Search

The regulatory role of the inhibitor of NF-kB kinase ε (IKKε) in postmyocardial infarction (MI) inflammation remains uncertain. Using an MI mouse model, we examined the cardiac outcomes of IKKε knockout (KO) mice and wild-type mice. We employed single-cell RNA sequencing (scRNA-seq) and phosphorylated protein array techniques to profile cardiac macrophages. IKKε KO mice exhibited compromised survival, heightened inflammation, pronounced cardiac fibrosis, and a reduced ejection fraction. A distinct cardiac macrophage subset in IKKε KO mice exhibited increased fibrotic marker expression and decreased phosphorylated p38 (p-p38) levels, indicating an enhanced macrophage-myofibroblast transition (MMT) post-MI. While cardiac inflammation is crucial for initiating compensatory pathways, the timely resolution of inflammation was impaired in the IKKε KO group, while the MMT in macrophages accelerated post-MI, leading to cardiac failure. Additionally, our study highlighted the potential of 5-azacytidine (5-Aza), known for its anti-inflammatory and cardioprotective effects, in restoring p-p38 levels in stimulated macrophages. The administration of 5-Aza significantly reduced the MMT in cardiac macrophages from the IKKε KO group. These findings underscore the regulation of the inflammatory response and macrophage transition by the IKKε-p38 axis, indicating that the MMT is a promising therapeutic target for ischemic heart disease., (© 2024. The Author(s).)

Recent research has revealed that hemodynamic changes caused by lung recruitment maneuvers (LRM) with continuous positive airway pressure can be used to identify fluid responders. We investigated the usefulness of stepwise LRM with increasing positive end-expiratory pressure and constant driving pressure for predicting fluid responsiveness in patients under lung protective ventilation (LPV). Forty-one patients under LPV were enrolled when PPV values were in a priori considered gray zone (4% to 17%). The FloTrac-Vigileo device measured stroke volume variation (SVV) and stroke volume (SV), while the patient monitor measured pulse pressure variation (PPV) before and at the end of stepwise LRM and before and 5 min after fluid challenge (6 ml/kg). Fluid responsiveness was defined as a ≥ 15% increase in the SV or SV index. Seventeen were fluid responders. The areas under the curve for the augmented values of PPV and SVV, as well as the decrease in SV by stepwise LRM to identify fluid responders, were 0.76 (95% confidence interval, 0.61-0.88), 0.78 (0.62-0.89), and 0.69 (0.53-0.82), respectively. The optimal cut-offs for the augmented values of PPV and SVV were > 18% and > 13%, respectively. Stepwise LRM -generated augmented PPV and SVV predicted fluid responsiveness under LPV., (© 2024. The Author(s).)

To determine the effect of hypertension (HTN) on the peripapillary microvasculature in type 2 diabetes mellitus (T2DM) patients without diabetic retinopathy (DR). The patients were classified into three groups: the control group (group 1), T2DM group (group 2), and both T2DM and HTN group (group 3). Peripapillary vessel density (VD) was compared using analysis of covariance and linear regression analysis was performed to identify the factors affecting the peripapillary VD. A total of 286 eyes were enrolled: 124 in group 1, 111 in group 2, and 51 in group 3. The peripapillary VDs for the full area were 18.3 ± 0.6, 17.8 ± 1.0, and 17.3 ± 1.2 mm -1 in group 1, group 2, and group 3, respectively, which were significantly different after adjustment for age and best-corrected visual acuity (P < 0.001). In post hoc analyses, group 1 versus group 2 (P < 0.001), group 1 versus group 3 (P < 0.001), and group 2 versus group 3 (P = 0.001) showed significant differences. In linear regression analysis, HTN (B =  - 0.352, P = 0.043) and peripapillary retinal nerve fiber layer (pRNFL) thickness (B = 0.045, P < 0.001) were significantly associated with peripapillary VD in T2DM patients. Peripapillary VD in T2DM patients without clinical DR were lower compared to normal controls, and they were more decreased when HTN was comorbid. The combination of ischemic damage by high blood pressure and impairment of the neurovascular unit by hyperglycemia would result in more severe deterioration of peripapillary microvasculature, and this impairment could be also reflected by pRNFL thinning., (© 2023. The Author(s).)

