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Abstract Lean body mass (LBM) serves as an indicator of muscle mass in body composition. Recently, studies have revealed increased mortality rates in dialysis patients with low LBM. However, studies analyzing the impact of age on LBM and mortality in dialysis patients remain limited. This study analyzed data from 26,625 adult hemodialysis patients registered in the Korean Society of Nephrology (KSN) registry from 2001 to 2020. We used the lean body mass index (LBMI), standardized by the square of height, to normalize lean body mass. Patients were first categorized by age group (20–49, 50–69, and ≥ 70 years). Subsequently, patients were categorized into quartile groups based on their LBMI (≤ 15.55, 15.55 17.59). This study revealed that the lowest LBMI group (≤ 15.55) was associated with decreased survival across all age groups, with this trend being particularly prominent in the older age groups. Within the 20–49 age group, factors such as diabetes exhibited a notable influence on mortality rates among hemodialysis patients. In the age group over 50, a low LBMI (≤ 15.55) had a greater impact on mortality rates in hemodialysis patients than diabetes. Understanding the importance of LBM in older patients undergoing dialysis is crucial for improving their prognosis.

Abstract Background Patients with estrogen receptor (ER)-positive breast cancer (BC) can be treated with endocrine therapy targeting ER, however, metastatic recurrence occurs in 25% of the patients who have initially been treated. Secreted proteins from tumors play important roles in cancer metastasis but previous methods for isolating secretory proteins had limitations in identifying novel targets. Methods We applied an in situ secretory protein labeling technique using TurboID to analyze secretome from tamoxifen-resistant (TAMR) BC. The increased expression of LGALS3BP was validated using western blotting, qPCR, ELISA, and IF. Chromatin immunoprecipitation was applied to analyze estrogen-dependent regulation of LGALS3BP transcription. The adhesive and angiogenic functions of LGALS3BP were evaluated by abrogating LGALS3BP expression using either shRNA-mediated knockdown or a neutralizing antibody. Xenograft mouse experiments were employed to assess the in vivo metastatic potential of TAMR cells and the LGALS3BP protein. Clinical evaluation of LGALS3BP risk was carried out with refractory clinical specimens from tamoxifen-treated ER-positive BC patients and publicly available databases. Results TAMR secretome analysis revealed that 176 proteins were secreted at least 2-fold more from MCF7/TAMR cells than from sensitive cells, and biological processes such as cell adhesion and angiogenesis were associated with the TAMR secretome. Galectin-3 binding protein (LGALS3BP) was one of the top 10 most highly secreted proteins in the TAMR secretome. The expression level of LGALS3BP was suppressed by estrogen signaling, which involves direct ERα binding to its promoter region. Secreted LGALS3BP in the TAMR secretome helped BC cells adhere to the extracellular matrix and promoted the tube formation of human umbilical vein endothelial cells. Compared with sensitive cells, xenograft animal experiments with MCF7/TAMR cells showed increased pulmonary metastasis, which completely disappeared in LGALS3BP-knockdown TAMR cells. Finally, higher levels of LGALS3BP were associated with poor prognosis in ER-positive BC patients treated with adjuvant tamoxifen in the clinic. Conclusion TAMR secretome analysis identified secretory proteins, such as LGALS3BP, that are involved in biological processes closely related to metastasis. Secreted LGALS3BP from the TAMR cells promoted adhesion of the cells to the extracellular matrix and vasculature formation, which may support metastasis of TAMR cells.

Abstract Background Lac color, a natural red dye derived from the larvae of laccifer lacca kerr, is one of the most commonly used substances in food. To date, no studies have reported on the antigenicity of lac color and the other biomarkers that can determine anaphylactic reactions. To address this, we evaluated the antigenicity of lac color through active systemic anaphylaxis (ASA) in addition to identifying potential biomarkers performing exploratory studies. For ASA test, Guinea pigs (n = 5) were sensitized with 0(negative control), 4 mg/kg of lac color, 4 mg/kg of lac color + FCA, and 5 mg/kg of ovalbumin + FCA (positive control) 3 times a week for three weeks. Fourteen days after the last sensitization, animals were challenged intravenously weekly for two weeks. Hematological and histopathological analyses were performed and compared to control groups. Results In the ASA test, all lac color groups showed mild symptoms such as nose rubbing, urination, and evacuation, which are insufficient indicators of anaphylaxis. Exploratory studies identified several biomarkers: decreased platelet count, and increased basophil count; distention in the lung, and redness on the inner wall of trachea; mononuclear inflammatory cell infiltration (MICI) in the ear, and heart hemorrhage. When these biomarkers were applied to the ASA test of lac color, in comparison to the negative control group, the positive control group (ovalbumin + FCA) showed a significant over 60-fold reduction in platelet count and nearly threefold higher basophil count compared to other groups. Furthermore, only positive control group exhibited full lung distention and severe redness on the inner wall of the trachea. Mononuclear inflammatory cell infiltration (MICI) in the ear was about three times higher, and heart hemorrhage was only present in the positive control group compared to others. None of the lac color groups were different from the negative control group (p > 0.05), whereas the positive control group was significantly different (p

Abstract Unabated 21st-century climate change will accelerate Arctic-Subarctic permafrost thaw which can intensify microbial degradation of carbon-rich soils, methane emissions, and global warming. The impact of permafrost thaw on future Arctic-Subarctic wildfires and the associated release of greenhouse gases and aerosols is less well understood. Here we present a comprehensive analysis of the effect of future permafrost thaw on land surface processes in the Arctic-Subarctic region using the CESM2 large ensemble forced by the SSP3-7.0 greenhouse gas emission scenario. Analyzing 50 greenhouse warming simulations, which capture the coupling between permafrost, hydrology, and atmosphere, we find that projected rapid permafrost thaw leads to massive soil drying, surface warming, and reduction of relative humidity over the Arctic-Subarctic region. These combined processes lead to nonlinear late-21st-century regime shifts in the coupled soil-hydrology system and rapid intensification of wildfires in western Siberia and Canada.

Abstract Background Kidney biopsy is the standard of care for the diagnosis of various kidney diseases. In particular, chronic histopathologic lesions, such as interstitial fibrosis and tubular atrophy, can provide prognostic information regarding chronic kidney disease progression. In this study, we aimed to evaluate historadiological correlations between CT-based radiomic features and chronic histologic changes in native kidney biopsies and to construct and validate a radiomics-based prediction model for chronicity grade. Methods We included patients aged ≥ 18 years who underwent kidney biopsy and abdominal CT scan within a week before kidney biopsy. Left kidneys were three-dimensionally segmented using a deep learning model based on the 3D Swin UNEt Transformers architecture. We additionally defined isovolumic cortical regions of interest near the lower pole of the left kidneys. Shape, first-order, and high-order texture features were extracted after resampling and kernel normalization. Correlations and diagnostic metrics between extracted features and chronic histologic lesions were examined. A machine learning-based radiomic prediction model for moderate chronicity was developed and compared according to the segmented regions of interest (ROI). Results Overall, moderate correlations with statistical significance (P

Abstract Loss of parvalbumin (PV) expressing neurons (PV neurons) is relevant to the underlying mechanisms of the pathogenesis of neurological and psychiatric diseases associated with the dysregulation of neuronal excitatory networks and brain metabolism. Although PV modulates mitochondrial morphology, volume and dynamics, it is largely unknown whether mitochondrial dynamics affect PV expression and what the molecular events are responsible for PV neuronal degeneration. In the present study, L-buthionine sulfoximine (BSO, an inhibitor of glutathione synthesis) did not degenerate PV neurons under physiological condition. However, BSO-induced oxidative stress decreased PV expression and facilitated cyclin-dependent kinase 5 (CDK5) tyrosine (Y) 15 phosphorylation, dynamin-related protein 1 (DRP1)-mediated mitochondrial fission and glutathione peroxidase-1 (GPx1) downregulation in PV neurons. Co-treatment of roscovitine (a CDK5 inhibitor) or mitochondrial division inhibitor-1 (Mdivi-1, an inhibitor of mitochondrial fission) attenuated BSO-induced PV downregulation. WY14643 (an inducer of mitochondrial fission) reduced PV expression without affecting CDK5 Y15 phosphorylation. Following status epilepticus (SE), CDK5 Y15 phosphorylation and mitochondrial fission were augmented in PV neurons. These were accompanied by reduced GPx1-mediated inhibition of NF-κB p65 serine (S) 536 phosphorylation. N-acetylcysteine (NAC), roscovitine and Mdivi-1 ameliorated SE-induced PV neuronal degeneration by mitigating CDK5 Y15 hyperphosphorylation, aberrant mitochondrial fragmentation and reduced GPx1-mediated NF-κB inhibition. Furthermore, SN50 (a NF-κB inhibitor) alleviated SE-induced PV neuronal degeneration, independent of dysregulation of mitochondrial fission, CDK5 hyperactivation and GPx1 downregulation. These findings provide an evidence that oxidative stress may activate CDK5-DRP1- and GPx1-NF-κB-mediated signaling pathways, which would be possible therapeutic targets for preservation of PV neurons in various diseases.

