Electromagnetic fields regulate iron metabolism in living organisms: A review of effects and mechanism.

The emergence, evolution, and spread of life on Earth have all occurred in the geomagnetic field, and its extensive biological effects on living organisms have been documented. The charged characteristics of metal ions in biological fluids determine that they are affected by electromagnetic field forces, thus affecting life activities. Iron metabolism, as one of the important metal metabolic pathways, keeps iron absorption and excretion in a relatively balanced state, and this process is precisely and completely controlled. It is worth paying attention to how the iron metabolism process of living organisms is changed when exposed to electromagnetic fields. In this paper, the processes of iron absorption, storage and excretion in animals (mammals, fish, arthropods), plants and microorganisms exposed to electromagnetic field were summarized in detail as far as possible, in order to discover the regulation of iron metabolism by electromagnetic field. Studies and data on the effects of electromagnetic field exposure on iron metabolism in organisms show that exposure profiles vary widely across species and cell lines. This process involves a variety of factors, and the complexity of the results is not only related to the magnetic flux density/operating frequency/exposure time and the heterogeneity of the observed object. A systematic review of the biological regulation of iron metabolism by electromagnetic field exposure will not only contributes to a more comprehensive understanding of its biological effects and mechanism, but also is necessary to improve human awareness of the health related risks of electromagnetic field exposure.

Moderate static magnetic field promotes fracture healing and regulates iron metabolism in mice.

BACKGROUND: Fractures are the most common orthopedic diseases. It is known that static magnetic fields (SMFs) can contribute to the maintenance of bone health. However, the effect and mechanism of SMFs on fracture is still unclear. This study is aim to investigate the effect of moderate static magnetic fields (MMFs) on bone structure and metabolism during fracture healing. METHODS: Eight-week-old male C57BL/6J mice were subjected to a unilateral open transverse tibial fracture, and following treatment under geomagnetic field (GMF) or MMF. The micro-computed tomography (Micro-CT) and three-point bending were employed to evaluate the microarchitecture and mechanical properties. Endochondral ossification and bone remodeling were evaluated by bone histomorphometric and serum biochemical assay. In addition, the atomic absorption spectroscopy and ELISA were utilized to examine the influence of MMF exposure on iron metabolism in mice. RESULTS: MMF exposure increased bone mineral density (BMD), bone volume per tissue volume (BV/TV), mechanical properties, and proportion of mineralized bone matrix of the callus during fracture healing. MMF exposure reduced the proportion of cartilage in the callus area during fracture healing. Meanwhile, MMF exposure increased the number of osteoblasts in callus on the 14th day, and reduced the number of osteoclasts on the 28th day of fracture healing. Furthermore, MMF exposure increased PINP and OCN levels, and reduced the TRAP-5b and ß-CTX levels in serum. It was also observed that MMF exposure reduced the iron content in the liver and callus, as well as serum ferritin levels while elevating the serum hepcidin concentration. CONCLUSIONS: MMF exposure could accelerate fracture healing via promote the endochondral ossification and bone formation while regulating systemic iron metabolism during fracture healing. This study suggests that MMF may have the potential to become a form of physical therapy for fractures.

A novel artificial vertebral implant with Gyroid porous structures for reducing the subsidence and mechanical failure rate after vertebral body replacement.

BACKGROUND: Prosthesis subsidence and mechanical failure were considered significant threats after vertebral body replacement during the long-term follow-up. Therefore, improving and optimizing the structure of vertebral substitutes for exceptional performance has become a pivotal challenge in spinal reconstruction. METHODS: The study aimed to develop a novel artificial vertebral implant (AVI) with triply periodic minimal surface Gyroid porous structures to enhance the safety and stability of prostheses. The biomechanical performance of AVIs under different loading conditions was analyzed using the finite element method. These implants were fabricated using selective laser melting technology and evaluated through static compression and subsidence experiments. RESULTS: The results demonstrated that the peak stress in the Gyroid porous AVI was consistently lower than that in the traditional porous AVI under all loading conditions, with a maximum reduction of 73.4%. Additionally, it effectively reduced peak stress at the bone-implant interface of the vertebrae. Static compression experiments demonstrated that the Gyroid porous AVI was about 1.63 times to traditional porous AVI in terms of the maximum compression load, indicating that Gyroid porous AVI could meet the safety requirement. Furthermore, static subsidence experiments revealed that the subsidence tendency of Gyroid porous AVI in polyurethane foam (simulated cancellous bone) was approximately 15.7% lower than that of traditional porous AVI. CONCLUSIONS: The Gyroid porous AVI exhibited higher compressive strength and lower subsidence tendency than the strut-based traditional porous AVI, indicating it may be a promising substitute for spinal reconstruction.