The perioperative milieu following curative lung cancer surgery is accompanied by a stress response. Inflammasomes mediate inflammation resulting in the unfavorable immunomodulation of natural killer (NK) cell activity, thus promoting cancer progression. This study aimed to investigate the effects of dexmedetomidine (DEX) on the innate immune system, chronic inflammation, and lung cancer progression in a clinically relevant human-to-mouse xenograft model. The human lung cancer cell line A549-luc was subcutaneously injected into BALB/c nude mice. Saline or dexmedetomidine was administered for 2 weeks via an implanted osmotic minipump. After 4 weeks, the tumor size and weight were measured. NK cell activity, serum interferon-γ, interleukin (IL)-1β and tumor necrosis factor (TNF)-α levels were also measured. IL-10, IL-18, and inflammasome expression levels were assessed in the tumor tissues. DEX caused a decrease in tumor size, tumor weight, and IL-1β and TNF-α levels and an increase in NK cell activity and IFN-γ level. IL-10 and IL-18 expression was significantly decreased in the DEX-treated group. NLRP3, CTP1A, TXNIP, ASC, IL-1β, and caspase-1 protein levels were decreased in the DEX-treated group. In conclusion, the use of DEX for 2 weeks inhibited lung cancer progression by suppressing inflammasome- and IL-1β signaling-induced inflammation and enhancing NK cell activity., (© 2023. The Author(s).)

Atherosclerosis, the leading cause of death, is a vascular disease of chronic inflammation. We recently showed that angiopoietin-like 4 (ANGPTL4) promotes cardiac repair by suppressing pathological inflammation. Given the fundamental contribution of inflammation to atherosclerosis, we assessed the role of ANGPTL4 in the development of atherosclerosis and determined whether ANGPTL4 regulates atherosclerotic plaque stability. We injected ANGPTL4 protein twice a week into atherosclerotic Apoe-/- mice and analyzed the atherosclerotic lesion size, inflammation, and plaque stability. In atherosclerotic mice, ANGPTL4 reduced atherosclerotic plaque size and vascular inflammation. In the atherosclerotic lesions and fibrous caps, the number of α-SMA(+), SM22α(+), and SM-MHC(+) cells was higher, while the number of CD68(+) and Mac2(+) cells was lower in the ANGPTL4 group. Most importantly, the fibrous cap was significantly thicker in the ANGPTL4 group than in the control group. Smooth muscle cells (SMCs) isolated from atherosclerotic aortas showed significantly increased expression of CD68 and Krüppel-like factor 4 (KLF4), a modulator of the vascular SMC phenotype, along with downregulation of α-SMA, and these changes were attenuated by ANGPTL4 treatment. Furthermore, ANGPTL4 reduced TNFα-induced NADPH oxidase 1 (NOX1), a major source of reactive oxygen species, resulting in the attenuation of KLF4-mediated SMC phenotypic changes. We showed that acute myocardial infarction (AMI) patients with higher levels of ANGPTL4 had fewer vascular events than AMI patients with lower levels of ANGPTL4 (p < 0.05). Our results reveal that ANGPTL4 treatment inhibits atherogenesis and suggest that targeting vascular stability and inflammation may serve as a novel therapeutic strategy to prevent and treat atherosclerosis. Even more importantly, ANGPTL4 treatment inhibited the phenotypic changes of SMCs into macrophage-like cells by downregulating NOX1 activation of KLF4, leading to the formation of more stable plaques., (© 2023. The Author(s).)

