ABSTRACT
The potential effect of hydrological conditions on distribution and loadings of Hg species was investigated in the microtidal Hyeongsan River Estuary (HRE). Dissolved Hg (DHg) and dissolved methylmercury (DMeHg) from the creek receiving industrial wastes were effectively settled to sediment during the post-typhoon period, while persistent input from the Hg-contaminated creek without settling was observed during the dry periods. The event-based mean approach was applied to explore the hydrological effects on the annual flux of Hg. The largest inputs of DHg and particulate Hg (PHg) were found in the Hg-contaminated creek, and DHg input was higher in the dry than wet periods whereas PHg input was higher in the wet than dry periods. In sediment, Hg and MeHg concentrations decreased after the typhoon, attributed to erosion of surface sediments. Overall, the HRE serves as an effective sink of Hg that reduces the degree of Hg contamination in coastal water.
Subject(s)
Environmental Monitoring , Estuaries , Geologic Sediments , Hydrology , Mercury , Rivers , Water Pollutants, Chemical , Mercury/analysis , Water Pollutants, Chemical/analysis , Rivers/chemistry , Geologic Sediments/chemistry , Methylmercury Compounds/analysisABSTRACT
The understanding of the essential environmental factors affecting the spatiotemporal variation in methylmercury (MeHg) in river water is limited to date, despite its importance for predicting the effect of ongoing climate change on MeHg accumulation in freshwater ecosystems. This study aimed to explore the variation in MeHg concentration and related environmental factors in the downstream zone of the Yeongsan River under highly dynamic hydrologic conditions by using water quality and hydrologic data collected from 1997 to 2022, and Hg and MeHg data collected from 2017 to 2022. The mean concentration of unfiltered MeHg was 35.7 ± 13.7 pg L-1 (n = 24) in summer and 26.7 ± 7.43 pg L-1 (n = 24) in fall. Dissolved oxygen (DO), conductivity, nitrate, and dissolved organic carbon (DOC) were determined to be the most influential variables in terms of MeHg variation based on the partial least squares regression model, and their effects on the MeHg concentration were negative, except for DOC. Heatmaps representing the similarity distances between temporal trends of hydrologic and water quality variables were constructed to determine fundamental factors related to the time-based variations in DO, conductivity, nitrate, and DOC using a dynamic time warping algorithm. The heatmap cluster analysis showed that the temporal trends of these variables were closely related to rainfall variation rather than irradiance or water temperature. Overall, biogeochemical factors directly related to in situ methylation rate of Hg(II)-rather than transport of Hg(II) and MeHg from external sources-mainly control the spatiotemporal variation of MeHg in the downstream zone of the Yeongsan River.
ABSTRACT
Biotite, a phyllosilicate mineral, possesses significant potential for cesium (Cs) adsorption owing to its negative surface charge, specific surface area (SSA), and frayed edge sites (FES). Notably, FES are known to play an important role in the adsorption of Cs. The objectives of this study were to investigate the Cs adsorption capacity and behavior of artificially weathered biotite and identify mineralogical characteristics for the development of an eco-friendly geologically-based Cs adsorbent. Through various analyses, it was confirmed that the FES of biotite was mainly formed by mineral structural distortion during artificial weathering. The Cs adsorption capacity is improved by approximately 39% (from 20.53 to 28.63 mg g-1) when FES are formed in biotite through artificial weathering using a low-concentration acidic solution mixed with hydrogen peroxide (H2O2). Especially, the Cs selectivity in Cs-containing seawater, including high concentrations of cations and organic matter, was significantly enhanced from 203.2 to 1707.6 mL g-1, an increase in removal efficiency from 49.5 to 89.2%. These results indicate that FES of artificially weathered biotite play an essential role in Cs adsorption. Therefore, this simple and economical weathering method, which uses a low-concentration acidic solution mixed with H2O2, can be applied to natural minerals for use as Cs adsorbents.
