ABSTRACT
Melanosomes are specific organelles dedicated to melanin synthesis and accumulation in melanocytes. Autophagy is suggestively involved in melanosome degradation, although the potential underlying molecular mechanisms remain elusive. In selective autophagy, autophagy receptors and E3-ligases are the key factors conferring cargo selectivity. In B16F10 cells, ß-mangostin efficiently induced melanosome degradation without affecting other organelles such as mitochondria, peroxisomes, and the endoplasmic reticulum. Among various autophagy receptors, optineurin (OPTN) contributes TANK-binding kinase 1 (TBK1)-dependently to melanosome degradation and its knockdown inhibited ß-mangostin-mediated melanosome degradation. OPTN translocation to melanosomes was dependent on its ubiquitin-binding domain. Moreover, OPTN-mediated TBK1 activation and subsequent TBK1-mediated S187 OPTN phosphorylation were essential for melanosome degradation. ß-mangostin increased K63-linked melanosome ubiquitination. Finally, the E3-ligase RCHY1 knockdown inhibited the melanosome ubiquitination required for OPTN- and TBK1-phosphorylation as well as melanosome degradation. This study suggests that melanophagy, melanosome-selective autophagy, contributes to melanosome degradation, and OPTN and RCHY1 are an essential autophagy receptor and a E3-ligase, respectively, conferring cargo selectivity in melanophagy.
Subject(s)
Autophagy , Melanosomes , Melanosomes/metabolism , Ubiquitin-Protein Ligases/metabolism , Xanthones , Melanoma, Experimental , Animals , MiceABSTRACT
Genome-level clonal decomposition of a single specimen has been widely studied; however, it is mostly limited to cancer research. In this study, we developed a new algorithm CLEMENT, which conducts accurate decomposition and reconstruction of multiple subclones in genome sequencing of non-tumor (normal) samples. CLEMENT employs the Expectation-Maximization (EM) algorithm with optimization strategies specific to non-tumor subclones, including false variant call identification, non-disparate clone fuzzy clustering, and clonal allele fraction confinement. In the simulation and in vitro cell line mixture data, CLEMENT outperformed current cancer decomposition algorithms in estimating the number of clones (root-mean-square-error = 0.58-0.78 versus 1.43-3.34) and in the variant-clone membership agreement (â¼85.5% versus 70.1-76.7%). Additional testing on human multi-clonal normal tissue sequencing confirmed the accurate identification of subclones that originated from different cell types. Clone-level analysis, including mutational burden and signatures, provided a new understanding of normal-tissue composition. We expect that CLEMENT will serve as a crucial tool in the currently emerging field of non-tumor genome analysis.
Subject(s)
Algorithms , Genomics , Humans , Genomics/methods , Neoplasms/genetics , Mutation , Genome, Human , Clone CellsABSTRACT
Rat animal models are widely used owing to their relatively superior cognitive abilities and higher similarity compared with mouse models to human physiological characteristics. However, their use is limited because of difficulties in establishing embryonic stem cells and performing genetic modifications, and insufficient embryological research. In this study, we established optimal superovulation and fertilized-egg transfer conditions, including optimal hormone injection concentration (≥150 IU/kg of PMSG and hCG) and culture medium (mR1ECM), to obtain high-quality zygotes and establish in vitro fertilization conditions for rats. Next, sgRNA with optimal targeting activity was selected by performing PCR analysis and the T7E1 assay, and the CRISPR/Cas9 system was used to construct a rat model for muscular dystrophy by inducing a deficiency in the fukutin gene without any off-target effect detected. The production of fukutin knockout rats was phenotypically confirmed by observing a drop-in body weight to one-third of that of the control group. In summary, we succeeded in constructing the first muscular dystrophy disease rat model using the CRISPR/CAS9 system for increasing future prospects of producing various animal disease models and encouraging disease research using rats.