The purpose of this study was to identify how chronic hypertension (HTN) and hypertensive retinopathy (HTNR) have different effects on retinal damage including inner retinal thinning and microvasculature impairment. The subjects were divided into three groups: controls, HTN patients without HTNR (HTN group), and patients with relieved HTNR (HTNR group). The ganglion cell-inner plexiform layer (GC-IPL) thickness, vessel density (VD), and GC-IPL/VD ratio were compared among the groups. A total of 241 eyes were enrolled; 101 in the control group, 92 in the HTN group, and 48 in the HTNR group. The mean GC-IPL thicknesses were 83.5 ± 5.7, 82.1 ± 6.2, and 75.9 ± 10.7 μm in each group, respectively (P < 0.001). The VD was 20.5 ± 1.3, 19.6 ± 1.4, and 19.5 ± 1.6 mm -1 in each group, respectively (P = 0.001). The GC-IPL/VD ratio was 4.10 ± 0.33, 4.20 ± 0.40, and 3.88 ± 0.56 in each group, respectively (P < 0.001). In the HTNR group, HTN duration (B = 0.054, P = 0.013) and systolic blood pressure (SBP) (B = -0.012, P = 0.004) were significantly associated with the GC-IPL/VD ratio. In conclusion, inner retinal reduction and retinal microvasculature impairment were observed in patients with HTN and HTNR, and the GC-IPL/VD ratio of HTNR patients was significantly lower than that of HTN patients, indicating more prominent damage to the inner retina than microvasculature in HTNR patients. Additionally, the GC-IPL/VD ratio was significantly associated with SBP in HTNR patients, so more strict BP control is required in HTNR patients., (© 2022. The Author(s).)

This study sought to describe the use of deep-frozen donor corneal remnants preserved after keratoplasty procedures for therapeutic or tectonic keratoplasty without subsequent optical keratoplasty. This single-center retrospective consecutive case series analyzed the electronic medical records of patients who had undergone therapeutic or tectonic keratoplasty using deep-frozen donor remains preserved in Optisol-GS, for the past 11 years at Keimyung University Dongsan Medical Center. Fifty-five surgical cases in 46 patients were included. Twenty-three surgical cases in 18 patients underwent therapeutic keratoplasty for refractory infectious corneal ulcer. Complete eradication of primary infection was achieved in 14 patients (77.8%). Tectonic keratoplasty were performed 32 cases in 28 patients. Twenty-seven of 28 patients were ultimately able to maintain anatomical integrity (96.4%). Mean uncorrected visual acuity improved from 1.77 ± 0.94 preoperatively to 1.31 ± 0.95 at the last follow-up postoperatively in the tectonic graft group by logarithm of the minimal angle of resolution (P = 0.002). There were no cases of graft rejection. Keratoplasty using cryopreserved donor tissue is a suitable surgical alternative for infectious or non-infectious corneal ulcers in elderly patients or patients with poor general condition. It could be a viable alternative to overcome the shortage of corneal donors., (© 2022. The Author(s).)

Renal primary cilia are antenna-like organelles that maintain cellular homeostasis via multiple receptors clustered along their membranes. Recent studies have revealed that YAP/TAZ, key paralogous effectors of the Hippo pathway, are involved in ciliogenesis; however, their independent roles need to be further investigated. Here, we analyzed the renal phenotypes of kidney-specific TAZ knockout mice and observed ciliary defects only in glomeruli where mild cysts were formed. This finding prompted us to verify the role of TAZ specifically in renal tubule ciliary regulation. Therefore, we investigated the effects of TAZ silencing and compared them to those of YAP knockdown using three different types of renal tubular cells. We found that the absence of TAZ prevented proper cilia formation in glomerular cells, whereas it had a negligible effect in collecting duct and proximal tubule cells. IFT and NPHP protein levels were altered because of TAZ deficiency, accompanied by ciliary defects in glomerular cells, and ciliary recovery was identified by regulating some NPHP proteins. Although our study focused on TAZ, ciliogenesis, and other ciliary genes, the results suggest the very distinct roles of YAP and TAZ in kidneys, specifically in terms of ciliary regulation., (© 2022. The Author(s).)

