Biological Effects of Hypomagnetic Field: Ground-Based Data for Space Exploration.

The future of mankind is tied to the exploration and eventual colonization of space. Currently, people have resided in orbit at a space station. In the future, we will have opportunities to stay on the moon, Mars, or in deeper space, where astronauts are exposed to the hypomagnetic field (HMF), which refers to an extremely weak magnetic field environment compared with the geomagnetic field. However, the potential risks of HMF exposure to human health are often overlooked. Here, we summarize the literature related to the biological effects of HMF and calculate the magnitude of the effect. Briefly, HMF impairs multiple animal systems, especially in the central nervous system. Additionally, HMF is a stress factor in plant growth and reproduction. Finally, HMF combined with other space environments, such as radiation and microgravity, can affect organisms. Further studies are required to explore (i) countermeasures to the adverse effects of HMF, (ii) combined effects of HMF with other factors, and (iii) the intensity-effect relationship. © 2021 Bioelectromagnetics Society.

Iron Chelator Induces Apoptosis in Osteosarcoma Cells by Disrupting Intracellular Iron Homeostasis and Activating the MAPK Pathway.

Osteosarcoma is a common malignant bone tumor in clinical orthopedics. Iron chelators have inhibitory effects on many cancers, but their effects and mechanisms in osteosarcoma are still uncertain. Our in vitro results show that deferoxamine (DFO) and deferasirox (DFX), two iron chelators, significantly inhibited the proliferation of osteosarcoma cells (MG-63, MNNG/HOS and K7M2). The viability of osteosarcoma cells was decreased by DFO and DFX in a concentration-dependent manner. DFO and DFX generated reactive oxygen species (ROS), altered iron metabolism and triggered apoptosis in osteosarcoma cells. Iron chelator-induced apoptosis was due to the activation of the MAPK signaling pathway, with increased phosphorylation levels of JNK, p38 and ERK, and ROS generation; in this process, the expression of C-caspase-3 and C-PARP increased. In an orthotopic osteosarcoma transplantation model, iron chelators (20 mg/kg every day, Ip, for 14 days) significantly inhibited the growth of the tumor. Immunohistochemical analysis showed that iron metabolism was altered, apoptosis was promoted, and malignant proliferation was reduced with iron chelators in the tumor tissues. In conclusion, we observed that iron chelators induced apoptosis in osteosarcoma by activating the ROS-related MAPK signaling pathway. Because iron is crucial for cell proliferation, iron chelators may provide a novel therapeutic strategy for osteosarcoma.

Iron metabolism gene expression and prognostic features of hepatocellular carcinoma.

Iron metabolism is crucial to hepatocellular carcinoma progression and is a key determinant of prognosis. Protein-protein interactions within the iron metabolism gene network were analyzed using the European Molecular Biology Laboratory's Search Tool for Recurring Instances of Neighbouring Genes/Proteins database. We obtained 423 liver hepatocellular carcinoma gene expression profiles from the Cancer Genome Atlas database. The expression and pathway enrichment of representative iron intake genes (TFRC and DMT1), utilization genes (FTH1, FTL, HIF1A, HMOX1, SLC25A37, and SLC25A38), and efflux genes (FLVCR1 and SLC40A1) was investigated in tumor and adjacent tissues. We determined the relationship between iron metabolism and the prognostic features of liver hepatocellular carcinoma. The liver metabolism genes TFRC and FLVCR1 were related to survival, disease status, and prognosis in patients with hepatocellular carcinoma. Our results provide novel insight into liver cancer therapy.

Study on the poroelastic behaviors of the defected osteochondral unit.

Osteoarthritis has become a major disease threatening human health. The mechanism of injury under fluid involvement can be studied by finite element method. However, most models only model the articular cartilage to study the subchondral bone structure, which is too simplistic. In this study, a complete osteochondral unit was modeled and provided with a poroelastic material, and as osteoarthritis develops and the size, thickness, and shape of the osteochondral unit defect varies, the fluid flow behavior is altered, which may have functional consequences that feed back into the progression of the injury. The results of the study showed that interstitial fluid pressure and velocity decreased in defective osteochondral units. This trend was exacerbated as the size and thickness of the defect in the osteochondral unit increased. When the defect reached the trabeculae, pressure around the cartilage defect in the osteochondral unit was greatest, flow velocity in the subchondral cortical bone was greatest, and pressure and flow velocity around the trabecular defect were lowest. As osteoarthritis develops, the osteochondral unit becomes more permeable, and the pressure of the interstitial fluid decreases while the flow rate increases, resulting in severe nutrient loss. This may be the fluid flow mechanism behind osteochondral defects and osteoarthritis.

