Feasibility study of multimodal imaging for redox status and glucose metabolism in tumor.

Understanding the tumor redox status is important for efficient cancer treatment. Here, we noninvasively detected changes in the redox environment of tumors before and after cancer treatment in the same individuals using a novel compact and portable electron paramagnetic resonance imaging (EPRI) device and compared the results with glycolytic information obtained through autoradiography using 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG). Human colon cancer HCT116 xenografts were used in the mice. We used 3-carbamoyl-PROXYL (3CP) as a paramagnetic and redox status probe for the EPRI of tumors. The first EPRI was followed by the intraperitoneal administration of buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, or X-ray irradiation of the tumor. A second EPRI was performed on the following day. Autoradiography was performed after the second EPRI. After imaging, the tumor sections were evaluated by histological analysis and the amount of reducing substances in the tumor was measured. BSO treatment and X-ray irradiation significantly decreased the rate of 3CP reduction in tumors. Redox maps of tumors obtained from EPRI can be compared with tissue sections of approximately the same cross section. BSO treatment reduced glutathione levels in tumors, whereas X-ray irradiation did not alter the levels of any of the reducing substances. Comparison of the redox map with the autoradiography of [18F]FDG revealed that regions with high reducing power in the tumor were active in glucose metabolism; however, this correlation disappeared after X-ray irradiation. These results suggest that the novel compact and portable EPRI device is suitable for multimodal imaging, which can be used to study tumor redox status and therapeutic efficacy in cancer, and for combined analysis with other imaging modalities.

Progression of albuminuria and podocyte injury in focal segmental glomerulosclerosis inhibited by enhanced glycosphingolipid GM3 via valproic acid.

Focal segmental glomerulosclerosis, characterized by decreased numbers of podocytes in glomeruli, is a common cause of refractory nephrotic syndrome. Recently, we showed that enhanced glycosphingolipid GM3 expression after administration of valproic acid, an upregulator of ST3GAL5/St3gal5, was effective in preventing albuminuria and podocyte injury. We also revealed the molecular mechanism for this preventive effect, which involves GM3 directly binding nephrin that then act together in glycolipid-enriched membrane (GEM) fractions under normal conditions and in non-GEM fractions under nephrin injury conditions. Kidney disease is frequently referred to as a "silent killer" because it is often difficult to detect subjective symptoms. Thus, primary treatment for these diseases is initiated after the onset of disease progression. Consequently, the efficacy of enhanced levels of GM3 induced by valproic acid needs to be evaluated after the onset of the disease with severe albuminuria such as focal segmental glomerulosclerosis. Here, we report the therapeutic effect of enhanced GM3 expression induced via administration of valproic acid on albuminuria and podocyte injury after the onset focal segmental glomerulosclerosis in anti-nephrin antibody treated mice. Our findings suggest elevated levels of GM3 following treatment with valproic acid has therapeutic utility for kidney disease associated with severe albuminuria and podocyte injury.

Effects of low concentrations of ozone gas exposure on percutaneous oxygen saturation and inflammatory responses in a mouse model of Dermatophagoides farinae-induced asthma.

Ozone gas is widely used in hospitals as well as homes to control COVID-19 infection owing to its cost-effectiveness. Safety standard value and the tolerable value of ozone gas are set at 0.05 ppm and 0.1 ppm, respectively, in developed countries; however, this value was principally determined for healthy individuals, and the risks associated with ozone gas inhalation in patients with pulmonary diseases remains unknown. Recently, we demonstrated that 0.1 ppm ozone gas exposure significantly aggravates the symptoms of acute lung injury in mice. In the present study, we further examined the influence of ≤ 0.1 ppm ozone gas exposure on percutaneous oxygen saturation (SpO2) and pro-inflammatory responses in a mouse model of asthma. Female BALB/c mice were subjected to repetitive intranasal sensitization of Dermatophagoides farinae to generate a mouse model of asthma. Inhalation exposure of ozone gas (0.1, 0.03, 0.01 ppm), generated using an ultraviolet lamp, was performed for five consecutive days immediately before the final sacrifice. There were no abnormal findings in control mice exposed to 0.1 ppm ozone; however, 0.1 ppm ozone exposure significantly reduced the SpO2 level in asthmatic mice. Histological evaluation and gene expression analysis revealed that pro-inflammatory cytokine levels were significantly increased in mice exposed to 0.1 ppm ozone, indicating that 0.1 ppm ozone exposure affects the development of asthma symptoms. Notably, 0.03 and 0.01 ppm ozone exposure did not have any effects even in asthmatic mice. Our findings indicate that the tolerable level of ozone gas should be adjusted for individuals based on a history of respiratory disorders.

