Search Results (1,074)

The plants from the Ocimum genus, belonging to the Labiatae family, serve as important bioresources of essential oils (EOs) rich in biologically active secondary metabolites, widely used in medicine, food, and cosmetics. This study explored the volatile composition, enantiomeric distribution, and in vitro biological activities of EOs from three Ocimum species native to Nepal: O. tenuiflorum L., O. basilicum L., and O. americanum L. EOs were extracted via hydro-distillation and analyzed using gas chromatography–mass spectrometry (GC-MS) for chemical profiling and chiral GC-MS for enantiomeric composition. Hierarchical cluster analysis was performed for major chemotypes. Antioxidant activity was assessed using DPPH and ABTS assays. Antimicrobial efficacy was evaluated using the microbroth dilution method, and cytotoxicity was tested on NIH-3T3 (normal) and MCF-7 (breast cancer) cell lines via the Cell Counting Kit-8 assay. EO yield was highest in O. tenuiflorum (1.67 ± 0.13%) during autumn and lowest in O. americanum (0.35 ± 0.02%) during winter among all Ocimum spp. The major compounds identified in O. tenuiflorum were eugenol (32.15–34.95%), trans-β-elemene (29.08–32.85%), and β–caryophyllene (19.85–21.64%). In O. americanum, the major constituents included camphor (51.33–65.88%), linalool (9.72–9.91%), germacrene D (7.75–1.83%), and β–caryophyllene (6.35–3.97%). For O. basicilum, EO was mainly composed of methyl chavicol (62.16–64.42%) and linalool (26.92–27.05%). The oxygenated monoterpenes were a dominant class of terpenes in the EOs except for O. tenuiflorum (sesquiterpene hydrocarbon). A hierarchical cluster analysis based on the compositions of EOs revealed at least three different chemotypes in Ocimum species. Chiral GC-MS analysis revealed β-caryophyllene and germacrene D as enantiomerically pure, with linalool consistently dominant in its levorotatory form. O. tenuiflorum exhibited the strongest antimicrobial activity, particularly against Candida albicans, and showed notable anticancer activity against MCF-7 cells (IC₅₀ = 23.43 µg/mL), with lower toxicity to normal cells. It also demonstrated the highest antioxidant activity (DPPH IC₅₀ = 69.23 ± 0.10 µg/mL; ABTS IC₅₀ = 9.05 ± 0.24 µg/mL). The EOs from Ocimum species possess significant antioxidant, antimicrobial, and cytotoxic properties, especially O. tenuiflorum. These findings support their potential application as natural agents in medicine, food, and cosmetics, warranting further validation. Full article

Heart failure (HF) remains a global health challenge with high rates of hospitalization and mortality, particularly among the elderly. Many episodes of worsening HF occur before symptoms arise, underscoring the need for sensitive monitoring tools. Respiratory Stability Time (RST) is a novel index that quantifies the duration of stable respiration during sleep, reflecting pulmonary congestion and circulatory status. RST can be measured continuously and non-invasively using a contactless under-mattress sensor. Observational cohort studies show that low RST predicts poor prognosis, while its improvement parallels recovery from decompensation. Importantly, recent prospective multicenter observations involving 100 patients demonstrated that sustained RST decline often precedes HF readmission, probably enabling early intervention. A multicenter trial (ITMETHOD-HF III), involving 80 patients, is currently testing whether RST-guided therapy can reduce HF readmissions. RST might substantially enhance current HF management by enabling us to provide proactive therapeutic intervention, though further validation is warranted. Full article