Subject(s)
Aluminum Silicates , Cesium , Hydrogen Peroxide , Cesium/chemistry , Minerals/chemistry , Ferrous Compounds/chemistry , AdsorptionABSTRACT
Tobacco and alcohol are risk factors for human papillomavirus-negative head and neck squamous cell carcinoma (HPV- HNSCC), which arises from the mucosal epithelium of the upper aerodigestive tract. Notably, despite the mutagenic potential of smoking, HPV- HNSCC exhibits a low mutational load directly attributed to smoking, which implies an undefined role of smoking in HPV- HNSCC. Elevated YAP (Yes-associated protein) mRNA is prevalent in HPV- HNSCC, irrespective of the YAP gene amplification status, and the mechanism behind this upregulation remains elusive. Here, we report that oxidative stress, induced by major risk factors for HPV- HNSCC such as tobacco and alcohol, promotes YAP transcription via TM4SF19 (transmembrane 4 L six family member 19). TM4SF19 modulates YAP transcription by interacting with the GABP (Guanine and adenine-binding protein) transcription factor complex. Mechanistically, oxidative stress induces TM4SF19 dimerization and topology inversion in the endoplasmic reticulum membrane, which in turn protects the GABPß1 subunit from proteasomal degradation. Conversely, depletion of TM4SF19 impairs the survival, proliferation, and migration of HPV- HNSCC cells, highlighting the potential therapeutic relevance of targeting TM4SF19. Our findings reveal the roles of the key risk factors of HPV- HNSCC in tumor development via oxidative stress, offering implications for upcoming therapeutic approaches in HPV- HNSCC.
Subject(s)
Head and Neck Neoplasms , Squamous Cell Carcinoma of Head and Neck , Humans , Head and Neck Neoplasms/genetics , Papillomaviridae , Papillomavirus Infections/pathology , Risk Factors , Squamous Cell Carcinoma of Head and Neck/geneticsABSTRACT
OBJECTIVE: The aim of the present study was to investigate the influence of comorbid oppositional defiant disorder (ODD) on clinical features and neuropsychological profiles of children with attention-deficit/hyperactivity disorder (ADHD). METHODS: We divided the participants into three groups: the ADHD with ODD (ADHD/ODD) (n=36), ADHD without ODD (ADHD/noODD) (n=307), and control groups (n=128). Parents of the participants completed the ADHD Rating Scale, Social Responsiveness Scale (SRS), Korean Personality Rating Scale for Children (K-PRC), and 10-item mania scale from the Parent General Behavior Inventory (P-GBI-10M). Neuropsychological profiles were assessed using the Advanced Test of Attention (ATA), Children's Color Trails Test, and Stroop Color and Word Test. RESULTS: The ADHD/ODD group had more ADHD symptoms and functional impairments in relationships with teachers and peers, and self-esteem than the ADHD/noODD group. The ADHD/ODD group scored higher in Social Communication (p<0.001) and Autistic Mannerisms (p<0.001) subscales of SRS, P-GBI-10M (p<0.001), and Delinquency (p<0.001) and Psychosis (p<0.001) subscales of K-PRC than the ADHD/noODD group. Commission Errors (p<0.001) and Response-Time Variability (p<0.001) in Visual ATA and Commission Errors (p<0.001) in Auditory ATA were significantly higher in the ADHD/ODD group than in the ADHD/noODD group. CONCLUSION: The present study suggests that patients with ADHD with ODD experience more ADHD symptoms and neuropsychological deficits than those with ADHD without ODD. These results also imply that comorbid ODD is associated with greater social impairment and emotional dysregulation.
