Ablation of Proton/Glucose Exporter SLC45A2 Enhances Melanosomal Glycolysis to Inhibit Melanin Biosynthesis and Promote Melanoma Metastasis.

Sequence variation in SLC45A2 are responsible for oculocutaneous albinism type 4 in many species and are associated with melanoma susceptibility, but the molecular mechanism is unclear. In this study, we used Slc45a2-deficient melanocyte and mouse models to elucidate the roles of SLC45A2 in melanogenesis and melanoma metastasis. We found that the acidified cellular environment impairs the activity of key melanogenic enzyme tyrosinase in Slc45a2-deficient melanocytes. SLC45A2 is identified as a proton/glucose exporter in melanosomes, and its ablation increases the acidification of melanosomal pH through enhanced glycolysis. Intriguingly, 13C-glucose-labeled metabolic flux and biochemical assays show that melanosomes are active glucose-metabolizing organelles, indicating that elevated glycolysis mainly occurs in melanosomes owing to Slc45a2 deficiency. Moreover, Slc45a2 deficiency significantly upregulates the activities of glycolytic enzymes and phosphatidylinositol 3-kinase/protein kinase B signaling to promote glycolysis-dependent survival and metastasis of melanoma cells. Collectively, our study reveals that the proton/glucose exporter SLC45A2 mediates melanin synthesis and melanoma metastasis primarily by modulating melanosomal glucose metabolism.

Self-Organization of Tissue Growth by Interfacial Mechanical Interactions in Multilayered Systems.

Morphogenesis is a spatially and temporally regulated process involved in various physiological and pathological transformations. In addition to the associated biochemical factors, the physical regulation of morphogenesis has attracted increasing attention. However, the driving force of morphogenesis initiation remains elusive. Here, it is shown that during the growth of multilayered tissues, a morphogenetic process can be self-organized by the progression of compression gradient stemmed from the interfacial mechanical interactions between layers. In tissues with low fluidity, the compression gradient is progressively strengthened during growth and induces stratification by triggering symmetric-to-asymmetric cell division reorientation at the critical tissue size. In tissues with high fluidity, compression gradient is dynamic and induces cell rearrangement leading to 2D in-plane morphogenesis instead of 3D deformation. Morphogenesis can be tuned by manipulating tissue fluidity, cell adhesion forces, and mechanical properties to influence the progression of compression gradient during the development of cultured cell sheets and chicken embryos. Together, the dynamics of compression gradient arising from interfacial mechanical interaction provides a conserved mechanism underlying morphogenesis initiation and size control during tissue growth.

Extracellular Matrix Stiffness Regulates DNA Methylation by PKCα-Dependent Nuclear Transport of DNMT3L.

Extracellular matrix (ECM) stiffness has profound effects on the regulation of cell functions. DNA methylation is an important epigenetic modification governing gene expression. However, the effects of ECM stiffness on DNA methylation remain elusive. Here, it is reported that DNA methylation is sensitive to ECM stiffness, with a global hypermethylation under stiff ECM condition in mouse embryonic stem cells (mESCs) and embryonic fibroblasts compared with soft ECM. Stiff ECM enhances DNA methylation of both promoters and gene bodies, especially the 5' promoter regions of pluripotent genes. The enhanced DNA methylation is functionally required for the loss of pluripotent gene expression in mESCs grown on stiff ECM. Further experiments reveal that the nuclear transport of DNA methyltransferase 3-like (DNMT3L) is promoted by stiff ECM in a protein kinase C α (PKCα)-dependent manner and DNMT3L can be binding to Nanog promoter regions during cell-ECM interactions. These findings unveil DNA methylation as a novel target for the mechanical sensing mechanism of ECM stiffness, which provides a conserved mechanism for gene expression regulation during cell-ECM interactions.

SLC22A14 is a mitochondrial riboflavin transporter required for sperm oxidative phosphorylation and male fertility.