ABSTRACT
BACKGROUND: Tumor initiation and progression necessitate a metabolic shift in cancer cells. Consequently, the progression of prostate cancer (PCa), a leading cause of cancer-related deaths in males globally, involves a shift from lipogenic to glycolytic metabolism. Androgen deprivation therapy (ADT) serves as the standard treatment for advanced-stage PCa. However, despite initial patient responses, castrate resistance emerges ultimately, necessitating novel therapeutic approaches. Therefore, in this study, we aimed to investigate the role of monocarboxylate transporters (MCTs) in PCa post-ADT and evaluate their potential as therapeutic targets. METHODS: PCa cells (LNCaP and C4-2 cell line), which has high prostate-specific membrane antigen (PSMA) and androgen receptor (AR) expression among PCa cell lines, was used in this study. We assessed the expression of MCT1 in PCa cells subjected to ADT using charcoal-stripped bovine serum (CSS)-containing medium or enzalutamide (ENZ). Furthermore, we evaluated the synergistic anticancer effects of combined treatment with ENZ and SR13800, an MCT1 inhibitor. RESULTS: Short-term ADT led to a significant upregulation in folate hydrolase 1 (FOLH1) and solute carrier family 16 member 1 (SLC16A1) gene levels, with elevated PSMA and MCT1 protein levels. Long-term ADT induced notable changes in cell morphology with further upregulation of FOLH1/PSMA and SLC16A1/MCT1 levels. Treatment with ENZ, a nonsteroidal anti-androgen, also increased PSMA and MCT1 expression. However, combined therapy with ENZ and SR13800 led to reduced PSMA level, decreased cell viability, and suppressed expression of cancer stem cell markers and migration indicators. Additionally, analysis of human PCa tissues revealed a positive correlation between PSMA and MCT1 expression in tumor regions. CONCLUSIONS: Our results demonstrate that ADT led to a significant upregulation in MCT1 levels. However, the combination of ENZ and SR13800 demonstrated a promising synergistic anticancer effect, highlighting a potential therapeutic significance for patients with PCa undergoing ADT.
Subject(s)
Androgen Antagonists , Benzamides , Monocarboxylic Acid Transporters , Nitriles , Phenylthiohydantoin , Prostatic Neoplasms , Symporters , Male , Humans , Monocarboxylic Acid Transporters/metabolism , Monocarboxylic Acid Transporters/antagonists & inhibitors , Monocarboxylic Acid Transporters/genetics , Cell Line, Tumor , Phenylthiohydantoin/pharmacology , Phenylthiohydantoin/analogs & derivatives , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Prostatic Neoplasms/metabolism , Androgen Antagonists/pharmacology , Androgen Antagonists/therapeutic use , Nitriles/pharmacology , Symporters/metabolism , Symporters/antagonists & inhibitors , Symporters/genetics , Benzamides/pharmacologyABSTRACT
PURPOSE: [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) has limitations in prostate cancer (PCa) detection owing to low glycolysis in the primary tumour. Recently, prostate-specific membrane antigen (PSMA) PET/CT has been useful for biochemical failure detection and radioligand therapy (RLT) guidance. However, few studies have evaluated its use in primary prostate tumours using PSMA and [18F]FDG PET/CT. This study aimed to evaluate [18F]PSMA-1007 and [18F]FDG PET/CT for primary tumour detection and understand the association of metabolic heterogeneity with clinicopathological characteristics at staging and postoperatively. METHOD: This prospective study included 42 index tumours (27 acinar and 15 ductal-dominant) in 42 patients who underwent [18F]PSMA-1007 and [18F]FDG PET/CT and subsequent radical prostatectomy. All patients were followed for a median of 26 mo, and serum prostate-specific antigen levels were measured every 3 mo to evaluate biochemical failure. One-way analysis of variance, Tukey's multiple comparison test, and Fisher's exact test were performed. RESULTS: All 42 index tumours were detected on [18F]PSMA-1007 PET/CT, whereas only 15 were detected on [18F]FDG PET/CT (62.3% vs. 37.7%, p < 0.0001). A high SUVmax for [18F]PSMA-1007 was observed in tumours with high Gleason scores (GS 6-7 vs. GS 8-10; 12.1 vs. 20.1, p < 0.05). Tumours with [18F]FDG uptake were mostly ductal dominant (acinar-dominant 4/27; ductal-dominant; 11/15, p < 0.001), with lower [18F]PSMA-1007 uptake than tumours without [18F]FDG uptake (SUVmax 16.58 vs. 11.19, p < 0.001). There were 16.6% (7/42) of patients with pStage IV in whom the primary tumours were [18F]FDG positive. Biochemical failure was observed in 14.8% (4/27) of patients with [18F]FDG negative tumours but in 53.3% (8/15) of patients with [18F]FDG positive tumours (p = 0.013). CONCLUSIONS: [18F]PSMA-1007 PET/CT was superior to [18F]FDG PET/CT in detecting primary PCa. In contrast, tumours with [18F]FDG uptake are associated with larger size, a ductal-dominant type, and likely to undergo metastasis at staging and biochemical failure postoperatively.