Biomechanical analysis of a lacunar-canalicular system under different cyclic displacement loading.

The objective of this study is to use the finite element (FE) method to predict the mechanical signals (interstitial fluid velocity, strain, pore pressure, and pore fluid velocity) produced by osteocyte during physiological activities. The model predicts that the amplitude and distribution of the mechanical signals are mainly affected by the loading rate. The magnitude of mechanical signals in the lacunar-canalicular system increases as the amplitude, frequency and amount of direction of load increase. Collagen hillocks can effectively amplify strain signals at the process. The established model can be used for studying the mechanism of bone mechanotransduction at the micro-level.

The biomechanical effects of different membrane layer structures and material constitutive modeling on patient-specific cerebral aneurysms.

The prevention, control and treatment of cerebral aneurysm (CA) has become a common concern of human society, and by simulating the biomechanical environment of CA using finite element analysis (FEA), the risk of aneurysm rupture can be predicted and evaluated. The target models of the current study are mainly idealized single-layer linear elastic cerebral aneurysm models, which do not take into account the effects of the vessel wall structure, material constitution, and structure of the real CA model on the mechanical parameters. This study proposes a reconstruction method for patient-specific trilaminar CA structural modeling. Using two-way fluid-structure interaction (FSI), we comparatively analyzed the effects of the differences between linear and hyperelastic materials and three-layer and single-layer membrane structures on various hemodynamic parameters of the CA model. It was found that the numerical effects of the different CA membrane structures and material constitution on the stresses and wall deformations were obvious, but does not affect the change in its distribution pattern and had little effect on the blood flow patterns. For the same material constitution, the stress of the three-layer membrane structure were more than 10.1% larger than that of the single-layer membrane structure. For the same membrane structure, the stress of the hyperelastic material were more than 5.4% larger than that of the linear elastic material, and the displacement of the hyperelastic material is smaller than that of the linear elastic material by about 20%. And the maximum value of stress occurred in the media, and the maximum displacement occurred in the intima. In addition, the upper region of the tumor is the maximum rupture risk region for CA, and the neck of the tumor and the bifurcation of the artery are also the sub-rupture risk regions to focus on. This study can provide data support for the selection of model materials for CA simulation and analysis, as well as a theoretical basis for clinical studies and subsequent research methods.

Biomechanical evaluation and optimal design of a pedicle screw with double bent rods internal fixation system based on PE-PLIF fusion.

Problems, such as broken screws, broken rods, and cage subsidence after clinical spinal fusion surgery affect the success rate of fusion surgery and the fixation effect of fusion segments, and these problems still affect the treatment and postoperative recovery of patients. In this study, we used the biomechanical finite element analysis method to analyze and study the fixation effect of three kinds of spinal internal fixation systems on L4-L5 lumbar spine segments in percutaneous endoscopic posterior lumbar interbody fusion (PE-PLIF). The three different fixation systems compared in this study include bilateral pedicle screw fixation (M1); bilateral pedicle screw with cross-link fixation (M2); bilateral pedicle screws with double bent rods fixation (M3). The internal fixation systems with different structures were analyzed with the help of Hypermesh, and Abaqus. It was found that the internal fixation system with double bent rods reduced screw stresses by 23.8 and 22.2% in right and left axial rotation than the traditional bilateral pedicle screw system, while titanium rod stresses were reduced by 9.6, 3.7, 9.6, and 2.9% in flexion, left and right lateral bending, and right axial rotation, respectively, and L5 upper endplate stresses were reduced by 35.5, 18.9, 38.4, 10.2, and 48.3% in flexion, left and right lateral bending, and left and right axial rotation, respectively. The spinal range of motion (ROM) of the M3 internal fixation system was less than that of the M1 and M2 internal fixation systems in left lateral bending, left lateral rotation, and right axial rotation, and the intact vertebral ROM was reduced by 93.7, 94.9, and 90.9%, respectively. The double bent rod structure of the spinal internal fixation system has better biomechanical properties, which can effectively reduce the risk of screw breakage, loosening, cage subsidence, and endplate collapse after fusion surgery.

