ABSTRACT
The mRNA 5'cap-binding eukaryotic translation initiation factor 4E (eIF4E) plays a critical role in the control of mRNA translation in health and disease. One mechanism of regulation of eIF4E activity is via phosphorylation of eIF4E by MNK kinases, which promotes the translation of a subset of mRNAs encoding pro-tumorigenic proteins. Work on eIF4E phosphatases has been paltry. Here, we show that PPM1G is the phosphatase that dephosphorylates eIF4E. We describe the eIF4E-binding motif in PPM1G that is similar to 4E-binding proteins (4E-BPs). We demonstrate that PPM1G inhibits cell proliferation by targeting phospho-eIF4E-dependent mRNA translation.
Subject(s)
Cell Proliferation , Eukaryotic Initiation Factor-4E , Protein Biosynthesis , Protein Phosphatase 2C , RNA, Messenger , Eukaryotic Initiation Factor-4E/metabolism , Eukaryotic Initiation Factor-4E/genetics , Humans , Cell Proliferation/genetics , Protein Phosphatase 2C/metabolism , Protein Phosphatase 2C/genetics , Phosphorylation , RNA, Messenger/genetics , RNA, Messenger/metabolism , Phosphoprotein Phosphatases/metabolism , Phosphoprotein Phosphatases/genetics , Protein Binding , HEK293 Cells , AnimalsABSTRACT
In this study, we explored the oncogenic mechanism of cleavage and polyadenylation-specific factor 6 (CPSF6) in hepatocellular carcinoma (HCC). CPSF6 was overexpressed in HCC tissues with poor survival rates compared to normal tissues. Hence, CPSF6 depletion suppressed cell viability and colony formation, induced apoptosis via PARP cleavage, and increased the sub-G1 population of Hep3B and Huh7 cells. In addition, CPSF6 enhanced the stability of c-Myc via their binding through nuclear co-localization by binding to c-Myc at the site of 258-360. Furthermore, c-Myc degradation by CPSF6 depletion was disturbed by FBW7 depletion or treatment with the proteasomal inhibitor MG132. Additionally, CPSF6 depletion suppressed the Warburg effect by inhibiting glucose, HK2, PKM2, LDH, and lactate; showed a synergistic effect with Sorafenib in Hep3B cells; and inhibited angiogenesis by tube formation and CAM assays, along with decreased expression and production of vascular endothelial growth factor (VEGF). Notably, CPSF6 depletion attenuated PD-L1 expression and increased Granzyme B levels, along with an increase in the percentage of CD4/CD8 cells in the splenocytes of BALB/c nude mice bearing Hep3B cells. Consistently, immunohistochemistry showed that CPSF6 depletion reduced the growth of Hep3B cells in BALB/c mice in orthotopic and xenograft tumor models by inhibiting tumor microenvironment-associated proteins. Overall, these findings suggest that CPSF6 enhances the Warburg effect for immune escape and angiogenesis, leading to cancer progression via c-Myc, mediated by the HK, PD-L1, and VEGF networks, with synergistic potential with sorafenib as a molecular target for liver cancer therapy.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Proto-Oncogene Proteins c-myc , Signal Transduction , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/drug therapy , Cell Line, Tumor , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/drug therapy , Proto-Oncogene Proteins c-myc/metabolism , Animals , Neovascularization, Pathologic/metabolism , Mice , Sorafenib/therapeutic use , Sorafenib/pharmacology , Warburg Effect, Oncologic , Mice, Nude , Mice, Inbred BALB C , Apoptosis , AngiogenesisABSTRACT
PURPOSE: Cancer treatments often become ineffective because of acquired drug resistance. To characterize changes in breast cancer cells accompanying development of resistance to inhibitors of the oncogenic transcription factor, FOXM1, we investigated the suppression of cell death pathways, especially ferroptosis, in FOXM1 inhibitor-resistant cells. We also explored whether ferroptosis activators can synergize with FOXM1 inhibitors and can overcome FOXM1 inhibitor resistance. METHODS: In estrogen receptor-positive and triple-negative breast cancer cells treated with FOXM1 inhibitor NB73 and ferroptosis activators dihydroartemisinin and JKE1674, alone and in combination, we measured suppression of cell viability, motility, and colony formation, and monitored changes in gene and protein pathway expressions and mitochondrial integrity. RESULTS: Growth suppression of breast cancer cells by FOXM1 inhibitors is accompanied by increased cell death and alterations in mitochondrial morphology and metabolic activity. Low doses of FOXM1 inhibitor strongly synergize with ferroptosis inducers to reduce cell viability, migration, colony formation, and expression of proliferation-related genes, and increase intracellular Fe+2 and lipid peroxidation, markers of ferroptosis. Acquired resistance to FOXM1 inhibition is associated with increased expression of cancer stem-cell markers and proteins that repress ferroptosis, enabling cell survival and drug resistance. Notably, resistant cells are still sensitive to growth suppression by low doses of ferroptosis activators, effectively overcoming the acquired resistance. CONCLUSION: Delineating changes in viability and cell death pathways that can overcome drug resistance should be helpful in determining approaches that might best prevent or reverse resistance to therapeutic targeting of FOXM1 and ultimately improve patient clinical outcomes.