Abstract The study investigated the effects of temperature and centrifugation time on the efficacy of removing uncured resin from 3D-printed clear aligners. Using a photo-polymerizable polyurethane resin (Tera Harz TC-85, Graphy Inc., Seoul, Korea), aligners were printed and subjected to cleaning processes using isopropyl alcohol (IPA) or centrifugation (g-force 27.95g) at room temperature (RT, 23 °C) and high temperature (HT, 55 °C) for 2, 4, and 6 min. The control group received no treatment (NT). Cleaning efficiency was assessed through rheological analysis, weight measurement, transparency evaluation, SEM imaging, 3D geometry evaluation, stress relaxation, and cell viability tests. Results showed increased temperature and longer centrifugation times significantly reduced aligner viscosity, weight (P

Background: A comparative 12-week dietary intervention of red yeast rice (RYR, Beni-koji, Kobayashi, Japan) and Cuban policosanol (PCO, Raydel®, Thornleigh, Australia) was assessed for dyslipidemia, antioxidant status, and vital organ functionality in hyperlipidemic zebrafish. Methods: Hyperlipidemic zebrafish were supplemented with a high-cholesterol diet (HC, final 4%, w/w) infused with either a powdered RYR tablet (final 1.0%, w/w), a PCO tablet (final 1.0%, w/w), or a combination of 0.5% (w/w) each of RYR and PCO powder for 12 weeks. Subsequently, blood and organs were collected and processed for biochemical and histological examination. Results: RYR and PCO consumption showed a substantial effect against HC-induced hyperlipidemia by reducing the total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C). Exclusively, PCO supplementation revealed a significant elevation in the HC-diminished high-density lipoprotein cholesterol (HDL-C). In addition, PCO supplementation showed a significant elevation in plasma ferric ion-reducing ability (FRA) and sulfhydryl content, as well as alleviating the blood glucose level of hyperlipidemic zebrafish. The most noteworthy impact, with a significant two-fold (p < 0.001) augmentation of HC-diminished plasma paraoxonase (PON) activity, was observed in response to PCO. In contrast, the RYR supplementation failed to establish curative effects against HC-disturbed plasma antioxidant variables and blood glucose levels. The histological outcome revealed a severe toxicological impact of the RYR on the liver, reflected by fatty liver changes and three-fold heightened IL-6 production compared to HC control. Contrastingly, PCO exhibited significant hepatoprotection and effectively neutralized the hepatic toxicity triggered by HC and RYR. Also, RYR showed kidney atrophy, intense ROS generation, apoptosis, and senescence. Conversely, the PCO supplementation protected the kidney from HC- and RYR-induced toxicity. Likewise, PCO supplementation notably alleviated histological alterations and oxidative stress in the brain, ovary, and testis of hyperlipidemic zebrafish. Conclusions: This comparative study establishes PCO’s therapeutic effect against the challenges posed by HC, while RYR emerged with serious toxicological concerns towards the liver, kidney, and other organs of hyperlipidemic zebrafish.

A plant-based beverage enhanced with GABA was developed through serial co-fermentation using Leuconostoc citreum S5 and Lactiplantibacillus plantarum KS2020. The first lactic acid fermentation was performed by Leu. citreum S5 with a vegetable mixture consisting of sliced radish, ginger, garlic, red pepper, bell pepper, and sucrose. The viable cell count of Leu. citreum S5 increased to 9.11–9.42 log CFU/mL with higher sucrose contents, indicating the highest value of 9.42 log CFU/mL at 5% sucrose on day 1. Mannitol and dextran production levels in the first fermented vegetable mixture were 6.66–14.54 mg/mL and 0.44–2.26%, respectively. A higher sucrose content produced more dextran, resulting in a concomitant increase in viscosity of 49.4 mPa·s. The second co-fermentation for the kimchi beverage base was performed by Lb. plantarum KS2020 for 5 days, resulting in 8.22–9.60 log CFU/mL. The pH of the co-fermented kimchi beverage base increased to 6.19–9.57 with an increasing monosodium glutamate (MSG) content (3–7%), while titratable acidity significantly decreased to 0.0–0.8%. The final co-fermented kimchi beverage base was enriched with 2.6% GABA. Consequently, a GABA kimchi beverage base with probiotics, a red pigment, and a pleasant flavor was developed using only vegetable ingredients by serial co-fermentation using lactic acid bacteria.

IntroductionThe carbon isotope ratios (δ13C) of essential amino acids (EAAs), including valine, leucine, isoleucine, threonine, and phenylalanine, in producers are crucial for explaining food-web structures in marine ecosystems. However, few studies have tested the variability of δ13C-EAA values in marine macrophytes, such as seagrass and macroalgae, under changing environmental conditions.MethodsIn this study, we examined the responses of δ13C-EAA values in macrophytes to environmental changes and explored their usefulness in characterizing macrophyte groups and local environments. We tested seagrass and macroalgae collected at different spatial and temporal scales in the field, as well as lab-cultured Ulva algae at various temperature gradients (12°C, 20°C, and 27.5°C) with additional nitrogen sources.ResultsWe found that δ13C-EAA values in macroalgae were significantly altered by seasonality and the interactive effects of temperature and nitrogen addition in comparison with mean-centered δ13C-EAA values (normalized δ13C-EAA values relative to the mean of the overall EAAs). The δ13C-EAA values detected in macroalgae within a local environment correlated with those of a co-occurring grazer, Caprella. Based on mean-centered δ13C-EAA values, macrophyte groups were distinguishable from other group (i.e., the bacteria group) even under diverse environmental conditions. Moreover, the seagrass group did not overlap with the green and the brown macroalgal group, but overlapped considerably with the red macroalgal group.DiscussionThese results suggest that the macrophyte-specific mean-centered δ13C-EAA values may be fairly consistent across broad spatial and temporal scales. Despite significant variation in δ13C-EAA values, the consistency in mean-centered δ13C-EAA values among specific macrophyte groups provides valuable insight into the characteristics of local trophic bases in regions under pressure from dramatic environmental changes.

Abstract Constipation is a highly prevalent gastrointestinal disorder in patients with chronic kidney disease (CKD). However, our understanding of its epidemiology and management in CKD is limited. We aimed to explore real-world data on constipation and laxative use in patients with CKD in a nationwide population-based cohort from the Korean Health Insurance Review and Assessment-National Patient Sample database. This study analyzed retrospective health claims data in Korea from 2012 to 2017 that were transformed into the Observational Medical Outcomes Partnership Common Data Model. The pooled proportion of constipation diagnoses was 30.5% in all patients with CKD and 15.9%, 16.5%, 17.4%, 29.9%, and 43.3% in patients with CKD stages 1–5, respectively, suggesting a higher prevalence in advanced CKD. Patients receiving peritoneal dialysis or hemodialysis had the highest prevalence of constipation, while transplant recipients showed a prevalence comparable to that of patients with early CKD. Patients with CKD had a significantly higher risk of constipation than age- and sex-matched non-CKD individuals (range of odds ratio [OR]:1.66–1.90). Laxative prescribing patterns differed by CKD severity. Osmotic agents were prescribed in more than half of patients with advanced CKD, while magnesium salts and bulking agents were prescribed less frequently. The CKD patients with constipation were more likely to be prescribed constipation-inducing medications, including antipsychotic and neurological medications. Our findings provide real-world constipation and laxative prescription status in the Korean CKD population, revealing a significantly higher risk of constipation and different laxative prescribing patterns in patients with CKD.

Abstract Background Patients with fibro-calcific aortic valve disease (FCAVD) have lipid depositions in their aortic valve that engender a proinflammatory impetus toward fibrosis and calcification and ultimately valve leaflet stenosis. Although the lipoprotein(a)-autotaxin (ATX)-lysophosphatidic acid axis has been suggested as a potential therapeutic target to prevent the development of FCAVD, supportive evidence using ATX inhibitors is lacking. We here evaluated the therapeutic potency of an ATX inhibitor to attenuate valvular calcification in the FCAVD animal models. Methods ATX level and activity in healthy participants and patients with FCAVD were analyzed using a bioinformatics approach using the Gene Expression Omnibus datasets, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and western blotting. To evaluate the efficacy of ATX inhibitor, interleukin-1 receptor antagonist-deficient (Il1rn -/-) mice and cholesterol-enriched diet-induced rabbits were used as the FCAVD models, and primary human valvular interstitial cells (VICs) from patients with calcification were employed. Results The global gene expression profiles of the aortic valve tissue of patients with severe FCAVD demonstrated that ATX gene expression was significantly upregulated and correlated with lipid retention (r = 0.96) or fibro-calcific remodeling-related genes (r = 0.77) in comparison to age-matched non-FCAVD controls. Orally available ATX inhibitor, BBT-877, markedly ameliorated the osteogenic differentiation and further mineralization of primary human VICs in vitro. Additionally, ATX inhibition significantly attenuated fibrosis-related factors’ production, with a detectable reduction of osteogenesis-related factors, in human VICs. Mechanistically, ATX inhibitor prohibited fibrotic changes in human VICs via both canonical and non-canonical TGF-β signaling, and subsequent induction of CTGF, a key factor in tissue fibrosis. In the in vivo FCAVD model system, ATX inhibitor exposure markedly reduced calcific lesion formation in interleukin-1 receptor antagonist-deficient mice (Il1rn -/-, P = 0.0210). This inhibition ameliorated the rate of change in the aortic valve area (P = 0.0287) and mean pressure gradient (P = 0.0249) in the FCAVD rabbit model. Moreover, transaortic maximal velocity (Vmax) was diminished with ATX inhibitor administration (mean Vmax = 1.082) compared to vehicle control (mean Vmax = 1.508, P = 0.0221). Importantly, ATX inhibitor administration suppressed the effects of a high-cholesterol diet and vitamin D2-driven fibrosis, in association with a reduction in macrophage infiltration and calcific deposition, in the aortic valves of this rabbit model. Conclusions ATX inhibition attenuates the development of FCAVD while protecting against fibrosis and calcification in VICs, suggesting the potential of using ATX inhibitors to treat FCAVD.

