An ependymin-related blue carotenoprotein decorates marine blue sponge.

Marine animals display diverse vibrant colors, but the mechanisms underlying their specific coloration remain to be clarified. Blue coloration is known to be achieved through a bathochromic shift of the orange carotenoid astaxanthin (AXT) by the crustacean protein crustacyanin, but other examples have not yet been well investigated. Here, we identified an ependymin (EPD)-related water-soluble blue carotenoprotein responsible for the specific coloration of the marine blue sponge Haliclona sp. EPD was originally identified in the fish brain as a protein involved in memory consolidation and neuronal regeneration. The purified blue protein, designated as EPD-related blue carotenoprotein-1, was identified as a secreted glycoprotein. We show that it consists of a heterodimer that binds orange AXT and mytiloxanthin and exhibits a bathochromic shift. Our crystal structure analysis of the natively purified EPD-related blue carotenoprotein-1 revealed that these two carotenoids are specifically bound to the heterodimer interface, where the polyene chains are aligned in parallel to each other like in ß-crustacyanin, although the two proteins are evolutionary and structurally unrelated. Furthermore, using reconstitution assays, we found that incomplete bathochromic shifts occurred when the protein bound to only AXT or mytiloxanthin. Taken together, we identified an EPD in a basal metazoan as a blue protein that decorates the sponge body by binding specific structurally unrelated carotenoids.

An efficient selenium transport pathway of selenoprotein P utilizing a high-affinity ApoER2 receptor variant and being independent of selenocysteine lyase.

Selenoprotein P (SeP, encoded by the SELENOP gene) is a plasma protein that contains selenium in the form of selenocysteine residues (Sec, a cysteine analog containing selenium instead of sulfur). SeP functions for the transport of selenium to specific tissues in a receptor-dependent manner. Apolipoprotein E receptor 2 (ApoER2) has been identified as a SeP receptor. However, diverse variants of ApoER2 have been reported, and the details of its tissue specificity and the molecular mechanism of its efficiency remain unclear. In the present study, we found that human T lymphoma Jurkat cells have a high ability to utilize selenium via SeP, while this ability was low in human rhabdomyosarcoma cells. We identified an ApoER2 variant with a high affinity for SeP in Jurkat cells. This variant had a dissociation constant value of 0.67 nM and a highly glycosylated O-linked sugar domain. Moreover, the acidification of intracellular vesicles was necessary for selenium transport via SeP in both cell types. In rhabdomyosarcoma cells, SeP underwent proteolytic degradation in lysosomes and transported selenium in a Sec lyase-dependent manner. However, in Jurkat cells, SeP transported selenium in Sec lyase-independent manner. These findings indicate a preferential selenium transport pathway involving SeP and high-affinity ApoER2 in a Sec lyase-independent manner. Herein, we provide a novel dynamic transport pathway for selenium via SeP.

Multiple pneumatoceles and lung abscesses caused by early-onset E. coli sepsis in a preterm neonate.

Early-onset sepsis (EOS) is a serious and fatal illness in neonates, Group B Streptococcus and Escherichia coli are major causative pathogens. We report a case of EOS and pneumonia caused by E. coli in a preterm neonate with multiple pneumatoceles and lung abscesses. A male neonate weighing 1670g was delivered at 33 6/7 weeks' gestation by a mother with clinical chorioamnionitis. He showed respiratory distress soon after birth and developed septic shock. He was intubated and mechanical ventilation was started. E.coli was detected in blood culture obtained from both the patient and his mother. He developed multiple pneumatoceles and lung abscesses. Surgical drainage was complicated, cefotaxime was thus continued until day 74. Pneumatoceles and lung abscesses are complications of neonatal pneumonia, rarely reported by E. coli. Multiple lung abscesses in our patient are distinct from single abscesses in previous case studies of neonatal lung abscesses. We speculate that bacteremia along with pneumatoceles led to multiple lung abscesses in our patient. These complications require long-term antibiotic therapy, to minimize morbidity and mortality, and should thus be considered when managing EOS caused by E. coli.

Thyroid function in asphyxiated newborns who received hypothermia therapy.

