Stilbene dendrimers with energy harvesting chromophores, such as naphthalene and benzophenone, have been prepared and their photochemical and photophysical properties have been examined. These ...dendrimers underwent trans–cis mutual photoisomerization on excitation of the core stilbene or the peripheral naphthalene and benzophenone chromophores through several energy transfer processes, and photophysical processes such as intersystem crossing finally resulted in cis-trans isomerization of the core stilbene.
Lysosomes are acidic and highly dynamic organelles that are essential for macromolecule degradation and many other cellular functions. However, little is known about lysosomal function during early ...embryogenesis. Here, we found that the number of lysosomes increased after fertilization. Lysosomes were abundant during mouse preimplantation development until the morula stage, but their numbers decreased slightly in blastocysts. Consistently, the protein expression level of mature cathepsins B and D was high from the one-cell to morula stages but low in the blastocyst stage. One-cell embryos injected with siRNAs targeted to both lysosome-associated membrane protein 1 and 2 (LAMP1 and LAMP2) were developmentally arrested at the two-cell stage. Pharmacological inhibition of lysosomes also caused developmental retardation, resulting in accumulation of lipofuscin. Our findings highlight the functional changes in lysosomes in mouse preimplantation embryos.
Accurate cancer risk assessment of low-dose radiation poses many challenges that are partly due to the inability to distinguish radiation-induced tumors from spontaneous ones. To elucidate ...characteristic features of radiation-induced tumors, we analyzed 163 medulloblastomas that developed either spontaneously or after X-ray irradiation at doses of 0.05–3 Gy in Ptch1 heterozygous mice. All spontaneous tumors showed loss of heterozygosity in broad regions on chromosome 13, with losses at all consecutive markers distal to Ptch1 locus (S-type). In contrast, all tumors that developed after 3 Gy irradiation exhibited interstitial losses around Ptch1 with distal markers retained (R-type). There was a clear dose-dependent increase in the proportion of R-type tumors within the intermediate dose range, indicating that the R-type change is a reliable radiation signature. Importantly, the incidence of R-type tumors increased significantly (P = 0.007) at a dose as low as 50 mGy. Integrated array-comparative genomic hybridization and expression microarray analyses demonstrated that expression levels of many genes around the Ptch1 locus faithfully reflected the signature-associated reduction in genomic copy number. Furthermore, 573 genes on other chromosomes were also expressed differently between S-type and R-type tumors. They include genes whose expression changes during early cerebellar development such as Plagl1 and Tgfb2, suggesting a recapitulation of gene subsets functioning at distinct developmental stages. These findings provide, for the first time, solid experimental evidence for a significant increase in cancer risk by low-dose radiation at diagnostic levels and imply that radiation-induced carcinogenesis accompanies both genomic and gene expression signatures.
To clarify the effect of loofah Luffa cylindrica and fermented loofah on hyperlipidemia, the in vitro bile acid lowering capacity and blood lipid levels of ddY mice fed high-fat diet supplemented ...with loofah were determined. Furthermore, the caecal microbiomes patterns were analysed using 16S rDNA amplicon sequencing with a next generation sequencer (MiSeq) system. Green loofah was homogenized and autoclaved (LH), and subsequently fermented with Lactobacillus plantarum Uruma-SU4 (FL). In vitro bile acid (taurocholic, glycocholic and deoxycholic acids (DCA)) lowering capacity was significantly high in FL. The levels of plasma triacylglyceride in mice which were fed a high-fat diet containing 17% beef tallow was lowered by 5% dried FL (FLD) and was unaffected by dried LH (LHD). Caecal Lactobacillus johnsonii and Clostridium disporicum known as predominant lactic acid bacteria in mice gut and urso-DCA producer, respectively, were increased by FLD. On the other hand, Flintibacter butyricus was lowered by both LHD and FLD. These results suggest that if green loofah cannot be consumed as a fresh vegetable, lactic acid fermentation may be useful in generating effective nutritional supplements and functional foods.