Abstract Background Coronavirus disease 2019 (COVID-19) was first reported in December 2019 and the first case in Korea was confirmed on January 20, 2020. Due to the absence of therapeutic agents and vaccines, the Korean government implemented social distancing on February 29, 2020. This study aimed to examine the effect of physical activity (PA) on health through changes in multi-omics biomarkers with a 6-month of exercise intervention during the first wave of COVID-19 in Korea. Methods Twenty-seven healthy middle-aged women were recruited and 14 subjects completed the exercise intervention. The mean age (± SD) was 46.3 (± 5.33) and the mean BMI (± SD) was 24.9 (± 3.88). A total of three blood and stool samples were collected at enrollment, after period 1, and after period 2 (3-month intervals). The amount of PA was measured with an accelerometer and by questionnaire. Clinical variables were used, including blood pressure, grip strength, flexibility, and blood glucose levels and lipid markers obtained from laboratory tests. The concentration of blood metabolites was measured by targeted metabolomics. Fecal microbiome data were obtained by 16 S rRNA gene amplicon sequencing. Results During the second half period (period 2), Coronavirus disease 2019 occurred and spread out in Korea, and PA decreased compared with the first half period (period 1) (185.9 ± 168.73 min/week to 102.5 ± 82.30 min/week; p = 0.0101). Blood pressure, hemoglobin A1c (HbA1c), and low-density lipoprotein cholesterol (LDL-C) decreased in period 1 (p

Objectives: The present study describes the comparative effect of 24-week supplementation of beeswax alcohol (BWA, Raydel®, 0.5% and 1.0%, wt/wt) and coenzyme Q10 (CoQ10, 0.5% and 1.0%, wt/wt) on plasma oxidative variables and the prevention of organ injury in adult zebrafish subjected to a high-cholesterol (HC, 4%, wt/wt) and -D-galactose (Gal, 30%, wt/wt) diet. Methods: Adult zebrafish were fed various HC+Gal diets enriched with either BWA or CoQ10. After 24 weeks of dietary intervention, blood and organs were harvested for subsequent biochemical and histological evaluations. Results: The HC+Gal-elevated plasma oxidative variables were reverted by the consumption of BWA, marked by the lowest plasma malondialdehyde (MDA) level and highest sulfhydryl content. The HC+Gal-impaired zebrafish swimming ability (staggering movement) was substantially recovered by BWA, manifested by a ~three-fold (p < 0.001) enhancement in swimming distance and speed. Also, the intake of BWA affected the morphology of HC+Gal-compromised kidney and induced histological changes by mitigating reactive oxygen species (ROS) production and cellular senescence, which was markedly more effective than the results seen in the CoQ10 group. Likewise, BWA proved effective in preventing HC+Gal-induced testis damage, apparent in the 48.3% (p < 0.05) higher spermatozoa and 26.3% (p < 0.01) reduced interstitial space between the seminiferous tubules. BWA substantially prevented HC+Gal-induced ovary damage by suppressing oxidative stress, lipid deposition and senescence, leading to the restoration of mature vitellogenic oocyte counts. Conclusion: BWA demonstrated a greater ability than CoQ10 to enhance plasma antioxidant status, suppress ROS generation, delay organ aging and alleviate HC+Gal-induced adversity in zebrafish.

Oxidative stress is the key cause of the etiopathogenesis of several diseases associated with constipation. This study examined whether the green pine cone can improve the symptoms of constipation based on the antioxidant activities. The changes in the key parameters for the antioxidant activity and laxative effects were examined in the loperamide (Lop)-induced constipation of Sprague-Dawley (SD) rats after being treated with the methanol extracts of green pine cone (MPC, unripe fruits of Pinus densiflora). MPC contained several bioactive compounds, including diterpenoid compounds such as dehydroabietic acid, taxodone, and ferruginol. In addition, it exhibited high scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals. These effects of MPC successfully reflected the improvement in nicotinamide adenine dinucleotide phosphate oxidase (NADP) H oxidase transcription, superoxide dismutase (SOD) levels, and nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation levels in the mid colon of Lop+MPC-treated SD rats. Furthermore, significant improvements in the stool parameters, gastrointestinal (GI) transit, intestine length, and histopathological structure of the mid colon were detected in the Lop-induced constipation rats after MPC treatment. The other parameters, including the regulators for the adherens junction (AJ) and tight junction (TJ), and GI hormone secretion for laxative effects, were improved significantly in Lop+MPC-treated SD rats. These effects were also verified in Lop+MPC-treated primary rat intestine smooth muscle cells (pRISMCs) through analyses for antioxidant defense mechanisms. Overall, the finding of this study offers novel scientific evidence that MPC could be considered as a significant laxative for chronic constipation based on its antioxidant activity.

Background/Objectives: Influenza poses significant risks in children, causing complications like febrile seizures and hospitalizations. Antiviral treatments include oseltamivir and peramivir, both FDA-approved neuraminidase inhibitors. This study aims to compare the effectiveness of intravenous peramivir and oral oseltamivir in pediatric patients presenting to an emergency department, with a primary focus on the revisit rate within 72 h post-treatment. Methods: A retrospective study analyzed 1327 children aged 1–15 years diagnosed with influenza A or B between 1 January 2019 and 29 February 2020, at a single urban hospital. Patients were divided into oseltamivir (n = 1243) and peramivir (n = 84) groups. Data included demographics, clinical symptoms, emergency department stays, and revisit rates. Fisher’s exact test was used for analysis, with p-values < 0.05 considered significant. Results: A total of 1327 pediatric patients were included, with 1243 receiving oseltamivir and 84 receiving peramivir. Patients in the peramivir group were older (median age 5.88 years vs. 4.54 years, p = 0.002) and had higher rates of gastrointestinal symptoms. The emergency department length of stay was significantly longer in the peramivir group (167 min vs. 63 min, p < 0.001). The revisit rate within 3 days was 5.63% for oseltamivir and 9.52% for peramivir, with no statistically significant difference (p = 0.22). Conclusions: Peramivir presents as an effective alternative treatment for influenza in children, particularly in situations where oral administration is not feasible due to gastrointestinal intolerance, highlighting the importance of an alternative route of antiviral administration.

The prolonged consumption of D-galactose (Gal) has been associated with severe damage in the liver and brain via exacerbation of oxidative stress, non-enzymatic glycation, and the aging process. The current study was initiated for a comparative assessment of beeswax alcohol (BWA, final 0.5% and 1.0% w/w) and coenzyme Q10 (CoQ10, final 0.5% and 1.0% w/w) against high-cholesterol (HC, final 4%, w/w) and -galactose (Gal, final 30%, w/w)-induced adverse events in zebrafish during 24 weeks of consumption. The survivability of zebrafish decreased to 82.1% due to HC+Gal exposure, but this was substantially improved (91.0%) with the consumption of 0.5% and 1.0% BWA. In contrast, no protective effect of CoQ10 consumption (1.0%) was observed on the survivability of zebrafish. Nevertheless, both BWA and CoQ10 displayed a significant (p < 0.001) preventive effect against HC+Gal-induced body weight enhancement. The HC+Gal-induced cognitive changes, marked by staggered and confused swimming behavior, and retarded swimming speed and motion patterns (restricted to the bottom of the tank), were efficiently restored by BWA. A significantly higher residence time in the upper half of the tank, 3.1-and 4.5-fold reduced latency time along with 3.5-fold and 4.1-fold higher swimming distance, was logged in the 0.5% and 1.0% BWA groups, respectively, than the zebrafish that consumed HC+Gal. In addition, BWA effectively enhanced plasma ferric ion reduction (FRA) and paraoxonase (PON) activity and alleviated the total cholesterol (TC), triglyceride (TG), and blood glucose levels disrupted by the consumption of HC+Gal. Also, the HC+Gal-alleviated plasma high-density lipoprotein-cholesterol (HDL-C) was 2.6-fold (p < 0.001) enhanced in the group that consumed 1.0% BWA, which was significantly 1.5-fold (p < 0.001) better than the effect of 1.0% CoQ10. Similarly, BWA displayed a superior impact over CoQ10 to mitigate HC+Gal-induced plasma AST and ALT levels, hepatic IL-6 production, generation of oxidized species, cellular senescence, and fatty liver changes. Moreover, BWA protects the brain against HC+Gal-induced oxidative stress, apoptosis, and myelin sheath degeneration. Conclusively, compared to CoQ10, BWA efficiently can the HC+Gal-impaired brain and liver functionality to subside and improves the dyslipidemia and cognitive behavior of zebrafish.