Study on fast algorithm of neutron radiation field under complex terrain scenario based on ensemble learning approach.

In this study a prediction algorithm has been proposed to rapidly figure out neutron radiation field for nuclear explosion under complex terrain scenario based on ensemble learning approach, which could be an impossibility for traditional radiation transport simulation methodology. By analyzing the influence of complex surface morphology on the radiation field, a series of characteristic parameters which could characterize the topographic features and their influence on the transport of neutrons and secondary gamma in the atmosphere have been extracted with the application of DEM, and the sample sethas been constructedwith the MC simulation results of terrain samples generated by random algorithm, to be used to train the prediction model for the neutron radiation field of nuclear explosion. In order to verify the actual prediction performance of the model, the study has implemented the prediction for the neutron flux, neutron tissue dose and secondary gamma tissue dose under the authentic urban and mountainous terrain scenarios, and analyzed and compared the results from fast prediction and MC simulation in different evaluation dimensions. The comparisons suggest that both of the results are in good agreement with each other, demonstrating that the fast prediction models preliminarily possess the engineering application value. In addition, a feasible approach to improve the generalization performance of the prediction model for various radiation scenarios has been proposed, which could be deemed as a reference for further research.

A Novel Method for Recognizing Space Radiation Sources Based on Multi-Scale Residual Prototype Learning Network.

As a basic task and key link of space situational awareness, space target recognition has become crucial in threat analysis, communication reconnaissance and electronic countermeasures. Using the fingerprint features carried by the electromagnetic signal to recognize is an effective method. Because traditional radiation source recognition technologies are difficult to obtain satisfactory expert features, automatic feature extraction methods based on deep learning have become popular. Although many deep learning schemes have been proposed, most of them are only used to solve the inter-class separable problem and ignore the intra-class compactness. In addition, the openness of the real space may invalidate the existing closed-set recognition methods. In order to solve the above problems, inspired by the application of prototype learning in image recognition, we propose a novel method for recognizing space radiation sources based on a multi-scale residual prototype learning network (MSRPLNet). The method can be used for both the closed- and open-set recognition of space radiation sources. Furthermore, we also design a joint decision algorithm for an open-set recognition task to identify unknown radiation sources. To verify the effectiveness and reliability of the proposed method, we built a set of satellite signal observation and receiving systems in a real external environment and collected eight Iridium signals. The experimental results show that the accuracy of our proposed method can reach 98.34% and 91.04% for the closed- and open-set recognition of eight Iridium targets, respectively. Compared to similar research works, our method has obvious advantages.

A static magnetic field improves bone quality and balances the function of bone cells with regulation on iron metabolism and redox status in type 1 diabetes.