BACKGROUND: Thyroid function in asphyxiated newborns who received hypothermia therapy and its relation to neurological outcome are not well described. METHODS: We performed a prospective study to measure thyroid function in 12 asphyxiated newborns who received hypothermia therapy. We measured serum thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) on admission, at 24, 72, and 96 h after birth, and at discharge (range, 17-54 days). The 12 newborns were divided into two groups based on the presence of brain injury on head magnetic resonance imaging (six in the abnormal imaging group and six in the normal imaging group), and thyroid function was compared between the two groups. RESULTS: Serum TSH was within the normal range in the 12 newborns. Serum FT3 and FT4 remained low at 24, 72, and 96 h after birth, and returned to normal range at discharge in the 12 newborns. There was no significant difference in serum TSH between the two groups, but serum FT3 at 96 h after birth, and serum FT4 at 72 and 96 h after birth, were significantly lower in the abnormal imaging group than in the normal imaging group (P = 0.02; P = 0.03; and P = 0.01, respectively). CONCLUSIONS: Asphyxiated newborns have transient low thyroid hormone levels at 24-96 h after birth. Serum FT3 and FT4 between 72 and 96 h after birth may predict brain injury in asphyxiated newborns.

[A case of long-term survival of small intestinal adenocarcinoma treated by resection and chemotherapy].

A 60-year-old man had visited our hospital a few times due to vomiting since July 2008. In January 2009, because he was no longer able to eat, he was hospitalized to receive close examination. Single balloon enteroscopy revealed jejunal adenocarcinoma. After examination of the whole body, as there was no distant metastasis, jejunum partial resection was performed in February 2009. One dissemination nodule was recognized on the serosa near the main tumor. We obtained the final pathological diagnosis as Stage IV. From April 2009, adjuvant chemotherapy with combination of oxaliplatin, 5-fluorouracil and Leucovorin (mFOLFOX6) was performed 8 times. In April 2009, a small metastatic lesion appeared in the upper lobe of the right lung. We started administering combination of irinotecan, 5-fluorouracil and Leucovorin (FOLFIRI) from January 2010, but stopped because of side effects after the second cycle. Administration of capecitabine was started in March 2010. The metastatic lesion had diminished for a time but was found to be enlarged in March 2011. Thus, a partial right lung resection was performed in April 2012. After lung resection, systemic chemotherapy was not performed. The patient remains alive without a recurrence 3 years after lung resection and over 5 years after detection of the small intestinal adenocarcinoma.

Selenoprotein P expression in glioblastoma as a regulator of ferroptosis sensitivity: preservation of GPX4 via the cycling-selenium storage.

Glioblastoma (GBM) is one of the most aggressive and deadly brain tumors; however, its current therapeutic strategies are limited. Selenoprotein P (SeP; SELENOP, encoded by the SELENOP gene) is a unique selenium-containing protein that exhibits high expression levels in astroglia. SeP is thought to be associated with ferroptosis sensitivity through the induction of glutathione peroxidase 4 (GPX4) via selenium supplementation. In this study, to elucidate the role of SeP in GBM, we analyzed its expression in GBM patients and found that SeP expression levels were significantly higher when compared to healthy subjects. Knock down of SeP in cultured GBM cells resulted in a decrease in GPX1 and GPX4 protein levels. Under the same conditions, cell death caused by RSL3, a ferroptosis inducer, was enhanced, however this enhancement was canceled by supplementation of selenite. These results indicate that SeP expression contributes to preserving GPX and selenium levels in an autocrine/paracrine manner, i.e., SeP regulates a dynamic cycling-selenium storage system in GBM. We also confirmed the role of SeP expression in ferroptosis sensitivity using patient-derived primary GBM cells. These findings indicate that expression of SeP in GBM can be a significant therapeutic target to overcome anticancer drug resistance.

Subjective and objective image quality of low-dose CT images processed using a self-supervised denoising algorithm.