Background/Objectives: This article reports pyrrolidine iminosugars of L-gulose absolute stereochemical configuration that are functionalised via N-alkylation to bear boronate ester and boronic acid pharmacophores. Inclusion of boron pharmacophores has been shown to reduce toxicity profiles of drugs and can expand the range of interactions between drugs and target enzymes. Methods: The synthetic development, detailed spectroscopic analysis, and biological investigation against glycosidase enzymes and cancer cell lines of these novel five-membered ring iminosugars are reported. Results: This family of iminosugars displays selective, moderate-to-weak inhibition (IC₅₀s = 133–501 μM) of β-d-galactosidase (bovine liver) and emerging inhibition of β-d-glucosidases (almond) and (bovine liver). The boronic acid pharmacophore may be suitable for the management of lysosomal storage disorders to support the restoration of biological activity of mutant enzymes via the chaperone-mediated therapy approach. From a structure–activity perspective, the cancer screening revealed slight growth inhibition in a panel of cancer cell lines, with A2780 ovarian carcinoma cells showing the strongest response across all compounds. Beyond the growth inhibition capabilities, the real therapeutic potential of these borylated drugs lies in their switch-on/switch-off activation under BNCT radiotherapeutic conditions. Conclusions: This is an important novel family of drug leads capable of interacting with drug targets via intermolecular and intramolecular interactions, changing shape and electronics. Introduction of organic boron atoms to organic molecules presents significant synthetic and purification challenges, as well as analysis of the equilibria that arise in aqueous systems. We provide a methodology to achieve all this and introduce boron pharmacophores onto carbohydrate scaffolds in a systematic manner to facilitate a more widespread adoption of boron pharmacophores. Full article

Objectives: To clarify the need for a kidney exchange program (KEP) in Japan by conducting a questionnaire survey on KEPs and simulated KEPs by virtual cross-matching based on past cases of transplantation avoidance. Methods: In addition to the content regarding KEPs, an electronic survey was conducted to investigate the number of cases of kidney transplant abandonment due to “immunological” reasons over the past 10 years (2012–2021). Virtual cross-matching was conducted to simulate the feasibility of avoiding immunological risks and enabling kidney transplantation in patients who were previously unable to undergo the procedure. Results: The survey received responses from 107 facilities (response rate: 81.7%). In response to the question about the necessity of a KEP in Japan, 71 facilities (66.4%) indicated that KEPs are necessary. In addition, 251 living-donor kidney transplants were abandoned for “immunological” reasons over the past decade (2012–2021). Among the 80 pairs for which detailed information was available, virtual cross-matching simulations showed that 37/80 pairs (46.3%) were donor-specific antibody (DSA)-negative for blood type-matched combinations, and 41/80 pairs (51.3%) were DSA-negative for blood type-incompatible transplants. Conclusions: The need for a KEP in Japan and its potential usefulness were demonstrated. Full article

The clinical use of 1,25-dihydroxycholecalciferol (1,25D3), the active form of vitamin D₃, is limited by its calcemic side effects and rapid metabolic degradation. To overcome these limitations, we designed novel vitamin D analogs with extended, rigidified, and branched side chains. Among them, PRI-1938, featuring a 5,6-trans triene system and 22,24-all-trans side-chain geometry, demonstrated markedly enhanced resistance to enzymatic catabolism. In vitro assays revealed that metabolic conversion of PRI-1938 by the nonselective cytochrome P450 3A4 (CYP3A4) enzyme was ca. 4-fold lower than that of the previously obtained PRI-1906 and over 9-fold lower than 1,25D3. All new analogs, including PRI-1927 and PRI-1937, exhibited significantly higher stability toward mitochondrial cytochrome P450 24A1 (CYP24A1), the vitamin D-selective catabolic enzyme, than that of 1,25D3. Molecular modeling and quantum mechanical calculations indicated that PRI-1938 adopts a highly stable conformation in the CYP24A1 active site, stabilized by four hydrogen bonds and multiple hydrophobic interactions. The spatially optimized interaction network reduces access to the catalytic heme, resulting in the lowest observed metabolic conversion. These findings highlight the critical role of the side-chain geometry in modulating metabolic stability and support the further development of PRI-1938 as a promising anticancer vitamin D analog. Full article