Subject(s)
Fluorodeoxyglucose F18 , Neoplasm Staging , Niacinamide/analogs & derivatives , Positron Emission Tomography Computed Tomography , Prostatic Neoplasms , Humans , Male , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/surgery , Prostatic Neoplasms/pathology , Aged , Middle Aged , Oligopeptides/chemistry , Prospective Studies , Radiopharmaceuticals , Postoperative PeriodABSTRACT
INTRODUCTION: Balloon flower root-derived exosome-like nanoparticles (BDEs) have recently been proposed as physiologically active molecules with no cytotoxicity. However, the therapeutic effects of drug-induced hepatotoxicity of BDEs have not been elucidated. BDEs contain a large amount of platycodin D, which is widely known to be effective in regulating inflammation and ameliorating systemic toxicity. Thus, the main therapeutic activity of BDEs is attributed to inhibiting the inflammatory response and alleviating toxicity. In this study, we fabricated the hybrid BDEs fused with liposomes containing silymarin (SM) to enhance the synergistic effect on inhibition of acetaminophen-induced hepatotoxicity (APAP). OBJECTIVE: Considering the potential therapeutic effects of BDEs, and the potential to achieve synergistic effects to improve therapeutic outcomes, we constructed hybrid BDEs with a soy lecithin-based liposome loaded with SM. Since liposomes can provide higher thermal stability and have greater structural integrity, these might be more resistant to clearance and enzymatic degradation of drug molecules. METHODS: Hybrid BDEs with liposome-loaded SM (BDEs@lipo-SM) were fabricated by thin-film hydration and extrusion. BDEs@lipo-SM were characterized using dynamic light scattering and high-performance liquid chromatography. After confirmation of the physical properties of BDEs@lipo-SM, various therapeutic properties were evaluated. RESULTS: BDEs@lipo-SM were internalized by hepatocytes and immune cells and significantly decreased mRNA expression of apoptosis and inflammation-relevant cytokines by inhibiting the hepatocyte MAPK pathway. BDEs@lipo-SM significantly induced an increase in glutathione levels and inhibited APAP-induced hepatotoxicity. CONCLUSION: From this study, we know that BDEs are reliable and safe nanovesicles containing natural metabolites derived from balloon flower, and they can facilitate intercellular communication. BDEs are also easily modified to enhance drug loading capacity, targeting effects, and long-term accumulation in vivo. BDEs@lipo-SM have therapeutic benefits for acute liver injury and can alleviate cell death and toxicity. They can be efficiently delivered to the liver and effectively inhibit APAP-induced hepatotoxicity by inhibiting the MAPK signaling pathway and apoptosis, which accelerates liver recovery in the APAP-induced acute liver injury model. These findings highlight that BDEs represent an attractive delivery vehicle for drug delivery.
Subject(s)
Acetaminophen , Apoptosis , Exosomes , Hepatocytes , MAP Kinase Signaling System , Nanoparticles , Silymarin , Apoptosis/drug effects , Animals , Nanoparticles/chemistry , Exosomes/metabolism , Hepatocytes/drug effects , Hepatocytes/metabolism , Silymarin/pharmacology , Silymarin/administration & dosage , MAP Kinase Signaling System/drug effects , Mice , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/metabolism , Humans , Liposomes/chemistry , Male , Plant Roots , Mice, Inbred C57BLABSTRACT
PURPOSE AND METHOD: The purpose of this study was to determine the changes in the Blood Oxygen Level Dependent signal of Primary somatosensory area (S1) and Brodmann area 3 (BA3) per finger and phalanx in comparison to the activation voxel when 250 Hz vibratory stimulation with high sensitivity for the Pacinian corpuscle was given to the four fingers and three phalanges. RESULTS: The result of analyzing the activation voxel showed a significant difference for S1 per finger and phalanx, but for BA3, no significant difference was observed despite a similar trend to S1. In contrast, the activation intensity (BOLD) displayed a significant difference for S1 per finger and phalanx and for BA3, where the activation voxel had no significant variation. In addition, while the result of S1 did not indicate whether the index or the little fingers had the highest sensitivity based on the BOLD signal per finger, the result of BA3 marked the strongest BOLD signal for the little finger as a response to 250 Hz vibratory stimulation. The activation intensity per phalanx was the highest for the intermediate phalanx for S1 and BA3, which was in line with a previous study comparing the activation voxel. CONCLUSIONS: The method based on the intensity of the nerve activation is presumed to have high sensitivity as the signal intensity is monitored within a specific, defined area. Thus, for the extraction of brain activation patterns of micro-domains, such as BA3, monitoring the BOLD signal that reflects the nerve activation intensity more sensitively is likely to be advantageous.
