Acetaminophen overdose-induced acute liver injury can be alleviated by static magnetic field.

Acetaminophen (APAP), the most frequently used mild analgesic and antipyretic drug worldwide, is implicated in causing 46% of all acute liver failures in the USA and between 40% and 70% in Europe. The predominant pharmacological intervention approved for mitigating such overdose is the antioxidant N-acetylcysteine (NAC); however, its efficacy is limited in cases of advanced liver injury or when administered at a late stage. In the current study, we discovered that treatment with a moderate intensity static magnetic field (SMF) notably reduced the mortality rate in mice subjected to high-dose APAP from 40% to 0%, proving effective at both the initial liver injury stage and the subsequent recovery stage. During the early phase of liver injury, SMF markedly reduced APAP-induced oxidative stress, free radicals, and liver damage, resulting in a reduction in multiple oxidative stress markers and an increase in the antioxidant glutathione (GSH). During the later stage of liver recovery, application of vertically downward SMF increased DNA synthesis and hepatocyte proliferation. Moreover, the combination of NAC and SMF significantly mitigated liver damage induced by high-dose APAP and increased liver recovery, even 24 h post overdose, when the effectiveness of NAC alone substantially declines. Overall, this study provides a non-invasive non-pharmaceutical tool that offers dual benefits in the injury and repair stages following APAP overdose. Of note, this tool can work as an alternative to or in combination with NAC to prevent or minimize liver damage induced by APAP, and potentially other toxic overdoses.

Mitochondrial targeting sequence of magnetoreceptor MagR: More than just targeting.

Iron-sulfur clusters are essential cofactors for proteins involved in various biological processes, such as electron transport, biosynthetic reactions, DNA repair, and gene expression regulation. Iron-sulfur cluster assembly protein IscA1 (or MagR) is found within the mitochondria of most eukaryotes. Magnetoreceptor (MagR) is a highly conserved A-type iron and iron-sulfur cluster-binding protein, characterized by two distinct types of iron-sulfur clusters, [2Fe-2S] and [3Fe-4S], each conferring unique magnetic properties. MagR forms a rod-like polymer structure in complex with photoreceptive cryptochrome (Cry) and serves as a putative magnetoreceptor for retrieving geomagnetic information in animal navigation. Although the N-terminal sequences of MagR vary among species, their specific function remains unknown. In the present study, we found that the N-terminal sequences of pigeon MagR, previously thought to serve as a mitochondrial targeting signal (MTS), were not cleaved following mitochondrial entry but instead modulated the efficiency with which iron-sulfur clusters and irons are bound. Moreover, the N-terminal region of MagR was required for the formation of a stable MagR/Cry complex. Thus, the N-terminal sequences in pigeon MagR fulfil more important functional roles than just mitochondrial targeting. These results further extend our understanding of the function of MagR and provide new insights into the origin of magnetoreception from an evolutionary perspective.

A safety study on ultra­high or moderate static magnetic fields combined with platycodin D against lung cancer.

Due to the serious side effects of chemotherapy drugs against lung cancer, and the antitumor properties and high safety of magnetic fields, the present study combined moderate or ultra-high intensity statics magnetic fields (SMFs) with platycodin D (PD) to explore the antitumor efficiency and biosafety. The antitumor effects of PD with or without moderate and ultra-high SMFs on A549 cells bearing mice were compared. Mouse body weight, food/water intake, hematology routine, blood biochemistry, tumor weight and tissues hematoxylin and eosin (H&E) staining were examined. Behavior was measured using the elevated plus maze, open field and vital signs tests. The combined targets of PD and SMFs were detected using RNA-sequencing (RNA-seq). The results showed that the antitumor effect of 22 Tesla (T) SMF group was 3.6-fold higher compared with that of the 2 mg/kg PD group (tumor growth inhibition=10.08%), while the antitumor effect of 150 mT SMF was only 1.56-fold higher compared with that of PD. Although PD reduced the food intake, there was no significant difference in body weight, water intake or food consumption among PD and SMF groups. Behavioral results indicated that PD ameliorated dysphoria in mice, but SMFs reduced this effect. However, no significant abnormalities were found in routine blood, blood biochemistry test, H&E staining or organ index, except renal index which was reduced by PD with or without SMFs. RNA-sequencing (RNA-seq) demonstrated that SMFs and PD synergistically targeted the expression of genes associated with tumor growth, inflammation and neurological disease. The present study showed the antitumor efficacy and biosafety of moderate or ultra-high SMF combined with PD, which exhibited only few side effects in the treatment of lung cancer, thus supporting further research for the clinical application of magnetic fields.