In our previous research showed that tramadol having potential anti-tumor effect was associated with enhancement of oncological prognosis in patients with breast cancer surgery. As these effects have not been confirmed by clinical dose-regulated animal or prospective human studies, we investigated the anti-tumor effect of tramadol in vivo. Female nude mice orthotopically inoculated with luciferase-expressing MCF-7 cells, were randomly divided into the control (saline), tramadol group 1 (1.5 mg kg -1 day -1 ), tramadol group 2 (3 mg kg -1 day -1 ), and morphine (0.5 mg kg -1 day -1 ) (n = 5/group). Bioluminescence signals after D-luciferin injection, tumor size, and tumor weight were compared among groups after 4 weeks. Estrogen receptor (ER), progesterone receptor (PR), and transient receptor potential vanilloid (TRPV)-1 expression, natural killer (NK) cell activity, and serum interleukin (IL)-1β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-6 were then examined. Tumour growth was attenuated in tramadol-treated groups (P < 0.05). NK cell activity was significantly decreased only in the morphine treated group not in sham, control, and tramadol groups. The expression levels of ERα, PRα and β, and TRPV1 were decreased in tramadol group 2 compared with those in the morphine group, but not compared to the control group. Serum levels of IL-6 and TNFα were reduced in both tramadol-treated group 1 and 2 compared to the control group. Overall, clinical dose of tramadol has anti-tumour effects on MCF-7 cell-derived breast cancer in a xenograft mouse model., (© 2021. The Author(s).)

Uncontrolled retinal pigment epithelial (RPE) cell proliferation/migration contribute to the pathological tractional membrane development in proliferative vitreoretinopathy. Recent studies reported that microRNA (miR)-124 controls various cellular functions via the direct targeting of small Ras homolog family member G (RHOG). Therefore, we investigated the role of the neuron-specific miR-124 and RHOG in RPE cell proliferation/migration. Alterations in miR-124 and RhoG expression, as per cell confluence were evaluated through quantitative real-time PCR and western blotting, respectively. After transfection with miR-124, we quantified RPE cell viability and migration and observed cell polarization and lamellipodia protrusions. We evaluated the expression of RHOG/RAC1 pathway molecules in miR-124-transfected RPE cells. Endogenous miR-124 expression increased proportionally to RPE cell density, but decreased after 100% confluence. Overexpression of miR-124 decreased cell viability and migration, BrdU incorporation, and Ki-67 expression. Inhibition of endogenous miR-124 expression promoted RPE cell migration. Transfection with miR-124 reduced cell polarization, lamellipodia protrusion, and RHOG mRNA 3' untranslated region luciferase activity. Like miR-124 overexpression, RhoG knockdown decreased RPE cell viability, wound healing, and migration, and altered the expression of cell cycle regulators. These results suggest that miR-124 could be a therapeutic target to alleviate fibrovascular proliferation in retinal diseases by regulating RPE proliferation/migration via RHOG.

We aimed to validate a tear MMP-9 in-situ immunoassay (InflammaDry) and to identify factors that could affect results or interpretation. Three factors were examined: sample concentration, volume, and time. Recombinant human (rh) MMP-9 (10 or 20 μl; 0, 12.5, 25, 50, 100, 200, 500, and 1,000 ng/ml) was applied to the kit and the detection limit and assay reproducibility were examined. At a rhMMP-9 volume of 10 μl (≥ 50 ng/ml), all positive results were identified by densitometry at 10 and 20 min; however, after 20 min, more than half of the nine ophthalmologists interpreted a positive result. At a rhMMP-9 volume of 20 μl (≥ 25 ng/ml), ophthalmologists and densitometry identified almost all test lines at 10 and 20 min. At 10 μl, densitometry showed a linear dose-response pattern. At 20 μl, densitometry showed a linear dose-response pattern at concentrations up to 500 ng/ml; however, full saturation was achieved at concentrations ≥ 500 ng/ml. When the same amount of rhMMP-9 was applied, the density result increased significantly upon doubling of the solvent volume (i.e., by adding the same volume of PBS to a sample). InflammaDry showed a high inter- and intra-assay coefficient of variation at 10 min (28.4% and 24.7%, respectively). The results of the MMP-9 in-situ immunoassay varied significantly depending on sample volume. Therefore, when interpreting the results, careful attention must be paid to tear volume.