Subject(s)
Magnetic Resonance Imaging , Somatosensory Cortex , Somatosensory Cortex/physiology , Magnetic Resonance Imaging/methods , Fingers/innervation , Brain Mapping/methodsABSTRACT
BACKGROUND: Despite the well-known health benefits of exercise, women's participation in exercise is low worldwide. As women are at risk of developing various chronic diseases as they age, suggesting effective exercise methods that can maximize energy consumption is needed to prevent such conditions. Excess post-exercise oxygen consumption (EPOC) can maximize energy consumption. In this crossover, randomized controlled trial, we aimed to compare the EPOC for different exercise modalities including continuous exercise (CE), interval exercise (IE), and accumulated exercise (AE) that spent the homogenized energy expenditure during exercise in healthy women. METHODS: Forty-four participants (age, 36.09 ± 11.73 years) were recruited and randomly allocated to three groups. The intensity of each modality was set as follows: CE was performed for 30 min at 60% peak oxygen uptake (VO2peak). IE was performed once for 2 min at 80% VO2peak, followed by 3 min at 80% VO2peak, and 1 min at 40% VO2peak, for a total of six times over 26 min. AE was performed for 10 min with a 60% VO2peak and was measured thrice a day. RESULTS: During exercise, energy metabolism was higher for IE and CE than that for AE. However, this was reversed for AE during EPOC. Consequently, the greatest energy metabolism was shown for AE during total time (exercise and EPOC). CONCLUSIONS: By encouraging regular exercises, AE can help maintain and improve body composition by increasing compliance with exercise participation, given its short exercise times, and by efficiently increasing energy consumption through the accumulation of EPOC. TRIAL REGISTRATION: Clinical number (KCT0007298), 18/05/2022, Institutional Review Board of Konkuk University (7001355-202201-E-160).
Subject(s)
Cross-Over Studies , Energy Metabolism , Exercise , Oxygen Consumption , Humans , Female , Oxygen Consumption/physiology , Adult , Exercise/physiology , Energy Metabolism/physiology , Middle Aged , Young AdultABSTRACT
BACKGROUND: Free tissue transfer is often required for the reconstruction of complex and deep anterior chest wall wounds, for which the identification of suitable recipient vessels is crucial. Although the internal mammary arteries (IMAs) are a representative option, identifying secondary options when these vessels are compromised remains a challenge. This report evaluated the efficacy of using the thoracoacromial vessels (TAVs) as recipients for chest wall reconstruction by reviewing our experience. METHODS: We conducted a retrospective review of patients undergoing free-flap-based chest wall reconstruction using TAVs as recipient vessels from February 2020 to March 2023. Patient demographics and surgery-related characteristics data were collected. The primary outcome of interest was the occurrence of flap perfusion-related complications. RESULTS: In total, 12 cases utilized TAVs as recipients, primarily for defects following sternotomy, where bilateral IMA was unavailable due to prior surgery. The TAVs with reliable perfusion were consistently identified beneath the pectoralis major muscle. The anterolateral thigh flap was predominantly employed, with musculocutaneous or chimeric flaps introduced for bony defects. The mean pedicle length of the harvested flap was 7.2 cm (range, 3-13), and in cases with a vascular gap, the pedicle was extended using an arteriovenous interposition graft. This resulted in a mean pedicle length needed to reach recipient vessels of 9.9 cm (range, 6.5-19). All flaps survived, with only one experiencing partial necrosis. CONCLUSIONS: The TAV could be considered as an attractive alternative recipient vessel in microsurgical reconstruction of complicated chest wall defects when the use of IMA is not feasible.