Osteoporosis is one of the chronic complications of type 1 diabetes with high risk of fracture. The prevention of diabetic osteoporosis is of particular importance. Static magnetic fields (SMFs) exhibit advantages on improvement of diabetic complications. The biological effects and mechanism of SMFs on bone health of type 1 diabetic mice and functions of bone cells under high glucose have not been clearly clarified. In animal experiment, six-week-old male C57BL/6J mice were induced to type 1 diabetes and exposed to SMF of 0.4-0.7 T for 4 h/day lasting for 6 weeks. Bone mass, biomechanical strength, microarchitecture and metabolism were determined by DXA, three-point bending assay, micro-CT, histochemical and biochemical methods. Exposure to SMF increased BMD and BMC of femur, improved biomechanical strength with higher ultimate stress, stiffness and elastic modulus, and ameliorated the impaired bone microarchitecture in type 1 diabetic mice by decreasing Tb.Pf, Ct.Po and increasing Ct.Th. SMF enhanced bone turnover by increasing the level of markers for bone formation (OCN and Collagen I) as well as bone resorption (CTSK and NFAT2). In cellular experiment, MC3T3-E1 cells or primary osteoblasts and RAW264.7 cells were cultured in 25 mM high glucose-stimulated diabetic marrow microenvironment under differentiation induction and exposed to SMF. SMF promoted osteogenesis with higher ALP level and mineralization deposition in osteoblasts, and it also enhanced osteoclastogenesis with higher TRAP activity and bone resorption in osteoclasts under high glucose condition. Further, SMF increased iron content with higher FTH1 expression and regulated the redox level through activating HO-1/Nrf2 in tibial tissues, and lowered hepatic iron accumulation by BMP6-mediated regulation of hepcidin and lipid peroxidation in mice with type 1 diabetes. Thus, SMF may act as a potential therapy for improving bone health in type 1 diabetes with regulation on iron homeostasis metabolism and redox status.

Viromics Reveals the High Diversity of Viruses from Fishes of the Tibet Highland.

Aquaculture is important for food security and nutrition. The economy has recently been significantly threatened and the risk of zoonoses significantly increased by aquatic diseases, and the ongoing introduction of new aquatic pathogens, particularly viruses, continues to represent a hazard. Yet, our knowledge of the diversity and abundance of fish viruses is still limited. Here, we conducted a metagenomic survey of different species of healthy fishes caught in the Lhasa River, Tibet, China, and sampled intestinal contents, gills, and tissues. To be more precise, by identifying and analyzing viral genomes, we aim to determine the abundance, diversity, and evolutionary relationships of viruses in fish with other potential hosts. Our analysis identified 28 potentially novel viruses, 22 of which may be associated with vertebrates, across seven viral families. During our research, we found several new strains of viruses in fish, including papillomavirus, hepadnavirus, and hepevirus. Additionally, we discovered two viral families, Circoviridae and Parvoviridae, which were prevalent and closely related to viruses that infect mammals. These findings further expand our understanding of highland fish viruses and highlight the emerging view that fish harbor large, unknown viruses. IMPORTANCE The economy and zoonoses have recently been significantly threatened by aquatic diseases. Yet, our knowledge of the diversity and abundance of fish viruses is still limited. We identified the wide genetic diversity of viruses that these fish were harboring. Since there are currently few studies on the virome of fish living in the Tibet highland, our research adds to the body of knowledge. This discovery lays the groundwork for future studies on the virome of fish species and other highland animals, preserving the ecological equilibrium on the plateau.

Hypoxia Pathway in Osteoporosis: Laboratory Data for Clinical Prospects.

The hypoxia pathway not only regulates the organism to adapt to the special environment, such as short-term hypoxia in the plateau under normal physiological conditions, but also plays an important role in the occurrence and development of various diseases such as cancer, cardiovascular diseases, osteoporosis. Bone, as a special organ of the body, is in a relatively low oxygen environment, in which the expression of hypoxia-inducible factor (HIF)-related molecules maintains the necessary conditions for bone development. Osteoporosis disease with iron overload endangers individuals, families and society, and bone homeostasis disorder is linked to some extent with hypoxia pathway abnormality, so it is urgent to clarify the hypoxia pathway in osteoporosis to guide clinical medication efficiently. Based on this background, using the keywords "hypoxia/HIF, osteoporosis, osteoblasts, osteoclasts, osteocytes, iron/iron metabolism", a matching search was carried out through the Pubmed and Web Of Science databases, then the papers related to this review were screened, summarized and sorted. This review summarizes the relationship and regulation between the hypoxia pathway and osteoporosis (also including osteoblasts, osteoclasts, osteocytes) by arranging the references on the latest research progress, introduces briefly the application of hyperbaric oxygen therapy in osteoporosis symptoms (mechanical stimulation induces skeletal response to hypoxic signal activation), hypoxic-related drugs used in iron accumulation/osteoporosis model study, and also puts forward the prospects of future research.

LIGHT Amplification by NF-κB Contributes to TLR3 Signaling Pathway-Induced Acute Hepatitis.