Therapeutic potential of ozone water treatment in alleviating atopic dermatitis symptoms in mouse models: Exploring its bactericidal and direct anti-inflammatory properties.

Currently, ozone water is utilized for antibacterial and antiviral purposes without any reported safety concerns. Therefore, ozone water may have clinical applications in treating staphylococcal-specific cutaneous diseases, such as atopic dermatitis (AD) and pyoderma. This study aimed to verify the bactericidal effects of ozone water at different concentrations (3 and 11 mg/L) against staphylococcal species in vitro, as well as evaluate the anti-inflammatory effects of ozone water in a mouse model of AD and pyoderma. Initially, the bactericidal properties of several concentrations of ozone water were confirmed with Staphylococcus aureus and methicillin-resistant S. pseudintermedius. Both 3 and 11 mg/L of ozone water exhibited a significant bactericidal effect against staphylococci at less than 100 times dilution. We next examined the cellular cytotoxicity and cytokine production (Interleukin (IL)-6 and IL-8) induced by S. pseudintermedius pre-treated with ozone water, and our findings indicated that cytotoxicity and cytokine production induced by staphylococci were significantly inhibited after ozone water pre-treatment. In vivo experiments showed that ozone water-pre-treated S. pseudintermedius significantly inhibited the development of pyoderma in mice; however, limited effects were observed in a therapeutic setting. Interestingly, ozone water at concentrations of 3 and 11 mg/L exhibits dual bactericidal and anti-inflammatory effects in mice with AD. This observation was corroborated by the significant inhibition of cytokine production in interferon-γ/tumor necrosis factor-stimulated human epidermal keratinocyte cells exposed to ozone in vitro. These findings indicate that administering ozone can be a novel therapeutic approach for managing allergic skin diseases, such as AD.

Chronic oral exposure to low-concentration fumonisin B2 significantly exacerbates the inflammatory responses of allergies in mice via inhibition of IL-10 release by regulatory T cells in gut-associated lymphoid tissue.

Contamination with fumonisins produced by Fusarium spp. is rapidly growing in both developing and developed countries. The purpose of this study was to determine whether oral exposure to fumonisin contributed to the development of allergic diseases. We initially examined the immunotoxic potential of short-term, oral administration of fumonisin B1 (FB1, 1 mg/kg) and fumonisin B2 (FB2, 1 mg/kg), both naturally occurring fumonisins, using a BALB/c mouse model of allergic contact dermatitis and Dermatophagoides farina-induced asthma. Using an NC/nga mouse model of atopic dermatitis (AD), we evaluated the adverse effects of subchronic oral exposure to low concentrations of FB2 (2 or 200 µg/kg). Finally, we explored the influence of FB2 on regulatory T cell proliferation and function in mesenteric lymph nodes after 1-week oral exposure to FB2 in BALB/c mice. Oral exposure to FB2 markedly exacerbated the symptoms of allergy, including skin thickness, histological evaluation, immunocyte proliferation, and proinflammatory cytokine production, although no change was observed following exposure to FB1. Furthermore, oral exposure to low concentrations of FB2 considerably exacerbated the AD scores, skin thickness, transepidermal water loss, histological features, and proinflammatory cytokine production. The aggravated allergic symptoms induced by oral exposure to FB2 could be attributed to the direct inhibition of IL-10 production by regulatory T cells in mesenteric lymph nodes. Our findings indicate that the recommended maximum fumonisin level should be reconsidered based on the potential for allergy development.