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•L. plantarum Uruma-SU4 was selected for loofah homogenate (LH) fermentation.•In vitro bile acid lowering capacity of fermented LH (FL) was higher than that of LH.•Dried FL (FLD) rather than dried LH (LHD) showed hypolipidemic effect in beef-tallow fed mice.•Caecal Lactobacillus johnsonii, regarded as a beneficial symbiont, was increased by FLD.•Cl. disporicum, a ursodeoxicholic acid producer, was also increased by FLD.
The recently developed anti-human epidermal growth factor receptor 2 (HER2) therapy has substantially improved the prognosis of HER2-positive breast cancer. The DESTINY-Breast04 trial results showed ...that trastuzumab deruxtecan (T-DXd) significantly prolonged the survival of patients with HER2-low breast cancer, thus presenting a paradigm shift in anti-HER2 therapy. This may facilitate a change in the treatment strategy for HER2-low breast cancer. However, the implication of HER2-low in hormone receptor (HR)-positive breast cancer is unclear. In this retrospective study, we aimed to reveal the association between HER2 status, namely HER2-low and HER2-zero, and prognosis in HR-positive breast cancer.
We collected the data of 247 patients with estrogen receptor (ER)-positive/HER2-negative breast cancer (159 with HER2-low and 88 with HER2-zero breast cancer) who underwent surgery. Patients were divided into HER2-low and HER2-zero groups. Univariate analysis was performed to evaluate the baseline characteristics using the Wilcoxon rank sum test and Fisher's exact test. Survival analysis of the HER2-low and HER2-zero groups was performed using the Kaplan-Meier method.
The median observation period was 2,706 days, and the median period until recurrence was 1,380 days; 25 patients (10%) had recurrences. Age (P=0.004) and menopausal status (P=0.04) were significant variables in the univariate analysis of baseline characteristics. In the subgroup analysis of luminal A- and B-like breast cancers, there was a significant difference in overall survival (OS) only in patients with luminal A-like breast cancer, but relapse-free survival (RFS) of the HER2-low luminal B-like cancer subgroups tended to be relatively short.
We inferred that the HER2-low and HER2-zero statuses do not affect the RFS and OS of patients with ER-positive breast cancer. The prognostic significance of HER2-low or HER2-zero status in luminal A- and B-like breast cancers might differ, and a new treatment strategy is required for the HER2-low subgroup.
Sympathetic activation of brown adipose tissue (BAT) thermogenesis can ameliorate obesity and related metabolic abnormalities. However, crucial subtypes of the β-adrenergic receptor (AR), as well as ...effects of its genetic variants on functions of BAT, remains unclear in humans. We conducted association analyses of genes encoding β-ARs and BAT activity in human adults.
Single nucleotide polymorphisms (SNPs) in β1-, β2-, and β3-AR genes (ADRB1, ADRB2, and ADRB3) were tested for the association with BAT activity under mild cold exposure (19 °C, 2 h) in 399 healthy Japanese adults. BAT activity was measured using fluorodeoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT). To validate the results, we assessed the effects of SNPs in the two independent populations comprising 277 healthy East Asian adults using near-infrared time-resolved spectroscopy (NIR
) or infrared thermography (IRT). Effects of SNPs on physiological responses to intensive cold exposure were tested in 42 healthy Japanese adult males using an artificial climate chamber.
We found a significant association between a functional SNP (rs1042718) in ADRB2 and BAT activity assessed with FDG-PET/CT (p < 0.001). This SNP also showed an association with cold-induced thermogenesis in the population subset. Furthermore, the association was replicated in the two other independent populations; BAT activity was evaluated by NIR
or IRT (p < 0.05). This SNP did not show associations with oxygen consumption and cold-induced thermogenesis under intensive cold exposure, suggesting the irrelevance of shivering thermogenesis. The SNPs of ADRB1 and ADRB3 were not associated with these BAT-related traits.
The present study supports the importance of β2-AR in the sympathetic regulation of BAT thermogenesis in humans. The present collection of DNA samples is the largest to which information on the donor's BAT activity has been assigned and can serve as a reference for further in-depth understanding of human BAT function.