Background: Vericiguat, a soluble guanylate cyclase stimulator, reduces cardiovascular events in patients with heart failure with reduced ejection fraction following clinical deterioration against guideline-directed medical therapy. However, the optimal timing for initiating vericiguat remains unclear. Methods: We retrospectively analyzed heart failure patients with reduced/mild-reduced ejection fraction who received vericiguat between 2021 and 2025 upon optimal guideline-directed medical therapy. The primary outcome was a composite of all-cause mortality and heart failure hospitalization. Patients were stratified by the number of prior heart failure hospitalizations (<2 vs. ≥2), and outcomes were assessed using multivariable Cox regression and biomarker trajectories over 6 months. Results: A total of 43 patients (with a median age of 73 years, 35 were men) were included. Of these, 26 (60%) patients had ≥2 prior hospitalizations. A number of hospitalizations ≥ 2 independently predicted the primary outcome (hazard ratio: 8.43; 95% confidence interval: 1.79–39.7; p = 0.007). Only patients with <2 prior hospitalizations showed significant improvements in plasma B-type natriuretic peptide levels (p = 0.049) and left ventricular ejection fraction (p = 0.016). In contrast, no meaningful biomarker changes were observed in patients with ≥2 hospitalizations. Conclusions: A history of two or more heart failure hospitalizations is a strong predictor of poor outcomes during vericiguat therapy. These findings suggest that initiating vericiguat earlier—before recurrent hospitalizations—may yield greater clinical benefit. Full article

Micro Electrode Dot Array (MEDA) biochips have recently attracted considerable attention in the biochemical and medical industries. MEDA biochips manipulate micro droplets for biochemical experiments such as DNA analysis. Droplets on MEDA biochips are moved using the Electrowetting on Dielectric (EWOD) effect, but a portion of a droplet may remain on a cell after passing through, contaminating the cell. Other droplets cannot pass through a contaminated cell. In previous studies, contaminated cells were considered unavailable for droplet routing. As the number of contaminated cells increases, droplets may be prevented from moving to the desired position. Therefore, we propose a method for simultaneous routing of target functional and washing droplets based on a shape-dependent velocity model. In a simulation, the proposed method reduced the routing time by about 10% compared with an existing method. Full article

The increasing frequency of wildfires in larch forests across the discontinuous permafrost zone of Eastern Eurasia heightens the vulnerability of soil organic matter (SOM) under a warming climate. However, post-fire SOM thermal stability in this frequently burned forest region remain poorly understood. We assessed the long-term effects of wildfire on SOM structure and thermal stability in burned and unburned larch forests using complex analytical approaches: pyrolysis–gas chromatography/mass spectrometry (TMAH-py-GC/MS) and thermogravimetry/differential thermal analysis (TG/DTA). The focus was on the upper mineral soil horizon, where fire impacts may persist for decades. Sixteen years post-fire, total carbon content did not differ significantly between burned and control soils. Nonetheless, the molecular composition and thermal properties of SOM showed marked post-fire alterations. Burned soils exhibited higher proportions of lignin-derived compounds and reduced levels of short-chain fatty acid methyl esters. A lower degradation temperature (T50) and a higher thermal mass loss of labile fractions indicate a decrease in the thermal stability of SOM after fire. Our study shows that recurrent forest fires in larch forests of the Russian Far East decrease the thermal stability of soil organic matter, thereby increasing its vulnerability to subsequent fire degradation. Full article

We investigated the clinical significance of positive surgical margins (PSMs) in index tumors following radical prostatectomy (RP), with particular attention to the tumor’s zonal origin. Among 1148 patients with localized prostate cancer who underwent RPs, 973 were included after excluding those who received perioperative therapy or had incomplete data. Index tumors were categorized by zonal origin: transition zone, peripheral zone, or central zone (CZ). Overall, PSMs were observed in 26.4% of index tumors. Although CZ index tumors were relatively uncommon (6.5%), they exhibited the highest PSM rate (42.9%) and showed the most aggressive pathological features. The 5-year biochemical recurrence (BCR)-free survival rate was significantly lower in patients with PSMs in index tumors than in those with negative surgical margins (45.6% vs. 86.8%, p < 0.0001). Notably, patients with PSMs in CZ index tumors had the worst outcomes, with a 5-year BCR-free survival rate of 22.0%. Multivariate analysis identified PSMs in index tumors as an independent predictor of BCR (HR: 3.4; 95% CI: 2.5–4.5), with a similar trend observed in early recurrence. These findings highlight the prognostic significance of PSMs in index tumors during RP, especially in CZ tumors, and emphasize the importance of securing local control in these cases. Full article