Ablation of Slc22a14 causes male infertility in mice, but the underlying mechanisms remain unknown. Here, we show that SLC22A14 is a riboflavin transporter localized at the inner mitochondrial membrane of the spermatozoa mid-piece and show by genetic, biochemical, multi-omic, and nutritional evidence that riboflavin transport deficiency suppresses the oxidative phosphorylation and reprograms spermatozoa energy metabolism by disrupting flavoenzyme functions. Specifically, we find that fatty acid ß-oxidation (FAO) is defective with significantly reduced levels of acyl-carnitines and metabolites from the TCA cycle (the citric acid cycle) but accumulated triglycerides and free fatty acids in Slc22a14 knockout spermatozoa. We demonstrate that Slc22a14-mediated FAO is essential for spermatozoa energy generation and motility. Furthermore, sperm from wild-type mice treated with a riboflavin-deficient diet mimics those in Slc22a14 knockout mice, confirming that an altered riboflavin level causes spermatozoa morphological and bioenergetic defects. Beyond substantially advancing our understanding of spermatozoa energy metabolism, our study provides an attractive target for the development of male contraceptives.

[Different Energy Spectrum CT Findings between Anterior Mediastinal Lymphoma and Thymic Carcinoma].

Objective To investigate the differences in energy spectrum CT findings between anterior mediastinal lymphoma and thymic carcinoma. Methods Twenty-two cases of anterior mediastinal lymphoma and 28 cases of thymic carcinoma confirmed by biopsy in Tangshan People's Hospital were selected.The CT values and changes of iodine content and water content in lesion sites were measured by energy spectrum analysis software.The differences between anterior mediastinal lymphoma and thymic carcinoma were compared. Results The single-energy CT value of 40-80 keV in thymus carcinoma was higher than that in anterior mediastinal lymphoma(P=0.001,P=0.037,P=0.042,P=0.034,P=0.002;P=0.016,P=0.013,P=0.018,P=0.024,P=0.012).The difference in the single-energy CT value of 90-110 keV between anterior mediastinal lymphoma and thymic carcinoma showed no statistical significance(all P>0.05).The concentrations of water in the arterial and venous stages of thymic carcinoma were significantly lower than those in the anterior mediastinal lymphoma(P=0.030,P=0.037),whereas the iodine concentrations were significantly higher(P=0.026,P=0.000). Conclusion Anterior mediastinal lymphoma and thymic carcinoma have remarkably different 40-80 keV single energy CT value and iodine concentration in arterial and venous phases,which may be helpful for the differential diagnosis of these two malignancies.

[Correlation of Transluminal Attenuation Gradientdistal with Corrected Contrast Opacification with Anterior Coronary Atherosclerosis].

Objective To explore the correlation between the transluminal attenuation gradient with corrected contrast opacification(TAG-CCO)and the severity of atherosclerotic stenosis in the anterior segment of myocrardial bridge(MB). Methods The imaging data of 200 patients diagnosed with left anterior descending branch(LAD)single MB and coronary atherosclerosis in the anterior segment of MB were retrospectively analyzed.According to MB types,the patients were divided into two groups:incomplete and complete.There were some significant differences in TAG-CCO between patients with the same degree of coronary atherosclerosis(mild,moderate,and severe stenosis)in two groups.The relationships among groups with different degrees(mild,moderate,and severe stenosis)of the same type of MB were further compared. Results Among 84 patients with complete MB,36,30,and 18 patients had mild,moderate,or severe coronary atherosclerosis in the anterior segment of MB;among 116 patients with incomplete MB,45,42,and 29 patients had mild,moderate,or severe coronary atherosclerosis in the anterior segment of MB.In the complete MB group,the TAG-CCO in the anterior segment of MB subgroups were(-0.0086±0.0014)/10 mm,(-0.0170±0.0180)/10 mm,and(-0.0230±0.0026)/10 mm,respectively,in mild,moderate,and severe subgroups(F = 404.728, P<0.001).In the incomplete MB group,the TAG-CCO of patients with mild,moderate and severe coronary stenosis in the anterior segment of MB were(-0.0039±0.0011)/10 mm,(-0.0100±0.0140)/10 mm,and(-0.0160±0.0020)/10 mm,respectively,and the difference among the different stenosis groups was statistically significant(F = 17.756, P < 0.001);the TAG-CCO of patients with mild(t = 16.519, P < 0.001),moderate(t = 2.570, P = 0.012)and severe anterior segment coronary stenosis(t = 10.714, P < 0.001)were significantly lower in the complete MB group than in the incomplete MB group. Conclusions TAG-CCO is correlated with the MB type and the degree of anterior coronary artery stenosis.Thus,TAG-CCO can be used as a predictive indicator for the degree of atheroscleratic stenosis in the anterior segment of MB.