Background/Objectives: Beeswax alcohol (BWA; Raydel®) is a blend of six long-chain aliphatic alcohols extracted from honeybee wax and is well known for its diverse functionality and health benefits. Herein, the efficacy of a BWA dietary intervention for 20 weeks was assessed to ameliorate high-cholesterol diet (HCD)-induced dyslipidemia and adverse effects on the vital organs of adult zebrafish. Methods: Adult zebrafish were fed different high-cholesterol diets (HCDs; final concentration of 4%, w/w) supplemented with BWA (final concentrations of 0.1%, 0.5% and 1.0%, w/w) or CoQ10 (final concentration of 1.0%). Following 20 weeks of supplementation, blood and different organs (liver, kidney, testes and ovaries) were collected, and biochemical, histological and immunohistochemical analyses were performed. Results: The results demonstrate a dose-dependent effect of BWA of mitigating HCD-induced mortality in zebrafish over the 20-week supplementation period, which was noticeably better than the effect exerted by coenzyme Q10 (CoQ10). Consistently, a dose-dependent effect of BWA consumption of curtailing HCD-induced total cholesterol (TC) and triglyceride (TG) levels and increasing high-density-lipoprotein cholesterol (HDL-C) levels was noticed. Compared with CoQ10 (final concentration of 1.0%, w/w), BWA (final concentration of 1.0%, w/w) displayed a significantly better effect of mitigating HCD-induced dyslipidemia, as evidenced by 1.2-fold (p < 0.05) and 2.0-fold (p < 0.05) lower TC and TG levels and 2.4-fold (p < 0.01) higher HDL-C levels. The histological analysis revealed substantial prevention of fatty liver changes, reactive oxygen species (ROS) generation, cellular senescence and interleukin (IL)-6 production in the hepatic tissue of BWA zebrafish, which was significantly better than the effect exerted by CoQ10. Consistently, compared with CoQ10, significant 25% (p < 0.05) and 35% (p < 0.01) reductions in the HCD-induced elevated levels of the hepatic function biomarkers aspartate aminotransferase and alanine aminotransferase was observed in the BWA group. Likewise, BWA consumption efficiently ameliorated HCD-induced kidney, ovary and testis damage by inhibiting ROS generation, cellular senescence and lipid accumulation. Conclusion: Supplementation with BWA demonstrated higher therapeutic potential than that with CoQ10 to prevent dyslipidemia and organ damage associated with long-term consumption of HCDs.

ABSTRACTCardiomyocytes derived from human pluripotent stem cells (hPSCs) can be used in various applications including disease modeling, drug safety screening, and novel cell-based cardiac therapies. Here, we report an optimized selection and maturation method to induce maturation of cardiomyocytes into a specific subtype after differentiation driven by the regulation of Wnt signaling. The medium used to optimize selection and maturation was in a glucose starvation conditions, supplemented with either a nutrition complex or ascorbic acid. Following optimized selection and maturation, more cardiac Troponin T (cTnT)-positive cardiomyocytes were detected using albumin and ascorbic acid than B27. In addition, ascorbic acid enriched maturation of ventricular cardiomyocytes. We compared cardiomyocyte-specific gene expression patterns under different selection and maturation conditions by next-generation sequencing (NGS) analysis. Our optimized conditions will enable simple and efficient maturation and specification of the desired cardiomyocyte subtype, facilitating both biomedical research and clinical applications.

Antioxidant activities of an aqueous extract of sesame meal (SM-HW) and an ultrasonicated sesame meal (SSM-HW) were evaluated and anti-obesity activity of SSM-HW was determined using in vitro assays. In addition, metabolite analyses were conducted using GC/MS to determine major non-volatile compounds in SM-HW and SSM-HW. Antioxidant activities of SSM-HW were significantly higher than those of SM-HW. SSM-HW had higher concentrations of some organic acids and amino acids than SM-HW. Differentiation of 3T3-L1 adipocytes was decreased by 20 % after treatment with 10 μg/mL SSM-HW compared to control. Expression levels of several adipocyte marker genes and proteins were significantly decreased compared to control (p

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as Non-Alcoholic Fatty Liver Disease, is a widespread liver condition characterized by excessive fat buildup in hepatocytes without significant alcohol consumption. Manipulation of the gut microbiome has been considered to prevent and improve the occurrence and progression of MASLD, particularly through the gut-liver axis. This study aimed to investigate the correlation between the gut microbiome and liver function and determine whether the gut microbiome can ameliorate MASLD. We comparatively analyzed the gut microbiome composition between mice fed normal chow and those fed a high-fat diet and observed that the abundance of Kineothrix alysoides decreased in the high-fat group. Further analysis showed that treatment with K. alysoides in the high-fat diet group led to decreased weight loss, and MASLD attenuation. Importantly, K. alysoides treatment attenuated MASLD in mice fed a high-fat, high-fructose diet (HFHF), which can cause advanced liver damage. Furthermore, administration of K. alysoides altered the gut microbial composition in the HFHF diet group and improved MASLD. Overall, these findings demonstrate the potential of K. alysoides in restoring gut health and facilitating lipid metabolism to prevent and treat MASLD.

Abstract To evaluate the associations of periodontal disease (PD) with systemic diseases, including diabetes mellitus (DM) and cardiovascular disease (CVD), as well as the reciprocal association. The CVD included the cases of coronary heart disease and heart failure. A prospective study was conducted from 2007 to 2019 using linked data from three databases in Korea. Three separate study groups were formed to individually determine the risks of PD (n = 10,533), DM (n = 14,523) and CVD (n = 14,315). All diseases were confirmed based on physicians’ diagnoses using medical records and self-reports. Cox proportional hazard regression was applied with 95% confidence intervals (CIs) to obtain hazard ratios (HRs). PD was significantly associated with an elevated risk of DM (HR [95% CI]: 1.22 [1.07–1.39]) after full adjustment for age, sex, lifestyle factors, body mass index, dental behaviour and CVD. PD was also found to increase the risk of CVD (1.27 [1.03–1.57]), whereas CVD increased the risk of PD (1.20 [1.09–1.32]) after full adjustment for other covariates including DM. This study found a bidirectional association between PD and CVD, as well as a positive association of PD with DM.

Abstract Protein disulfide isomerase (PDI) is a redox-active enzyme and also serves as a nitric oxide donor causing S-nitrosylation of cysteine residues in various proteins. Although PDI knockdown reduces α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR)-mediated neuronal activity, the underlying mechanisms are largely unknown. In the present study, we found that under physiological condition PDI knockdown increased CaMKII activity (phosphorylation) in the mouse hippocampus. However, PDI siRNA inhibited protein phosphatase (PP) 2A-mediated GluA2 S880 dephosphorylation by increasing PP2A oxidation, independent of S-nitrosylation. PDI siRNA also enhanced glutamate ionotropic receptor AMPA type subunit 1 (GluA1) S831 and GluA2 S880, but not GluA1 S845 and GluA2 Y869/Y873/Y876 phosphorylations, concomitant with the enhanced protein interacting with C kinase 1 (PICK1)-mediated AMPAR internalization. Furthermore, PDI knockdown attenuated seizure activity and neuronal damage in response to kainic acid (a non-desensitizing agonist of AMPAR). Therefore, these findings suggest that PDI may regulate surface AMPAR expression through PP2A-GluA2-PICK1 signaling pathway, and that PDI may be one of the therapeutic targets for epilepsy via AMPAR internalization without altering basal neurotransmission.

Abstract Background Toll-like receptor 4 (TLR4) conducts a highly regulated inflammatory process by limiting the extent of inflammation to avoid toxicity and tissue damage, even in bone tissues. Thus, it is plausible that strategies for the maintenance of normal bone-immunity to prevent undesirable bone damage by TLR4 activation can exist, but direct evidence is still lacking. Methods Osteoclast precursors (OCPs) obtained from WT or Slit3-deficient mice were differentiated into osteoclast (OC) with macrophage colony-stimulating factor (M-CSF), RANK ligand (RANKL) and lipopolysaccharide (LPS) by determining the number of TRAP-positive multinuclear cells (TRAP+ MNCs). To determine the alteration of OCPs population, fluorescence-activated cell sorting (FACS) was conducted in bone marrow cells in mice after LPS injection. The severity of bone loss in LPS injected WT or Slit3-deficient mice was evaluated by micro-CT analysis. Result We demonstrate that TLR4 activation by LPS inhibits OC commitment by inducing the concomitant expression of miR-218–2-3p and its host gene, Slit3, in mouse OCPs. TLR4 activation by LPS induced SLIT3 and its receptor ROBO1 in BMMs, and this SLIT3-ROBO1 axis hinders RANKL-induced OC differentiation by switching the protein levels of C/EBP-β isoforms. A deficiency of SLIT3 resulted in increased RANKL-induced OC differentiation, and the elevated expression of OC marker genes including Pu.1, Nfatc1, and Ctsk. Notably, Slit3-deficient mice showed expanded OCP populations in the bone marrow. We also found that miR-218–2 was concomitantly induced with SLIT3 expression after LPS treatment, and that this miRNA directly suppressed Tnfrsf11a (RANK) expression at both gene and protein levels, linking it to a decrease in OC differentiation. An endogenous miR-218–2 block rescued the expression of RANK and subsequent OC formation in LPS-stimulated OCPs. Aligned with these results, SLIT3-deficient mice displayed increased OC formation and reduced bone density after LPS challenge. Conclusion Our findings suggest that the TLR4-dependent concomitant induction of Slit3 and miR-218–2 targets RANK in OCPs to restrain OC commitment, thereby avoiding an uncoordinated loss of bone through inflammatory processes. These observations provide a mechanistic explanation for the role of TLR4 in controlling the commitment phase of OC differentiation. Video Abstract

Abstract Background Physical activity (PA) is recommended to improve the survival of cancer patients. However, the prognostic impact of specific PAs is not well understood. Therefore, we investigated the associations of the duration, type, intensity, and number of PAs one participates in pre‐ and post‐diagnosis with mortality in Korean patients with cancer. Methods Among the participants aged 40–69 years recruited from the Health Examines study, those diagnosed with cancer after baseline (n = 7749) and within 10 years before baseline (n = 3008) were included in the analyses for pre‐ and post‐diagnosis PA, respectively. Duration, intensity, type, and number of leisure‐time physical activities participated in were assessed using questionnaires. The Cox proportional hazard model was used to characterize the association between PA and cancer‐specific mortality, adjusting for demographics, behaviors, comorbidities, and cancer stage based on the Surveillance, Epidemiology, and End Results program. Results Pre‐diagnosis, patients participating in vigorous‐intensity activities (hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.61–0.82), walking (HR: 0.85, 95% CI: 0.74–0.97), climbing (HR: 0.65, 95% CI: 0.55–0.77), sports (HR: 0.39, 95% CI: 0.25–0.61), and more than two activities (HR: 0.73, 95% CI: 0.63–0.86) had significantly lower all‐cause mortality. Importantly, these associations were only found in patients with colorectal cancer participating in vigorous‐intensity activities (HR: 0.40, 95% CI: 0.23–0.70). Post‐diagnosis, only patients who performed more than two activities (HR: 0.65, 95% CI: 0.44–0.95) had significantly lower all‐cause mortality. Similar associations were found for cancer mortality, both pre‐ and post‐diagnosis. Conclusion Specific characteristics of PA pre‐ and post‐diagnosis may influence the survival of cancer patients.

