Effects of Taxifolin on Osteoclastogenesis in vitro and in vivo

Osteoporosis is a highly prevalent disease which has been a major public health problem and considered to be associated with chronic low-grade systemic inflammation and oxidative damage. Taxifolin is a natural flavonoid and possesses many pharmacological activities including antioxidant and anti-inflammatory. Because flavonoids have been confirmed to fight osteoporosis and promote bone health, the aim of this study was to investigate the effects of taxifolin on the formation and function of osteoclast. In this study, we examined the effects of taxifolin on osteoclast using both in vitro and in vivo studies. Taxifolin suppressed the activation of nuclear factor-κB, C-Fos and mitogen-activated protein kinase, and also decreased osteoclast-specific genes expression, including Trap, Mmp-9, Cathepsin K, C-Fos, Nfatc1, and Rank. Taxifolin also prevented reactive oxygen species (ROS) production following RANKL stimulation. In addition, taxifolin alleviated ovariectomized-induced bone loss by repressing osteoclast activity and decreasing serum levels of tumor necrosis factor-α, interleukin-1β, interleukin-6 and receptor activator of nuclear factor-κB ligand (RANKL) in vivo. Our results indicated that taxifolin inhibits osteoclastogenesis via regulation of modulation of several RANKL signaling pathways. Therefore, taxifolin may be considered as a potential alternative therapeutic agent for treating osteoclast-related diseases

A lightweight network based on dual-stream feature fusion and dual-domain attention for white blood cells segmentation

IntroductionAccurate white blood cells segmentation from cytopathological images is crucial for evaluating leukemia. However, segmentation is difficult in clinical practice. Given the very large numbers of cytopathological images to be processed, diagnosis becomes cumbersome and time consuming, and diagnostic accuracy is also closely related to experts' experience, fatigue and mood and so on. Besides, fully automatic white blood cells segmentation is challenging for several reasons. There exists cell deformation, blurred cell boundaries, and cell color differences, cells overlapping or adhesion.MethodsThe proposed method improves the feature representation capability of the network while reducing parameters and computational redundancy by utilizing the feature reuse of Ghost module to reconstruct a lightweight backbone network. Additionally, a dual-stream feature fusion network (DFFN) based on the feature pyramid network is designed to enhance detailed information acquisition. Furthermore, a dual-domain attention module (DDAM) is developed to extract global features from both frequency and spatial domains simultaneously, resulting in better cell segmentation performance.ResultsExperimental results on ALL-IDB and BCCD datasets demonstrate that our method outperforms existing instance segmentation networks such as Mask R-CNN, PointRend, MS R-CNN, SOLOv2, and YOLACT with an average precision (AP) of 87.41%, while significantly reducing parameters and computational cost.DiscussionOur method is significantly better than the current state-of-the-art single-stage methods in terms of both the number of parameters and FLOPs, and our method has the best performance among all compared methods. However, the performance of our method is still lower than the two-stage instance segmentation algorithms. in future work, how to design a more lightweight network model while ensuring a good accuracy will become an important problem

Reactive oxygen species may be involved in the distinctive biological effects of different doses of 12C6+ ion beams on Arabidopsis

IntroductionHeavy ion beam is a novel approach for crop mutagenesis with the advantage of high energy transfer line density and low repair effect after injury, however, little investigation on the biological effect on plant was performed. 50 Gy irradiation significantly stimulated the growth of Arabidopsis seedlings, as indicated by an increase in root and biomass, while 200 Gy irradiation significantly inhibited the growth of seedlings, causing a visible decrease in plant growth.MethodsThe Arabidopsis seeds were irradiated by 12C6+. Monte Carlo simulations were used to calculate the damage to seeds and particle trajectories by ion implantation. The seed epidermis received SEM detection and changes in its organic composition were detected using FTIR. Evidence of ROS and antioxidant systems were analyzed. RNA-seq and qPCR were used to detect changes in seedling transcript levels.Results and discussionMonte Carlo simulations revealed that high-dose irradiation causes various damage. Evidence of ROS and antioxidant systems implies that the emergence of phenotypes in plant cells may be associated with oxidative stress. Transcriptomic analysis of the seedlings demonstrated that 170 DEGs were present in the 50 Gy and 200 Gy groups and GO enrichment indicated that they were mainly associated with stress resistance and cell wall homeostasis. Further GO enrichment of DEGs unique to 50 Gy and 200 Gy revealed 58 50Gy-exclusive DEGs were enriched in response to oxidative stress and jasmonic acid entries, while 435 200 Gy-exclusive DEGs were enriched in relation to oxidative stress, organic cyclic compounds, and salicylic acid. This investigation advances our insight into the biological effects of heavy ion irradiation and the underlying mechanisms

Kruppel-like factor 4 is a tumor suppressor in B-cell non-Hodgkin lymphoma and in classical Hodgkin lymphoma

