 4 between groups A, C and F (P = 0.033, P = 0.025 and P = 0.034, respectively). Significant differences were detected in the levels of TNF-α, IL1-ß, IL-6 and CRP between the groups (all P<0.001). The colonic and rectal pathological inflammation scores of the experimental groups were significantly different compared with group A (B vs. A, P = 0.002; others, all P<0.001). These findings indicated that an antibiotic-induced IBD model was successfully established in SD rats; this animal model may serve as a useful model for clinical IBD research.

Hydroxyapatite-Coated Titanium by Micro-Arc Oxidation and Steam-Hydrothermal Treatment Promotes Osseointegration.

Titanium (Ti)-based alloys are widely used in tissue regeneration with advantages of improved biocompatibility, high mechanical strength, corrosion resistance, and cell attachment. To obtain bioactive bone-implant interfaces with enhanced osteogenic capacity, various methods have been developed to modify the surface physicochemical properties of bio-inert Ti and Ti alloys. Nano-structured hydroxyapatite (HA) formed by micro-arc oxidation (MAO) is a synthetic material, which could facilitate osteoconductivity, osteoinductivity, and angiogenesis on the Ti surface. In this paper, we applied MAO and steam-hydrothermal treatment (SHT) to produce HA-coated Ti, hereafter called Ti-M-H. The surface morphology of Ti-M-H1 was observed by scanning electron microscopy (SEM), and the element composition and the roughness of Ti-M-H1 were analyzed by energy-dispersive X-ray analysis, an X-ray diffractometer (XRD), and Bruker stylus profiler, demonstrating the deposition of nano-HA particles on Ti surfaces that were composed of Ca, P, Ti, and O. Then, the role of Ti-M-H in osteogenesis and angiogenesis in vitro was evaluated. The data illustrated that Ti-M-H1 showed a good compatibility with osteoblasts (OBs), which promoted adhesion, spreading, and proliferation. Additionally, the secretion of ALP, Col-1, and extracellular matrix mineralization was increased by OBs treated with Ti-M-H1. Ti-M-H1 could stimulate endothelial cells to secrete vascular endothelial growth factor and promote the formation of capillary-like networks. Next, it was revealed that Ti-M-H1 also suppressed inflammation by activating macrophages, while releasing multiple active factors to mediate osteogenesis and angiogenesis. Finally, in vivo results uncovered that Ti-M-H1 facilitated a higher bone-to-implant interface and was more attractive for the dendrites, which promoted osseointegration. In summary, MAO and SHT-treated Ti-M-H1 not only promotes in vitro osteogenesis and angiogenesis but also induces M2 macrophages to regulate the immune environment, which enhances the crosstalk between osteogenesis and angiogenesis and ultimately accelerates the process of osseointegration in vivo.

Molecular mechanisms of mechanical load-induced osteoarthritis.

INTRODUCTION: Mechanical loading enhances the progression of osteoarthritis. However, its molecular mechanisms have not been established. OBJECTIVE: The aim of this review was to summarize the probable mechanisms of mechanical load-induced osteoarthritis. METHODS: A comprehensive search strategy was used to search PubMed and EMBASE databases (from the 15th of January 2015 to the 20th of October 2020). Search terms included "osteoarthritis", "mechanical load", and "mechanism". RESULTS: Abnormal mechanical loading activates the interleukin-1ß, tumour necrosis factor-α, nuclear factor kappa-B, Wnt, transforming growth factor-ß, microRNAs pathways, and the oxidative stress pathway. These pathways induce the pathological progression of osteoarthritis. Mechanical stress signal receptors such as integrin, ion channel receptors, hydrogen peroxide-inducible clone-5, Gremlin-1, and transient receptor potential channel 4 are present in the articular cartilages. CONCLUSION: This review highlights the molecular mechanisms of mechanical loading in inducing chondrocyte apoptosis and extracellular matrix degradation. These mechanisms provide potential targets for osteoarthritis prevention and treatment.

Mtu1 defects are correlated with reduced osteogenic differentiation.

Accumulating evidence has revealed that mitochondria dynamics and function regulation is essential for the successful mesenchymal stem cell (MSC) differentiation. In the present study, the researchers reported for the first time that Mtu1 defects are correlated with reduced osteogenic differentiation. Using in vitro cultured bone marrow MSCs and stromal cell line MS5, we demonstrated that depressed Mtu1 expression was associated with reduced 2-thiouridine modification of the U34 of mitochondrial tRNAGln, tRNAGlu, and tRNALys, which led to respiratory deficiencies and reduced mitochondrial ATP production, and finally suppressed osteogenic differentiation. As expected, these Mtu1-deficient mice exhibited obvious osteopenia. Therefore, our findings in this study provide new insights into the pathophysiology of osteopenia.

The effects of low-color-temperature dual-primary-color light-emitting diodes on three kinds of retinal cells.