ABSTRACT
Oyster aquaculture has progressively increased to meet growing demands for seafood worldwide; however, its effects on methylmercury (MeHg) production in sediment and accumulation in oysters are largely unknown. In this study, total Hg (THg) and MeHg in sediments collected from aquaculture and reference sites and in farmed and wild oysters were measured and compared to explore potential factors that regulate MeHg production and bioaccumulation at the aquaculture sites. The results showed that the mean concentrations of THg and MeHg in varying sediment depths at the aquaculture site were 34 ± 4.1 ng g-1 and 16 ± 12 pg g-1, respectively. In comparison, the mean concentrations of THg and MeHg in sediments at the reference site were 25 ± 2.5 ng g-1 and 63 ± 28 pg g-1, respectively. While the MeHg/THg in the aquaculture sediments increased with organic carbon content, the slope of MeHg/THg versus organic carbon content was suppressed by high concentrations of dissolved sulfide in the pore water. Multiple parameters (total sulfur, total nitrogen and acid volatile sulfide in sediment, and dissolved sulfide in pore water) showed significant negative relationships with MeHg/THg in the sediment, and the total sulfur content in the sediment showed the highest inverse correlation factor with MeHg/THg (r = - 0.83). The mean concentrations of THg and MeHg in farmed oysters (mean weight 3.2 ± 1.5 g) were 36 ± 10 ng g-1 and 15 ± 6.7 ng g-1, respectively, while those in wild oysters (mean weight 0.92 ± 0.32 g) were 47 ± 9.9 ng g-1 and 15 ± 6.7 ng g-1, respectively. Concerning oysters of the same size range, THg and MeHg levels were higher in farmed oysters than in wild oysters despite the faster growth rate of farmed oysters, suggesting that the Hg content of food sources is more important than growth dilution rates in the control of Hg levels. The mean hazardous quotient for MeHg in farmed oyster was calculated as 0.044 ± 0.020, suggesting no expected health risk from farmed oyster consumption.
Subject(s)
Mercury , Methylmercury Compounds , Ostreidae , Water Pollutants, Chemical , Animals , Mercury/analysis , Water Pollutants, Chemical/analysis , Environmental Monitoring/methods , Water , Sulfur , Carbon , Sulfides , Geologic SedimentsABSTRACT
OBJECTIVE: This study compared parenting stress in preschool children with developmental disabilities (DD) or typical development (TD). We also investigated children's factors that affect parenting stress. METHODS: A total of 196 preschool children participated in the study (aged 54.8±9.2 months). There were 79 children with DD (59 with autism spectrum disorder, 61 with intellectual disability, 12 with language disorder) and 117 with TD. The high parenting stress and the low parenting stress groups were divided based on the Total Stress of Korean Parenting Stress Index Fourth Edition (K-PSI-4) with an 85-percentile cutoff score. Pearson's correlation analysis was conducted to calculate the correlation between K-PSI-4 and the children's or parents' measures. RESULTS: The difference in parenting stress between DD and TD was significant in the Total Stress of K-PSI-4 (p<0.001). The Total Stress scale of K-PSI-4 represented a modest to strong correlation with cognitive development, adaptive functioning, social communication, and behavioral problems in children with DD. Our results showed that caregivers of children with DD reported higher parenting stress than those with TD. Parenting stress was strongly associated with cognitive development, adaptive functioning, social communication, and behavioral problems in children with DD. Among the children's factors, especially social communication, attention problems, and aggressive behavior had association with caregivers' higher parenting stress. CONCLUSION: These findings suggest the need for early intervention for parenting stress in caregivers by assessing child characteristics, including social cognition, awareness, communication, and inattention and hyperactivity, in the evaluation of children with DD.
ABSTRACT
Excessive methylmercury (MeHg) accumulation in dietary fish is a global concern due to its harmful effects on human health, however, environmental factors affecting MeHg accumulation in reservoir ecosystems are not clearly known. In this study, we aim to identify the main sources of MeHg in the water column and the critical factors related to MeHg concentration and methylation rate constant (km) in sediment and total Hg concentration in fish using five-year (2016-2020) monitoring data of the five artificial reservoirs. The preliminary mass budgets constructed using the measurement and online data showed that sediment transport dominated over runoff in the long residence time reservoirs (400-475 days), while runoff dominated over sediment transport in the short residence time reservoirs (10 days). Whereas the sediment km showed a comparable variation with the algal biomass, the sediment MeHg concentration and the length-normalized Hg concentration in the barbel steed and bluegill increased in the longer residence time reservoirs with lower algal biomass. As MeHg accumulation in sediment and fish tends to increase in the slowly overturning reservoirs, the hydraulic residence time should be carefully managed to meet the best protection of human health from chronic Hg exposure by fish consumption.