ABSTRACT
As the prevalence of chronic non-specific spinal pain rises, the utilization of diverse massage devices for therapeutic intervention increases rapidly. However, research on their mechanisms, particularly those involving spinal twisting, is limited. This study was designed to evaluate the impact of heat application and spinal twisting massage techniques on individuals suffering from chronic non-specific spinal pain. A total of 36 individuals were divided into two groups: a control group (18 participants) and an experimental group (18 participants). The experimental group received heat treatment plus spinal twisting massage twice a week for four weeks, while the control group received heat therapy plus traditional vibration massage techniques. Effectiveness was measured using the Visual Analog Scale (VAS), the Pressure Pain Threshold (PPT), the Korean Western Ontario and McMaster Universities (K-WOMAC) Index, spine tilt, and Cobb angle. VAS, K-WOMAC, and PPT significantly improved in both groups at all three time points. VAS notably decreased in the experimental group compared to the control group (p-value: 0.0369). Despite improvements in K-WOMAC and PPT scores within the experimental group, statistical significance remained elusive. Furthermore, spine tilt and Cobb angle showed no significant differences from baseline to the 6th week. In conclusion, the application of thermotherapy coupled with twisting massage demonstrates significant efficacy in mitigating chronic non-specific spinal pain, surpassing the pain-relief outcomes achieved through heat therapy in combination with standard vibration massage techniques.
Subject(s)
Massage , Pain Measurement , Humans , Massage/methods , Female , Male , Middle Aged , Adult , Pain Measurement/methods , Hyperthermia, Induced/methods , Treatment Outcome , Back Pain/therapy , Chronic Pain/therapy , Pain Management/methods , Vibration/therapeutic useABSTRACT
This study developed and validated a machine learning model to accurately predict acute kidney injury (AKI) after non-cardiac surgery, aiming to improve patient outcomes by assessing its clinical feasibility and generalizability. We conducted a retrospective cohort study using data from 76,032 adults who underwent non-cardiac surgery at a single tertiary medical center between March 2019 and February 2021, and used data from 5512 patients from the VitalDB open dataset for external model validation. The predictive variables for model training consisted of demographic, preoperative laboratory, and intraoperative data, including calculated statistical values such as the minimum, maximum, and mean intraoperative blood pressure. When predicting postoperative AKI, our gradient boosting machine model incorporating all the variables achieved the best results, with AUROC values of 0.868 and 0.757 for the internal and external validations using the VitalDB dataset, respectively. The model using intraoperative data performed best in internal validation, while the model with preoperative data excelled in external validation. In this study, we developed a predictive model for postoperative AKI in adult patients undergoing non-cardiac surgery using preoperative and intraoperative data, and external validation demonstrated the efficacy of open datasets for generalization in medical artificial modeling research.