Subject(s)
Free Tissue Flaps , Mammary Arteries , Plastic Surgery Procedures , Thoracic Wall , Humans , Thoracic Wall/surgery , Mammary Arteries/surgery , NecrosisABSTRACT
Malignant melanoma represents a form of skin cancer characterized by a bleak prognosis and heightened resistance to traditional therapies. Quercetin has demonstrated notable anti-carcinogenic, anti-inflammatory, anti-oxidant, and pharmacological effects across various cancer types. However, the intricate relationship between quercetin's anti-cancer properties and ganglioside expression in melanoma remains incompletely understood. In this study, quercetin manifests specific anti-proliferative, anti-migratory, and cell-cycle arrest effects, inducing mitochondrial dysfunction and apoptosis in two melanoma cancer cell lines. This positions quercetin as a promising candidate for treating malignant melanoma. Moreover, our investigation indicates that quercetin significantly reduces the expression levels of ganglioside GD3 and its synthetic enzyme. Notably, this reduction is achieved through the inhibition of the FAK/paxillin/Akt signaling pathway, which plays a crucial role in cancer development. Taken together, our findings suggest that quercetin may be a potent anti-cancer drug candidate for the treatment of malignant melanoma.
Subject(s)
Apoptosis , Gangliosides , Melanoma , Mitochondria , Quercetin , Quercetin/pharmacology , Humans , Melanoma/metabolism , Melanoma/drug therapy , Melanoma/pathology , Apoptosis/drug effects , Mitochondria/metabolism , Mitochondria/drug effects , Cell Line, Tumor , Gangliosides/metabolism , Cell Proliferation/drug effects , Signal Transduction/drug effects , Down-Regulation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Cell Movement/drug effects , Skin Neoplasms/metabolism , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
OBJECTIVES: To identify the characteristics of individuals transitioning from metabolically healthy obesity (MHO) to unhealthy obesity and the factors influencing the change. DESIGN: This is a nationwide cohort study using data from the National Health Insurance Service in South Korea. SAMPLE: Individuals with obesity but metabolically healthy in 2009 and 2010 and those still obese 4 years later were selected. MEASUREMENTS: Sociodemographic, physical, metabolic, and health behavior variables were collected, and logistic regression was used to find an association with the transition. RESULTS: We analyzed 1,564,467 individuals, observing significant differences in all variables and the transition from MHO to unhealthy obesity. Among males, the transition was associated with smoking and drinking positively and physical activity negatively. Among females, drinking demonstrated a negative correlation. Regardless of age, regular exercise was negatively associated with the transition for all individuals. Except for older adults, all age groups showed a positive correlation with smoking and drinking. CONCLUSIONS: Considering the significant factors in the transition, it is essential to develop and implement interventions varied by gender and age to delay and prevent the change in metabolic status. The necessity of developing interventions enables individuals to engage in regular exercise, regardless of age and gender.
Subject(s)
Health Behavior , Humans , Male , Female , Republic of Korea/epidemiology , Middle Aged , Adult , Cohort Studies , Aged , Life Style , Exercise , Obesity/epidemiology , Obesity, Metabolically Benign/epidemiology , Logistic ModelsABSTRACT
BACKGROUND: With the introduction of new anti-tuberculosis drugs, all-oral regimens with shorter treatment durations for multidrug-resistant tuberculosis have been anticipated. We aimed to investigate whether a new all-oral regimen was non-inferior to the conventional regimen including second-line anti-tuberculosis drugs for 20-24 months in the treatment of fluoroquinolone-sensitive multidrug-resistant tuberculosis. METHODS: In this multicentre, randomised, open-label phase 2/3 non-inferiority trial, we enrolled men and women aged 19-85 years with multidrug-resistant tuberculosis confirmed by phenotypic or genotypic drug susceptibility tests or rifampicin-resistant tuberculosis by genotypic tests at 12 participating hospitals throughout South Korea. Participants with fluoroquinolone-resistant multidrug-resistant tuberculosis were excluded. Participants were randomly assigned (1:1) to two groups using a block randomisation, stratified by the presence of diabetes and cavitation on baseline chest radiographs. The investigational group received delamanid, linezolid, levofloxacin, and pyrazinamide for 9 months, and the control group received a conventional 20-24-month regimen, according to the 2014 WHO guidelines. The primary outcome was the treatment success rate at 24 months after treatment initiation in the modified intention-to-treat population and the per-protocol population. Participants who were "cured" and "treatment completed" were defined as treatment success following the 2014 WHO guidelines. Non-inferiority was confirmed if the lower limit of a 97·5% one-sided CI of the difference between the groups was greater than -10%. Safety data were collected for 24 months in participants who received a predefined regimen at least once. This study is registered with ClinicalTrials.gov, NCT02619994. FINDINGS: Between March 4, 2016, and Sept 14, 2019, 214 participants were enrolled, 168 (78·5%) of whom were included in the modified intention-to-treat population. At 24 months after treatment initiation, 60 (70·6%) of 85 participants in the control group had treatment success, as did 54 (75·0%) of 72 participants in the shorter-regimen group (between-group difference 4·4% [97·5% one-sided CI -9·5% to ∞]), satisfying the predefined non-inferiority margin. No difference in safety outcomes was identified between the control group and the shorter-regimen group. INTERPRETATION: 9-month treatment with oral delamanid, linezolid, levofloxacin, and pyrazinamide could represent a new treatment option for participants with fluoroquinolone-sensitive multidrug-resistant tuberculosis. FUNDING: Korea Disease Control and Prevention Agency, South Korea.