Magnetic Fields Affect Alcoholic Liver Disease by Liver Cell Oxidative Stress and Proliferation Regulation.

It is well known that alcohol consumption leads to substantially increased free radical levels and health risks, which lacks effective treatment besides alcohol abstinence. Here, we compared different static magnetic field (SMF) settings and found that a downward quasi-uniform SMF of ~0.1 to 0.2 T could effectively alleviate alcohol-induced liver damage and lipid accumulation and improve hepatic function. SMFs of two different directions can reduce the inflammation, reactive oxygen species levels, and oxidative stress in the liver, while the downward SMF had more obvious effects. Moreover, we found that the upward direction SMF of ~0.1 to 0.2 T could inhibit DNA synthesis and regeneration in hepatocytes, which caused detrimental effects on the lifespan of "heavy drinking" mice. In contrast, the downward SMF prolongs survival of "heavy drinking" mice. On one hand, our study shows that ~0.1 to 0.2 T moderate quasi-uniform SMFs with a downward direction have great promises to be developed into a physical method to reduce alcohol-induced liver damage; on the other hand, although the internationally recognized upper limit for SMF public exposure is 0.4 T, people should also pay extra attention to SMF strength, direction, and inhomogeneity that could generate harmful effects on specific severe pathological conditions.

Histone H3 phospho-regulation by KimH3 in both interphase and mitosis.

Histone H3 is phosphorylated at Ser10 by multiple kinases, and many of them are anti-cancer targets. Here, we report the first kinase that can phosphorylate H3Ser10 in both interphase and mitosis, which we named KimH3 (kinase of interphase and mitotic Histone H3). Meta-analysis indicates that KimH3 is upregulated in a broad spectrum of human cancers and its high expression is correlated with reduced the median survival time of cancer patients. In mitosis, CDK1 phosphorylates KimH3, which then phosphorylates H3Ser10 to regulate cell cycle procession. In interphase, EGF induces KimH3 activation and H3Ser10 phosphorylation, which is involved in MAPK-ERK1/2 signaling pathway to activate immediate-early genes transcription. Consequently, a small molecule inhibitor of KimH3 significantly inhibited tumor growth in mice. This is not only consistent with the dual roles of KimH3 in both interphase and mitotic Histone H3 phosphorylation, but also reveals it as an important potential anti-cancer target.

Effects of gradient high-field static magnetic fields on diabetic mice.

Although 9.4 T magnetic resonance imaging (MRI) has been tested in healthy volunteers, its safety in diabetic patients is unclear. Furthermore, the effects of high static magnetic fields (SMFs), especially gradient vs. uniform fields, have not been investigated in diabetics. Here, we investigated the consequences of exposure to 1.0-9.4 T high SMFs of different gradients (>10 T/m vs. 0-10 T/m) on type 1 diabetic (T1D) and type 2 diabetic (T2D) mice. We found that 14 h of prolonged treatment of gradient (as high as 55.5 T/m) high SMFs (1.0-8.6 T) had negative effects on T1D and T2D mice, including spleen, hepatic, and renal tissue impairment and elevated glycosylated serum protein, blood glucose, inflammation, and anxiety, while 9.4 T quasi-uniform SMFs at 0-10 T/m did not induce the same effects. In regular T1D mice (blood glucose ≥16.7 mmol/L), the >10 T/m gradient high SMFs increased malondialdehyde ( P<0.01) and decreased superoxide dismutase ( P<0.05). However, in the severe T1D mice (blood glucose ≥30.0 mmol/L), the >10 T/m gradient high SMFs significantly increased tissue damage and reduced survival rate. In vitro cellular studies showed that gradient high SMFs increased cellular reactive oxygen species and apoptosis and reduced MS-1 cell number and proliferation. Therefore, this study showed that prolonged exposure to high-field (1.0-8.6 T) >10 T/m gradient SMFs (35-1 380 times higher than that of current clinical MRI) can have negative effects on diabetic mice, especially mice with severe T1D, whereas 9.4 T high SMFs at 0-10 T/m did not produce the same effects, providing important information for the future development and clinical application of SMFs, especially high-field MRI.

The Effect of Long-Term Moderate Static Magnetic Field Exposure on Adult Female Mice.