Subject(s)
Mercury , Methylmercury Compounds , Water Pollutants, Chemical , Animals , Ecosystem , Environmental Monitoring , Geologic Sediments , Humans , Mercury/analysis , Water Pollutants, Chemical/analysisABSTRACT
Long-term exposure to childhood abuse and occurrence of mental illness are positively correlated. Using long-term tracking data in Korea, we identified the characteristics of children and adolescents who experienced abuse and impact thereof on their psychopathology. Using the Korea Welfare Panel data, 354 teenagers in grades 4-6 of elementary school participated, were assessed at baseline, and monitored 3 years later. They were categorized into Never, Occurrence, Continuation, and Discontinuation groups according to changes in the abuse experienced. Psychopathology was evaluated using K-CBCL. Childhood abuse experience significantly affected psychopathology. At the baseline, the Continuation and Discontinuation groups had a higher severity of psychopathology than the Never group. Psychopathology at the baseline was associated with whether the patient experienced abuse that year. In the follow-up observation, the risk of psychopathology in the Occurrence and Continuation groups was higher than that in the Never group. The Discontinuation group had decreased psychopathology, which was not clinically significant in the follow-up observation (INT aRR = 2.09; 95% CI 0.61-7.13, EXT aRR = 4.23; 95% CI 1.12-16.07). Stopping abuse in late childhood reduces adolescents' psychopathology in the long term, meaning they can recover their normal developmental trajectory according to risk groups and provide effective interventions including discontinuation of abuse.
Subject(s)
Child Abuse , Mental Disorders , Adolescent , Child , Humans , Longitudinal Studies , Mental Disorders/epidemiology , Psychopathology , Risk FactorsABSTRACT
Cortical circuits process both sensory and motor information in animals performing perceptual tasks. However, it is still unclear how sensory inputs are transformed into motor signals in the cortex to initiate goal-directed actions. In this study, we found that a visual-to-motor inhibitory circuit in the anterior cingulate cortex (ACC) triggers precise action in mice performing visual Go/No-go tasks. Three distinct features of ACC neurons-visual amplitudes of sensory neurons, suppression times of motor neurons and network activity from other neurons-predicted response times of the mice. Moreover, optogenetic activation of visual inputs in the ACC, which drives fast-spiking sensory neurons, prompted task-relevant actions in mice by suppressing ACC motor neurons and disinhibiting downstream striatal neurons. Notably, when mice terminated actions in response to stop signals, both motor neuron and network activity increased. Collectively, our data demonstrate that visual inputs to the frontal cortex trigger gated feedforward inhibition to initiate goal-directed actions.
Subject(s)
Feedback, Psychological , Frontal Lobe/physiology , Goals , Inhibition, Psychological , Animals , Gyrus Cinguli/physiology , Mice , Mice, Inbred C57BL , Motor Neurons/physiology , Neostriatum/cytology , Neostriatum/physiology , Nerve Net/physiology , Optogenetics , Psychomotor Performance/physiology , Reaction Time , Visual Perception/physiologyABSTRACT
Glia contribute to synapse elimination through phagocytosis in the central nervous system. Despite the important roles of this process in development and neurological disorders, the identity and regulation of the "eat-me" signal that initiates glia-mediated phagocytosis of synapses has remained incompletely understood. Here, we generated conditional knockout mice with neuronal-specific deletion of the flippase chaperone Cdc50a, to induce stable exposure of phosphatidylserine, a well-known "eat-me" signal for apoptotic cells, on the neuronal outer membrane. Surprisingly, acute Cdc50a deletion in mature neurons causes preferential phosphatidylserine exposure in neuronal somas and specific loss of inhibitory post-synapses without effects on other synapses, resulting in abnormal excitability and seizures. Ablation of microglia or the deletion of microglial phagocytic receptor Mertk prevents the loss of inhibitory post-synapses and the seizure phenotype, indicating that microglial phagocytosis is responsible for inhibitory post-synapse elimination. Moreover, we found that phosphatidylserine is used for microglia-mediated pruning of inhibitory post-synapses in normal brains, suggesting that phosphatidylserine serves as a general "eat-me" signal for inhibitory post-synapse elimination.