Prebiotic effect of poly-D-3-hydroxybutyrate prevents dyslipidemia in obese mice.

Obesity is a global health problem caused by genetic, environmental, and psychological factors and is associated with various health disorders. As such, there is a growing focus on the prevention of obesity and related diseases. The gut microbiota plays a crucial role in these diseases and has become a therapeutic target. Prebiotics, such as poly-d-3-hydroxybutyric acid (PHB), have gained attention for their potential to alter the gut microbiota, promote beneficial bacterial growth, and alleviate obesity. In this study, we examined the prebiotic effects of PHB in obese mice. We found that, in C57BL/6N mice, PHB reduced blood lipid levels. Analysis of the intestinal microflora also revealed an increase in short-chain fatty acid-producing bacteria. When PHB was administered to obese mice, subcutaneous fat and dyslipidemia were reduced, and the number of beneficial bacteria in the intestinal microflora increased. Furthermore, fatty degradation and oxidative stress were suppressed in the liver. PHB regulates gut bacterial changes related to obesity and effectively inhibits dyslipidemia, suggesting that it could be a prebiotic agent for curing various obesity-related diseases. In summary, PHB increases the beneficial gut microbiota, leading to an alleviation of obesity-associated dyslipidemia.

Identification of Methylsulochrin as a Partial Agonist for Aryl Hydrocarbon Receptors and Its Antiviral and Anti-inflammatory Activities.

Although aryl hydrocarbon receptors (AhRs) are related to the metabolic pathway of xenobiotics, recent studies have revealed that this receptor is also associated with the life cycle of viruses and inflammatory reactions. For example, flutamide, used to treat prostate cancer, inhibits hepatitis C virus proliferation by acting as an AhR antagonist, and methylated-pelargonidin, an AhR agonist, suppresses pro-inflammatory cytokine production. To discover a novel class of AhR ligands, we screened 1000 compounds derived from fungal metabolites using a reporter assay and identified methylsulochrin as a partial agonist of the aryl hydrocarbon receptor. Methylsulochrin was found to inhibit the production of hepatitis C virus (HCV) in Huh-7.5.1 cells. Methylsulochrin also suppressed the production of interleukin-6 in RAW264.7 cells. Furthermore, a preliminary structure-activity relationship study using sulochrin derivatives was performed. Our findings suggest the use of methylsulochrin derivatives as anti-HCV compounds with anti-inflammatory activity.

Ganglioside GM3 deficiency enhances mast cell sensitivity.

Mast cells are a significant source of cytokines and chemokines that play a role in pathological processes. Gangliosides, which are complex lipids with a sugar chain, are present in all eukaryotic cell membranes and comprise lipid rafts. Ganglioside GM3, the first ganglioside in the synthetic pathway, is a common precursor of the specifying derivatives and is well known for its various functions in biosystems. Mast cells contain high levels of gangliosides; however, the involvement of GM3 in mast cell sensitivity is unclear. Therefore, in this study, we elucidated the role of ganglioside GM3 in mast cells and skin inflammation. GM3 synthase (GM3S)-deficient mast cells showed cytosolic granule topological changes and hyperactivation upon IgE-DNP stimulation without affecting proliferation and differentiation. Additionally, inflammatory cytokine levels increased in GM3S-deficient bone marrow-derived mast cells (BMMC). Furthermore, GM3S-KO mice and GM3S-KO BMMC transplantation showed increased skin allergic reactions. Besides mast cell hypersensitivity caused by GM3S deficiency, membrane integrity decreased and GM3 supplementation rescued this loss of membrane integrity. Additionally, GM3S deficiency increased the phosphorylation of p38 mitogen-activated protein kinase. These results suggest that GM3 increases membrane integrity, leading to the suppression of the p38 signalling pathway in BMMC and contributing to skin allergic reaction.