An antiferromagnetic topological insulator has been predicted to be preserved by breaking both time-reversal symmetry and primitive lattice translational symmetry. However, the topological surface state has often been observed to disappear in an antiferromagnetic phase because the doped magnetic impurity acts as an extrinsic defect. In this study, we report the experimental signature of topological surface states coexisting with antiferromagnetic order in Sm-doped Bi 2 Te 3 . We fabricate single crystals of Sm x Bi 2-x Te 3 with x = 0.004, 0.010, and 0.025, where the Curie-Weiss law is satisfied at low temperatures but is violated at high temperatures due to the influence of the high energy states of J multiplets of Sm. For x = 0.025, e xotic physical properties are observed, such as the antiferromagnetic phase with the Néel temperature T N  = 3.3 K, multi-band Hall effect with two conduction channel, and anisotropic Shubnikov-de Haas oscillations. In the antiferromagnetic phase, we detect the signature of nontrivial topological surface states with surface electron density n s  = 7.9 × 10 11  cm -2 and its high mobility μ s  = 2,200 cm 2 /Vs, compared to n b  = 2.0 × 10 19  cm -3 and μ b  = 2.3 cm 2 /Vs for bulk electrons. These observations suggest that Sm x Bi 2-x Te 3 is a candidate creating the new stage for the potential application of topological antiferromagnetic spintronics.

Outcomes of cardiac surgery are influenced by systemic inflammation. High mobility group box 1 (HMGB1), a pivotal inflammatory mediator, plays a potential role as a prognostic biomarker in cardiovascular disease. The aim of this prospective, observational study was to investigate the relationship between serum HMGB1 concentrations and composite of morbidity endpoints in cardiac surgery. Arterial blood samples for HMGB1 measurement were collected from 250 patients after anaesthetic induction (baseline) and 1 h after weaning from cardiopulmonary bypass (post-CPB). The incidence of composite of morbidity endpoints (death, myocardial infarction, stroke, renal failure and prolonged ventilator care) was compared in relation to the tertile distribution of serum HMGB1 concentrations. The incidence of composite of morbidity endpoints was significantly different with respect to the tertile distribution of post-CPB HMGB1 concentrations (p = 0.005) only, and not to the baseline. Multivariable analysis revealed post-CPB HMGB1 concentration (OR, 1.072; p = 0.044), pre-operative creatinine and duration of CPB as independent risk factors of adverse outcome. Accounting for its prominent role in mediating sterile inflammation and its relation to detrimental outcome, HMGB1 measured 1 h after weaning from CPB would serve as a useful biomarker for accurate risk stratification in cardiac surgical patients and may guide tailored anti-inflammatory therapy.

This study aimed to evaluate the most valid index among various indices of low muscle mass in assessing cardiometabolic risks in a Korean population. Appendicular lean mass index (ALMI, kg/m 2 ), fat mass index (FMI, kg/m 2 ), FMI-adjusted ALMI (ALM fmi ), ratio of ALM to weight index (ALM wt ), ratio of ALM to body mass index (ALM bmi ) and ratio of ALM to truncal fat index (ALM trunkfat ) were measured by dual energy X-ray absorptiometry in 17,870 participants from 2008 to 2011. We adopted all the aforementioned indices of low muscle mass expressed as sex- and age-specific standard deviation scores (Z-scores). Low muscle mass for age was defined as Z-score <-1. The prevalence of low muscle mass was approximately 16% across all indices. Low muscle mass defined by ALMI had low muscle mass and low fat mass, and ALM fmi had low muscle mass at the same FMI. However, low muscle mass defined by ALM wt , ALM bmi and ALM trunkfat had similar muscle mass with high FMI. The receiver operating characteristic curve in metabolic syndrome showed that the ALM trunkfat was 0.74 in male and 0.69 in female, indicating that ALM trunkfat was the best discrimination index for metabolic syndrome. This study showed that ALM trunkfat could be a useful indicator for screening cardiometabolic risk factors, particularly in normal or overweight Asian population.