2020 update on human coronaviruses: One health, one world.

Since human coronavirus (HCoVs) was first described in the 1960s, seven strains of respiratory human coronaviruses have emerged and caused human infections. After the emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), a pneumonia outbreak of coronavirus disease 2019 (COVID-19) caused by a novel coronavirus (SARS-CoV-2) has represented a pandemic threat to global public health in the 21st century. Without effectively prophylactic and therapeutic strategies including vaccines and antiviral drugs, these three coronaviruses have caused severe respiratory syndrome and high case-fatality rates around the world. In this review, we detail the emergence event, origin and reservoirs of all HCoVs, compare the differences with regard to structure and receptor usage, and summarize therapeutic strategies for COVID-19 that cause severe pneumonia and global pandemic.

Slc6a8-Mediated Creatine Uptake and Accumulation Reprogram Macrophage Polarization via Regulating Cytokine Responses.

Macrophage polarization is accompanied by drastic changes in L-arginine metabolism. Two L-arginine catalytic enzymes, iNOS and arginase 1, are well-characterized hallmark molecules of classically and alternatively activated macrophages, respectively. The third metabolic fate of L-arginine is the generation of creatine that acts as a key source of cellular energy reserve, yet little is known about the role of creatine in the immune system. Here, genetic, genomic, metabolic, and immunological analyses revealed that creatine reprogrammed macrophage polarization by suppressing M(interferon-γ [IFN-γ]) yet promoting M(interleukin-4 [IL-4]) effector functions. Mechanistically, creatine inhibited the induction of immune effector molecules, including iNOS, by suppressing IFN-γ-JAK-STAT1 transcription-factor signaling while supporting IL-4-STAT6-activated arginase 1 expression by promoting chromatin remodeling. Depletion of intracellular creatine by ablation of the creatine transporter Slc6a8 altered macrophage-mediated immune responses in vivo. These results uncover a previously uncharacterized role for creatine in macrophage polarization by modulating cellular responses to cytokines such as IFN-γ and IL-4.

Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity.

Zoledronate is a bisphosphonate that is widely used in the treatment of metabolic bone diseases. However, zoledronate induces significant nephrotoxicity associated with acute tubular necrosis and renal fibrosis when administered intravenously. There is speculation that zoledronate-induced nephrotoxicity may result from its pharmacological activity as an inhibitor of the mevalonate pathway but the molecular mechanisms are not fully understood. In this report, human proximal tubular HK-2 cells and mouse models were combined to dissect the molecular pathways underlying nephropathy caused by zoledronate treatments. Metabolomic and proteomic assays revealed that multiple cellular processes were significantly disrupted, including the TGFß pathway, fatty acid metabolism and small GTPase signaling in zoledronate-treated HK-2 cells (50 µM) as compared with those in controls. Zoledronate treatments in cells (50 µM) and mice (3 mg/kg) increased TGFß/Smad3 pathway activation to induce fibrosis and kidney injury, and specifically elevated lipid accumulation and expression of fibrotic proteins. Conversely, fatty acid transport protein Slc27a2 deficiency or co-administration of PPARA agonist fenofibrate (20 mg/kg) prevented zoledronate-induced lipid accumulation and kidney fibrosis in mice, indicating that over-expression of fatty acid transporter SLC27A2 and defective fatty acid ß-oxidation following zoledronate treatments were significant factors contributing to its nephrotoxicity. These pharmacological and genetic studies provide an important mechanistic insight into zoledronate-associated kidney toxicity that will aid in development of therapeutic prevention and treatment options for this nephropathy.