The novel sustained 3-hydroxybutyrate donor poly-D-3-hydroxybutyric acid prevents inflammatory bowel disease through upregulation of regulatory T-cells.

Inflammatory bowel disease (IBD) is a chronic persistent intestinal disorder, with ulcerative colitis and Crohn's disease being the most common. However, the physio-pathological development of IBD is still unknown. Therefore, research on the etiology and treatment of IBD has been conducted using a variety of approaches. Short-chain fatty acids such as 3-hydroxybutyrate (3-HB) are known to have various physiological activities. In particular, the production of 3-HB by the intestinal microflora is associated with the suppression of various inflammatory diseases. In this study, we investigated whether poly-D-3-hydroxybutyric acid (PHB), a polyester of 3-HB, is degraded by intestinal microbiota and works as a slow-release agent of 3-HB. Further, we examined whether PHB suppresses the pathogenesis of IBD models. As long as a PHB diet increased 3-HB concentrations in the feces and blood, PHB suppressed weight loss and histological inflammation in a dextran sulfate sodium-induced IBD model. Furthermore, PHB increased the accumulation of regulatory T cells in the rectum without affecting T cells in the spleen. These results indicate that PHB has potential applications in treating diseases related to the intestinal microbiota as a sustained 3-HB donor. We show for the first time that biodegradable polyester exhibits intestinal bacteria-mediated bioactivity toward IBD. The use of bioplastics, which are essential materials for sustainable social development, represents a novel approach to diseases related to dysbiosis, including IBD.

Cyclic Phthalate Esters as Liver X Receptor Antagonists with Anti-hepatitis C Virus and Anti-severe Acute Respiratory Syndrome Coronavirus 2 Properties.

The liver X receptor is a nuclear hormone receptor that regulates lipid metabolism. Previously, we had demonstrated the antiviral properties of a liver X receptor antagonist associated with the hepatitis C virus and severe acute respiratory syndrome coronavirus 2. In this study, we screened a chemical library and identified two potential liver X receptor antagonists. Spectroscopic analysis revealed that the structures of both antagonists (compounds 1 and 2) were cyclic dimer and trimer of esters, respectively, that consisted of phthalate and 1,6-hexane diol. This study is the first to report the structure of the cyclic trimer of phthalate ester. Further experiments revealed that the compounds were impurities of solvents used for purification, although their source could not be traced. Both phthalate esters exhibited anti-hepatitis C virus activity, whereas the cyclic dimer showed anti-severe acute respiratory syndrome coronavirus 2 activity. Cyclic phthalate derivatives may constitute a novel class of liver X receptor antagonists and broad-spectrum antivirals.

Glycosphingolipid GM3 prevents albuminuria and podocytopathy induced by anti-nephrin antibody.

Podocytopathy, which is characterized by injury to podocytes, frequently causes proteinuria or nephrotic syndrome. There is currently a paucity of effective therapeutic drugs to treat proteinuric kidney disease. Recent research suggests the possibility that glycosphingolipid GM3 maintains podocyte function by acting on various molecules including nephrin, but its mechanism of action remains unknown. Here, various analyses were performed to examine the potential relationship between GM3 and nephrin, and the function of GM3 in podocytes using podocytopathy mice, GM3 synthase gene knockout mice, and nephrin injury cells. Reduced amounts of GM3 and nephrin were observed in podocytopathy mice. Intriguingly, this reduction of GM3 and nephrin, as well as albuminuria, were inhibited by administration of valproic acid. However, when the same experiment was performed using GM3 synthase gene knockout mice, valproic acid administration did not inhibit albuminuria. Equivalent results were obtained in model cells. These findings indicate that GM3 acts with nephrin in a collaborative manner in the cell membrane. Taken together, elevated levels of GM3 stabilize nephrin, which is a key molecule of the slit diaphragm, by enhancing the environment of the cell membrane and preventing albuminuria. This study provides novel insight into new drug discovery, which may offer a new therapy for kidney disease with albuminuria.