Subject(s)
Pyrazinamide , Tuberculosis, Multidrug-Resistant , Male , Female , Humans , Pyrazinamide/therapeutic use , Linezolid/therapeutic use , Levofloxacin/therapeutic use , Fluoroquinolones/therapeutic use , Drug Therapy, Combination , Tuberculosis, Multidrug-Resistant/drug therapy , Antitubercular Agents/therapeutic use , Treatment OutcomeABSTRACT
Background: This study investigated the effects of 12-week resistance training on body composition, blood pressure, blood lipid levels, muscle cross-sectional area (CSA), isokinetic muscle function, and hemorheological properties in middle-aged obese women. Methods: Twenty-eight obese women with a mean age of 50.79 ± 5.80 years were randomly assigned to the control (CON, n = 13) or experimental (EXP, n = 15) group. The EXP group underwent a resistance training program composed of warm-up, main resistance exercise (deadlift, barbell squat, seated leg extension, and lying leg curl, bench press, preacher bench biceps curl, barbell rowing, and dumbbell shoulder press), and cool-down. The resistance exercise consisted of three sets of 8-10 repetitions (reps) performed with 70-80% of 1-rep maximum, and reps and sets were increased every 3 weeks. The training frequency was 80 min, 3 days per week for 12 weeks. The CON group maintained their daily lifestyle without training. All participants underwent measurements of body composition (weight, body mass index, lean body mass, fat mass, and % body fat), blood pressure (systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure), blood lipid levels (triglycerides, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), CSA of the muscles (quadriceps, hamstring, and total thigh muscle), isokinetic muscle function (peak torque [PT], relative PT, mean power, and total work [TW]), and hemorheological properties (erythrocyte deformability and aggregation) before and after 12 weeks of training. Results: The EXP group showed a significant improved muscle function, including PT (p < 0.001), relative PT (p < 0.001) in extension 60°/s, TW (p < 0.001) in extension 180°/s, and TW (p = 0.018) in flexion 180°/s. Regarding hemorheological properties, the EXP group showed significant improvement in erythrocyte aggregation (p < 0.001) and deformability (p < 0.001). Conclusions: The present study verified that our resistance training program resulted in greater muscle function, decreased fat mass, and improved hemorheological properties. Clinical Trial Registration: This study was registered with cris.nih.go.kr (No. KCT0007412).
ABSTRACT
Activating NRF2-driven transcription with non-electrophilic small molecules represents an attractive strategy to therapeutically target disease states associated with oxidative stress and inflammation. In this study, we describe a campaign to optimize the potency and efficacy of a previously identified bis-sulfone based non-electrophilic ARE activator 2. This work identifies the efficacious analog 17, a compound with a non-cytotoxic profile in IMR32 cells, as well as ARE activators 18 and 22, analogs with improved cellular potency. In silico drug-likeness prediction suggested the optimized bis-sulfones 17, 18, and 22 will likely be of pharmacological utility.