Abstract Climate model simulations run under the Coupled Model Intercomparison Project Phase 6 (CMIP6) use an inhomogeneous biomass burning aerosol (BBA) emission dataset, which exhibits pronounced interannual variability from 1997–2014 due to the infusion of satellite data. Using the Community Earth System Model version 2 Large Ensemble (CESM2-LE) with original and smoothed CMIP6 BBA forcings, we show that the CMIP6 data inhomogeneity causes spurious decadal subarctic land warming. During years with reduced aerosol concentrations, increased solar radiation can trigger abrupt subarctic permafrost thawing, increased soil water drainage, upper soil drying, and subsequent surface warming. This slow process, which is further amplified by nonlinear cloud-aerosol interactions, cannot be completely offset during years of increased aerosol fluxes, thereby reddening surface temperature spectra in response to large-amplitude interannual aerosol forcing. More generally, our CESM2 experiments identify a pathway for generating decadal variability in high latitudes, involving interannual shortwave forcing and slow nonlinear soil responses.

Natural products with high antioxidant activity are considered as innovative prevention strategies to effectively prevent age-related macular degeneration (AMD) in the early stage because the generation of reactive oxygen species (ROS) leading to the development of drusen is reported as an important cause of this disease. To investigate the prevention effects of the methanol extracts of Euphorbia heterophylla L. (MEE) on AMD, its effects on the antioxidant activity, inflammatory response, apoptosis pathway, neovascularization, and retinal tissue degeneration were analyzed in N-retinylidene-N-retinylethanolamine (A2E)-landed spontaneously arising retinal pigment epithelia (ARPE)-19 cells and BALB/c mice after exposure to blue light (BL). The MEE contained 10 active components and showed high free radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and nitric oxide (NO) radicals. The pretreatments of high-dose MEE remarkably suppressed the production of intracellular ROS (88.2%) and NO (25.2%) and enhanced (SOD) activity (84%) and the phosphorylation of nuclear factor erythroid 2–related factor 2 (Nrf2) in A2E + BL-treated ARPE-19 cells compared to Vehicle-treated group. The activation of the inducible nitric oxide synthase (iNOS)-induced cyclooxygenase-2 (COX-2) mediated pathway, inflammasome activation, and expression of inflammatory cytokines was significantly inhibited in A2E + BL-treated ARPE-19 cells after the MEE pretreatment. The activation of the apoptosis pathway and increased expression of neovascular proteins (36% for matrix metalloproteinase (MMP)-9) were inhibited in the MEE pretreated groups compared to the Vehicle-treated group. Furthermore, the thickness of the whole retina (31%), outer nuclear layer (ONL), inner nuclear layer (INL), and photoreceptor layer (PL) were significantly increased by the MEE pretreatment of BALB/c mice with BL-induced retinal degeneration. Therefore, these results suggest that the MEE, with its high antioxidative activity, protects against BL-induced retinal degeneration through the regulation of the antioxidative system, inflammatory response, apoptosis, and neovascularization in the AMD mouse model.

The current study was designed to compare in vivo efficacy between beeswax alcohol (BWA) and coenzyme Q10 (CoQ10) to treat fatty liver changes, oxidative stress, and damages in major organs of zebrafish by 12 weeks with high-cholesterol (HC) and galactose (Gal) supplementation. At week 12, the HC control and HC+Gal control groups showed 96% and 92% survivability, respectively, while co-supplementation of the 0.5% BWA and 1.0% BWA groups exhibited 96% and 100% survivability. However, co-supplementation of the 0.5% CoQ10 and 1.0% CoQ10 groups revealed the lowest survivability, around 92% and 89%, respectively. The 0.5% BWA and 1.0% BWA groups showed 21% (p < 0.001) and 41% (p < 0.001), respectively, lower total cholesterol (TC) than the HC+Gal control, while the 1.0% CoQ10 group showed only 15% lower TC than the control. Interestingly, the 0.5% BWA and 1.0% BWA groups showed 22% (p < 0.001) and 38% (p < 0.001), respectively, lower triglyceride (TG) than the HC+Gal control. However, both the 0.5% CoQ10 and 1.0% CoQ10 groups showed similar TG levels as the control, suggesting that CoQ10 supplementation had no effect on lowering serum TG. The 1.0% BWA group showed the highest plasma HDL-C and HDL-C/TC (%) up to 3.2-fold and 5.5-fold, respectively, higher than those of the HC+Gal control, while the 1.0% CoQ10 group showed 2.4-fold and 2.8-fold higher plasma HDL-C and HDL-C/TC (%), respectively, than the control. The plasma aspartate transaminase (AST) and alanine transaminase (ALT) levels were lowest in the 1.0% BWA group, 51% and 72%, respectively, lower than HC+Gal control, suggesting the lowest extent of hepatic damage. In hepatic tissue, neutrophil infiltration and interleukin (IL)-6 production were the lowest in the 1.0% BWA group, around 67% and 85%, respectively, lower than the HC+Gal control. Fatty liver change, cellular apoptosis, and cell senescence in hepatic tissue were remarkably lowered in the 1.0% BWA group, while the CoQ10 group showed much less effect than the BWA group. In kidney, ovary, and testis tissue, the 1.0% BWA group showed the lowest production of reactive oxygen species, the extent of cellular senescence, and cellular apoptosis with the healthiest cell morphology. In conclusion, supplementation of BWA remarkably protected the liver, kidney, ovary, and testis from oxidative damage by cholesterol and galactose consumption, with the least serum AST and ALT levels, inflammatory parameters, and senescence markers.

Policosanol is a blend of long-chain aliphatic alcohols (LCAAs) and is well-known for several health-beneficial activities; however, the functionality of policosanol varied substantially based on the composition of LCAAs. In this study, two distinct policosanols, Raydel® (extracted from Cuban sugarcane wax) and BOC Sciences (extracted from Chinese sugarcane wax), were dietarily supplemented (0.1% w/w) for 12 weeks in hyperlipidemic zebrafish to examine their influence on the blood lipid profile and functionality of the liver, kidney, and reproductive organs. The results demonstrated a noteworthy impact of both policosanols on preventing high-cholesterol diet (HCD, 4% w/w)-induced dyslipidemia by decreasing total cholesterol (TC) and triglyceride (TG) levels in the plasma. However, compared to BOC Sciences, the Raydel® policosanol exhibited a significantly (p < 0.05) higher efficacy in reducing HCD-induced TC and TG levels. A substantial effect was observed exclusively with the Raydel® policosanol in mitigating HCD-impaired low-density-lipoprotein cholesterol (LDL-C) and high-density-lipoprotein cholesterol (HDL-C) levels. Hepatic histology and immunohistochemistry (IHC) analysis revealed the higher efficacy of Raydel® policosanol over BOC Sciences policosanol to prevent HCD-provoked fatty liver changes, cellular senescence, oxidative stress, and interleukin (IL)-6 production. Consistently, a significantly higher effect of Raydel® over BOC Sciences policosanol was observed on the protection of kidney, testis, and ovary morphology hampered by HCD consumption. In addition, Raydel® policosanol exhibited a notably stronger effect (~2-fold, p < 0.05) on the egg-laying ability of the zebrafish compared to policosanol from BOC Sciences. Furthermore, Raydel® policosanol plays a crucial role in improving embryo viability and mitigating developmental defects caused by the intake of an HCD. Conclusively, Raydel® policosanol displayed a substantially higher efficacy over BOC Sciences policosanol to revert HCD-induced dyslipidemia, the functionality of vital organs, and the reproductive health of zebrafish.