Effect of High Static Magnetic Field (2 T-12 T) Exposure on the Mineral Element Content in Mice.

Relative stability of mineral elements in tissues is necessary for health. High static magnetic fields (HiSMFs) have been widely used in biomedical research and industry. However, the bioeffect of HiSMFs on animals is still unclear. In this study, we investigated the effects of HiSMF exposure on the levels of Mg, Fe, Zn, Ca, and Cu in the main organs of mice. The 8-week male C57BL/6 mice were treated by 2-4 T, 6-8 T, 10-12 T HiSMFs for 28 days. The mass fractions of Mg, Fe, Zn, Ca, and Cu in the liver, brain, kidney, and heart in mice were respectively measured by atomic absorption spectroscopy, and used to evaluate mineral element content in tissues. The 2-4 T HiSMF exposure has increased the Mg, Fe, and Ca content in the kidney, as well as the Zn content in the brain. The 6-8 T HiSMF exposure has increased the Zn level in the liver; Mg, Fe, and Ca levels in the kidney; and Fe level in the heart, while the Zn in the kidney, and Zn and Ca in the heart was decreased by 6-8 T HiSMF exposure. For the 10-12 T HiSMF exposure, the Mg in the kidney, the Fe in the liver and kidney, and Cu in the brain have been increased significantly. However, the Zn in the kidney and the Ca in the brain and the heart were reduced by 10-12 T HiSMF exposure. The HiSMF exposure for 28 days can alter the Mg, Fe, Zn, Ca, and Cu content in mice, and change with the different magnetic flux density of HiSMFs (2-4 T, 6-8 T, 10-12 T), elements, and organ types.

Blocking glucocorticoid signaling in osteoblasts and osteocytes prevents mechanical unloading-induced cortical bone loss.

Bone loss has been supposed to be the greatest damage to the health of astronauts. It is generally believed that the mechanical unloading induced by microgravity is the main cause of bone loss. However, besides mechanical unloading, many evidences from animal models and spaceflight missions indicate that microgravity conditions can cause some stress reactions and elevated endogenous glucocorticoid (GC) levels. High levels of GCs can lead to bone loss. This study aimed to investigate whether elevated GC levels are involved in hindlimb unloading (HLU)-induced bone loss in mice. Col2.3-11ß-hydroxysteroid dehydrogenase type 2 (Col2.3-11ß-HSD2) transgenic mice which are characterized by specific blocking GC signaling in mature osteoblasts and osteocytes were used. Male 14-week-old Col2.3-11ß-HSD2 transgenic mice and wild type littermates were tail-suspended or kept under ambulatory conditions. At the endpoint, the tibias were examined by micro-computed tomography and histomorphometry, and bone turnover was analyzed by serum biochemistry, histochemistry staining, immunohistochemistry, and real-time PCR. Mice exposed to unloading occurred a significant increase in serum GC concentrations. Compared with non-unloaded controls, HLU led to a severe damage in cortical bone microstructure and bone strength of the tibia in wild type mice but not transgenic littermates. Osteoblast activity and bone formation were inhibited, whereas osteoclast activity and bone resorption were promoted in the tibial cortical bone of wild type mice following HLU, features absented in transgenic mice. Furthermore, HLU resulted in a significant increase in the number of sclerostin-producing and receptor activator of nuclear factor-κ B ligand (RANKL)-positive osteocytes, and apoptotic osteoblasts and osteocytes in wild type mice of unloading but not in unloaded transgenic mice. In conclusion, cortical bone loss during HLU is mediated through enhancing GC signaling in osteoblasts and osteocytes and subsequently restraining bone formation and activating bone resorption. It suggests that elevated GC levels play an important role in cortical bone loss in response to mechanical unloading.

An organoselenium-catalyzed N1- and N2-selective aza-Wacker reaction of alkenes with benzotriazoles.