Impact of Myocardial Bridge-mural Coronary Artery on Myocardial Functions.

Objective To study the impact of myocardial bridge (MB)-mural coronary artery (MCA) on myocardial functions.Methods Totally 82 patients presenting with chest tightness and chest pain who were diagnosed with the MB in the left anterior descending artery by CT coronary angiography were enrolled as the MB group,in which the thickness and length of MB and the systolic stenosis degree of MCA were measured.In addition,82 healthy subjects,as confirmed by health check-up,were set as the control group.The age,gender,body mass index (BMI),heart rate (HR),smoking history,interventricular septal thickness,left ventricular posterior wall thickness,diameter of left atrium,left ventricular end-diastolic diameter,left ventricular end-systolic diameter,left ventricular ejection fraction,and the cases of E'/A'<1 were compared between MB group and control group.The potential correlations among the thicken/length of MB,the systolic stenosis degree of MCA and early diastolic peak strain rate(SRe)/late diastolic peak strain rate(SRa) were analyzed.Results The age (t=0.97,P=0.65),gender (χ2=0.10,P=0.75),BMI (t=1.82,P=0.07),HR (t=0.87,P=0.39) and smoking history (χ2=0.43,P=0.51) were not significantly difference between these two group.The interventricular septal thickness (t=1.54,P=0.13),left ventricular posterior wall thickness (t=1.47,P=0.14),diameter of left atrium (t=1.62,P=0.11),left ventricular end-diastolic diameter (t=0.49,P=0.63),left ventricular end-systolic diameter (t=1.29,P=0.20),and left ventricular ejection fraction (t=0.56,P=0.57) were also not significantly different between the normal and MB group.However,there was significant difference in the cases of E'/A'<1 (χ2=38.22,P=0.00).The SRe (r=-0.97,P=0.00;r=-0.93,P=0.00)and SRa (r=-0.89,P=0.00;r=-0.90,P=0.00) the left ventricular anterior wall were negatively correlated with the thickness of MB and the systolic stenosis degree of MCA and were not correlated with the length of MB (r=-0.09,P=0.76;r=-0.13,P=0.66).Conclusions MB is not correlated with myocardial systolic function,but can affect myocardial diastolic function.When the MB thickness increases,the systolic stenosis degree of MCA increases,the myocardial diastolic function gradually decreases,but the MB length is not related to myocardial systolic function.

A network integration approach for drug-target interaction prediction and computational drug repositioning from heterogeneous information.

The emergence of large-scale genomic, chemical and pharmacological data provides new opportunities for drug discovery and repositioning. In this work, we develop a computational pipeline, called DTINet, to predict novel drug-target interactions from a constructed heterogeneous network, which integrates diverse drug-related information. DTINet focuses on learning a low-dimensional vector representation of features, which accurately explains the topological properties of individual nodes in the heterogeneous network, and then makes prediction based on these representations via a vector space projection scheme. DTINet achieves substantial performance improvement over other state-of-the-art methods for drug-target interaction prediction. Moreover, we experimentally validate the novel interactions between three drugs and the cyclooxygenase proteins predicted by DTINet, and demonstrate the new potential applications of these identified cyclooxygenase inhibitors in preventing inflammatory diseases. These results indicate that DTINet can provide a practically useful tool for integrating heterogeneous information to predict new drug-target interactions and repurpose existing drugs.Network-based data integration for drug-target prediction is a promising avenue for drug repositioning, but performance is wanting. Here, the authors introduce DTINet, whose performance is enhanced in the face of noisy, incomplete and high-dimensional biological data by learning low-dimensional vector representations.