This study aimed to investigate the effects of smoking habit change on the risks of all-cause mortality and cardiovascular diseases (CVDs) among patients with newly diagnosed diabetes using the Korean National Sample Cohort data. Survival regression analyses for the risks of all-cause mortality and CVDs were performed. Quitters without body mass index (BMI) change (adjusted hazard ratio [aHR], 0.68; 95% confidence interval [CI], 0.46-1.00) and quitters with BMI loss (aHR, 1.76; 95% CI, 1.13-2.73) showed significantly reduced and substantially the increased risk of all-cause mortality, respectively, compared with sustained smokers. Smoking reduction after diabetes diagnosis may have potential positive effects. However, definite benefits on the health outcomes were not identified in this study. Participants who started smoking after diabetes diagnosis had higher risks of all-cause mortality and CVDs than those who were never smokers or ex-smokers, although not statistically significant. In conclusion, smoking cessation after diabetes diagnosis could reduce the risks of all-cause mortality and cardiovascular events among patients with newly diagnosed diabetes when accompanied by proper weight management. Therefore, physicians should advice patients with newly diagnosed type 2 diabetes on the importance of smoking cessation in combination with long-term weight management to maximize the benefits of smoking cessation.

Smoking cessation reduces the risk of cardiovascular disease (CVD), but also elevates fasting serum glucose (FSG) levels. The effect of post-cessation hyperglycemia on cardiovascular disease is unknown. The study population consisted of 127,066 men without type 2 diabetes from the Korean National Health Insurance System - Health Screening Cohort database. Change in smoking habits and FSG was determined by the difference in smoking status and FSG levels from the first (2002 and 2003) and second (2004 and 2005) health examinations. Continual smokers, quitters, ex-smokers, and never smokers were stratified according to FSG elevation. The study participants were followed-up for CVD and CVD-related death from 2006 to 2013. Compared to continual smokers, quitters had decreased risk of CVD among those without FSG elevation (hazard ratio, HR, 0.76, 95% confidence interval, CI, 0.66-0.86) and with FSG elevation (HR 0.83, 95% CI 0.72-0.96). Similarly, quitters had a tendency towards reduced risk of CVD-related death among those without FSG elevation (HR 0.74, 95% CI 0.51-1.09) and with FSG elevation (HR 0.68, 95% CI 0.46-1.03). Post-cessation hyperglycemia did not attenuate the beneficiary risk-reducing effects of quitting on CVD and CVD-related death.

Dormant blastocysts during delayed implantation undergo autophagic activation, which is an adaptive response to prolonged survival in utero during less favorable environment. We observed that multivesicular bodies (MVBs) accumulate in the trophectoderm of dormant blastocysts upon activation for implantation. Since autophagosomes are shown to fuse with MVBs and efficient autophagic degradation requires functional MVBs, we examined if MVB formation in activated blastocysts are associated with protracted autophagic state during dormancy. We show here that autophagic activation during dormancy is one precondition for MVB formation in activated blastocysts. Furthermore, the blockade of FGF signaling with PD173074 partially interferes with MVB formation in these blastocysts, suggesting the involvement of FGFR signaling in this process. We believe that MVB formation in activated blastocysts after dormancy is a potential mechanism of clearing subcellular debris accumulated during prolonged autophagy., Competing Interests: The authors declare no competing financial interests.

Humans process a plethora of sensory information that is provided by various entities in the surrounding environment. Among the five major senses, technology for touch, haptics, is relatively young and has relatively limited applications largely due to its need for physical contact. In this article, we suggest a new way for non-contact haptic stimulation that uses laser, which has potential advantages such as mid-air stimulation, high spatial precision, and long working distance. We demonstrate such tactile stimulation can be enabled by laser-induced thermoelastic effects by means of physical and perceptual studies, as well as simulations. In the physical study, the mechanical effect of laser on a human skin sample is detected using low-power radiation in accordance with safety guidelines. Limited increases (< ~2.5 °C) in temperature at the surface of the skin, examined by both thermal camera and the Monte Carlo simulation, indicate that laser does not evoke heat-induced nociceptive sensation. In the human EEG study, brain responses to both mechanical and laser stimulation are consistent, along with subjective reports of the non-nociceptive sensation of laser stimuli.