An organoselenium-catalyzed N1- and N2-selective aza-Wacker reaction of alkenes with benzotriazoles is reported, which provides easy access to N1- and N2-olefinated benzotriazole derivatives. The wide substrate scope, good functional group tolerance, and facile scale-up of this method are expected to promote its potential application in synthetic chemistry. A preliminary mechanism is proposed to explain the N1- and N2-selectivities.

Iron Promotes Dihydroartemisinin Cytotoxicity via ROS Production and Blockade of Autophagic Flux via Lysosomal Damage in Osteosarcoma.

Osteosarcoma cellular iron concentration is higher than that in normal bone cells and other cell types. High levels of cellular iron help catalyze the Fenton reaction to produce reactive oxygen species (ROS), which promotes cancer cell proliferation. Dihydroartemisinin (DHA), a classic anti-malarial drug, kills plasmodium through iron-dependent ROS generation. In this research, we observed the anti-osteosarcoma effects and mechanisms of DHA. We found that DHA induced ROS production, caused mitochondrial damage, and activated autophagy via stimulation of the ROS/Erk1/2 pathway. As the storage site for a pool of ferrous iron, lysosomes are often the key organelles affected by drugs targeting iron. In this study, we observed that DHA induced lysosomal superoxide production, leading lysosomal membrane permeabilization (LMP), and autophagic flux blockage. By reducing or increasing cellular iron using deferoxamine (DFO) or ferric ammonium citrate (FAC), respectively, we found that DHA inhibited osteosarcoma in an iron-dependent manner. Therefore, iron may be a potential adjuvant for DHA in osteosarcoma treatment.

Disorder of Iron Metabolism Inhibits the Recovery of Unloading-Induced Bone Loss in Hypomagnetic Field.

Exposure of humans and animals to microgravity in spaceflight results in various deleterious effects on bone health. In addition to microgravity, the hypomagnetic field (HyMF) is also an extreme environment in space, such as on the Moon and Mars; magnetic intensity is far weaker than the geomagnetic field (GMF) on Earth. Recently, we showed that HyMF promoted additional bone loss in hindlimb unloading-induced bone loss, and the underlying mechanism probably involved an increase of body iron storage. Numerous studies have indicated that bone loss induced by mechanical unloading can be largely restored after skeletal reloading in GMF conditions. However, it is unknown whether this bone deficit can return to a healthy state under HyMF condition. Therefore, the purpose of this study is to examine the effects of HyMF on the recovery of microgravity-induced bone loss, and illustrates the changes of body iron storage in this process. Our results showed that there was lower bone mineral content (BMC) in the HyMF reloading group compared to the GMF reloading group. Reloaded mice in the HyMF condition had a worse microstructure of femur than in the GMF condition. Femoral mechanical properties, including elastic modulus, stiffness, and ultimate stress, were poorer and toughness was higher in the HyMF group compared with the GMF group. Simultaneously, more iron content in serum, the tibia, liver, and spleen was found under HyMF reloading than GMF reloading. The iron chelator deferoxamine mesylate (DFO) decreased the iron content in the bone, liver, and spleen, and significantly relieved unloading-induced bone loss under HyMF reloading. These results showed that HyMF inhibits the recovery of microgravity-induced bone loss, probably by suppressing the elevated iron levels' return to physiological level. © 2019 American Society for Bone and Mineral Research.

HAMP Downregulation Contributes to Aggressive Hepatocellular Carcinoma via Mechanism Mediated by Cyclin4-Dependent Kinase-1/STAT3 Pathway.