Organ functions generally decline with age, but the ovary is a prototypical organ that undergoes functional loss over time. Autophagy plays a crucial role in maintaining organ homeostasis, and age-related upregulation of the autophagy inhibitor protein, Rubicon, has been linked to cellular and tissue dysfunction. This review describes how granulosa cell autophagy supports follicular growth and oocyte selection and maturation by regulating cellular energy metabolism and protein quality control. We then introduce the role of selective autophagy, including mitophagy or lipophagy, in steroidogenesis and cellular remodeling during luteinization. In aged ovaries, Rubicon accumulation suppresses autophagic flux, leading to diminished oxidative-stress resilience and enhanced DNA damage. Moreover, impaired autophagy drives the accumulation of ATP citrate lyase, which correlates with poor oocyte quality and reduced ovarian reserve. Following fertilization, oocytes further upregulate autophagy to provide the energy required for blastocyst transition. Conversely, in infertility-related disorders, such as premature ovarian insufficiency, endometriosis, and polycystic ovary syndrome, either deficient or excessive autophagy contributes to disease pathogenesis. Both autophagy inhibitors (e.g., Rubicon) and activators (e.g., Beclin1) could be emerging as promising biomarkers for assessing ovarian autophagy status. Therapeutically, Rubicon inhibition by trehalose in aged ovaries and autophagy suppression by agents such as hydroxychloroquine in polycystic ovary syndrome and endometriosis hold potential. Establishing robust methods to evaluate ovarian autophagy will be essential for translating these insights into targeted treatments. Full article

Background/Objectives: Obesity is associated with various skin complications, yet its impact on dermal elastic fibers—key components maintaining skin elasticity—remains unclear, particularly in cases of mild obesity prevalent in East Asian populations. The aim of this study was to investigate whether mild obesity is associated with the early structural deterioration of dermal elastic fibers and alterations in elastin-related gene expression in Japanese individuals. Methods: Abdominal skin samples from 31 Japanese women (the mean body mass index [BMI] 23.9 ± 3.2 kg/m², mean age 49.5 ± 4.8) undergoing breast reconstruction surgery were analyzed. Gene expression levels of elastin-regenerative and -degradative molecules were assessed by quantitative polymerase chain reaction in the epidermis, dermis, and subcutaneous fat. Dermal elastic fiber content was evaluated histologically using Elastica van Gieson staining. Results: No statistically significant correlations between the BMI and elastin-degrading gene expression (NE, MMP2, MMP9, and NEP) were observed. ELN expression in the dermis showed a significant positive correlation with the BMI (ρ = 0.517, p = 0.003), potentially reflecting a compensatory response. Histological analysis revealed a significant inverse correlation between dermal elastic fiber content and the BMI (r = −0.572, p = 0.001), independent of age or smoking history. Conclusions: Even mild obesity is associated with the early degradation of dermal elastic fibers despite limited transcriptional alterations. These findings underscore the need for early skin care interventions to mitigate obesity-related skin fragility, especially in populations with predominantly mild obesity. Full article

Background/Objectives: Ascites is a major complication in patients with decompensated cirrhosis. Spontaneous bacterial peritonitis (SBP), an infection of the ascitic fluid, is a life-threatening condition in patients with cirrhosis. This study aimed to assess the utility of Tm mapping, a novel high-efficacy method for bacterial detection and quantification, in the early diagnosis of SBP and its pathogenesis. Methods: Ascitic fluid samples from 29 patients with cirrhosis were analyzed using Tm mapping for bacterial identification. Inflammatory cytokine and pathogen-associated molecular pattern levels in ascitic fluid were measured and correlated with SBP pathophysiology. Additionally, the role of ascitic macrophages was investigated in vitro. Results: Tm mapping detected bacteria more effectively than conventional culture methods. In samples where bacteria were identified, ascitic interleukin (IL)-6 levels were elevated. A positive correlation was observed between extracellular vesicle (EV) levels and IL-6, suggesting a role for EVs in peritoneal inflammation. Furthermore, EVs derived from Gram-negative bacteria induced M1 macrophage differentiation via the signal transducer and activator of transcription 1 signaling pathway. Conclusions: Tm mapping is a valuable tool for the early detection of bacteria in ascitic fluid. Additionally, EVs promote M1 macrophage differentiation, implicating them in the pathogenesis of cirrhotic complications, including SBP. Full article

