A novel S-sulfhydrated human serum albumin preparation suppresses melanin synthesis

Products of ultraviolet (UV) irradiation such as reactive oxygen species (ROS) and nitric oxide (NO) stimulate melanin synthesis. Reactive sulfur species (RSS) have been shown to have strong ROS and NO scavenging effects. However, the instability and low retention of RSS limit their use as inhibitors of melanin synthesis. The free thiol at Cys34 on human serum albumin (HSA) is highly stable, has a long retention and possess a high reactivity for RSS. We report herein on the development of an HSA based RSS delivery system. Sulfane sulfur derivatives released from sodium polysulfides (Na2Sn) react readily with HSA. An assay for estimating the elimination of sulfide from polysulfide showed that almost all of the sulfur released from Na2Sn bound to HSA. The Na2Sn-treated HSA was found to efficiently scavenge ROS and NO produced from chemical reagents. The Na2Sn-treated HSA was also found to inhibit melanin synthesis in B16 melanoma cells and this inhibition was independent of the number of added sulfur atoms. In B16 melanoma cells, the Na2Sn-treated HSA also inhibited the levels of ROS and NO induced by UV radiation. Finally, the Na2Sn-treated HSA inhibited melanin synthesis from L-DOPA and mushroom tyrosinase and suppressed the extent of aggregation of melanin pigments. These data suggest that Na2Sn-treated HSA inhibits tyrosinase activity for melanin synthesis via two pathways; by directly inhibiting ROS signaling and by scavenging NO. These findings indicate that Na2Sn-treated HSA has potential to be an attractive and effective candidate for use as a skin whitening agent

Efficacy and safety of single-dose ivermectin in mild-to-moderate COVID-19: the double-blind, randomized, placebo-controlled CORVETTE-01 trial

BackgroundTo investigate whether ivermectin inhibits SARS-CoV-2 proliferation in patients with mild-to-moderate COVID-19 using time to a negative COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) test.MethodsCORVETTE-01 was a double-blind, randomized, placebo-controlled study (August 2020–October 2021) conducted in Japan. Overall, 248 patients diagnosed with COVID-19 using RT-PCR were assessed for eligibility. A single oral dose of ivermectin (200  μg/kg) or placebo was administered under fasting. The primary outcome was time to a negative COVID-19 RT-PCR test result for SARS-CoV-2 nucleic acid, assessed using stratified log-rank test and Cox regression models.ResultsOverall, 112 and 109 patients were randomized to ivermectin and placebo, respectively; 106 patients from each group were included in the full analysis set (male [%], mean age: 68.9%, 47.9 years [ivermectin]; 62.3%, 47.5 years [placebo]). No significant difference was observed in the occurrence of negative RT-PCR tests between the groups (hazard ratio, 0.96; 95% confidence interval [CI] 0.70–1.32; p = 0.785). Median (95% CI) time to a negative RT-PCR test was 14.0 (13.0–16.0) and 14.0 (12.0–16.0) days for ivermectin and placebo, respectively; 82.1% and 84% of patients achieved negative RT-PCR tests, respectively.ConclusionIn patients with COVID-19, single-dose ivermectin was ineffective in decreasing the time to a negative RT-PCR test.Clinical Trial RegistrationClinicalTrials.gov, NCT04703205

In-situ mechanical weakness of subducting sediments beneath a plate boundary décollement in the Nankai Trough

© 2018, The Author(s). The study investigates the in-situ strength of sediments across a plate boundary décollement using drilling parameters recorded when a 1180-m-deep borehole was established during International Ocean Discovery Program (IODP) Expedition 370, Temperature-Limit of the Deep Biosphere off Muroto (T-Limit). Information of the in-situ strength of the shallow portion in/around a plate boundary fault zone is critical for understanding the development of accretionary prisms and of the décollement itself. Studies using seismic reflection surveys and scientific ocean drillings have recently revealed the existence of high pore pressure zones around frontal accretionary prisms, which may reduce the effective strength of the sediments. A direct measurement of in-situ strength by experiments, however, has not been executed due to the difficulty in estimating in-situ stress conditions. In this study, we derived a depth profile for the in-situ strength of a frontal accretionary prism across a décollement from drilling parameters using the recently established equivalent strength (EST) method. At site C0023, the toe of the accretionary prism area off Cape Muroto, Japan, the EST gradually increases with depth but undergoes a sudden change at ~ 800 mbsf, corresponding to the top of the subducting sediment. At this depth, directly below the décollement zone, the EST decreases from ~ 10 to 2 MPa, with a change in the baseline. This mechanically weak zone in the subducting sediments extends over 250 m (~ 800–1050 mbsf), corresponding to the zone where the fluid influx was discovered, and high-fluid pressure was suggested by previous seismic imaging observations. Although the origin of the fluids or absolute values of the strength remain unclear, our investigations support previous studies suggesting that elevated pore pressure beneath the décollement weakens the subducting sediments. [Figure not available: see fulltext.]