This study aimed to assess the subjective and objective image quality of low-dose computed tomography (CT) images processed using a self-supervised denoising algorithm with deep learning. We trained the self-supervised denoising model using low-dose CT images of 40 patients and applied this model to CT images of another 30 patients. Image quality, in terms of noise and edge sharpness, was rated on a 5-point scale by two radiologists. The coefficient of variation, contrast-to-noise ratio (CNR), and signal-to-noise ratio (SNR) were calculated. The values for the self-supervised denoising model were compared with those for the original low-dose CT images and CT images processed using other conventional denoising algorithms (non-local means, block-matching and 3D filtering, and total variation minimization-based algorithms). The mean (standard deviation) scores of local and overall noise levels for the self-supervised denoising algorithm were 3.90 (0.40) and 3.93 (0.51), respectively, outperforming the original image and other algorithms. Similarly, the mean scores of local and overall edge sharpness for the self-supervised denoising algorithm were 3.90 (0.40) and 3.75 (0.47), respectively, surpassing the scores of the original image and other algorithms. The CNR and SNR for the self-supervised denoising algorithm were higher than those for the original images but slightly lower than those for the other algorithms. Our findings indicate the potential clinical applicability of the self-supervised denoising algorithm for low-dose CT images in clinical settings.

Sulforaphane decreases serum selenoprotein P levels through enhancement of lysosomal degradation independent of Nrf2.

Selenoprotein P (SeP) is a major selenoprotein in serum predominantly produced in the liver. Excess SeP impairs insulin secretion from the pancreas and insulin sensitivity in skeletal muscle, thus inhibition of SeP could be a therapeutic strategy for type 2 diabetes. In this study, we examine the effect of sulforaphane (SFN), a phytochemical of broccoli sprouts and an Nrf2 activator, on SeP expression in vitro and in vivo. Treatment of HepG2 cells with SFN decreases inter- and intra-cellular SeP levels. SFN enhances lysosomal acidification and expression of V-ATPase, and inhibition of this process cancels the decrease of SeP by SFN. SFN activates Nrf2 in the cells, while Nrf2 siRNA does not affect the decrease of SeP by SFN or lysosomal acidification. These results indicate that SFN decreases SeP by enhancing lysosomal degradation, independent of Nrf2. Injection of SFN to mice results in induction of cathepsin and a decrease of SeP in serum. The findings from this study are expected to contribute to developing SeP inhibitors in the future, thereby contributing to treating and preventing diseases related to increased SeP.

Interleukin-6 polymorphism and bronchopulmonary dysplasia risk in very low-birthweight infants.

BACKGROUND: The aim of the present study was to evaluate the role of interleukin (IL)-6-634 polymorphism in neonatal disorders such as bronchopulmonary dysplasia (BPD) and periventricular leukomalacia (PVL) in very low-birthweight (VLBW) infants. METHODS: This prospective cohort study included 202 infants (gestational age at birth, 23-34 weeks; birthweight, 500-1499 g). Genotypic analysis (polymerase chain reaction-restriction fragment length polymorphism) was performed with DNA extracted from whole-blood samples. RESULTS: Genotype distribution (66.8% CC, 28.2% CG, 5.0% GG) was similar to that in the adult Japanese population. BPD occurred in 85 infants (42.1%) among 202 VLBW infants. The duration of O(2) therapy in infants with CG/GG genotypes was significantly longer than that in infants with the CC genotype (CG/GG vs CC: 40.3 ± 52.2 days vs 28.4 ± 32.6 days, P < 0.05), but the prevalence of BPD was not associated with the CG/GG genotype (CG/GG, 40.0%; CC, 46.3%, P= 0.24). Infants with CG/GG genotypes were more likely to have received postnatal corticosteroid therapy for BPD than those with the CC genotype (CG/GG vs CC: 20.9% vs 11.1%, P = 0.05). PVL occurred in six infants (3.0%). There was no significant difference in the prevalence of PVL among IL-6-634 polymorphisms (CG/GG, 3.0%; CC, 3.0%, P = 0.65). CONCLUSIONS: IL-6-634 polymorphism is associated with duration of oxygen therapy in VLBW infants. This suggests that the IL-6-634 polymorphism G allele is an aggravating factor of BPD. IL-6-634 polymorphism is not associated with PVL.

Antioxidant action of persulfides and polysulfides against free radical-mediated lipid peroxidation.