ABSTRACT
OBJECTIVES: Fertility-sparing treatment (FST) might be considered an option for reproductive patients with low-risk endometrial cancer (EC). On the other hand, the matching rates between preoperative assessment and postoperative pathology in low-risk EC patients are not high enough. We aimed to predict the postoperative pathology depending on preoperative myometrial invasion (MI) and grade in low-risk EC patients to help extend the current criteria for FST. METHODS/MATERIALS: This ancillary study (KGOG 2015S) of Korean Gynecologic Oncology Group 2015, a prospective, multicenter study included patients with no MI or MI <1/2 on preoperative MRI and endometrioid adenocarcinoma and grade 1 or 2 on endometrial biopsy. Among the eligible patients, Groups 1-4 were defined with no MI and grade 1, no MI and grade 2, MI <1/2 and grade 1, and MI <1/2 and grade 2, respectively. New prediction models using machine learning were developed. RESULTS: Among 251 eligible patients, Groups 1-4 included 106, 41, 74, and 30 patients, respectively. The new prediction models showed superior prediction values to those from conventional analysis. In the new prediction models, the best NPV, sensitivity, and AUC of preoperative each group to predict postoperative each group were as follows: 87.2%, 71.6%, and 0.732 (Group 1); 97.6%, 78.6%, and 0.656 (Group 2); 71.3%, 78.6% and 0.588 (Group 3); 91.8%, 64.9%, and 0.676% (Group 4). CONCLUSIONS: In low-risk EC patients, the prediction of postoperative pathology was ineffective, but the new prediction models provided a better prediction.
Subject(s)
Endometrial Neoplasms , Myometrium , Neoplasm Grading , Neoplasm Invasiveness , Humans , Female , Endometrial Neoplasms/pathology , Endometrial Neoplasms/surgery , Myometrium/pathology , Myometrium/surgery , Middle Aged , Adult , Republic of Korea/epidemiology , Prospective Studies , Aged , Preoperative Period , Magnetic Resonance Imaging , Carcinoma, Endometrioid/pathology , Carcinoma, Endometrioid/surgeryABSTRACT
The estrogen receptor-α (ER) is thought to function only as a homodimer but responds to a variety of environmental, metazoan, and therapeutic estrogens at subsaturating doses, supporting binding mixtures of ligands as well as dimers that are only partially occupied. Here, we present a series of flexible ER ligands that bind to receptor dimers with individual ligand poses favoring distinct receptor conformations-receptor conformational heterodimers-mimicking the binding of two different ligands. Molecular dynamics simulations showed that the pairs of different ligand poses changed the correlated motion across the dimer interface to generate asymmetric communication between the dimer interface, the ligands, and the surface binding sites for epigenetic regulatory proteins. By examining the binding of the same ligand in crystal structures of ER in the agonist vs. antagonist conformers, we also showed that these allosteric signals are bidirectional. The receptor conformer can drive different ligand binding modes to support agonist vs. antagonist activity profiles, a revision of ligand binding theory that has focused on unidirectional signaling from the ligand to the coregulator binding site. We also observed differences in the allosteric signals between ligand and coregulator binding sites in the monomeric vs. dimeric receptor, and when bound by two different ligands, states that are physiologically relevant. Thus, ER conformational heterodimers integrate two different ligand-regulated activity profiles, representing different modes for ligand-dependent regulation of ER activity.
Subject(s)
Estrogen Receptor alpha , Estrogens , Molecular Dynamics Simulation , Protein Multimerization , Estrogen Receptor alpha/metabolism , Estrogen Receptor alpha/chemistry , Allosteric Regulation , Humans , Ligands , Estrogens/metabolism , Estrogens/chemistry , Binding Sites , Protein Binding , Protein ConformationABSTRACT
We investigated the recent spatial variation in the mesozooplankton community on the broad shelf of the RSR MPA during the bloom season. The mesozooplankton community was geographically divided into three regions: the Terra Nova Bay polynya, the Ross Sea polynya, and the marginal polynya. Larval euphausiids were dominant in the two polynya regions, whereas copepods were predominant in the marginal polynya region. Salinity, sea ice, and dissolved oxygen related to the different water mass compositions were the most significant factors distinguishing the mesozooplankton community. The key environmental variable separating the three groups was salinity. In accordance with the relatively high mesozooplankton abundance in the polynya regions, the occurrence and size of the polynyas in the December Ross Sea are thought to affect the spatial distribution of mesozooplankton. Consequently, this study indicates that two polynyas in the Ross Sea are vital habitats for krill during summer. Our observation results provide fundamental information for evaluating marine ecosystems and establishing a management plan for the RSR MPA.