Three-dimensional organization of flagellar basal apparatus in Ectocarpus gametes

The flagellar basal apparatus of the brown alga Ectocarpus siliculosus was re-investigated in details using transmission electron microscopy and electron tomography. As a result, three-dimensional structures with spatial arrangement of bands and microtubular flagellar rootlets were observed. Fibrous structures linking the anterior flagellar basal body to the major anterior rootlet (R3) or the bypassing rootlet was newly discovered in this study. A direct attachment from the minor anterior rootlet (R4) to the anterior and posterior basal bodies was also discovered, as were attachments from the minor posterior rootlet (R1) to the deltoid striated band and from the major posterior rootlet (R2) to the posterior fibrous band. The microtubular flagellar rootlets were connected to the bands and to the anterior or posterior basal body. These bands may have a role in maintaining the spatial arrangement of the anterior and posterior flagellar basal bodies and the microtubular flagellar rootlets. A numbering system of the basal body triplets was established by tracing axonemal doublets in the serial sections. From these observations, the precise position of two flagellar basal bodies, bands, and flagellar rootlets was determined

Flagellar waveforms of gametes in the brown alga Ectocarpus siliculosus

Brown algae are members of the Stramenopiles and their gametes generally have two heterogeneous flagella: a long anterior flagellum (AF) with mastigonemes and a short posterior flagellum (PF). In this study, swimming paths and flagellar waveforms in free-swimming and thigmotactic-swimming male and female gametes and in male gametes during chemotaxis, were quantitatively analysed in the model brown alga Ectocarpus siliculosus. This analysis was performed using a high-speed video camera. It was revealed that the AF plays a role in changing the locomotion of male and female gametes from free-swimming to thigmotactic-swimming and also in changing the swimming path of male gametes from linear to circular during chemotaxis. In the presence of a sex pheromone, male gametes changed their swimming path from linear (swimming path curvature, 0-0.02 mu m(-1)) to middle and small circular path (swimming path curvature, 0.04-0.20 mu m(-1)). The flagellar asymmetry and the deflection angle of the AF became larger, whereas the oscillation pattern of the AF was stable. However, there was no correlation between the flagellar asymmetry and the deflection angle of the AF and the path curvature when the male gametes showed middle to small circular paths. The PF irregularly changed the deflection angle and the oscillation pattern was unstable depending on the gradient of the sex pheromone concentration. AF waveforms were independent of PF locomotion during chemotaxis. This means that the AF has the ability to change the swimming path of male gametes - for example, from a highly linear path to a circular path - while changes in locomotion from a middle circle path to a small circle path is the result of beating of the PF

Enantioselective Total Synthesis of Multifidene, a Sex Pheromone of Brown Algae

The total synthesis of multifidene, a sex pheromone found in brown algae, is described. The synthesis features the highly enantioselective and diastereoselective addition reaction of an aldehyde to a nitroolefin in the presence of a Hayashi–Jørgensen catalyst and a Nef reaction initiated by visible light irradiation. These key reactions enabled the 11-step synthesis from commercially available compounds. The synthetic pheromones are examined with gametes

Human Skeletal Muscle Cells Derived from the Orbicularis Oculi Have Regenerative Capacity for Duchenne Muscular Dystrophy

Skeletal muscle stem cells (MuSCs) have been proposed as suitable candidates for cell therapy in muscular disorders since they exhibit good capacity for myogenic regeneration. However, for better therapeutic outcomes, it is necessary to isolate human MuSCs from a suitable tissue source with high myogenic differentiation. In this context, we isolated CD56+CD82+ cells from the extra eyelid tissue of young and aged patients, and tested in vitro myogenic differentiation potential. In the current study, myogenic cells derived from extra eyelid tissue were characterized and compared with immortalized human myogenic cells. We found that myogenic cells derived from extra eyelid tissue proliferated and differentiated myofibers in vitro, and restored DYSTROPHIN or PAX7 expression after transplantation with these cells in mice with Duchenne muscular dystrophy. Thus, human myogenic cells derived from extra eyelid tissue including the orbicularis oculi might be good candidates for stem cell-based therapies for treating muscular diseases