Subject(s)
Microglia/metabolism , Phosphatidylserines/metabolism , Seizures/physiopathology , Synapses/physiology , c-Mer Tyrosine Kinase/metabolism , Animals , Brain/physiopathology , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Phagocytosis/physiology , Seizures/genetics , c-Mer Tyrosine Kinase/geneticsABSTRACT
The transcriptional regulator YAP, which plays important roles in the development, regeneration, and tumorigenesis, is activated when released from inhibition by the Hippo kinase cascade. The regulatory mechanism of YAP in Hippo-low contexts is poorly understood. Here, we performed a genome-wide RNA interference screen to identify genes whose loss of function in a Hippo-null background affects YAP activity. We discovered that the coatomer protein complex I (COPI) is required for YAP nuclear enrichment and that COPI dependency of YAP confers an intrinsic vulnerability to COPI disruption in YAP-driven cancer cells. We identified MAP2K3 as a YAP regulator involved in inhibitory YAP phosphorylation induced by COPI subunit depletion. The endoplasmic reticulum stress response pathway activated by COPI malfunction appears to connect COPI and MAP2K3. In addition, we provide evidence that YAP inhibition by COPI disruption may contribute to transcriptional up-regulation of PTGS2 and proinflammatory cytokines. Our study offers a resource for investigating Hippo-independent YAP regulation as a therapeutic target for cancers and suggests a link between YAP and COPI-associated inflammatory diseases.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Coat Protein Complex I/metabolism , MAP Kinase Kinase 3/metabolism , Neoplasms/metabolism , RNA Interference , Transcription Factors/metabolism , Adaptor Proteins, Signal Transducing/genetics , Animals , Cell Line, Tumor , Coat Protein Complex I/genetics , Gene Expression Regulation, Neoplastic , Genome , Hippo Signaling Pathway , Humans , MAP Kinase Kinase 3/genetics , Mice , Neoplasms/genetics , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Signal Transduction , Transcription Factors/genetics , YAP-Signaling ProteinsABSTRACT
Proteins specialized in the detection, generation, or stabilization of membrane curvature play important roles in establishing various morphologies of cells and cellular organelles. Primary cilia are cellular organelles that protrude from the cell surface using a microtubule-based cytoskeleton called the axoneme as a structural support. It is unclear whether the integrity of the high curvature of the ciliary membrane depends on membrane curvature-related proteins. Charged Multivesicular Body Protein 4B (CHMP4B), a subunit of the endosomal sorting complexes required for transport (ESCRT), can stabilize membrane curvature. Here we show that CHMP4B is involved in the assembly and maintenance of primary cilia. CHMP4B was localized to primary cilia in mammalian cells. Knockdown of CHMP4B interfered with cilium assembly and also caused fragmentation of preexisting cilia. By contrast, cilium formation was unaffected by the interruption of the ESCRT-dependent endocytic degradation pathway. Morpholino (MO)-mediated CHMP4B depletion in zebrafish embryos induced characteristic phenotypes of ciliary defects such as curved body axis, hydrocephalus, otolith malformation, and kidney cyst. Our study reveals a new role for the multifunctional protein CHMP4B as a key factor in maintaining the structural integrity of primary cilia.