Relationship of parathyroid hormone-related protein and neonatal mineral metabolism in dairy cow placentas.

Parathyroid hormone-related protein (PTHrP) plays essential roles in placental calcium (Ca) transport, and it has been speculated that PTHrP in the placenta is regulated by calcium-sensing receptors (CaSR). This study clarified the relationship between PTHrP in the placenta of dairy cows and minerals in the fetal blood. Blood samples were obtained from 21 Holstein cows and 17 neonatal calves as well as 12 umbilical veins and arteries during cesarean section. After fetus removal, 13 caruncles and cotyledons were obtained. Concentrations of plasma PTHrP and serum minerals were measured. Real-time polymerase chain reaction (RT-qPCR) analyzed the gene expression of PTHrP and CaSR in the placenta. As a result, serum Ca and inorganic phosphorus concentrations in the neonate, umbilical vein, and artery were significantly higher than in the mother. Additionally, plasma PTHrP was detected in the bovine neonatal jugular vein, umbilical artery, and vein. PTHrP gene expression was significantly higher in the caruncles than in cotyledons; however, CaSR gene expression was higher in the cotyledons than in caruncles. These findings suggest that the PTHrP obtained from the placenta influences Ca homeostasis in the bovine fetus.

Sphingomyelin maintains the cutaneous barrier via regulation of the STAT3 pathway.

Epidermal tissues play vital roles in maintaining homeostasis and preventing the dysregulation of the cutaneous barrier. Sphingomyelin (SM), a sphingolipid synthesized by sphingomyelin synthase (SMS) 1 and 2, is involved in signal transduction via modulation of lipid-raft functions. Though the implications of SMS on inflammatory diseases have been reported, its role in dermatitis has not been clarified. In this study, we investigated the role of SM in the cutaneous barrier using a dermatitis model established by employing Sgms1 and 2 deficient mice. SM deficiency impaired the cutaneous inflammation and upregulated signal transducer and activator of transcription 3 (STAT3) phosphorylation in epithelial tissues. Furthermore, using mouse embryonic fibroblast cells, the sensitivity of STAT3 to Interleukin-6 stimulation was increased in Sgms-deficient cells. Using tofacitinib, a clinical JAK inhibitor, the study showed that SM deficiency might participate in STAT3 phosphorylation via JAK activation. Overall, these results demonstrate that SM is essential for maintaining the cutaneous barrier via the STAT3 pathway, suggesting SM could be a potential therapeutic target for dermatitis treatment.

Glucosylceramide in T cells regulates the pathology of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease in the colon characterized by excessive activation of T cells. Glycosphingolipids (GSLs) are composed of lipid rafts in cellular membranes, and their content is linked to immune cell function. In the present study, we investigated the involvement of GSLs in IBD. Microarray data showed that in IBD patients, the expression of only UDP-glucose ceramide glucosyltransferase (UGCG) decreased among the GSLs synthases. Ad libitum access to dextran sulfate sodium (DSS) resulted in decreased UGCG and glucosylceramide (GlcCer) content in mesenteric lymph nodes and T cells from the spleen. Furthermore, the knockdown of Ugcg in T cells exacerbated the pathogenesis of colitis, which was accompanied by a decrease in Treg levels. Treatment with GlcCer nanoparticles prevented DSS-induced colitis. These results suggested that GlcCer in T cells is involved in the pathogenesis of IBD. Furthermore, GlcCer nanoparticles are a potential efficacious therapeutic target for IBD patients.

Flower lose, a cell fitness marker, predicts COVID-19 prognosis.