LIGHT is a member of the TNF superfamily and a proinflammatory cytokine involved in liver pathogenesis. Many liver diseases involve activation of Toll-like receptor 3 (TLR3), which is activated by double-stranded RNA (dsRNA). However, the involvement of LIGHT in TLR3 implicated liver diseases is not clear. In this study, we investigated the role of LIGHT in TLR3 involved liver pathogenesis by using a mouse model of TLR3 agonist poly(I:C)-induced hepatitis. We found LIGHT expression at both protein and mRNA level in liver tissues is dramatically increased during the course of poly(I:C)-induced liver injury. This induction depends on NF-κB activation as pretreating the mice with a NF-κB inhibitor abrogates LIGHT upregulation. Importantly, blockade of the LIGHT signaling pathway with the recombinant LIGHT receptor HVEM protein ameliorates liver injury in poly(I:C)-induced hepatitis. Conclusions. These results indicate that LIGHT amplification by NF-κB plays a significant role in TLR3 involved hepatitis and points LIGHT to be a potential drug target for liver disease therapy.

Static magnetic field: A potential tool of controlling stem cells fates for stem cell therapy in osteoporosis.

Osteoporosis is a kind of bone diseases characterized by dynamic imbalance of bone formation and bone absorption, which is prone to fracture, and seriously endangers human health. At present, there is a lack of highly effective drugs for it, and the existing measures all have some side effects. In recent years, mesenchymal stem cell therapy has brought a certain hope for osteoporosis, while shortcomings such as homing difficulty and unstable therapeutic effects limit its application widely. Therefore, it is extremely urgent to find effective and reliable means/drugs for adjuvant stem cell therapy or develop new research techniques. It has been reported that static magnetic fields(SMFs) has a certain alleviating and therapeutic effect on varieties of bone diseases, also promotes the proliferation and osteogenic differentiation of mesenchymal stem cells derived from different tissues to a certain extent. Basing on the above background, this article focuses on the key words "static/constant magnetic field, mesenchymal stem cell, osteoporosis", combined literature and relevant contents were studied to look forward that SMFs has unique advantages in the treatment of osteoporosis with mesenchymal stem cells, which can be used as an application tool to promote the progress of stem cell therapy in clinical application.

1-2 ​T static magnetic field combined with Ferumoxytol prevent unloading-induced bone loss by regulating iron metabolism in osteoclastogenesis.

Objective: With the deepening of magnetic biomedical effects and electromagnetic technology, some medical instruments based on static magnetic field (SMF) have been used in orthopedic-related diseases treatment. Studies have shown SMF could combat osteoporosis by regulating the differentiation of mesenchymal stem cells (MSCs), osteoblast and osteoclast. With the development of nanotechnology, iron oxide nanoparticles (IONPs) have been reported to regulate the process of bone anabolism. As for SMF combined with IONPs, studies indicated osteogenic differentiation of MSCs were promoted by the combination of SMF and IONPs. However, there are few reports on the effects of SMF combined with IONPs on osteoclast. Herein, the purpose of this study was to investigate the effects of high static magnetic field (HiSMF) combined with IONPs on unloading-induced bone loss in vivo and osteoclastic formation in vitro, and elucidated the potential molecular mechanisms. Methods: In vivo, C57BL/6 â€‹J male mice were unloaded via tail suspension or housed normally. The hindlimb of mice were fixed and exposed to 1-2 â€‹T SMF for 1 â€‹h every day, 10 â€‹mg/kg of Ferumoxytol or saline were injected by tail vein once a week, last for 4 weeks. Bone microstructure, mechanical properties, and osteoclastogenesis were examined respectively. In vitro, the RAW264.7 â€‹cells were used to assess the effects of 1-2 â€‹T SMF combined with IONPs in osteoclastogenesis. The iron content was detected by atomic absorption spectrometry and Prussian blue staining. DCFH-DA and MitoSOX™ fluorescence staining were used to assess oxidative stress levels. NF-κB and MAPK signaling pathways were examined by western blot assay. Results: In vivo, the results showed 1-2 â€‹T SMF and IONPs prevented the damage to bone microstructure and improved the mechanical properties, diminished the number of osteoclasts in unloaded mice, 1-2 â€‹T SMF combined with IONPs was found more effective. The iron content in the liver and spleen was reduced by the combination of 1-2 â€‹T SMF and IONPs, enhancing iron levels in the femur. In vitro, osteoclast formation was inhibited by 1-2 â€‹T SMF and IONPs treatment, and 1-2 â€‹T SMF combined with IONPs had a more pronounced effect. Moreover, iron uptake of IONPs in osteoclast was reduced to 1-2 â€‹T SMF exposure. Oxidative stress levels were decreased in osteoclast differentiation under 1-2 â€‹T SMF combined with IONPs treatment. Molecularly, the expression of NF-κB and MAPK signaling pathways were inhibited under 1-2 â€‹T SMF combined with IONPs in osteoclastogenesis. Conclusions: Synthetically, our research illustrated 1-2 â€‹T SMF combined with IONPs prevented unloading-induced bone loss by regulating iron metabolism in osteoclastogenesis.Translational potential of this article: As a non-invasive alternative therapy, some medical instruments based on SMF have been used for orthopedic-related diseases treatment for their portability, cheapness and safety. Ferumoxytol (Feraheme™), the first FDA-approved IONP drug for the treatment of iron deficiency anemia, has been also adapted in translational research for osteoporosis. Based on the above-mentioned two points, we found the synergistic effects of SMF and Ferumoxytol for treatment of experimental osteoporosis. These results show translational potentials for clinical application.