CIGB-258 is known to exert anti-inflammatory activity via structural stabilization of apolipoprotein A-I (apoA-I) and functional enhancement of high-density lipoproteins (HDL) against acute toxicity of carboxymethyllysine (CML). The co-presence of CIGB-258 in reconstituted HDL (rHDL) formed larger rHDL particles and enhanced anti-inflammatory activity in a dose-dependent manner of apoA-I:CIGB-258, 1:0, 1:0.1, 1:0.5, and 1:1 of molar ratio, in the synthesis of the rHDL. However, no study has evaluated the enhancement of HDL functionality by the co-presence of lipid-free apoA-I and CIGB-258. The present study was therefore designed to compare the structural stabilization and functional improvement of HDL in the presence of lipid-free apoA-I and CIGB-258 in molar ratios of 1:0, 1:0.1, 1:0.5, and 1:1 within both HDL2 and HDL3. As the concentration of CIGB-258 increased, it effectively inhibited the cupric-ion-induced oxidation of HDL, thereby safeguarding apoA-I from proteolytic degradation. Additionally, the wound-healing activity of zebrafish was significantly (p < 0.01) enhanced by the co-addition of apoA-I:CIGB-258 (1:1) up to 1.6-fold higher than apoA-I alone (1:0) under the presence of CML. ApoA-I:CIGB-258 (1:1) treatment exhibited the lowest apoptosis and production of reactive oxygen species against CML-induced damage in the wound site. Also, an increase in wounded tissue granulation and epidermis thickness was observed with increasing concentration of CIGB-258 during 48 h post-treatment via the healing process. Intraperitoneal injection of apoA-I:CIGB-258 mixture remarkably ameliorated the acute paralysis and restored zebrafish swimming ability impaired by the acute toxicity of CML. The increase of CIGB-258 content, especially co-injection of apoA-I:CIGB-258 (1:1), leads to a significant 2.3-fold (p < 0.001) and 4.1-fold (p < 0.001) higher zebrafish survivability and recovery of swimming ability, respectively, than those of CML-control. In the apoA-I:CIGB-258 (1:1) group, neutrophil infiltration and interleukin (IL)-6 production was lowest in the hepatic tissue with the least cellular damage and apoptosis. Additionally, the group treated with apoA-I:CIGB-258 (1:1) demonstrated the lowest plasma levels of total cholesterol (TC) and triglycerides (TG), along with minimal damage to the kidney, ovary, and testicular cells. Conclusively, co-treatment of CIGB-258 with apoA-I effectively mitigated acute inflammation in zebrafish, safeguarded vital organs, structurally stabilized apoA-I, and enhanced HDL functionality.

This study fabricated an OER electrocatalyst with a hierarchical structure by electrodepositing Ni-Fe on NiO. The prepared electrocatalyst exhibited high activity and stability. Furthermore, the OER characteristics of the NiFe/NiO electrode were investigated by changing the metal (Ni and Fe) concentration and Ni:Fe ratio in the plating bath. As the plating bath concentration decreased, NiFe-layered double hydroxide was prominently formed due to an increase in local pH. The electrode obtained using a relatively low plating bath concentration of 130 mM demonstrated high activity with an overpotential of 245 mV and Tafel slope of 27.6 mV dec-1 at a current density of 10 mA/cm2. When the Ni:Fe ratio in the plating bath was adjusted, OER activity increased as the Fe content of the electrode increased to approximately 20.9 at.%, and as the Fe content increased beyond that, the activity gradually decreased. Fe inhibits Ni oxidation and acts as an active site owing to Fe3+ substitution in the γ-NiOOH structure, resulting in increased OER activity. However, when the Fe content was > 29 at.%, the inactive phase γ-FeOOH predominantly grew and the OER activity decreased.

Extracellular vesicles (EVs) are membrane-enclosed particles secreted by a variety of cell types. These vesicles encapsulate a diverse range of molecules, including proteins, nucleic acids, lipids, metabolites, and even organelles derived from their parental cells. While EVs have emerged as crucial mediators of intercellular communication, they also hold immense potential as both biomarkers and therapeutic agents for numerous diseases. A thorough understanding of EV biogenesis is crucial for the development of EV-based diagnostic developments since the composition of EVs can reflect the health and disease status of the donor cell. Moreover, when EVs are taken up by target cells, they can exert profound effects on gene expression, signaling pathways, and cellular behavior, which makes these biomolecules enticing targets for therapeutic interventions. Yet, despite decades of research, the intricate processes underlying EV biogenesis by donor cells and subsequent uptake by recipient cells remain poorly understood. In this review, we aim to summarize current insights and advancements in the biogenesis and uptake mechanisms of EVs. By shedding light on the fundamental mechanisms governing EV biogenesis and delivery, this review underscores the potential of basic mechanistic research to pave the way for developing novel diagnostic strategies and therapeutic applications.

Policosanol supplementation has been reported to increase high-density lipoprotein (HDL)-cholesterol (HDL-C). However, the association between Cuban policosanol supplementation and HDL cholesterol efflux capacity (CEC), an important function of HDL, remains unclear. We performed a lipoprotein analysis investigating 32 Japanese healthy participants (placebo, n = 17 or policosanol supplementation for 12 weeks, n = 15) from a randomized Cuban policosanol clinical trial. First, HDL CEC and HDL-related factors were measured before and after policosanol supplementation. Then, through electron microscopy after ultracentrifugation and high-performance liquid chromatography, HDL morphology and subclass were analyzed, respectively. Finally, the effects of policosanol supplementation regarding HDL function, HDL-related factors, and HDL morphology/component were examined. Cuban policosanol considerably increased the HDL CEC and HDL-C and apolipoprotein A-I (ApoA-I) levels. Furthermore, policosanol supplementation led to larger HDL particles, increased cholesterol content in larger HDL particles, and reduced triglyceride content in smaller HDL particles. In participants with high baseline HDL-C levels, the policosanol effects for HDL CEC are observed. HDL CEC fluctuation induced by policosanol was highly associated with HDL-C and ApoA-I changes. In conclusion, for the first time, we demonstrated that policosanol supplementation increased the HDL CEC in healthy participants.

Abstract Background Pyridoxal-5′-phosphate phosphatase/chronophin (PLPP/CIN) selectively dephosphorylates serine (S) 10 site on neurofibromin 2 (NF2, also known as merlin (moesin-ezrin-radixin-like protein) or schwannomin). p21-activated kinase 1 (PAK1) is a serine/threonine protein kinase, which is involved in synaptic activity and plasticity in neurons. NF2 and PAK1 reciprocally regulate each other in a positive feedback manner. Thus, the aim of the present study is to investigate the effects of PLPP/CIN-mediated NF2 S10 dephosphorylation on PAK1-related signaling pathways under physiological and neuroinflammatory conditions, which are largely unknown. Methods After kainate (KA) injection in wild-type, PLPP/CIN −/− and PLPP/CIN Tg mice, seizure susceptibility, PAK1 S204 autophosphorylation, nuclear factor-κB (NF-κB) p65 S276 phosphorylation, cyclooxygenase-2 (COX-2) upregulation, prostaglandin E synthase 2 (PTGES2) induction and neuronal damage were measured. The effects of 1,1'-dithiodi-2-naphthtol (IPA-3, a selective inhibitor of PAK1) pretreatment on these responses to KA were also validated. Results PLPP/CIN overexpression increased PAK1 S204 autophosphorylation concomitant with the enhanced NF2 S10 dephosphorylation in hippocampal neurons under physiological condition. Following KA treatment, PLPP/CIN overexpression delayed the seizure on-set and accelerated PAK1 S204 phosphorylation, NF-κB p65 S276 phosphorylation, COX-2 upregulation and PTGES2 induction, which were ameliorated by PLPP/CIN deletion or IPA-3. Furthermore, IPA-3 pretreatment shortened the latency of seizure on-set without affecting seizure severity (intensity) and ameliorated CA3 neuronal death induced by KA. Conclusions These findings indicate that PLPP/CIN may regulate seizure susceptibility (the latency of seizure on-set) and CA3 neuronal death in response to KA through NF2-PAK1-NF-κB-COX-2-PTGES2 signaling pathway.

Abstract Background Parkin dysfunction associated with the progression of parkinsonism contributes to a progressive systemic skeletal disease characterized by low bone mineral density. However, the role of parkin in bone remodeling has not yet been elucidated in detail. Result We observed that decreased parkin in monocytes is linked to osteoclastic bone-resorbing activity. siRNA-mediated knockdown of parkin significantly enhanced the bone-resorbing activity of osteoclasts (OCs) on dentin without any changes in osteoblast differentiation. Moreover, Parkin-deficient mice exhibited an osteoporotic phenotype with a lower bone volume accompanied by increased OC-mediated bone-resorbing capacity displaying increased acetylation of α-tubulin compared to wild-type (WT) mice. Notably, compared to WT mice, the Parkin-deficient mice displayed increased susceptibility to inflammatory arthritis, reflected by a higher arthritis score and a marked bone loss after arthritis induction using K/BxN serum transfer, but not ovariectomy-induced bone loss. Intriguingly, parkin colocalized with microtubules and parkin-depleted-osteoclast precursor cells (Parkin −/− OCPs) displayed augmented ERK-dependent acetylation of α-tubulin due to failure of interaction with histone deacetylase 6 (HDAC6), which was promoted by IL-1β signaling. The ectopic expression of parkin in Parkin −/− OCPs limited the increase in dentin resorption induced by IL-1β, accompanied by the reduced acetylation of α-tubulin and diminished cathepsin K activity. Conclusion These results indicate that a deficiency in the function of parkin caused by a decrease in parkin expression in OCPs under the inflammatory condition may enhance inflammatory bone erosion by altering microtubule dynamics to maintain OC activity.