Simvastatin ameliorates ionizing radiation-induced apoptosis in the thymus by activating the AKT/sirtuin 1 pathway in mice.

Simvastatin is a HMG-CoA reductase inhibitor widely used to lower plasma cholesterol and to protect against cardiovascular risk factors. The aim of this study was to investigate whether simvastatin attenuates ionizing radiation-induced damage in the mouse thymus and to elucidate the possible mechanisms invovled. For this purpose, male C57BL/6J mice aged 6 weeks were used and exposed to 4 Gy 60Co Î³-radiation with or without simvastatin (20 mg/kg/day, for 14 days). Apoptosis was determined by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) assay or transmission electron microscopy (TEM) examination. Thymocytes were also isolated and incubated in DMEM supplemented with 10% FBS at 37˚C and exposed to 8 Gy 60Co Î³-radiation with or without simvastatin (20 µM). The expression levels of Bcl-2, p53, p-p53, AKT, sirtuin 1 and poly(ADP-ribose) polymerase (PARP) were determined by western blot analysis. TUNEL and TEM examination revealed that simvastatin treatment significantly mitigated ionizing radiation-induced apoptosis in the mouse thymus. It was also found that simvastatin treatment increased AKT/sirtuin 1 expression following exposure to ionizing radiation in vivo and in vitro. In the in vivo model, but not in the in vitro model, Bcl-2 and PARP expression was augmented and that of p53/p-p53 decreased following treatment with simvastatin. On the whole, our findings indicate that simvastatin exerts a protective effect against ionizing radiation-induced damage in the mouse thymus, which may be partially attributed to the activation of the AKT/sirtuin 1 pathway.

Tenofovir and adefovir down-regulate mitochondrial chaperone TRAP1 and succinate dehydrogenase subunit B to metabolically reprogram glucose metabolism and induce nephrotoxicity.

Despite the therapeutic success of tenofovir (TFV) for treatment of HIV-1 infection, numerous cases of nephrotoxicity have been reported. Mitochondrial toxicity has been purported as the major target of TFV-associated renal tubulopathy but the underlying molecular mechanism remains unclear. In this report, we use metabolomics and proteomics with HK-2 cells and animal models to dissect the molecular pathways underlying nephropathy caused by TFV and its more toxic analog, adefovir (ADV). Proteomic analysis shows that mitochondrial chaperone TRAP1 and mtDNA replicating protein SSBP1 were significantly down-regulated in TFV and ADV treated HK-2 cells compared with controls. Transmission electron microscopy (TEM) revealed that TFV and ADV-treated HK-2 cells had accumulated glycogen, a phenotype that was also observed in mice treated with TFV and ADV. Analysis of the proteins in TCA cycle showed succinate dehydrogenase subunit B (SDHB) was nearly depleted in glucose oxidative phosphorylation pathway however certain enzymes in the glycolysis and glycogen synthesis pathway had elevated expression in TFV and ADV-treated HK-2 cells. These results suggest that TFV and ADV may cause mitochondrial dysfunction in renal tubular cells and reprogramming of glucose metabolism. The resulting glycogen accumulation may partially contribute to TFV and ADV induced renal dysfunction.

[Comparison between treadmill exercise test and stress-rest myocardial perfusion imaging in myocardial bridge with symptoms].