Sustained systemic inflammation increases autophagy and induces EMT/fibrotic changes in mouse liver cells: Protection by melatonin.

The unending lifestyle stressors along with genetic predisposition, environmental factors and infections have pushed the immune system into a state of constant activity, leading to unresolved inflammation and increased vulnerability to chronic diseases. Liver fibrosis, an early-stage liver condition that increases the risk of developing liver diseases like cirrhosis and hepatocellular carcinoma, is among the various diseases linked to inflammation that dominate worldwide morbidity and mortality. We developed a mouse model with low-grade lipopolysaccharide (LPS) exposure that shows hepatic damage and a pro-inflammatory condition in the liver. We show that inflammation and oxidative changes increase autophagy in liver cells, a degradation process critical in maintaining cellular homeostasis. Our findings from in vivo and in vitro studies also show that induction of both inflammation and autophagy trigger epithelial-mesenchymal transition (EMT) and pro-fibrotic changes in hepatocytes. Inhibiting the inflammatory pathways with a naturally occurring NF-κB inhibitor and antioxidant, melatonin, could assuage the changes in autophagy and activation of EMT/fibrotic pathways in hepatocytes. Taken together, this study shows a pathway linking inflammation and autophagy which could be targeted for future drug development to delay the progression of liver fibrosis.

Increased LCN2 (lipocalin 2) in the RPE decreases autophagy and activates inflammasome-ferroptosis processes in a mouse model of dry AMD.