Hydrogen sulfide, hydropersulfides, and hydropolysulfides have been revealed to play important physiological roles such as cell signaling and protection against oxidative stress, but the underlying mechanisms and dynamics of action remain elusive. It is generally accepted that these species act by two-electron redox mechanisms, while the involvement of one-electron redox chemistry has received less attention. In this study, the radical-scavenging activity of hydrogen persulfide, hydrogen polysulfides (HSnH n = 2-4), and diallyl- or dialkyl-sulfides (RSnR, n = 1-4) was measured. Furthermore, their antioxidant effects against free radical-mediated human plasma lipid peroxidation were assessed by measuring lipid hydroperoxides. It was found that disodium disulfide, trisulfide, and tetrasulfide acted as potent peroxyl radical scavengers, the rate constant for scavenging peroxyl radical being 3.5 × 105, 4.0 × 105, and 6.0 × 105 M-1 s-1 in PBS pH 7.4 at 37 °C respectively and that they inhibited plasma lipid peroxidation efficiently, the efficacy is increased with the catenation number. Disodium tetrasulfide was 1.5 times as reactive as Trolox toward peroxyl radical and inhibited plasma lipid peroxidation more efficiently than ascorbate and Trolox. On the other hand, diallyl- and dialkyl-sulfides did not exert significant radical-scavenging activity, nor did they inhibit lipid peroxidation efficiently, except for diallyl tetrasulfide, which suppressed plasma lipid peroxidation, despite less significantly than disodium tetrasulfide. Collectively, this study shows that hydrogen persulfide and hydrogen polysulfides act as potent radical-scavenging antioxidants and that, in addition to two-electron redox mechanisms, one electron redox reaction may also play important role in the in vivo defense against deleterious oxidative stress.

Clinical implications of interleukin-18 levels in pediatric patients with Mycoplasma pneumoniae pneumonia.

The immunological pathogenesis of Mycoplasma pneumoniae pneumonia is known to involve several cytokines. The serum levels of interleukin-18 (IL-18) were examined using enzyme-linked immunosorbent assay in 23 pediatric patients (median age 6 years; range 4-13 years; 14 girls and 9 boys) with M. pneumoniae pneumonia admitted to our hospital. Serum levels of IL-18 ranged from 22 to 1808 pg/ml with a mean of 543 pg/ml. We started steroid therapy in two cases with IL-18 values greater than 1000 pg/ml without being aware of IL-18 levels. Examination of associations between IL-18 levels determined by enzyme-linked immunosorbent assay and a routine laboratory test showed that levels of lactate dehydrogenase (LDH) and IL-18 were significantly correlated. To determine the appropriateness of steroid administration in M. pneumoniae pneumonia patients, serum LDH should be examined. Patients with elevated levels of LDH are likely to have significantly elevated IL-18 values (≥1000 pg/ml) and thus can be candidates for steroid therapy.

A case report of fatal tumor lysis syndrome after chemotherapy in a pregnant patient with Burkitt's lymphoma.

A 35-year-old Japanese woman in the 24th week of gestation with bilateral breast enlargement was referred to hospital. She was diagnosed with Burkitt's lymphoma and admitted for detailed evaluation and treatment. Early delivery and subsequent chemotherapy was chosen after considering the gestational week, her general condition and the wishes of the patient and her husband. She gave birth to a male infant by cesarean section in the 25(th) week of gestation. It had been planned to begin high-dose chemotherapy, such as CODOX-M/IVAC, on day 7 of the puerperium; however, her general condition worsened and chemotherapy was therefore begun on day 2 after the birth. Eight hours after chemotherapy (cyclophosphamide, vincristine and doxorubicin), she developed cardiac arrest due to tumor lysis syndrome. Despite medical treatment, her bleeding tendency did not improve and she died of respiratory failure with alveolar bleeding five days after chemotherapy.

Atypical hemophagocytic lymphohistiocytosis following bacterial tonsillitis in acute lymphoblastic leukemia.

We report a rare case of a cute lymphoblasticleukemia (ALL) who developed dyspnea, neurological disturbance with illusions, pancytopenia, phagocytosis and coagulation disturbances following bacterial tonsillitis. The values of soluble interleukin-2 receptor (sIL-2R), IL-6 and IL-8 were also elevated. Her clinicolaboratory findings were similar to hemophagocytic lymphohistiocytosis (HLH), which is a cytokine disease induced by activated T cells and macrophages. Atypical HLH following bacterial tonsillitis should be kept in mind in leukemia patients.