B-cell lymphoma is the most common form of hematological malignancies in the western world. Significant progress has been made over the past two decades concerning our understanding of B-cell lymphomas pathogenesis; nevertheless, further efforts are needed to elucidate the transforming events and identify the therapeutic targets. The transcription factor Kruppel-like factor 4 (KLF4) may act both as an oncogene and a tumor suppressor in a context-dependent manner. We found that the KLF4 promoter is often methylated in B-cell lymphoma cell lines and in primary cases of B-cell lymphomas. Promoter CpG island hypermethylation has been established as one of the key mechanisms that silence tumor suppressor genes and promote tumorigenesis. In the present study, the hypermethylation of KLF4 promoter was found to be associated with absence of its expression. Conditional over-expression of KLF4 in two BL cell lines moderately retarded their growth, mainly due to cell cycle arrest in the G0/G1 phase. In the cHL cell lines KM-H2 and L428 KLF4 expression induced massive cell death. Using a quantitative RT-PCR (Q-PCR) gene expression array we identified KLF4 target genes including the proapoptotic gene BAK1, activation level of which was much higher than that of other regulators of apoptosis. We further investigated role of BAK1 in KLF4-induced apoptosis in cHL cells. Using a shRNA-mediated knock-down approach we found that pro-apoptotic protein BAK1 is largely responsible for KLF4-induced cell death. Moreover, we found that KLF4 down-regulates musculin (MSC) / activated B-cell factor-1 (ABF-1) in cHL cell lines. Of note, aberrant expression of ABF-1 is proposed to be responsible for the unique loss of B-cell phenotype of cHL. We conclude that epigenetic silencing of KLF4 in B-cell lymphomas and particularly in cHL may play important role in lymphomagenesis and favor lymphoma survival by loosening cell cycle control and protecting from apoptosis

Review of various treatment options and potential therapies for osteonecrosis of the femoral head

Size and location of the lesion, subchondral collapse occurrence, and articular cartilage involvement are general disease progression criteria for direct osteonecrosis of the femoral head (ONFH) classifications. Treatment options for ONFH are usually based on individual factors and lesion characteristics. Although spontaneous repair of ONFH occurs in some cases, untreated ONFH is unlikely to escape the fate of subchondral collapse and usually ends up with total hip arthroplasty. Operations to preserve the femoral head, e.g., core decompression and bone grafting, are usually recommended in younger patients. They are helpful to relieve pain and improve function in the affected femoral head without subchondral collapse, however, poor prognosis after surgical procedures remains the major problem for ONFH. Pharmacological and physical therapies only work in the early stage of ONFH and have also been recommended as a supplement or prevention treatment for osteonecrosis. Following advances in basic science, many new insights focus on bone tissue engineering to optimize therapies and facilitate prognosis of ONFH. In this review, disease classifications, current treatment options, potential therapies, and the relevant translational barriers are reviewed in the context of clinical application and preclinical exploration, which would provide guidance for preferable treatment options and translation into novel therapies

Dihydromyricetin Protects against Bone Loss in Ovariectomized Mice by Suppressing Osteoclast Activity

Dihydromyricetin (DMY), the main flavonoid component of Ampelopsis grossedentata, possesses pharmacological activities useful for treatment of diseases associated with inflammation and oxidative damage. Because osteoclasts are often involved in chronic low-grade systemic inflammation and oxidative damage, we hypothesized that DMY may be an effective treatment for osteoclast-related diseases. The effects of DMY on osteoclast formation and activity were examined in vitro. Female C57BL/6 mice were ovariectomized to mimic menopause-induced bone loss and treated with DMY, and femur samples were subjected to bone structure and histological analysis, serum biochemical indicators were also measured. DMY suppressed the activation of nuclear factor-κB, c-Fos and mitogen-activated protein kinase, and prevented production of reactive oxygen species. DMY decreased expression of osteoclast-specific genes, including Trap, Mmp-9, Cathepsin K, C-Fos, Nfatc1, and Rank. In addition, DMY prevented bone loss and decreased serum levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6, and with a decrease in the ratio between receptor activator of nuclear factor-κB (RANK) ligand (RANKL) and osteoprotegerin (OPG) in vivo. These findings demonstrate that DMY attenuates bone loss and inhibits osteoclast formation and activity through modulation of multiple pathways both upstream and downstream of RANKL signaling. DMY may thus be a useful option for treatment of osteoclast-related diseases such as rheumatoid arthritis and osteoporosis

Urolithin A Inhibits the Catabolic Effect of TNFα on Nucleus Pulposus Cell and Alleviates Intervertebral Disc Degeneration in vivo