In dry age-related macular degeneration (AMD), LCN2 (lipocalin 2) is upregulated. Whereas LCN2 has been implicated in AMD pathogenesis, the mechanism remains unknown. Here, we report that in retinal pigmented epithelial (RPE) cells, LCN2 regulates macroautophagy/autophagy, in addition to maintaining iron homeostasis. LCN2 binds to ATG4B to form an LCN2-ATG4B-LC3-II complex, thereby regulating ATG4B activity and LC3-II lipidation. Thus, increased LCN2 reduced autophagy flux. Moreover, RPE cells from cryba1 KO, as well as sting1 KO and Sting1Gt mutant mice (models with abnormal iron chelation), showed decreased autophagy flux and increased LCN2, indicative of CGAS- and STING1-mediated inflammasome activation. Live cell imaging of RPE cells with elevated LCN2 also showed a correlation between inflammasome activation and increased fluorescence intensity of the Liperfluo dye, indicative of oxidative stress-induced ferroptosis. Interestingly, both in human AMD patients and in mouse models with a dry AMD-like phenotype (cryba1 cKO and KO), the LCN2 homodimer variant is increased significantly compared to the monomer. Sub-retinal injection of the LCN2 homodimer secreted by RPE cells into NOD-SCID mice leads to retinal degeneration. In addition, we generated an LCN2 monoclonal antibody that neutralizes both the monomer and homodimer variants and rescued autophagy and ferroptosis activities in cryba1 cKO mice. Furthermore, the antibody rescued retinal function in cryba1 cKO mice as assessed by electroretinography. Here, we identify a molecular pathway whereby increased LCN2 elicits pathophysiology in the RPE, cells known to drive dry AMD pathology, thus providing a possible therapeutic strategy for a disease with no current treatment options.Abbreviations: ACTB: actin, beta; Ad-GFP: adenovirus-green fluorescent protein; Ad-LCN2: adenovirus-lipocalin 2; Ad-LCN2-GFP: adenovirus-LCN2-green fluorescent protein; LCN2AKT2: AKT serine/threonine kinase 2; AMBRA1: autophagy and beclin 1 regulator 1; AMD: age-related macular degeneration; ARPE19: adult retinal pigment epithelial cell line-19; Asp278: aspartate 278; ATG4B: autophagy related 4B cysteine peptidase; ATG4C: autophagy related 4C cysteine peptidase; ATG7: autophagy related 7; ATG9B: autophagy related 9B; BLOC-1: biogenesis of lysosomal organelles complex 1; BLOC1S1: biogenesis of lysosomal organelles complex 1 subunit 1; C57BL/6J: C57 black 6J; CGAS: cyclic GMP-AMP synthase; ChQ: chloroquine; cKO: conditional knockout; Cys74: cysteine 74; Dab2: DAB adaptor protein 2; Def: deferoxamine; DHE: dihydroethidium; DMSO: dimethyl sulfoxide; ERG: electroretinography; FAC: ferric ammonium citrate; Fe2+: ferrous; FTH1: ferritin heavy chain 1; GPX: glutathione peroxidase; GST: glutathione S-transferase; H2O2: hydrogen peroxide; His280: histidine 280; IFNL/IFNλ: interferon lambda; IL1B/IL-1ß: interleukin 1 beta; IS: Inner segment; ITGB1/integrin ß1: integrin subunit beta 1; KO: knockout; LC3-GST: microtubule associated protein 1 light chain 3-GST; C-terminal fusion; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LCN2: lipocalin 2; mAb: monoclonal antibody; MDA: malondialdehyde; MMP9: matrix metallopeptidase 9; NLRP3: NLR family pyrin domain containing 3; NOD-SCID: nonobese diabetic-severe combined immunodeficiency; OS: outer segment; PBS: phosphate-buffered saline; PMEL/PMEL17: premelanosome protein; RFP: red fluorescent protein; rLCN2: recombinant LCN2; ROS: reactive oxygen species; RPE SM: retinal pigmented epithelium spent medium; RPE: retinal pigment epithelium; RSL3: RAS-selective lethal; scRNAseq: single-cell ribonucleic acid sequencing; SD-OCT: spectral domain optical coherence tomography; shRNA: small hairpin ribonucleic acid; SM: spent medium; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; STAT1: signal transducer and activator of transcription 1; STING1: stimulator of interferon response cGAMP interactor 1; TYR: tyrosinase; VCL: vinculin; WT: wild type.

BTA Deep Hole Vibration Drilling for Nickel-Based Alloys: Cooling Patterns and Cutter Tooth Wear Mechanisms.

The high cutting temperature and poor thermal diffusion efficiency of nickel-based alloys during deep hole machining have become technical challenges in the hole machining field. In this paper, a finite element simulation model of Inconel-718 BTA ordinary drilling and vibration drilling processes was established by using Deform-3D finite element simulation software. The variations in the temperatures of the tool teeth and the workpiece at different positions of the nickel-based alloy under ordinary drilling and vibration drilling were investigated. Additionally, the wear pattern of each tool tooth under the two drilling methods was further analyzed by building an experimental platform for workpiece temperature detection, which reveals the wear and cooling mechanism of nickel-based alloy BTA deep hole drilling. The results show that the average temperatures of the external, intermediate, and central teeth were reduced by 18.1%, 21.1%, and 17.8%, respectively, during vibration drilling. In addition, the workpiece hole wall and hole bottom temperatures were reduced by 5.7% and 4.6%, respectively. To conclude, the experimental tests were consistent with the simulated temperature trends. BTA vibration drilling optimizes the heat exchange conditions between the cutter teeth and the workpiece during the drilling of nickel-based alloys, which effectively reduces the cutting temperature and, thus, improves the wear resistance of the cutter teeth.