Subject(s)
Copepoda , Ecosystem , Seasons , Zooplankton , Animals , Salinity , Environmental Monitoring , Euphausiacea , Conservation of Natural ResourcesABSTRACT
The indiscriminate use of zinc oxide nanoparticles (ZnO NPs) in daily life can lead to their release into soil environment. These ZnO NPs can be taken up by crops and translocated to their edible part, potentially causing risks to the ecosystem and human health. In this study, we conducted pot experiments to determine phytotoxicity, bioaccumulation and translocation depending on the size (10 - 30â¯nm, 80 - 200â¯nm and 300â¯nm diameter) and concentration (0, 100, 500 and 1000â¯mg Zn/kg) of ZnO NPs and Zn ion (Zn2+) in bok choy, a leafy green vegetable crop. After 14 days of exposure, our results showed that large-sized ZnO NPs (i.e., 300â¯nm) at the highest concentration exhibited greater phytotoxicity, including obstruction of leaf and root weight (42.5â¯% and 33.8â¯%, respectively) and reduction of chlorophyll a and b content (50.2â¯% and 85.2â¯%, respectively), as well as changes in the activities of oxidative stress responses compared to those of small-sized ZnO NPs, although their translocation ability was relatively lower than that of smaller ones. The translocation factor (TF) values decreased as the size of ZnO NPs increased, with TF values of 0.68 for 10 - 30â¯nm, 0.55 for 80 - 200â¯nm, and 0.27 for 300â¯nm ZnO NPs, all at the highest exposure concentration. Both the results of micro X-ray fluorescence (µ-XRF) spectrometer and bio-transmission electron microscopy (bio-TEM) showed that the Zn elements were mainly localized at the edges of leaves exposed to small-sized ZnO NPs. However, the Zn elements upon exposure to large-sized ZnO NP were primarily observed in the primary veins of leaves in the µ-XRF data, indicating a limitation in their ability to translocate from roots to leaves. This study not only advances our comprehension of the environmental impact of nanotechnology but also holds considerable implications for the future of sustainable agriculture and food safety.
Subject(s)
Bioaccumulation , Brassica , Metal Nanoparticles , Particle Size , Plant Leaves , Soil Pollutants , Zinc Oxide , Zinc Oxide/toxicity , Zinc Oxide/chemistry , Soil Pollutants/toxicity , Brassica/drug effects , Brassica/metabolism , Brassica/growth & development , Plant Leaves/drug effects , Plant Leaves/metabolism , Metal Nanoparticles/toxicity , Soil/chemistry , Chlorophyll/metabolism , Oxidative Stress/drug effects , Plant Roots/drug effects , Plant Roots/metabolism , Chlorophyll A/metabolism , Nanoparticles/toxicityABSTRACT
Hand hygiene among anesthesia personnel is important to prevent hospital-acquired infections in operating rooms; however, an efficient monitoring system remains elusive. In this study, we leverage a deep learning approach based on operating room videos to detect alcohol-based hand hygiene actions of anesthesia providers. Videos were collected over a period of four months from November, 2018 to February, 2019, at a single operating room. Additional data was simulated and added to it. The proposed algorithm utilized a two-dimensional (2D) and three-dimensional (3D) convolutional neural networks (CNNs), sequentially. First, multi-person of the anesthesia personnel appearing in the target OR video were detected per image frame using the pre-trained 2D CNNs. Following this, each image frame detection of multi-person was linked and transmitted to a 3D CNNs to classify hand hygiene action. Optical flow was calculated and utilized as an additional input modality. Accuracy, sensitivity and specificity were evaluated hand hygiene detection. Evaluations of the binary classification of hand-hygiene actions revealed an accuracy of 0.88, a sensitivity of 0.78, a specificity of 0.93, and an area under the operating curve (AUC) of 0.91. A 3D CNN-based algorithm was developed for the detection of hand hygiene action. The deep learning approach has the potential to be applied in practical clinical scenarios providing continuous surveillance in a cost-effective way.