OBJECTIVE: To evaluate the feature and difference between treadmill exercise test (TET) and myocardial perfusion imaging (MPI) in myocardial bridge patients with symptoms.
 METHODS: The data from 97 patients, who underwent 256-slice CT coronary angiography (CTCA) on TET and MPI, were collected and analyzed retrospectively. The patients were divided into an incomplete MB group (n=41) and a complete MB group (n=56). They were also divided into three groups according to the narrow degree of mural coronary artery (MCA) during the cardiac systolic period (Nobel grade): a Nobel 1 grade group (n=44), a Nobel 2 grade group (n=42), and a Nobel 3 grade group (n=11). Besides, the abnormal TET and MPI patients were divided into a TET abnormal group (n=21) and a MPI abnormal group (n=31). The results of TET and MPI were compared among the total, the different MB type groups and the different Noble grade groups, while the complete MB thickness and length were also compared between the abnormal TET group and the MPI abnormal group.
 RESULTS: The positive rate of MPI (39/97) was higher than that of TET (26/97) in total (χ2=8.048, P<0.01). But there was no significant difference in the positive rate of TET (5/41) and MPI (8/41) in the incomplete group (χ2=1.000, P>0.05). There was a significant difference in the positive rate of TET (21/56) and MPI (31/56) in the complete MB group (χ2=8.333, P<0.01). There were significant difference in the positive rate of TET (6/44) and MPI (12/44) in the Noble 1 grade group (χ2=4.500, P<0.05), or TET (11/42) and MPI (18/42) in the Nobel 2 grade group (χ2=5.444, P<0.05). But there was no difference in Nobel 3 grade group (P>0.05). The complete MB thickness was (3.4±0.6) and (2.9±0.8) mm between the TET abnormal group and the MPI abnormal group, with statistically difference (t=2.229, P<0.05). But the MB length was (16.6±5.5) and (15.7±7.1) mm, with no statistical difference (t=0.489, P>0.05).
 CONCLUSION: MPI is more sensitive than TET in myocardial ischemia in patients with MB, especially to complete MB and mild-to-moderate systolic narrowing of MCA. The positive rate is low to incomplete MB, and it is highly sensitive to severe systolic narrowing of MCA. There is difference in the MB thickness between the two methods, but there is no difference in the MB length between the two methods.

Establishment of local searching methods for orbitrap-based high throughput metabolomics analysis.

Our method aims to establish local endogenous metabolite databases economically without purchasing chemical standards, giving strong bases for following orbitrap based high throughput untargeted metabolomics analysis. A new approach here is introduced to construct metabolite databases on the base of biological sample analysis and mathematic extrapolation. Building local metabolite databases traditionally requires expensive chemical standards, which is barely affordable for most research labs. As a result, most labs working on metabolomics analysis have to refer public libraries, which is time consuming and limited for high throughput analysis. Using this strategy, a high throughput orbitrap based metabolomics platform can be established at almost no cost within a couple of months. It enables to facilitate the application of high throughput metabolomics analysis to identify disease-related biomarkers or investigate biological functions using orbitrap.

Inhibitor Discovery for the Human GLUT1 from Homology Modeling and Virtual Screening.

The human Glucose Transporter 1 (hGLUT1 or SLC2A1) is a facilitative membrane transporter found in the liver, intestines, kidney, and brain, where it transports sugars such as d-glucose and d-galactose. Genetic variations in hGLUT1 are associated with a broad range of diseases and metabolic disorders. For example, hGLUT1 is upregulated in various cancer types (e.g., breast carcinoma) to support the increased anaerobic glycolysis and the Warburg effect. Thus, hGLUT1 is an emerging therapeutic target, which also transports commonly used cancer biomarkers (e.g., (18)F-DG). In this study, we use computational prediction followed by experimental testing, to characterize hGLUT1. We construct homology models of hGLUT1 in a partially occluded outward open ("occluded") conformation based on the X-ray structure of the E. coli xylose transporter, XylE. Comparison of the binding site of the occluded models to experimentally determined hGLUT structures revealed a hydrophobic pocket adjacent to the sugar-binding site, which was tested experimentally via site-directed mutagenesis. Virtual screening of various libraries of purchasable compounds against the occluded models, followed by experimental testing with cellular assays revealed seven previously unknown hGLUT1 ligands with IC50 values ranging from 0.45 µM to 59 µM. These ligands represent three unique chemotypes that are chemically different from any other known hGLUT1 ligands. The newly characterized hydrophobic pocket can potentially be utilized by the new ligands for increased affinity. Furthermore, the previously unknown hGLUT1 ligands can serve as chemical tools to further characterize hGLUT1 function or lead molecules for future drug development.