Abstract The Madden-Julian oscillation (MJO) has profound impacts on weather and climate phenomena, and thus changes in its activity have important implications under human-induced global climate change. Here, the time at which the MJO change signal emerges from natural variability under anthropogenic warming is investigated. Using simulations of the Community Earth System Model version 2 large ensemble forced by the shared socioeconomic pathways SSP370 scenario, an increase in ensemble mean MJO precipitation amplitude and a smaller increase in MJO circulation amplitude occur by the end of the 21st century, consistent with previous studies. Notably, the MJO precipitation amplitude change signal generally emerges more than a decade earlier than that of MJO wind amplitude. MJO amplitude changes also emerge earlier over the eastern Pacific than other parts of the tropics. Our findings provide valuable information on the potential changes of MJO variability with the aim of improving predictions of the MJO and its associated extreme events.

Mesenchymal-epithelial crosstalk plays a key role in gut development and stem cell homeostasis, though underlying mechanisms are still unclear. Here, the authors demonstrate that mesenchymal Polycomb Repressive Complex 2 controls niche signals for gut epithelial fate and growth.

We investigated the (de)activation of Raney nickel–iron anodes in various oxygen evolution reaction (OER) environments using accelerated deactivation testing (ADT) under the conditions of on/off voltage control (ADT1), constant current density (ADT2), and cyclic voltammetry (ADT3). ADT1 caused activation under OER conditions by promoting the leaching of residual zinc and thus increasing the electrode surface area and oxygen vacancy content, whereas deactivation was observed under the conditions of the hydrogen evolution reaction(H-ADT1). ADT2 decreased the OER activity by promoting NiO formation and iron leaching, while ADT3 slightly increased the OER activity by favoring the incorporation of iron into the nickel lattice and promoting nickel–iron hydroxide formation. Thus, this work facilitates the design of more efficient and durable Raney nickel–based OER anodes by providing insights into their (de)activation mechanisms.

Recently, the need to develop a robust three-dimensional (3D) cell culture system that serves as a valuable in vitro tumor model has been emphasized. This system should closely mimic the tumor growth behaviors observed in vivo and replicate the key elements and characteristics of human tumors for the effective discovery and development of anti-tumor therapeutics. Therefore, in this study, we developed an effective 3D in vitro model of human prostate cancer (PC) using a marine collagen-based biomimetic 3D scaffold. The model displayed distinctive molecular profiles and cellular properties compared with those of the 2D PC cell culture. This was evidenced by (1) increased cell proliferation, migration, invasion, colony formation, and chemoresistance; (2) upregulated expression of crucial multidrug-resistance- and cancer-stemness-related genes; (3) heightened expression of key molecules associated with malignant progressions, such as epithelial–mesenchymal transition transcription factors, Notch, matrix metalloproteinases, and pluripotency biomarkers; (4) robust enrichment of prostate cancer stem cells (CSCs); and (5) enhanced expression of integrins. These results suggest that our 3D in vitro PC model has the potential to serve as a research platform for studying PC and prostate CSC biology, as well as for screening novel therapies targeting PC and prostate CSCs.

Policosanol is a mixture of long-chain aliphatic alcohols (LCAAs) derived from various plant and insect origins that are marketed by various companies with distinct formulations and brand names. Policosanols offer several beneficial effects to treat dyslipidemia and hypertension; however, a comprehensive functionality comparison of various policosanol brands has yet to be thoroughly explored. In the present study five distinct policosanol brands from different origins and countries, Raydel-policosanol, Australia (PCO1), Solgar-policosanol, USA (PCO2), NutrioneLife-monacosanol, South Korea (PCO3), Mothernest-policosanol, Australia (PCO4), and Peter & John-policosanol, New Zealand (PCO5) were compared via dietary supplementation (1% in diet, final wt/wt) to zebrafish for six weeks to investigate their impact on survivability, blood lipid profile, and functionality of vital organs under the influence of a high-cholesterol diet (HCD, final 4%, wt/wt). The results revealed that policosanol brands (PCO1–PCO5) had a substantial preventive effect against HCD-induced zebrafish body weight elevation and hyperlipidemia by alleviating total cholesterol (TC) and triglycerides (TG) in blood. Other than PCO3, all the brands significantly reduced the HCD’s elevated low-density lipoprotein cholesterol (LDL-C). On the contrary, only PCO1 displayed a significant elevation in high-density lipoprotein cholesterol (HDL-C) level against the consumption of HCD. The divergent effect of PCO1–PCO5 against HCD-induced hepatic damage biomarkers, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), was observed. PCO1, PCO2, and PCO4 efficiently curtailed the AST and ALT levels; however, PCO3 and PCO5 potentially aggravated the HCD’s elevated plasma AST and ALT levels. Consistently, the hepatic histology outcome revealed the least effectiveness of PCO3 and PCO5 against HCD-induced liver damage. On the contrary, PCO1 exhibited a substantial hepatoprotective role by curtailing HCD-induced fatty liver changes, cellular senescent, reactive oxygen species (ROS), and interleukin-6 (IL-6) production. Likewise, the histological outcome from the kidney, testis, and ovary revealed the significant curative effect of PCO1 against the HCD-induced adverse effects. PCO2–PCO5 showed diverse and unequal results, with the least effective being PCO3, followed by PCO5 towards HCD-induced kidney, testis, and ovary damage. The multivariate interpretation based on principal component analysis (PCA) and hierarchical cluster analysis (HCA) validated the superiority of PCO1 over other policosanol brands against the clinical manifestation associated with HCD. Conclusively, different brands displayed distinct impacts against HCD-induced adverse effects, signifying the importance of policosanol formulation and the presence of aliphatic alcohols on the functionality of policosanol products.

Research on ozonated sunflower oil (OSO) is mostly restricted to its topical application, whereas the functional and toxicological assessment of oral OSO consumption is yet to be solved. Herein, OSO was orally supplemented in rats to assess the impact on plasma antioxidant status, low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Also, the functionality of HDL from the OSO-supplemented rats (OSO-HDL) was tested against carboxymethyllysine (CML)- induced hyperinflammation in embryo and adult zebrafish. The results revealed that four weeks of OSO supplementation (3 g/kg BW/day) had no adverse effect on rats’ hematological and blood biochemical profiles. Nonetheless, decreased interleukin (IL)-6, and LDL-C levels, along with enhanced ferric ion reduction ability (FRA) and sulfhydryl content, were observed in the plasma of OSO-supplemented rats compared to the control and sunflower oil (SO) supplemented group. In addition, OSO supplementation stabilized apoA-I/HDL and augmented HDL-allied paraoxonase (PON)-1 activity. The microinjection of OSO-HDL (10 nL, 2 mg/mL) efficiently prevented the CML (500 ng)-induced zebrafish embryo mortality and developmental deformities. Similarly, OSO-HDL thwarted CML-posed neurotoxicity and demonstrated a significant hepatoprotective effect against CML-induced fatty liver changes, hepatic inflammation, oxidative stress, and apoptosis, as well as exhibiting a noticeable influence to revert CML-induced dyslipidemia. Conclusively, OSO supplementation demonstrated no toxic effects on rats, ameliorated plasma antioxidant status, and positively influenced HDL stability and functionality, leading to a protective effect against CML-induced toxicity in zebrafish.

In algebra, the sedenions, an extension of the octonion system, form a 16-dimensional noncommutative and nonassociative algebra over the real numbers. It can be expressed as two octonions, and a function and differential operator can be defined to treat the sedenion, expressed as two octonions, as a variable. By configuring elements using the structure of complex numbers, the characteristics of octonions, the stage before expansion, can be utilized. The basis of a sedenion can be simplified and used for calculations. We propose a corresponding Cauchy–Riemann equation by defining a regular function for two octonions with a complex structure. Based on this, the integration theorem of regular functions with a sedenion of the complex structure is given. The relationship between regular functions and holomorphy is presented, presenting the basis of function theory for a sedenion of the complex structure.

Neuroinflammation is defined as a neurological inflammation within the brain and the spinal cord. In neuroinflammation, microglia are the tissue-resident macrophages of the central nervous system, which act as the first line of defense against harmful pathogens. Dexmedetomidine (Dex) has an anti-inflammatory effect in many neurological conditions. Additionally, the microRNA-30a-5p (miR-30a-5p) mimic has been proven to be effective in macrophages in inflammatory conditions. This study aimed to investigate the synergistic anti-inflammatory effects of both miR-30a-5p and Dex in lipopolysaccharide (LPS)-induced BV2 cells. This study showed that miR-30a-5p and Dex decreased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation in LPS-induced BV2 cells. MiR-30a-5p and Dex alleviated tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), LPS-induced phosphorylation c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinase (ERK) and p38. Also, the expression of the NOD-like receptor pyrin domain containing 3 inflammasome (NLRP3), cleaved caspase-1, and ASC was inhibited. Furthermore, LPS-stimulated nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) expression were attenuated by Dex and miR-30a-5p. Our results indicate that a combination of Dex and miR-30a-5p, attenuates NF-κB activation, the mitogen-activated protein kinase (MAPK) signaling pathway, and inflammatory mediators involved in LPS-induced inflammation and inhibits the activation of the NLRP3 inflammasome in LPS-activated BV2 cells.