ABSTRACT
BACKGROUND: Genetic studies implicate the oncogenic transcription factor Forkhead Box M1 (FOXM1) as a potential therapeutic target in high-grade serous ovarian cancer (HGSOC). We evaluated the activity of different FOXM1 inhibitors in HGSOC cell models. RESULTS: We treated HGSOC and fallopian tube epithelial (FTE) cells with a panel of previously reported FOXM1 inhibitors. Based on drug potency, efficacy, and selectivity, determined through cell viability assays, we focused on two compounds, NB-73 and NB-115 (NB compounds), for further investigation. NB compounds potently and selectively inhibited FOXM1 with lesser effects on other FOX family members. NB compounds decreased FOXM1 expression via targeting the FOXM1 protein by promoting its proteasome-mediated degradation, and effectively suppressed FOXM1 gene targets at both the protein and mRNA level. At the cellular level, NB compounds promoted apoptotic cell death. Importantly, while inhibition of apoptosis using a pan-caspase inhibitor rescued HGSOC cells from NB compound-induced cell death, it did not rescue FOXM1 protein degradation, supporting that FOXM1 protein loss from NB compound treatment is specific and not a general consequence of cytotoxicity. Drug washout studies indicated that FOXM1 reduction was retained for at least 72 h post-treatment, suggesting that NB compounds exhibit long-lasting effects in HGSOC cells. NB compounds effectively suppressed both two-dimensional and three-dimensional HGSOC cell colony formation at sub-micromolar concentrations. Finally, NB compounds exhibited synergistic activity with carboplatin in HGSOC cells. CONCLUSIONS: NB compounds are potent, selective, and efficacious inhibitors of FOXM1 in HGSOC cells and are worthy of further investigation as HGSOC therapeutics.
Subject(s)
Antineoplastic Agents , Apoptosis , Forkhead Box Protein M1 , Ovarian Neoplasms , Forkhead Box Protein M1/metabolism , Forkhead Box Protein M1/antagonists & inhibitors , Humans , Female , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Ovarian Neoplasms/metabolism , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/pathology , Cystadenocarcinoma, Serous/metabolism , Cell Survival/drug effects , Neoplasm GradingABSTRACT
Spinal cord injury (SCI) leads to motor and sensory impairment below the site of injury, thereby necessitating rehabilitation. An enriched environment (EE) increases social interaction and locomotor activity in a mouse model, similar to human rehabilitation. However, the impact of EE on presynaptic plasticity in gene expression levels remains unclear. Hence, this study aimed to investigate the therapeutic potential of EE in an SCI mouse model. Mice with spinal cord contusion were divided into two groups: those housed in standard cages (control) and those in EE conditions (EE). Each group was housed separately for either 2- or 8-weeks post-injury, after which RNA sequencing was performed and compared to a sham group (receiving only a dorsal laminectomy). The synaptic vesicle cycle (SVC) pathway and related genes showed significant downregulation after SCI at both time points. Subsequently, we investigated whether exposure to EE for 2- and 8-weeks post-SCI could modulate the SVC pathway and its related genes. Notably, exposure to EE for 8 weeks resulted in a marked reversal effect of SVC-related gene expression, along with stimulation of axon regeneration and mitigation of locomotor activity loss. Thus, prolonged exposure to EE increased presynaptic activity, fostering axon regeneration and functional improvement by modulating the SVC in the SCI mouse model. These findings suggest that EE exposure proves effective in inducing activity-dependent plasticity, offering a promising therapeutic approach akin to rehabilitation training in patients with SCI.
Subject(s)
Disease Models, Animal , Spinal Cord Injuries , Synaptic Vesicles , Animals , Spinal Cord Injuries/physiopathology , Spinal Cord Injuries/rehabilitation , Spinal Cord Injuries/metabolism , Mice , Synaptic Vesicles/metabolism , Locomotion , Female , Neuronal Plasticity , Environment , Recovery of Function , Mice, Inbred C57BL , Nerve RegenerationABSTRACT
The estrogen receptor-α (ER) is thought to function only as a homodimer, but responds to a variety of environmental, metazoan, and therapeutic estrogens at sub-saturating doses, supporting binding mixtures of ligands as well as dimers that are only partially occupied. Here, we present a series of flexible ER ligands that bind to receptor dimers with individual ligand poses favoring distinct receptor conformations -receptor conformational heterodimers-mimicking the binding of two different ligands. Molecular dynamics simulations showed that the pairs of different ligand poses changed the correlated motion across the dimer interface to generate asymmetric communication between the dimer interface, the ligands, and the surface binding sites for epigenetic regulatory proteins. By examining binding of the same ligand in crystal structures of ER in the agonist versus antagonist conformers, we also showed that these allosteric signals are bidirectional. The receptor conformer can drive different ligand binding modes to support agonist versus antagonist activity profiles, a revision of ligand binding theory that has focused on unidirectional signaling from ligand to the coregulator binding site. We also observed differences in the allosteric signals between ligand and coregulator binding sites in the monomeric versus dimeric receptor, and when bound by two different ligands, states that are physiologically relevant. Thus, ER conformational heterodimers integrate two different ligand-regulated activity profiles, representing new modes for ligand-dependent regulation of ER activity. Significance: The estrogen receptor-α (ER) regulates transcription in response to a hormonal milieu that includes low levels of estradiol, a variety of environmental estrogens, as well as ER antagonists such as breast cancer anti-hormonal therapies. While ER has been studied as a homodimer, the variety of ligand and receptor concentrations in different tissues means that the receptor can be occupied with two different ligands, with only one ligand in the dimer, or as a monomer. Here, we use X-ray crystallography and molecular dynamics simulations to reveal a new mode for ligand regulation of ER activity whereby sequence-identical homodimers can act as functional or conformational heterodimers having unique signaling characteristics, with ligand-selective allostery operating across the dimer interface integrating two different signaling outcomes.