Circulating galectin-3 promotes tumor-endothelium-adhesion by upregulating ICAM-1 in endothelium-derived extracellular vesicles.

The adhesion of tumor cells to vascular endothelial cells is an important process of tumor metastasis. Studies have shown that tumor could educate vascular endothelial cells to promote tumor metastasis through many ways. However, the effect of tumor cells on the functions of vascular endothelial cells-derived extracellular vesicles (H-EVs) and the mechanisms underlying their effects in tumor-endothelium adhesion in metastasis remain mysterious. In this study, we found that H-EVs promoted the adhesion of triple negative breast cancer cell to endothelial cells and cirGal-3 enhanced the adhesion-promoting effects of H-EVs. The underlying mechanism was related to the upregulation of glycolysis in endothelial cells induced by cirGal-3 which led to the increase of the ICAM-1 expression and its transmission to MDA-MB-231 cells by H-EVs. Targeting of cirGal-3 or glycolysis of vascular endothelium in breast cancer therefore represents a promising therapeutic strategy to reduce metastasis.

Reducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy.

The retinal pigment epithelium (RPE) plays an important role in the development of diabetic retinopathy (DR), a leading cause of blindness worldwide. Here we set out to explore the role of Akt2 signaling-integral to both RPE homeostasis and glucose metabolism-to DR. Using human tissue and genetically manipulated mice (including RPE-specific conditional knockout (cKO) and knock-in (KI) mice), we investigate whether Akts in the RPE influences DR in models of diabetic eye disease. We found that Akt1 and Akt2 activities were reciprocally regulated in the RPE of DR donor tissue and diabetic mice. Akt2 cKO attenuated diabetes-induced retinal abnormalities through a compensatory upregulation of phospho-Akt1 leading to an inhibition of vascular injury, inflammatory cytokine release, and infiltration of immune cells mediated by the GSK3ß/NF-κB signaling pathway; overexpression of Akt2 has no effect. We propose that targeting Akt1 activity in the RPE may be a novel therapy for treating DR.

DSC2 Suppresses the Metastasis of Gastric Cancer through Inhibiting the BRD4/Snail Signaling Pathway and the Transcriptional Activity of ß-Catenin.

Downregulated DSC2 involved in the metastasis of cancers. Unfortunately, its role on the development of gastric cancer (GC) and the potential mechanisms remain unclear. Bioinformatics analysis, Western blot, qRT-PCR, and immunohistochemistry were performed to detect the DSC2 levels of human GC and normal stomach tissues. The role of DSC2 and the downstream signaling in gastric carcinogenesis were explored by using GC specimens, GC cells with different DSC2 expression, inhibitors, and mouse metastasis models. We found that the level of DSC2 decreased significantly in GC tissues and cells. Recovered DSC2 inhibited the invasion and migration of GC cells both in culture and in xenografts. Mechanistically, DSC2 could not only decrease Snail level and nuclear BRD4 level by forming DSC2/BRD4, but also inhibit nuclear translocation of ß-catenin. We concluded that DSC2 inhibited the metastasis of GC, and the underlying mechanisms were closely related to the regulation on nuclear translocation of BRD4 and ß-catenin. Our results suggest that DSC2 may serve as a novel therapeutic target for GC.

12 T high static magnetic field suppresses osteosarcoma cells proliferation by regulating intracellular ROS and iron status.