BACKGROUND: Hepcidin encoded by HAMP is vital to regulating proliferation, metastasis, and migration. Hepcidin is secreted specifically by the liver. This study sought to examine the functional role of hepcidin in hepatocellular carcinoma (HCC). METHODS: Data in the Cancer Genome Atlas database was used to analyze HAMP expression as it relates to HCC prognosis. We then used the 5-ethynyl-20-deoxyuridine (EdU) incorporation assay, transwell assay, and flow cytometric analysis, respectively, to assess proliferation, migration, and the cell cycle. Gene set enrichment analysis (GSEA) was used to find pathways affected by HAMP. RESULTS: HAMP expression was lower in hepatocellular carcinoma samples compared with adjacent normal tissue controls. Low HAMP expression was linked with a higher rate of metastasis and poor disease-free status. Downregulation of HAMP induced SMMC-7721 and HepG-2 cell proliferation and promoted their migration. HAMP could affect the cell cycle pathway and Western blotting, confirming that reduced HAMP levels activated cyclin-dependent kinase-1/stat 3 pathway. CONCLUSION: Our findings indicate that HAMP functions as a tumor suppressor gene. The role of HAMP in cellular proliferation and metastasis is related to cell cycle checkpoints. HAMP could be considered as a diagnostic biomarker and targeted therapy in HCC.

Transferrin receptor 1 in cancer: a new sight for cancer therapy.

Iron as an important element plays crucial roles in various physiological and pathological processes. Iron metabolism behaves in systemic and cellular two levels that usually are in balance conditions. The disorders of the iron metabolism balances relate with many kinds of diseases including Alzheimer's disease, osteoporosis and various cancers. In systemic iron metabolism that is regulated by hepcidin-ferroportin axis, plasma iron is bound with transferrin (TF) which has two high-affinity binding sites for ferric iron. The generic cellular iron metabolism consists of iron intake, utilization and efflux. During the iron intake process in generic cells, transferrin receptors (TFRs) act as the most important receptor mediated controls. TFR1 and TFR2 are two subtypes of TFRs those bind with iron-transferrin complex to facilitate iron into cells. TFR1 is ubiquitously expressed on the surfaces of generic cells, whereas TFR2 is specially expressed in liver cells. TFR1 has attracted more attention than TFR2 by having diverse functions in both invertebrates and vertebrates. Recently reports showed that TFR1 involved in many kinds of diseases including anemia, neurodegenerative diseases and cancers. Most importantly, TFR1 has been verified to be abnormally expressed in various cancers. Some experimental and clinical drugs and antibodies targeting TFR1 have showed strong anti-tumor effects, herein TFR1 probably become a potential molecular target for diagnosis and treatment for cancer therapy. This paper reviewed the research progresses of the roles of TFR1 in the tumorigenesis and cancer progression, the regulations of TFR1, and the therapeutic effects of targeting TFR1 on many kinds of cancers.

Synthesis of ( E)-ß-Selenovinyl Sulfones through a Multicomponent Regio- and Stereospecific Selenosulfonation of Alkynes with Insertion of Sulfur Dioxide.

A novel and practical method for the selenosulfonation of alkynes with the insertion of sulfur dioxide has been developed. A series of ß-(seleno)vinyl sulfones with high levels of regio- and stereoselectivity have been prepared. The key features of this reaction include a broad substrate scope, excellent functional-group tolerance, and amenability to scale-up synthesis. A plausible radical mechanism is proposed to illustrate this reaction.

Iron overload involved in the enhancement of unloading-induced bone loss by hypomagnetic field.

During deep-space exploration missions, astronauts will be exposed to abnormal space environments including microgravity and hypomagnetic field (HyMF) that is 10,000 times weaker than geomagnetic field (GMF). It is well known that microgravity in space can induce bone loss; however, it is ill-defined whether HyMF involved in this process. Herein, we aimed to investigate the combined effects of HyMF and microgravity on bone loss. A mouse model of hindlimb suspension (HLU) was adopted to simulate microgravity-induced bone loss, that was exposed to a hypomagnetic field of <300 nanotesla (nT) generated by a geomagnetic field-shielding chamber. Besides, a recent study showed that HLU induced bone loss was orchestrated by iron overload. Therefore, the changes of iron content in unloading-induced bone loss under HyMF condition were detected simultaneously. The results showed HyMF exacerbated the loss of bone mineral content (BMC), induced more detrimental effects on microstructure of cancellous bone but not cortical bone and yielded greater negative effects on biomechanical characteristics in mice femur under unloading status. Concomitantly, there was more iron accumulation in serum, liver, spleen and bone in the combined treatment group than in the separate unloading group or HyMF exposure group. These results showed that HyMF promoted additional bone loss in mice femur during mechanical unloading, and the potential mechanism may be involved in inducing iron overload of mice.