ABSTRACT
BACKGROUND/AIM: Gefitinib exhibits anticancer activity against cervical cancer cells via anoikis, a type of apoptosis induced by cell detachment from the extracellular matrix. Previous studies have reported that Parkin expression affects the efficacy of anticancer drugs. However, the impact of Parkin expression on the therapeutic effects of gefitinib in human cervical cancer remains unclear. Thus, this study aimed to evaluate whether Parkin over-expression improves the therapeutic effects of gefitinib against HeLa cervical cancer cells. MATERIALS AND METHODS: Cell viability and apoptotic death of HeLa cells were measured by trypan blue dye exclusion assay and flow cytometry. Cell detachment, adhesion, spreading, and cell-cell interaction were observed by inverted microscopy. Alteration of adhesion-related molecules was evaluated by confocal microscopy and western blot assay. RESULTS: Parkin expression potentiated gefitinib-induced cell detachment by affecting the organization of the actin cytoskeleton. In addition, Parkin expression induced a further reduction in the reattachment of and interaction between detached cells. The therapeutic efficacy of low-dose gefitinib combined with Parkin expression was equivalent to that of high-dose gefitinib alone. CONCLUSION: Parkin expression promotes gefitinib-induced anoikis, consequently increasing the efficacy of gefitinib against HeLa human cervical cancer cells. Based on our results, we propose that Parkin can be used to increase the anti-cancer effect of gefitinib on cervical cancer cells.
Subject(s)
Anoikis , Gefitinib , Ubiquitin-Protein Ligases , Uterine Cervical Neoplasms , Female , Humans , Anoikis/drug effects , Antineoplastic Agents/pharmacology , Cell Adhesion/drug effects , Cell Survival/drug effects , Gefitinib/pharmacology , HeLa Cells , Quinazolines/pharmacology , Ubiquitin-Protein Ligases/drug effects , Ubiquitin-Protein Ligases/metabolism , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/metabolismABSTRACT
Though Isoimperatorin from Angelicae dahuricae is known to have antiviral, antidiabetic, anti-inflammatory and antitumor effects, its underlying antitumor mechanism remains elusive so far. Hence, the apoptotic mechanism of Isoimperatorin was explored in hepatocellular carcinomas (HCCs). In this study, Isoimperatorin inhibited the viability of Huh7 and Hep3B HCCs and increased the subG1 apoptotic portion and also abrogated the expression of pro-poly-ADP ribose polymerase (pro-PARP) and pro-caspase 3 in Huh7 and Hep3B cells. Also, Isoimperatorin abrogated the expression of cyclin D1, cyclin E1, CDK2, CDK4, CDK6 and increased p21 as G1 phase arrest-related proteins in Huh7 and Hep3B cells. Interestingly, Isoimperatorin reduced the expression and binding of c-Myc and Sirtuin 1 (SIRT1) by Immunoprecipitation (IP), with a binding score of 0.884 in Huh7 cells. Furthermore, Isoimperatorin suppressed the overexpression of c-Myc by the proteasome inhibitor MG132 and also disturbed cycloheximide-treated c-Myc stability in Huh7 cells. Overall, these findings support the novel evidence that the pivotal role of c-Myc and SIRT1 is critically involved in Isoimperatorin-induced apoptosis in HCCs as potent molecular targets in liver cancer therapy.