Adrenomedullin (AM) is a bioactive peptide that is strongly induced during severe inflammation, including pneumonia and sepsis, and serves as an organ-protective factor. The plasma concentration of AM is markedly increased in the novel coronavirus disease COVID-19 and is closely related to the severity of the disease and prognosis of patients. We performed two investigator-initiated trials to evaluate the efficacy and safety of AM in patients with moderate-to-severe COVID-19. This multicenter, double-blind, placebo-controlled phase-2a trial evaluated COVID-19 patients with severe (n = 33) and moderate (n = 31) pneumonia in Japan. Patients were randomly assigned to receive either 15 ng/kg/min AM or placebo. The primary endpoint was the duration of mechanical ventilation (MV) for severe pneumonia and oxygen support for moderate pneumonia. The main secondary endpoint was clinical status up to 30 days after the intervention. No differences in primary or secondary endpoints were observed between the AM and placebo groups in patients with severe or moderate pneumonia. In the severe pneumonia group, three patients in the placebo group died due to respiratory failure, and one patient in the AM group died due to respiratory failure. The respiratory function test at 30 days in the moderate pneumonia group tended to be better than that in the AM group and approached significance (p = 0.073). Although mild adverse events caused by the vasodilatory effects of AM were noted, the safety of AM for treating pneumonia was confirmed. In these trials, we did not observe a definitive efficacy of AM in moderate to severe pneumonia. Alternative strategies for the treatment of AM in pneumonia require further research. Full article

Ensuring the safety of large spherical water storage tanks in seismic environments is critical. Therefore, this study proposed a vibration control device applicable to general spherical water tanks. By utilizing the upper interior space of a spherical tank, a novel tuned mass damper (TMD) system composed of a mass block and four elastic springs was proposed. To enable practical implementation, the vibration control mechanism and tuning principle of the proposed TMD were examined. Subsequently, an experimental setup, including the spherical water tank and the TMD, was developed. Subsequently, shaking experiments were conducted using two types of spherical tanks with different leg stiffness values under various seismic waves and excitation directions. Shaking tests using actual El Centro NS and Taft NW earthquake waves demonstrated vibration reduction effects of 34.87% and 43.38%, respectively. Additional shaking experiments were conducted under challenging conditions, where the natural frequency of the spherical tank was adjusted to align closely with the dominant frequency of the earthquake waves, yielding vibration reduction effects of 18.74% and 22.42%, respectively. To investigate the influence of the excitation direction on the vibration control performance, shaking tests were conducted at 15-degree intervals. These experiments confirmed that an average vibration reduction of more than 15% was achieved, thereby verifying the validity and practicality of the proposed TMD vibration control system for spherical water tanks. Full article

Rivers play a crucial role in the hydrological cycle and serve as essential freshwater resources for both human populations and ecosystems. Climate change significantly alters precipitation patterns and river discharge variability. However, the impact of precipitation patterns (rainfall and snowfall) and air temperature on river discharge in coastal zones remains inadequately understood. This study focused on Toyama Prefecture, located along the Sea of Japan, as a representative coastal area. We analyzed over 30 years of datasets, including air temperature, precipitation, snowfall, and river discharge, to assess the effects of climate change on river discharge. Trends in hydroclimatic datasets were assessed using the rescaled adjusted partial sums (RAPS) method and the Mann–Kendall (MK) non-parametric test. Furthermore, a correlation analysis and the Structural Equation Model (SEM) were applied to construct a relationship between precipitation, temperature, and river discharge. Our findings indicated a significant increase in air temperature at a rate of 0.2 °C per decade, with notable warming observed in late winter (January and February) and early spring (March). The average river fluxes for the Jinzu, Oyabe, Kurobe, Shou, and Joganji rivers were 182.52 m³/s, 60.37 m³/s, 41.40 m³/s, 38.33 m³/s, and 18.72 m³/s, respectively. The tipping point for snowfall decline occurred in 1992, marked by an obvious decrease in snowfall depth. The SEM showed that, although rainfall dominated the changes in river discharge (loading = 0.94), the transition from solid (snow) to liquid (rain) precipitation may alter the river discharge regime. The percentage of flood occurrence increased from 19% (1940–1992) to 41% (1993–2020). These changes highlight the urgent need to raise awareness about the impacts of climate change on river floods and freshwater resources in global coastal regions. Full article