Subject(s)
Antioxidant Response Elements , Antioxidants , Antioxidants/pharmacology , NF-E2-Related Factor 2/metabolism , Oxidative StressABSTRACT
In the late 1970s, Flavobacterium bizetiae was first isolated from diseased fish in Canada. After four decades of preservation, it was reported as a novel species in 2020. Here, we report the first complete genome sequence of HJ-32-4, a novel strain of F. bizetiae. Interestingly, HJ-32-4 was isolated from soil in Gangwon-do, Republic of Korea, unlike the other two previously reported F. bizetiae strains which were isolated from fish. We generated a single circular chromosome of HJ-32-4, comprising 5,745,280 bp with a GC content of 34.2%. The average nucleotide identity (ANI) value of 96.2% indicated that HJ-32-4 belongs to F. bizetiae CIP 105534T. The virulence factor was not detected in the genome. Comparative genomic analysis of F. bizetiae and major flavobacterial pathogens revealed that F. bizetiae had a larger genome size and the ratio of peptidases (PEP) and glycoside hydrolase (GH) genes of F. bizetiae were lower than those of the rest strains, implying that F. bizetiae exhibits similar characteristics with non-pathogenic strains from a genomic point of view. However, further experimental verification is required to ensure these in silico predictions. This study will provide insight into the overall characteristics of HJ-32-4 compared to other strains.
Subject(s)
Flavobacterium , Soil , Animals , Flavobacterium/genetics , Sequence Analysis, DNA , Genomics , Virulence Factors/genetics , Fishes , Phylogeny , DNA, Bacterial/genetics , RNA, Ribosomal, 16S/genetics , Fatty AcidsABSTRACT
BACKGROUND: Nanodiamonds (NDs) have gained a rapidly growing interest in biomedical applications; however, little is known regarding their biokinetics owing to difficulties in measurements and limited synthesis/purification technologies. In this study, we investigated the distribution kinetics of detonation-synthesized NDs in mice via intravenous injection to evaluate the parameters that determine the behavior of the particles. We prepared two distinctive NDs that controlled the sp3/sp2 carbon ratio and particle size by coating them with serum proteins. The four control samples were intravenously injected into mice, and tissue distribution and clearance were evaluated at 30 min and 1, 7, and 28 days post-injection. RESULTS: The sp3/sp2 carbon ratio showed no correlation with the organ distribution of the NDs. However, hydrodynamic size showed an excellent correlation with organ distribution levels: a negative correlation in the liver and positive correlations in the spleen and lungs. Furthermore, the deposition levels of NDs in the lung suggest that particles smaller than 300 nm could avoid lung deposition. Finally, a similar organ distribution pattern was observed in mice injected with carbon black nanoparticles controlled hydrodynamic size. CONCLUSIONS: In conclusion, the tissue distribution of NDs is modulated not by the sp3/sp2 carbon ratio but by the hydrodynamic size, which can provide helpful information for targeting the tissue of NDs. Furthermore, the organ distribution pattern of the NDs may not be specific to NDs but also can apply to other nanoparticles, such as carbon black.
Subject(s)
Hydrodynamics , Nanodiamonds , Animals , Mice , Injections, Intravenous , Kinetics , Soot , Tissue Distribution , CarbonABSTRACT
Cerebral ischemia/reperfusion (CI/R) injury is a clinical conundrum during the treatment of ischemic stroke. Cell-derived exosomes (CDE) were proved to be therapeutically effective for CI/R injury. However, production of CDE is time and effort consuming. Increasing studies reported that plants can also generate exosome-like nanoparticles (ELN) which are therapeutically effective and have higher yield compared with CDE. In this study, a commonly used Chinese herb Panax notoginseng (PN), whose active ingredients were well-documented in the treatment of CI/R injury, was chosen as a source of ELNs. It was found that Panax notoginseng derived exosome like nanoparticles (PDN) could enter the brain without modification and ameliorate cerebral infarct volume, improve behavior outcome and maintained the integrity of BBB. PDNs attenuated CI/R injury by altering the phenotype of microglia from "pro-inflammation" M1 type to "anti-inflammation" M2 type. Also, we found that lipids from PDNs were the major therapeutic effective component. As a mechanism of action, PDN was proved to exert therapeutic effect via activating pI3k/Akt pathway.