Long-term illumination of the retina with blue-light-excited phosphor-converted light-emitting diodes (LEDs) may result in decreased retinal function, even if the levels of blue light emitted are low. New low-color-temperature dual-primary-color LEDs have been developed that are composed of only two LED chips: a red chip and a yellow chip. These LEDs are expected to become a new type of healthy lighting source because they do not emit blue light, they lack phosphor, and they solve the problem of low efficiency encountered with phosphor-converted low-color-temperature LEDs. Many studies have indicated that these new low-color-temperature LEDs are likely to have therapeutic effects. However, the biological safety of these LEDs needs to be explored before the therapeutic effects are explored. Therefore, this experiment was conducted to investigate the effects of the new low-color-temperature LEDs and fluorescent white LEDs on three types of retinal cells. We observed that the viability and numbers of retinal cells decreased gradually with increasing LED color temperature. The new low-color-temperature LEDs caused less death and adverse effects on proliferation than the fluorescent white LEDs. After irradiation with high-color-temperature LEDs, the expression of Zonula Occludens-1 (ZO-1) was decreased and discontinuous in ARPE-19 cells; the stress protein hemeoxygenase-1 (HO-1) was upregulated in R28 cells; and glial fibrillary acidic protein (GFAP) and vimentin were upregulated in rMC-1 cells. We therefore conclude that the new white LEDs cause almost no damage to retinal cells and reduce the potential human health risks of chronic exposure to fluorescent white LEDs.

Development and Verification of a Hypoxic Gene Signature for Predicting Prognosis, Immune Microenvironment, and Chemosensitivity for Osteosarcoma.

Objective: Hypoxic tumors contribute to local failure and distant metastases. Nevertheless, the molecular hallmarks of hypoxia remain ill-defined in osteosarcoma. Here, we developed a hypoxic gene signature in osteosarcoma prognoses. Methods: With the random survival forest algorithm, a prognostic hypoxia-related gene signature was constructed for osteosarcoma in the TARGET cohort. Overall survival (OS) analysis, receiver operating characteristic (ROC) curve, multivariate cox regression analysis, and subgroup analysis were utilized for assessing the predictive efficacy of this signature. Also, external validation was presented in the GSE21257 cohort. GSEA was applied for signaling pathways involved in the high- and low-risk samples. Correlation analyses between risk score and immune cells, stromal/immune score, immune checkpoints, and sensitivity of chemotherapy drugs were performed in osteosarcoma. Then, a nomogram was built by integrating risk score, age, and gender. Results: A five-hypoxic gene signature was developed for predicting survival outcomes of osteosarcoma patients. ROC curves confirmed that this signature possessed the well predictive performance on osteosarcoma prognosis. Furthermore, it could be independently predictive of prognosis. Metabolism of xenobiotics by cytochrome P450 and nitrogen metabolism were activated in the high-risk samples while cell adhesion molecules cams and intestinal immune network for IgA production were enriched in the low-risk samples. The low-risk samples were characterized by elevated immune cell infiltrations, stromal/immune scores, TNFRSF4 expression, and sensitivity to cisplatin. The nomogram accurately predicted 1-, 3-, and 5-years survival duration. Conclusion: These findings might offer an insight into the optimization of prognosis risk stratification and individualized therapy for osteosarcoma patients.

Composite Coating of Graphene Oxide/TiO2 Nanotubes/HHC-36 Antibacterial Peptide Construction and an Exploration of Its Bacteriostat and Osteogenesis Effects.

Graphene oxide (GO), a kind of polymer, is often selected as a controlled released agent, whereas titanium dioxide (TiO2) nanotubes are commonly used as a drug-coated carrier. This study was conducted to develop methods for manufacturing the GO/TiO2/HHC-36 composite coating and exploring its bacteriostat and osteogenesis properties. The GO/TiO2 nanotubes were prepared by electrochemical methods and HHC-36 was then adsorbed to GO/TiO2to obtain GO/TiO2/HHC-36. Sustained release of HHC-36 was analyzed and the antibacterial effect was examined by the inhibition zone test. The biocompatibility and osteogenesis in vitro of GO/TiO2/HHC-36 were explored. Finally, the osteogenesic property of the composite coating was investigated in a rat femoral defect model in vivo. GO/TiO2/HHC-36 was successfully prepared and had good controlled released performance in vitro. The inhibit zone size of S. aureus was 2.1 mm and that of E. coli was 3.0 mm. GO/TiO2/HHC-36 showed good biocompatibility with mesenchymal stem cells (MSCs) and promoted their adhesion, migration, and differentiation. In addition, the secretion of alkaline phosphatase, collagen, mineralized matrix and osteoblast-related nutrient factors of MSCs was increased after treatment with GO/TiO2/HHC-36. Furthermore, GO/TiO2/HHC-36 also stimulated endotheliocytes to secrete VEGF, leading to angiogenesis. Finally, implantation of GO/TiO2/HHC-36 in the rat femur defect model resulted in MSC migration and increased expression of osteoblast related proteins. The composite coating with controlled released of HHC-36 showed distinct antibacterial properties and promoted osteogenesis in vitro and in vivo.