Risk stratification of COVID-19 patients is essential for pandemic management. Changes in the cell fitness marker, hFwe-Lose, can precede the host immune response to infection, potentially making such a biomarker an earlier triage tool. Here, we evaluate whether hFwe-Lose gene expression can outperform conventional methods in predicting outcomes (e.g., death and hospitalization) in COVID-19 patients. We performed a post-mortem examination of infected lung tissue in deceased COVID-19 patients to determine hFwe-Lose's biological role in acute lung injury. We then performed an observational study (n = 283) to evaluate whether hFwe-Lose expression (in nasopharyngeal samples) could accurately predict hospitalization or death in COVID-19 patients. In COVID-19 patients with acute lung injury, hFwe-Lose is highly expressed in the lower respiratory tract and is co-localized to areas of cell death. In patients presenting in the early phase of COVID-19 illness, hFwe-Lose expression accurately predicts subsequent hospitalization or death with positive predictive values of 87.8-100% and a negative predictive value of 64.1-93.2%. hFwe-Lose outperforms conventional inflammatory biomarkers and patient age and comorbidities, with an area under the receiver operating characteristic curve (AUROC) 0.93-0.97 in predicting hospitalization/death. Specifically, this is significantly higher than the prognostic value of combining biomarkers (serum ferritin, D-dimer, C-reactive protein, and neutrophil-lymphocyte ratio), patient age and comorbidities (AUROC of 0.67-0.92). The cell fitness marker, hFwe-Lose, accurately predicts outcomes in COVID-19 patients. This finding demonstrates how tissue fitness pathways dictate the response to infection and disease and their utility in managing the current COVID-19 pandemic.

Endothelial ganglioside GM3 regulates angiogenesis in solid tumors.

Cancer cells require oxygen and nutrients for growth, making angiogenesis one of the essential components of tumor growth. Gangliosides, constituting membrane lipid rafts, regulate intracellular signal transduction and are involved in the malignancy of cancer cells. While endothelial cells, as well as cancer cells, express vast amounts of gangliosides, the precise function of endothelial gangliosides in angiogenesis remains unclear. In this study, we focused on gangliosides of vascular endothelial cells and analyzed their functions on tumor angiogenesis. In human breast cancer, GM3 synthase was highly expressed in vascular endothelial cells as well as immune cells. Angiogenesis increased in GM3S-KO mice. In BAEC, RNA interference of GM3S showed increased cellular invasion and oxidative stress tolerance through activation of ERK. In the breast cancer model, GM3-KO mice showed an increase in tumor growth and angiogenesis. These results suggest that the endothelial ganglioside GM3 regulates tumor angiogenesis by suppressing cellular invasion and oxidative stress tolerance in endothelial cells.

Lipid-soluble polyphenols from sweet potato exert antitumor activity and enhance chemosensitivity in breast cancer.

Polyphenols are abundant in vegetables and fruit. They have been shown to have various antitumor, antioxidant, and anti-inflammatory effects. Here, we extracted the lipid-soluble fraction of polyphenols from fermented sweet potato (Ipomoea batatas). These lipid-soluble polyphenols mainly contained caffeic acid derivatives with strong antioxidant ability, which we hypothesized to affect diseases for which oxidative stress is a factor, such as cancer. We therefore investigated the antitumor and chemo-sensitizing effects of lipid-soluble polyphenols on E0771 murine breast cancer cells. The lipid-soluble polyphenols accumulated in the cells' cytoplasm due to its high lipophilicity, and reduced reactive oxygen species through its strong antioxidant activity. The lipid-soluble polyphenols also arrested the cell cycle at G0/G1 by suppressing Akt activity, and enhanced the cytotoxicity of anticancer agents. In this model, lipid-soluble polyphenols inhibited tumor growth and enhanced the efficacy of chemotherapy drugs. These results suggest the potential of lipid-soluble polyphenols as a functional food to support cancer therapy.

Volatile Anesthetic Sevoflurane Precursor 1,1,1,3,3,3-Hexafluoro-2-Propanol (HFIP) Exerts an Anti-Prion Activity in Prion-Infected Culture Cells.