Subject(s)
Apoptosis , Carcinoma, Hepatocellular , Furocoumarins , Liver Neoplasms , Proto-Oncogene Proteins c-myc , Signal Transduction , Sirtuin 1 , Humans , Apoptosis/drug effects , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Proto-Oncogene Proteins c-myc/drug effects , Proto-Oncogene Proteins c-myc/metabolism , Signal Transduction/drug effects , Sirtuin 1/drug effects , Sirtuin 1/metabolism , Furocoumarins/pharmacologyABSTRACT
The mitogenome of Euphausia crystallorophias collected from the Ross Sea Region Marine Protected Area (RSR MPA) is described for the first time. The assembled mitogenome was 17,291 bp in length and consisted of two ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs), 13 protein-coding genes (PCGs), and noncoding regions, all of which were identical to those of other euphausiid species. The most common start codon for the 13 PCGs was ATG, and the most common termination codon was TAA. The overall G + C content was 33.2% in the heavy strand. Euphausia crystallorophias was sister to E. superba in the phylogenetic analysis. The mitogenome of E. crystallorophias provided significant DNA molecular data for further identification and phylogenetic analysis within the euphausiids.
ABSTRACT
Although the esophageal stethoscope is used for continuous auscultation during general anesthesia, few studies have investigated phonocardiographic data as a continuous hemodynamic index. In this study, we aimed to induce hemodynamic variations and clarify the relationship between the heart sounds and hemodynamic variables through an experimental animal study. Changes in the cardiac contractility and vascular resistance were induced in anesthetized pigs by administering dobutamine, esmolol, phenylephrine, and nicardipine. In addition, a decrease in cardiac output was induced by restricting the venous return by clamping the inferior vena cava (IVC). The relationship between the hemodynamic changes and changes in the heart sound indices was analyzed. Experimental data from eight pigs were analyzed. The mean values of the correlation coefficients of changes in S1 amplitude (ΔS1amp) with systolic blood pressure (ΔSBP), pulse pressure (ΔPP), and ΔdP/dt during dobutamine administration were 0.94, 0.96, and 0.96, respectively. The mean values of the correlation coefficients of ΔS1amp with ΔSBP, ΔPP, and ΔdP/dt during esmolol administration were 0.80, 0.82, and 0.86, respectively. The hemodynamic changes caused by the administration of phenylephrine and nicardipine did not correlate significantly with changes in the heart rate. The S1 amplitude of the heart sound was significantly correlated with the hemodynamic changes caused by the changes in cardiac contractility but not with the variations in the vascular resistance. Heart sounds can potentially provide a non-invasive monitoring method to differentiate the cause of hemodynamic variations.
Subject(s)
Heart Sounds , Propanolamines , Animals , Swine , Dobutamine/pharmacology , Nicardipine , Hemodynamics , Phenylephrine/pharmacologyABSTRACT
BACKGROUND: Due to the increasing proportion of older adults in Korea and growing interest in aging, the concepts of oral aging and oral hypofunction have recently been introduced. Thus, it is necessary to investigate the age-specific oral function levels of Korean older adults and develop expert intervention methods for healthy aging. METHODS: Dysphagia, independence of daily living, and oral hypofunction were assessed in 206 older adults living in Wonju, Gangwon State, South Korea. Subjective dysphagia was assessed through self-report questionnaires using the Dysphagia Handicap Index (DHI), the Korean version of Eating Assessment Tool-10, and the Korean version of the Modified Barthel Index. In addition, the oral hypofunction assessment items included decreased chewing ability, occlusal pressure, tongue pressure, oral dryness, and oral cleanliness. RESULTS: DHI increased significantly with age, with those in their 80 s reporting the most difficulty swallowing. Oral function in terms of chewing ability (maximum occlusal pressure and number of remaining teeth), maximum occlusal pressure, and maximum tongue pressure also declined with increasing age. While there was no significant difference in oral dryness by age, those in their 80 s had dry mouth according to the criteria of the oral moisture checking device. CONCLUSIONS: In an assessment of oral function in community-dwelling, independent Korean older adults, the number of items that were assessed as oral hypofunction increased with age. The findings can be used to standardize the oral hypofunction assessment item and develop age-based individualized intervention plans for the early management of oral health and individual oral myofunctional rehabilitation in Korean community-dwelling older adults.