Because of the high cost and safety of ultra-high magnetic resonance imaging (MRI), its application has certain limitations. Whereas 0.5−3 T MRI has been widely applied in hospitals, static magnetic fields (SMFs) have been shown to improve mice mental health and have anti-tumor potentials. Here, we compared the effects of the upward and downward 150 mT SMF groups with the sham group on C57BL/6J adult female mice. Locomotor and exploratory activity were also measured by behavioral tests, including the open field and elevated plus test. Additionally, physiology, pathology indicators and gut microbiota were examined. We found that 150 mT SMFs long-term exposure enhanced locomotive and exploratory activity of mice, especially the downward 150 mT SMF. Compared with the downward 150 mT SMF group, the movement speed and distance in the center area of the sham group were increased by 65.99% (p < 0.0001) and 68.58% (p = 0.0038), respectively. Moreover, compared to the sham group, downward 150 mT SMF increased the number of entrances to the center area by 67.0% (p = 0.0082) and time in the center area by 77.12% (p = 0.0054). Additionally, we observed that upward 150 mT SMF improved the number of follicles (~2.5 times, p = 0.0325) and uterine glands through increasing the total antioxidant capacity and reducing lipid peroxidation level in mice. Gut microbiome analysis showed that 150 mT SMFs long-term exposure improved the microbiota abundance (Clostridium, Bifidobacterium, Ralstonia and Yaniella) in the genus level, which may affect metabolism, anxiety and behavior in adult female mice. Our results demonstrated that 150 mT SMFs long-term exposure not only had good biosafety, but also improved athletic performance, emotion and the function of ovarian, uterine and gut microbiota abundance in adult female mice, which unraveled the potential of moderate long-term SMF exposure in clinical applications.

Static Magnetic Fields Reduce Oxidative Stress to Improve Wound Healing and Alleviate Diabetic Complications.

Although some studies have shown that some static magnetic fields (SMFs) can promote wound healing in diabetic mice, it is not clear whether the other diabetes complications, such as liver disease and diabetic nephropathy, can also be alleviated. Here, we constructed two simple magnetic plates using neodymium permanent magnets to examine the comprehensive effects of moderate SMFs on genetically obese leptin receptor-deficient db/db diabetic mice. We found that although the blood glucose was not obviously reduced by these two SMF settings, both of the glycated serum protein (GSP) and malondialdehyde (MDA) levels were significantly decreased (Cohen's d = 2.57-3.04). Moreover, the wound healing, liver lipid accumulation, and renal defects were all significantly improved by SMF treatment (Cohen's d = 0.91-2.05). Wound tissue examination showed obvious nuclear factor erythroid 2-related factor 2 (NRF2) level decrease (Cohen's d = 2.49-5.40) and Ki-67 level increase (Cohen's d = 2.30-3.40), indicating decreased oxidative stress and increased cell proliferation. In vitro cellular studies with fibroblast NIH3T3 cells showed that SMFs could reduce high glucose-induced NRF2 nucleus translocation (Cohen's d = 0.87-1.15) and cellular reactive oxygen species (ROS) elevation (Cohen's d = 0.92), indicating decreased oxidative stress. Consequently, high glucose-induced impairments in cell vitality, proliferation, and migration were all improved by SMF treatment. Therefore, our results demonstrate that these simple SMF devices could effectively reduce oxidative stress in diabetic mice and may provide a cost-effective physical therapy strategy to alleviate multiple diabetic complications in the future.

The Anti-Depressive Effects of Ultra-High Static Magnetic Field.