Royal jelly is a honeybee product with substantial pharmacological and health promotional activities. Nevertheless, the health implications associated with the prolonged dietary supplementation of royal jelly have yet to be elucidated extensively. Herein, 72 weeks of dietary supplementation of royal jelly at 5% and 10% (w/w) were investigated to assess the impact on zebrafish survivability, body weight, liver, testis, ovary functionality, and blood lipid profile. The results revealed no adverse effect of 72 weeks of royal jelly supplementation on zebrafish survivability. Conversely, a noteworthy enhancement in the zebrafish body weight was observed in royal-jelly-supplemented zebrafish in a concentration-dependent manner [5% and 10% (w/w)]. Interestingly, female zebrafish were found to be more biased, with a significant 17% (p < 0.001) and 23% (p < 0.001) higher body weight enhancement after 72 weeks of consumption of 5% and 10% (w/w) royal jelly, compared to the male zebrafish. The histological outcome revealed no sign of hepatotoxicity; moreover, diminished reactive oxygen species (ROS) and apoptosis were observed in the hepatic tissue of the royal-jelly-supplemented group. Consistent with the histological outcomes, the liver function biomarkers, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), exhibited a significant decrease of 1.9-fold (p = 0.006) and 1.4-fold (p = 0.003) in zebrafish supplemented with royal jelly compared to those on a normal diet (ND) and zebrafish given supplements. Also, no sign of ovary and testis-related toxicity was observed in the royal-jelly-supplemented group during the 72-week period. Furthermore, the 10% (w/w) royal-jelly-consuming zebrafish exhibited a notable 2.1-fold increase (p = 0.018) in egg-laying ability compared to the ND-supplemented zebrafish. The 10% (w/w) royal jelly supplementation also effectively maintained the blood lipid profile by curtailing serum triglycerides (TG) and elevating high-density lipoprotein cholesterol (HDL-C). Conclusively, royal jelly dietary supplementation for a prolonged time found royal jelly to be safe to consume, to efficiently improve hepatic function, reproduction, and sexual health, and to augment the serum HDL-C level.

The present study compares sugarcane-wax purified policosanols sourced from Cuba (Raydel®) and China (BOC Sciences) and utilized following the synthesis of reconstituted high-density lipoproteins (rHDL). The two policosanols exhibited distinctly different ingredient ratios of long-chain aliphatic alcohols, particularly 1-octacosanol (C28) and 1-tetratriacotanol (C34). After synthesizing rHDL with apolipoprotein A-I (apoA-I), the two policosanols bound well with phospholipid and apoA-I to form the discoidal rHDL. Notably, rHDL-1, containing Cuban policosanol, displayed the largest particle diameter at approximately 78 ± 3 nm. In contrast, both control rHDL (rHDL-0) and rHDL containing Chinese policosanol (rHDL-2) exhibited smaller particles, with diameters of approximately 58 ± 3 nm and 61 ± 2 nm, respectively. Furthermore, rHDL-1 demonstrated enhanced anti-glycation activity, safeguarding apoA-I from degradation within HDL, and displayed the antioxidant ability to inhibit LDL oxidation. A microinjection of each rHDL into zebrafish embryos in the presence of carboxymethyllysine (CML) revealed rHDL-1 to have the strongest antioxidant activity with the highest embryo survivability and normal developmental morphology. Dermal application to recover the wound revealed rHDL-1 to have the highest wound-healing activity (75%) and survivability (92%) in the cutaneous wound area in the presence of CML. In adult zebrafish, injecting CML (250 μg) caused acute death and hyperinflammation, marked by heightened neutrophil infiltration and interleukin (IL)-6 production in liver. However, co-administering rHDL-1 notably increased survival (85%) and exhibited strong anti-inflammatory properties, reducing IL-6 production while improving the blood lipid profile. However, a co-injection of rHDL-2 resulted in the lowest survivability (47%) with more hepatic inflammation. In conclusion, Cuban policosanol (Raydel®) has more desirable properties for the in vitro synthesis of rHDL with stronger anti-glycation and antioxidant activities than those of Chinese policosanol (BOC Sciences). Moreover, Raydel-policosanol-integrated rHDL demonstrates a noteworthy effect on accelerated wound healing and robust anti-inflammatory properties, leading to increased survivability in zebrafish embryos and adults by effectively suppressing CML-induced hyperinflammation.

Ozonated sunflower oil (OSO) is renowned for its diverse therapeutic benefits. Nonetheless, the consequences of extended dietary intake of OSO have yet to be thoroughly investigated. Herein, the effect of 2-year dietary supplementation of OSO was examined on the survivability, obesity, skeletal deformities, swimming behavior, and liver, kidney, ovary, and testis function of zebrafish. Results showed that the zebrafish feed supplemented with 20% (wt/wt) OSO for 2 years emerged with higher survivability and body weight management compared to sunflower oil (SO) and normal diet (ND)-supplemented zebrafish. Radio imaging (X-ray)-based analysis revealed 2.6° and 15.2° lower spinal curvature in the OSO-supplemented groups than in the SO and ND-supplemented groups; consistently, OSO-supplemented zebrafish showed better swimming behavior. The histology analysis of the liver revealed the least fatty liver change and interleukin (IL)-6 generation in the OSO-supplemented group. Additionally, a significantly lower level of reactive oxygen species (ROS), apoptotic, and senescent cells were observed in the liver of the OSO-supplemented zebrafish. Also, no adverse effect on the kidney, testis, and ovary morphology was detected during 2 years of OSO consumption. Moreover, lower senescence with diminished ROS and apoptosis was noticed in the kidney and ovary in response to OSO consumption. The OSO supplementation was found to be effective in countering age-associated dyslipidemia by alleviating total cholesterol (TC), triglycerides (TG), low-density lipoproteins (LDL-C) and elevating high-density lipoproteins (HDL-C)/TC levels. Conclusively, prolonged OSO consumption showed no adverse effect on the morphology and functionality of vital organs; in fact, OSO supplementation displayed a protective effect against age-associated detrimental effects on spinal deformities, vital organ functionality, cell senescence, and the survivability of zebrafish.

CIGB-258 is a 3 kDa altered peptide ligand from heat shock protein (HSP) 60 that exhibits anti-inflammatory activity against the acute toxicity of carboxymethyllysine (CML) with antioxidant and anti-glycation activities via protection of high-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I). It is necessary to test a synergistic interaction between apoA-I and CIGB-258 in reconstituted high-density lipoproteins (rHDL). Several rHDLs were synthesized containing palmitoyloleoyl phosphatidylcholine (POPC), cholesterol, apoA-I, and CIGB-258 at molar ratios of 95:5:1:0, 95:5:1:0.1, 95:5:1:0.5, and 95:5:1:1 for rHDL-(1:0), rHDL-(1:0.1), rHDL-(1:0.5), and rHDL-(1:1), respectively. As the CIGB-258 content in rHDL was increased, the particle size of rHDL was 1.4-times higher than rHDL-(1:0) to rHDL-(1:1), from 60 nm to 83 nm, respectively. As the CIGB-258 content was increased, the rHDL showed the most resistance to isothermal denaturation by a urea treatment, and rHDL-(1:1) exhibited the highest structural stability and the strongest antioxidant ability against LDL oxidation. Co-treatment of rHDL-(1:0), rHDL-(1:0.5), and rHDL-(1:1) resulted in up to 10%, 24%, and 34% inhibition of HDL glycation, inhibition of HDL glycation, which was caused by the CML, with protection of apoA-I. Microinjection of each rHDL into zebrafish embryos in the presence of CML showed that a higher CIGB-258 content in rHDL was associated with higher survivability with the least inflammation and apoptosis. Furthermore, an intraperitoneal injection of rHDL and CML showed that a higher CIGB-258 content in rHDL was also associated with higher survivability of zebrafish and faster recovery of swimming ability. The rHDL-(1:1) group showed the lowest triglyceride, AST, and ALT serum levels with the least production of interleukin-6, oxidized product, and neutrophil infiltration in hepatic tissue. In conclusion, CIGB-258 could bind well to phospholipids and cholesterol to stabilize apoA-I in the rHDL structure against denaturation stress and larger particle sizes. The rHDL containing CIGB-258 enhanced the in vitro antioxidant ability against LDL oxidation, the anti-glycation activity to protect HDL, and the in vivo anti-inflammatory activity against CML toxicity in zebrafish adults and embryos. Overall, incorporating apoA-I and CIGB-258 in rHDL resulted in a synergistic interaction to enhance the structural and functional correlations in a dose-dependent manner of CIGB-258.

Abstract Sphingosine-1-phosphate (S1P) is an important lipid mediator that regulates a diverse range of intracellular cell signaling pathways that are relevant to tissue engineering and regenerative medicine. However, the precise function of S1P in dental pulp stem cells (DPSCs) and its osteogenic differentiation remains unclear. We here investigated the function of S1P/S1P receptor (S1PR)-mediated cellular signaling in the osteogenic differentiation of DPSCs and clarified the fundamental signaling pathway. Our results showed that S1P-treated DPSCs exhibited a low rate of differentiation toward the osteogenic phenotype in association with a marked reduction in osteogenesis-related gene expression and AKT activation. Of note, both S1PR1/S1PR3 and S1PR2 agonists significantly downregulated the expression of osteogenic genes and suppressed AKT activation, resulting in an attenuated osteogenic capacity of DPSCs. Most importantly, an AKT activator completely abrogated the S1P-mediated downregulation of osteoblastic markers and partially prevented S1P-mediated attenuation effects during osteogenesis. Intriguingly, the pro-inflammatory TNF-α cytokine promoted the infiltration of macrophages toward DPSCs and induced S1P production in both DPSCs and macrophages. Our findings indicate that the elevation of S1P under inflammatory conditions suppresses the osteogenic capacity of the DPSCs responsible for regenerative endodontics.