Low back pain (LBP) is a common worldwide disease that causes an enormous social economic burden. Intervertebral disc degeneration (IDD) is considered as a major cause of LBP. The process of IDD is complicated and involves both inflammation and senescence. The production of pro-inflammatory cytokines, including tumor necrosis factor (TNF)α and interleukin (IL)-1β, is increased in the degenerating intervertebral disc, inducing extracellular matrix degradation. Urolithin A (UA) is a metabolite compound resulting from the degradation of ellagitannins by gut bacteria. UA has been reported to be useful for the treatment of diseases associated with inflammation, senescence, and oxidative damage. Therefore, we hypothesized that UA may be an effective treatment for IDD. This study examined the effects of UA on IDD in vitro and in vivo and explored their underlying mechanisms. Our findings indicated that UA could attenuate cellular senescence induced by hydrogen peroxide in nucleus pulposus cells. UA treatment decreased TNFα-induced matrix metalloproteinase production and the loss of collagen II. At the molecular level, UA considerably blocked the phosphorylation of the extracellular signal-regulated kinase, c-JUN N-terminal kinase, and Akt pathways. In vivo study illustrated that UA treatment could ameliorate IDD in a needle-punctured rat tail model, which was evaluated by X-ray imaging, magnetic resonance imaging, and histological analysis. Thus, the results of our study revealed that UA may be a useful therapeutic agent for the treatment of IDD

Insights into the Role of Circadian Rhythms in Bone Metabolism: A Promising Intervention Target?

Numerous physiological processes of mammals, including bone metabolism, are regulated by the circadian clock system, which consists of a central regulator, the suprachiasmatic nucleus (SCN), and the peripheral oscillators of the BMAL1/CLOCK-PERs/CRYs system. Various bone turnover markers and bone metabolism-regulating hormones such as melatonin and parathyroid hormone (PTH) display diurnal rhythmicity. According to previous research, disruption of the circadian clock due to shift work, sleep restriction, or clock gene knockout is associated with osteoporosis or other abnormal bone metabolism, showing the importance of the circadian clock system for maintaining homeostasis of bone metabolism. Moreover, common causes of osteoporosis, including postmenopausal status and aging, are associated with changes in the circadian clock. In our previous research, we found that agonism of the circadian regulators REV-ERBs inhibits osteoclast differentiation and ameliorates ovariectomy-induced bone loss in mice, suggesting that clock genes may be promising intervention targets for abnormal bone metabolism. Moreover, osteoporosis interventions at different time points can provide varying degrees of bone protection, showing the importance of accounting for circadian rhythms for optimal curative effects in clinical treatment of osteoporosis. In this review, we summarize current knowledge about circadian rhythms and bone metabolism

Large-Scale Heat-Tolerance Screening and Genetic Diversity of Pea (<i>Pisum sativum</i> L.) Germplasms

Pea (Pisum sativum L.) is an important legume crop. However, the yield of pea is adversely affected by heat stress in China. In this study, heat-tolerant germplasms were screened and evaluated in the field under multi-conditions. The results showed that heat stress could significantly affect pea yield. On the basis of grain weight per plant, 257 heat-tolerant and 175 heat-sensitive accessions were obtained from the first year’s screening, and 26 extremely heat-tolerant and 19 extremely heat-sensitive accessions were finally obtained in this study. Based on SNaPshot technology, two sets of SNP markers, including 46 neutral and 20 heat-tolerance-related markers, were used to evaluate the genetic diversity and population genetic structure of the 432 pea accessions obtained from the first year’s screening. Genetic diversity analysis showed that the average polymorphic information content was lower using heat-tolerance-related markers than neutral markers because of the selective pressure under heat stress. In addition, population genetic structure analysis showed that neutral markers divided the 432 pea accessions into two subpopulations associated with sowing date type and geographical origin, while the heat-tolerance-related markers divided these germplasms into two subpopulations associated with heat tolerance and sowing date type. Overall, we present a comprehensive resource of heat-tolerant and heat-sensitive pea accessions through heat-tolerance screenings in multi-conditions, which could help genetic improvements of pea in the future

Tantalum Nanoparticles Reinforced Polyetheretherketone Shows Enhanced Bone Formation

Polyetheretherketone (PEEK) has been used in orthopedic surgery for several decades. Numerous methods were invented to alter the properties of PEEK. By adding nanoparticles, fibers, etc., elastic modulus and strength of PEEK can be changed to meet certain demand. In this study, tantalum (Ta), a promising metal, was introduced to modify the properties of PEEK, in which PEEK was reinforced with different contents of tantalum nanoparticles (from 1 wt% to 9 wt%). Mechanical properties and biological functions (both in vitro and in vivo) were then investigated. The highest elastic modulus and compressive strength were observed in 3%Ta-PEEK. Cell experiments as cell adhesion, collagen secretion, biomineralization and osteogenesis related gene expression showed preferable results in 3%Ta-PEEK and 5%Ta-PEEK. Improved bone integration was shown in 3%Ta-PEEK and 5%Ta-PEEK in vivo. Above all, enhanced mechanical properties and promoted bone formation were proved for 3%Ta-PEEK and 5%Ta-PEEK compared to others groups both in vitro and in vivo, suggesting that the addition of tantalum nanoparticles modified the osseointegration ability of PEEK. This composite of tantalum and PEEK could have a clinical potential for orthopedic implants