BACKGROUND: Ultra-high field magnetic resonance imaging (MRI) has obvious advantages in acquiring high-resolution images. 7 T MRI has been clinically approved and 21.1 T MRI has also been tested on rodents. PURPOSE: To examine the effects of ultra-high field on mice behavior and neuron activity. STUDY TYPE: Prospective, animal model. ANIMAL MODEL: Ninety-eight healthy C57BL/6 mice and 18 depression model mice. FIELD STRENGTH: 11.1-33.0 T SMF (static magnetic field) for 1 hour and 7 T for 8 hours. Gradients were not on and no imaging sequence was used. ASSESSMENT: Open field test, elevated plus maze, three-chambered social test, Morris water maze, tail suspension test, sucrose preference test, blood routine, biochemistry examinations, enzyme-linked immunosorbent assay, immunofluorescent assay. STATISTICAL TESTS: The normality of the data was assessed by Shapiro-Wilk test, followed by Student's t test or the Mann-Whitney U test for statistical significance. The statistical cut-off line is P < 0.05. RESULTS: Compared to the sham group, healthy C57/6 mice spent more time in the center area (35.12 ± 4.034, increased by 47.19%) in open field test and improved novel index (0.6201 ± 0.02522, increased by 16.76%) in three-chambered social test a few weeks after 1 hour 11.1-33.0 T SMF exposure. 7 T SMF exposure for 8 hours alleviated the depression state of depression mice, including less immobile time in tail suspension test (58.32% reduction) and higher sucrose preference (increased by 8.80%). Brain tissue analysis shows that 11.1-33.0 T and 7 T SMFs can increase oxytocin by 164.65% and 36.03%, respectively. Moreover, the c-Fos level in hippocampus region was increased by 14.79%. DATA CONCLUSION: 11.1-33.0 T SMFs exposure for 1 hour or 7 T SMF exposure for 8 hours did not have detrimental effects on healthy or depressed mice. Instead, these ultra-high field SMFs have anti-depressive potentials. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Static Magnetic Fields Protect against Cisplatin-Induced Kidney Toxicity.

Cisplatin is one of the most widely used anti-cancer drugs that can effectively inhibit the growth of multiple types of cancer. However, its clinical application is limited by its severe side effects, especially kidney toxicity, caused by cisplatin-induced oxidative stress, inflammation and kidney cell apoptosis. Here, we found that moderate (a few hundred mT) quasi-uniform static magnetic fields (SMFs) could inhibit cisplatin-induced renal proximal tubular cell death, especially the vertically downward direction SMF. RNA-seq experiments demonstrate that SMFs induced differential gene expressions that are closely associated with oxidative stress, apoptosis, cytokine production, transmembrane transport and DNA repair. In vivo experiments show that SMFs can reduce cisplatin-induced kidney injury in cisplatin-administrated tumor-bearing mice by reducing oxidative stress, inflammation and cell apoptosis. Furthermore, high-dose cisplatin-induced acute nephrotoxicity can be effectively alleviated by SMF treatment of as little as one day, which significantly reduced the reactive oxygen species levels in kidneys and prolonged the mice's survival. Moreover, the concentration of cisplatin in the kidney was significantly attenuated in SMF-treated mice. Therefore, our study demonstrates the effects of moderate SMFs as a novel physical method to reduce oxidative stress, and revealed their future potential to be used against cisplatin-induced kidney toxicity in cancer treatment.

Moderate Static Magnet Fields Suppress Ovarian Cancer Metastasis via ROS-Mediated Oxidative Stress.

Metastasis is the leading cause of cancer patient death, which is closely correlated with reactive oxygen species (ROS) levels. It is well known that the effects of ROS on tumors are diverse, depending on ROS concentration and cell type. We found that ovarian cancer cells have significantly lower levels of ROS than normal ovarian cells. Moreover, increased ROS levels in ovarian cancer cells can substantially inhibit their migration and invasion ability. Furthermore, the results show that moderate static magnetic field (SMF) can inhibit ovarian cancer cell migration, invasion, and stemness in a ROS-dependent manner. RNA sequencing results confirm that SMFs increased the oxidative stress level and reduced the stemness of ovarian cancer cells. Consistently, the expressions of stemness-related genes were significantly decreased, including hyaluronan receptor (CD44), SRY-box transcription factor 2 (Sox2), and cell myc proto-oncogene protein (C-myc). Furthermore, moderate SMFs provided by a superconducting magnet and permanent magnet have good biosafety and can both inhibit ovarian cancer metastasis in mice. Therefore, our study demonstrates the effects of SMFs on oxidative stress and metastasis in the ovarian cancer cells, which reveals the potential of applying SMF as a physical method in cancer therapy in the future.

Linker Histone in Diseases.

The linker histone is a protein that binds with the nucleosome, which is generally considered to achieve chromatin condensation in the nucleus. Accumulating evidences suggest that the linker histone is essential in the pathogenesis of several diseases. In this review, we briefly introduce the current knowledge of the linker histone, including its structure, characteristics and functions. Also, we move forward to present the advances of the linker histone's association with certain diseases, such as cancer, Alzheimer's disease, infection, male infertility and aberrant immunity situations, focusing on the alteration of the linker histone under certain pathological conditions and its role in developing each disease.