Epidemiological studies have revealed that radiation causes brain development abnormalities in atomic bomb survivors exposed in utero. Rat and mouse studies have also shown that prenatal exposure to ...low-linear energy transfer radiation induces developmental brain anomalies. Because the effects of prenatal irradiation on adult behavior patterns remain largely unknown, the present study investigated the effects of neutron exposure in utero on postnatal behavior patterns in mice. C57BL/6J × C3H/He hybrid (B6C3F1) mice were exposed to cyclotron-derived fast neutrons with peak energy of 10 MeV (0.02-0.2 Gy) or Cs-137 gamma-rays (0.2-1.5 Gy) on embryonic day 13.5. At 5.5-8 months of age, the neurobehavior of male offspring was examined by Rota-rod treadmill and locomotor activity. The accumulation of radio-labeled drug at muscarinic acetylcholine and serotonin receptors in mice from control and neutron-irradiated groups was determined by the tracer method. Locomotor activity during the dark period increased in the 0.02 Gy neutron-irradiated group. Furthermore, at 5.5 months of age, tracer binding in vivo to the muscarinic acetylcholine increased and to the serotonin receptors decreased in the 0.02 Gy neutron-irradiated group. In conclusion, the present study reveals that a certain "low-dose window" may exist for radiation-induced changes in neurobehavior and binding to neurotransmitter receptors, because there was correlation in neurobehavior and binding to neurotransmitter receptors in the 0.02 Gy neutron-irradiated group though there was not correlation in the neutron-irradiated groups more than 0.05 Gy.
Abnormal regulation of placental apoptosis and proliferation has been implicated in placental disorders. Recently, several DNA-damaging agents were reported to induce excessive apoptosis and reduce ...cell proliferation in the placenta; however, the molecular pathways of these toxic effects on the placenta are unclear. The aim of the present study was to determine the involvement of TRP53, a tumor suppressor that mediates cellular responses to DNA damage, in the induction of apoptosis and cell cycle arrest in the developing placenta. For this purpose, we treated pregnant mice on Day 12 of gestation with 10 mg/kg of etoposide and 5-Gy gamma irradiation, potent inducers of DNA damage. We found an increase in the number of trophoblastic apoptoses 8 and 24 h after etoposide injection and 6 and 24 h after irradiation in the placental labyrinth zone. The number of mitoses and DNA syntheses in trophoblasts decreased after treatment. The accumulation and phosphorylation of TRP53 protein were detected 8 and 6 h after etoposide injection and irradiation, respectively. In Trp53-deficient placentas, the induction of etoposide-induced trophoblastic apoptosis is abrogated, while the reduction of proliferation occurred similarly as in wild-type placentas. CDC2A, a regulator of G2/M progression, was inactivated by phosphorylation after etoposide injection and irradiation, suggesting that the cell cycle was arrested at the G2/M border by treatment. Our study demonstrated that etoposide injection induced TRP53-dependent apoptosis and TRP53-independent cell cycle arrest in labyrinthine trophoblasts, providing insights into the molecular pathway of placental disorders.
To evaluate the relative biological effectiveness (RBE) of low doses of neutrons on fetal nervous development, C57BL/6J x C3H/He hybrid (B6C3F1) mice were exposed to cyclotron-derived fast neutrons ...with peak energy of 10 MeV (0.02-1.0 Gy) or 137Cs-generated gamma-rays (0.1-2.0 Gy) on embryonic day 13.5. We then evaluated the incidence of neuronal apoptosis in the cerebral cortex 24 hours after irradiation. Neuronal apoptosis increased in a dose-dependent manner in both neutron- and gamma-ray-irradiated groups: even at the lowest dose, a minimal increase in the apoptotic index was noted in response to both types of radiation. The dose-response curves were best fitted to linear quadratic models, and the evaluated RBE was 9.8, which was considered to be large for a prenatal effect and acute tissue injury induced by a low dose of neutrons.
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