Prion disease is a neurodegenerative disorder with progressive neurologic symptoms and accelerated cognitive decline. The causative protein of prion disease is the prion protein (PrP), and structural transition of PrP from the normal helix rich form (PrPC) to the abnormal ß-sheet rich form (PrPSc) occurs in prion disease. While so far numerous therapeutic agents for prion diseases have been developed, none of them are still useful. A fluorinated alcohol, hexafluoro isopropanol (HFIP), is a precursor to the inhalational anesthetic sevoflurane and its metabolites. HFIP is also known as a robust α-helix inducer and is widely used as a solvent for highly aggregated peptides. Here we show that the α-helix-inducing activity of HFIP caused the conformational transformation of the fibrous structure of PrP into amorphous aggregates in vitro. HFIP added to the ScN2a cell medium, which continuously expresses PrPSc, reduced PrPSc protease resistance after 24-h incubation. It was also clarified that ScN2a cells are more susceptible to HFIP than any of the cells being compared. Based on these findings, HFIP is expected to develop as a therapeutic agent for prion disease.

DNA damage response in vascular endothelial senescence: Implication for radiation-induced cardiovascular diseases.

A post-exposure cohort study in Hiroshima and Nagasaki reported that low-dose exposure to radiation heightened the risk of cardiovascular diseases (CVD), such as stroke and myocardial infarction, by 14-18% per Gy. Moreover, the risk of atherosclerosis in the coronary arteries reportedly increases with radiation therapy of the chest, including breast and lung cancer treatment. Cellular senescence of vascular endothelial cells (ECs) is believed to play an important role in radiation-induced CVDs. The molecular mechanism of age-related cellular senescence is believed to involve genomic instability and DNA damage response (DDR); the chronic inflammation associated with senescence causes cardiovascular damage. Therefore, vascular endothelial cell senescence is believed to induce the pathogenesis of CVDs after radiation exposure. The findings of several prior studies have revealed that ionizing radiation (IR) induces cellular senescence as well as cell death in ECs. We have previously reported that DDR activates endothelial nitric oxide (NO) synthase, and NO production promotes endothelial senescence. Endothelial NO synthase (eNOS) is a major isoform expressed in ECs that maintains cardiovascular homeostasis. Therefore, radiation-induced NO production, a component of the DDR in ECs, may be involved in CVDs after radiation exposure. In this article, we describe the pathology of radiation-induced CVD and the unique radio-response to radiation exposure in ECs.

Tumor hypoxia regulates ganglioside GM3 synthase, which contributes to oxidative stress resistance in malignant melanoma.

BACKGROUND: Tumor hypoxia drastically changes cancer phenotypes, including angiogenesis, invasion, and cell death. Gangliosides are sialic acid-containing glycosphingolipids that are ubiquitously distributed on plasma membranes and are involved in many biological processes, such as the endoplasmic reticulum stress response and apoptosis. In this study, we investigated the regulation and function of glycosphingolipids, which associate with lipid raft on mammalian plasma membranes under hypoxic condition. METHODS: B16F10 melanoma cells were subjected to chemical hypoxia and low pO2 condition, and the effect of hypoxia on expression of GM3 synthase were analyzed. Cellular resistance to oxidative stress was analyzed in GM3S-KO B16F10 cells. RESULTS: Hypoxia treatment decreased the expression of ganglioside GM3 synthase (GM3S; ST3GAL5), which synthesizes the common substrate of ganglioside biosynthesis. RNA interference of hypoxia inducible factor 1 subunit alpha (HIF-1α) inhibited hypoxia-induced GM3S suppression. Additionally, GM3S deficiency increased cellular resistance to oxidative stress and radiation therapy via upregulation of ERK. CONCLUSIONS: Altered synthesis of glycosphingolipids downstream of HIF-1α signaling increased the resistance of melanoma cells to oxidative stress. Furthermore, GM3 has important role on cellular adaptive response to hypoxia. GENERAL SIGNIFICANCE: This study indicates that tumor hypoxia regulates therapy-resistance via modulation of ganglioside synthesis.