Many studies indicated that static magnetic fields (SMFs) have anti-cancer effects. However, effect of SMFs on cancer cells with strength exceeding 12 T are rarely reported. The intracellular iron could participate in the reactive oxygen species (ROS) production and affect cell proliferation. This study aimed to investigate the effect of 12 T high static magnetic field (HiSMF) on osteosarcoma cells and the relationship with intracellular iron. The 12 T HiSMF was generated by a superconducting magnet. The proliferation was evaluated by CCK-8 assays and cell counting. The apoptosis, cell cycle distribution, and ROS were evaluated by flow cytometry. Intracellular iron status was evaluated by atomic absorption spectroscopy and Calcein-AM/2,2'-bipyridyl. The expression of cell cycle and iron metabolism-related genes were analyzed by Western Blot. The result showed that 12 T HiSMF exposure suppressed the proliferation of osteosarcoma cell lines MNNG/HOS, U-2 OS, and MG63 via cell cycle arrest in S and G2/M. Meanwhile, 12 T HiSMF increasing intracellular ROS, and its antitumor effect was reduced by antioxidant. Furthermore, the intracellular total and free iron levels, the expression of FTH1 and DMT1 were increased by 12 HiSMF. The iron chelator (DFO) could reduce the cytotoxicity of 12 T HiSMF on osteosarcoma cells. Moreover, 12 T HiSMF could enhance the cytotoxicity of cisplatin and sorafenib in osteosarcoma cells. In Conclusion, 12 T HiSMF could suppress osteosarcoma cells proliferation via intracellular iron and ROS related cell cycle arrest, and have application potential in osteosarcoma therapy combined with sorafenib and cisplatin.

Iron plays a role in sulfasalazine-induced ferroptosis with autophagic flux blockage in K7M2 osteosarcoma cells.

Osteosarcoma is the most common primary bone malignancy in children and young adults, with a very poor prognosis. It is of great importance to develop targeted therapeutic strategies for osteosarcoma. Sulfasalazine (SAS) is an FDA-approved drug for the treatment of Crohn's disease, rheumatoid arthritis, and inflammatory bowel disease. It acts as an inhibitor of cystine/glutamate system, which is important for cellular glutathione synthesis and maintenance of GPx4 activity. Nowadays, SAS has been repurposed as an antitumor drug for inducing ferroptosis in cancers. This study aimed to uncover the role of iron in SAS-induced ferroptotic cell death in K7M2 osteosarcoma cells. Herein, SAS led to an iron-dependent cell death mode in K7M2 cells, accompanied with decreased antioxidant defense and increased production of cytosolic and lipid reactive oxygen species. Results also showed that iron supplement with ferric ammonium citrate (FAC) or ferrous ammonium sulfate (FAS) exacerbated the declined cell viability of SAS-treated K7M2 cells, while in the case of iron depletion, it weakened such suppression. Furthermore, iron promoted SAS-induced alterations on cell cycle, cytoskeleton, mitochondria morphology and function, and redox system. Iron also induced the dysfunction of autophagic activity in SAS-treated K7M2 cells. In conclusion, our study uncovered the essential role of iron in SAS's effects on K7M2 cells and provided the potential combined therapy of inhibition on antioxidant defense and an increase in oxidative potential, which further disturbed the redox status in tumor cells.

System Xc- inhibition blocks bone marrow-multiple myeloma exosomal crosstalk, thereby countering bortezomib resistance.

Multiple myeloma (MM) cells derive proliferative signals from the bone marrow (BM) microenvironment via exosomal crosstalk. Therapeutic strategies targeting this crosstalk are still lacking. Bortezomib resistance in MM cells is linked to elevated expression of xCT (the subunit of system Xc-). Extracellular glutamate released by system Xc- can bind to glutamate metabotropic receptor (GRM) 3, thereby upregulating Rab27-dependent vesicular trafficking. Since Rab27 is also involved in exosome biogenesis, we aimed to investigate the role of system Xc- in exosomal communication between BM stromal cells (BMSCs) and MM cells. We observed that expression of xCT and GRMs was increased after bortezomib treatment in both BMSCs and MM cells. Secretion of glutamate and exosomes was simultaneously enhanced which could be countered by inhibition of system Xc- or GRMs. Moreover, glutamate supplementation increased exosome secretion by increasing expression of Alix, TSG101, Rab27a/b and VAMP7. Importantly, the system Xc- inhibitor sulfasalazine reduced BMSC-induced resistance to bortezomib in MM cells in vitro and enhanced its anti-MM effects in vivo. These findings suggest that system Xc- plays an important role within the BM and could be a potential target in MM.