Subject(s)
Deglutition Disorders , Xerostomia , Humans , Aged , Independent Living , Pressure , Tongue , Oral Health , Geriatric AssessmentABSTRACT
PURPOSE: To evaluate the safety and clinical outcome of two-session catheter-directed sclerotherapy (CDS) with 99% ethanol in patients with endometrioma. MATERIALS AND METHODS: This prospective study was approved by the institutional review board with written informed consent obtained from all participants and was registered on clinicaltrial.gov. Consecutive patients with ovarian endometrioma between June 2020 and March 2023 were prospectively evaluated for two sessions of CDS. After successful transvaginal ultrasound-guided puncture of the endometrioma, the biopsy needle was exchanged for a 7- or 8.5-F catheter for aspiration and ethanol injection. The catheter was retained in situ for a second session the next day. Endometrioma volume was measured on ultrasound before and 1, 3, and 6 months after CDS, and volume reduction ratio (VRR) was calculated. Serum anti-Müllerian hormone (AMH) was measured before and 6 months after CDS to assess ovarian reserve. RESULTS: Thirty-one endometriomas in 22 patients (mean age, 31.0 years; range, 19-44 years) were treated; 28 endometriomas were successfully treated with two-session CDS, while one session was incomplete in three endometriomas in three patients due to contrast medium leakage or pain. Minor procedure-related complications developed in four patients and resolved spontaneously before discharge on the same day of the second session. No recurrence was identified during follow-up. At the 6-month follow-up, the mean endometrioma diameter decreased from 5.5 ± 1.7 to 1.4 ± 0.9 cm (P < 0.001), and the serum AMH level was lowered without statistical significance (1.37 ± 0.96 ng/mL vs. 1.18 ± 0.92 ng/mL; P = 0.170). VRRs at 1, 3, and 6 months after CDS were 84.3 ± 13.7%, 94.3 ± 5.8%, and 96.4 ± 4.7%, respectively. CONCLUSION: Two-session CDS with 99% ethanol is safe, feasible, and effective for treating endometrioma with the ovarian function well preserved.
Subject(s)
Endometriosis , Ethanol , Sclerotherapy , Ultrasonography, Interventional , Humans , Female , Endometriosis/therapy , Sclerotherapy/methods , Adult , Ethanol/therapeutic use , Ethanol/administration & dosage , Prospective Studies , Treatment Outcome , Young Adult , Sclerosing Solutions/therapeutic use , Ovarian Diseases/therapy , Ovarian Diseases/diagnostic imagingABSTRACT
BACKGROUND: Exercise and dietary nutrition are considered crucial in human immunodeficiency virus (HIV)/ acquired immunodeficiency syndrome (AIDS) treatment protocols and people living with HIV/AIDS (PLWHA) rehabilitation care. However, there is no well-studied research evaluating the effects of combined interventions on the fitness and immune systems of PLWHA. Therefore, this study aimed to analyze the effects of exercise and dietary intervention on physical fitness, quality of life and immune response in PLWHA. METHODS: This was an experimental study, with a sample of 25 male PLWHA divided into two groups: the intervention group (IG: 12 participants) and the control group (CG: 13 participants). All participants have not had any exercise habits and nutritional supplements in the past six months. The participants in the IG completed 45 min of exercise (60-80% HRmax) 4 times per week for 4 weeks. The exercise was in the form of brisk walking or running. They were also given a nutritional dietary supplement 3 times a day for 4 weeks. The 13 individuals in the CG continued their normal daily life (physical activity and diet). The following parameters were evaluated before and after the intervention: body composition, physical fitness, immune response, quality of life (QoL), stress, dietary behavior, dietary habits, exercise motivation, and physical self-efficacy. RESULTS: The significant changes were observed in burnout of stress variables and physical efficiency index (PEI) of physical fitness in the IG (p =.023). Moreover, in the saliva samples, sal-T levels significantly increased only after the intervention in the IG (p =.012). Additionally, regarding the analysis of the interaction (group × time), there was a significant improvement in the reaction speed (p =.001) and grip strength (left: p =.002, right: p =.030) and a significant difference in physical satisfaction in QoL (p =.001), stress burnout (p =.043), self-confidence in physical efficacy (p =.045), external display (p =.008), and fulfillment (p =.047) in exercise motivation. Moreover, the significant effect of the intervention on emotional eating in dietary behavior was shown in the comparison of the IG before and after intervention (p =.001) and in the comparison of the IG group with the CG after the experiment (p =.013). However, there was no significant effect of time or interaction between the condition and time on body composition. CONCLUSIONS: In conclusion, exercise training and diet therapy caused changes in physical fitness and Sal-T levels, which had positive effects on the health promotion of PLWHA.