Impact of Myocardial Bridge-mural Coronary Artery on Myocardial Blood Supply.

Objective To explore the impact of myocardial bridge-mural coronary artery (MB-MCA) on myocardial blood supply. Methods The imaging data of 74 patients with the isolate MB in the left anterior descending artery undergoing 256-slice CT coronary angiography and myocardial perfusion imaging (MPI) were retrospectively analyzed. The subjects were divided into incomplete and complete MB types. The length of MB and the systolic stenosis degree of MCA were measured.The type and length of MB and the systolic stenosis degree of MCA (according to Noble grade) were compared between the normal and abnormal MPI groups. The clinical characteristics including age, gender, body mass index, hypertension, dyslipidemia, diabetes mellitus, and smoking history were also reviewed. Results There were 38 incomplete MB cases and 13 complete MB cases in the normal MPI group,and 5 and 18 in the abnormal MPI group (χ2=18.134,P=0.000). The MB length in the normal and abnormal MPI group were (14.7±3.7) mm and (15.5±4.5) mm (t=0.804,P=0.424). However, the systolic stenosis degree of MCA showed significant difference (χ2=17.839,P=0.000). The clinical characteristics were not significantly differentt between the normal and abnormal MPI groups (P>0.05). Conclusions The MB type and the systolic stenosis degree of MCA can affect myocardial perfusion.Patients with complete MB and the moderate-to-severe systolic stenosis degree of MCA are more susceptible to myocardial ischemia. However, the MB length is not correlated with myocardial ischemia.

Activation of alpha 7 nicotinic acetylcholine receptor protects mice from radiation-induced intestinal injury and mortality.

Radiation-induced gastrointestinal syndrome occurs when the body is exposed to a high dose of radiation. Currently, safe and effective radioprotectants are not available. Apoptosis was reported to play a primary role in radiation-induced injury. Recent evidence suggests that stimulation of α7 nicotinic acetylcholine receptor (α7nAChR) prevents cell death by inhibition of apoptosis. In this study, we demonstrated that a single dose of PNU282987 (100 µg/kg, i.p.), a selective α7nAChR agonist, protected mice from intestinal injury and significantly improved survival when administered prior to lethal 8 Gy total body irradiation. In vitro, PNU282987 protected against 8 Gy radiation-induced cell death in human umbilical venous endothelial cells by inhibiting apoptosis. We conclude that activation of α7nAChR may provide a new therapeutic pathway for the treatment of radiation-induced damage and mortality.

Simvastatin attenuates radiation-induced tissue damage in mice.

The aim of this study was to investigate the protective effect of simvastatin against radiation-induced tissue injury in mice. Mice were radiated with 4 Gy or 8 Gy after 20 mg/kg/d simvastatin treatment over 2 weeks. Morphological changes were observed in the jejunum and bone marrow, and apoptotic cells were determined in both tissues. Peripheral blood cells were counted, and the superoxide dismutase (SOD) activity and the malondialdehyde (MDA) level in tissues of both thymus and spleen were measured. Compared with the radiation-only group, 20 mg/kg/d simvastatin administration significantly increased the mean villi height and decreased apoptotic cells in jejunum tissue, and stimulated regeneration and reduced apoptotic cells in bone marrow. Peripheral blood cell analysis revealed that simvastatin treatment induced a larger number of red blood cells and increased the hemoglobin level present after 4 Gy of radiation. Interestingly, it was also found that the number of peripheral endothelial progenitor cells was markedly increased following simvastatin administration. Antioxidant determination for tissues displayed that simvastatin therapy increased the SOD activity after both 4 and 8 Gy of radiation, but only decreased the MDA level after 4 Gy. Simvastatin ameliorated radiation-induced tissue damage in mice. The radioprotective effect of simvastatin was possibly related to inhibition of apoptosis and improvement of oxygen-carrying and antioxidant activities.