Subject(s)
Brain Ischemia , Exosomes , Panax notoginseng , Reperfusion Injury , Microglia/metabolism , Exosomes/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Brain Ischemia/drug therapy , Brain Ischemia/metabolism , Reperfusion Injury/drug therapy , Reperfusion Injury/metabolismABSTRACT
Inhibition of tumor growth and normalization of immune responses in the tumor microenvironment (TME) are critical issues for improving cancer therapy. However, in the treatment of glioma, effective nanomedicine has limited access to the brain because of the blood-brain barrier (BBB). Previously, we demonstrated nano-sized ginseng-derived exosome-like nanoparticles (GENs) consisting of phospholipids including various bioactive components, and evaluated anti-tumor immune responses in T cells and Tregs to inhibit tumor progression. It was found that the enhanced targeting ability of GENs to the BBB and glioma induced a significant therapeutic effect and exhibited strong efficacy in recruiting M1 macrophage expression in the TME. GENs were demonstrated to be successful candidates in glioma therapeutics both in vitro and in vivo, suggesting excellent potential for inhibiting glioma progression and regulating tumor-associated macrophages (TAMs).
Subject(s)
Exosomes , Glioma , Nanoparticles , Panax , Humans , Blood-Brain Barrier/metabolism , Tumor Microenvironment , Exosomes/metabolism , Glioma/pathology , Cell Line, TumorABSTRACT
BACKGROUND: Kidney volume provides important information for the diagnosis and prognosis of autosomal dominant polycystic kidney disease (ADPKD), as well as for the evaluation of the effects of drugs such as tolvaptan. Non-contrast computed tomography (CT) is commonly used for volumetry, and this study examined the correspondence and correlation of kidney volume measured by standard-dose or low-dose CT. METHODS: Axial standard-dose and low-dose CT images with 1-mm slices were obtained from 24 ADPKD patients. The kidney was segmented in the Synapse 3D software and the kidney volume was calculated using stereology. The kidney volume was compared between the two sets of images using R2, Bland-Altman plots, coefficient of variation, and intra-class correlation coefficients (ICCs). RESULTS: The mean age of the 24 patients was 48.4 ± 10.9 years, and 45.8% were men (n = 11). The mean total kidney volume on standard-dose CT was 1501 ± 838.2 mL. The R2 of volume between standard-dose and low-dose CT was 0.995. In the Bland-Altman plot, except for one case with a large kidney volume, the two measurements were consistent, and the coefficient of variation and ICC were also good (0.02, 0.998). The CT radiation dose (dose-length product) was 229 ± 68 mGy·cm for standard-dose CT and 50 ± 19 mGy·cm for low-dose CT. A comparable volume was obtained with 20% of the radiation dose of standard-dose CT. CONCLUSIONS: Standard-dose and low-dose CT showed comparable kidney volume in ADPKD. Therefore, low-dose CT can substitute for ADPKD volumetry while minimizing radiation exposure.
Subject(s)
Polycystic Kidney, Autosomal Dominant , Male , Humans , Adult , Middle Aged , Female , Polycystic Kidney, Autosomal Dominant/diagnostic imaging , Kidney/diagnostic imaging , Tomography, X-Ray Computed/methods , Prognosis , Imaging, Three-DimensionalABSTRACT
BACKGROUND: Children receiving proton therapy require repeated sedation. In this study, we aimed to investigate the utility of the perfusion index (PI) for evaluating consciousness level during repeated propofol sedation. METHODS: In this prospective observational study, children aged from birth to 19 years old scheduled for proton therapy under repeated propofol sedation were enrolled. The primary outcome was the equivalence of PI values 5 min after anesthesia induction on consecutive sedation. Total consumption of propofol during sedation, time to reach the University of Michigan sedation scale (UMSS) score 1 after end of proton therapy, and duration of post-anesthesia care unit (PACU) stay were recorded. RESULTS: The PI values measured 5 min after induction of anesthesia were not equivalent to each other in consecutive sedation except for the second versus third (1st vs. 2nd: 97.5% CI: -1.34, 0.91; p = 0.206, 0.034; 2nd vs. 3rd: 97.5% CI: -0.87, 0.94; p = 0.023, 0.036 3rd vs. 4th: 97.5% CI: -2.08, -0.26; p < 0.99, <0.001; 4th vs. 5th: 97.5% CI: 0.21, 2.28; p < 0.001, >0.99; respectively). In consecutive sedation, there was not a significantly different difference in the time to reach UMSS score 1 (p > 0.99, all) for total consumption of propofol, time to reach UMSS score 1 after the end of proton therapy, and duration of PACU stay. CONCLUSIONS: During repeated propofol sedation in children, PI was insufficient to be used as an indicator of consciousness level assessment. However, we suggest that the information related to repeated sedation provided by this study may be helpful in clinical practice.