Subject(s)
Cell Membrane/metabolism , Cilia/metabolism , Endosomal Sorting Complexes Required for Transport/metabolism , Zebrafish Proteins/metabolism , Zebrafish/metabolism , Animals , Cell Membrane/genetics , Cilia/genetics , Endosomal Sorting Complexes Required for Transport/genetics , Gene Deletion , Humans , Mice , NIH 3T3 Cells , Zebrafish/genetics , Zebrafish Proteins/geneticsABSTRACT
Muscle development and lipid accumulation in muscle critically affect meat quality of livestock. However, the genetic factors underlying myofiber-type specification and intramuscular fat (IMF) accumulation remain to be elucidated. Using two independent intercrosses between Western commercial breeds and Korean native pigs (KNPs) and a joint linkage-linkage disequilibrium analysis, we identified a 488.1-kb region on porcine chromosome 12 that affects both reddish meat color (a*) and IMF. In this critical region, only the MYH3 gene, encoding myosin heavy chain 3, was found to be preferentially overexpressed in the skeletal muscle of KNPs. Subsequently, MYH3-transgenic mice demonstrated that this gene controls both myofiber-type specification and adipogenesis in skeletal muscle. We discovered a structural variant in the promotor/regulatory region of MYH3 for which Q allele carriers exhibited significantly higher values of a* and IMF than q allele carriers. Furthermore, chromatin immunoprecipitation and cotransfection assays showed that the structural variant in the 5'-flanking region of MYH3 abrogated the binding of the myogenic regulatory factors (MYF5, MYOD, MYOG, and MRF4). The allele distribution of MYH3 among pig populations worldwide indicated that the MYH3 Q allele is of Asian origin and likely predates domestication. In conclusion, we identified a functional regulatory sequence variant in porcine MYH3 that provides novel insights into the genetic basis of the regulation of myofiber type ratios and associated changes in IMF in pigs. The MYH3 variant can play an important role in improving pork quality in current breeding programs.
Subject(s)
Adipogenesis/genetics , Cytoskeletal Proteins/genetics , Muscle Fibers, Skeletal/metabolism , Muscle, Skeletal/growth & development , Myosins/genetics , Adipose Tissue/growth & development , Adipose Tissue/metabolism , Animals , Breeding , Gene Expression Regulation , Genome-Wide Association Study , Genotype , Meat , Mice , Mice, Transgenic , Muscle, Skeletal/metabolism , Myosin Heavy Chains/genetics , Nucleotide Motifs , Sus scrofa/genetics , Sus scrofa/metabolism , SwineABSTRACT
Ciliopathies are clinically overlapping genetic disorders involving structural and functional abnormalities of cilia. Currently, there are no small-molecule drugs available to treat ciliary defects in ciliopathies. Our phenotype-based screen identified the flavonoid eupatilin and its analogs as lead compounds for developing ciliopathy medication. CEP290, a gene mutated in several ciliopathies, encodes a protein that forms a complex with NPHP5 to support the function of the ciliary transition zone. Eupatilin relieved ciliogenesis and ciliary receptor delivery defects resulting from deletion of CEP290. In rd16 mice harboring a blinding Cep290 in-frame deletion, eupatilin treatment improved both opsin transport to the photoreceptor outer segment and electrophysiological responses of the retina to light stimulation. The rescue effect was due to eupatilin-mediated inhibition of calmodulin binding to NPHP5, which promoted NPHP5 recruitment to the ciliary base. Our results suggest that deficiency of a ciliopathy protein could be mitigated by small-molecule compounds that target other ciliary components that interact with the ciliopathy protein.
Subject(s)
Blindness , Cilia/metabolism , Ciliopathies , Flavonoids/pharmacology , Retina , Animals , Antigens, Neoplasm , Blindness/drug therapy , Blindness/genetics , Blindness/metabolism , Blindness/pathology , Calmodulin-Binding Proteins/genetics , Calmodulin-Binding Proteins/metabolism , Cell Cycle Proteins , Cilia/genetics , Cilia/pathology , Ciliopathies/drug therapy , Ciliopathies/genetics , Ciliopathies/metabolism , Ciliopathies/pathology , Cytoskeletal Proteins , Mice , Mutation , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Retina/metabolism , Retina/pathologyABSTRACT
Prolonged accumulation of misfolded or unfolded proteins caused by cellular stress, including oxidative stress, induces endoplasmic reticulum stress, which then activates an unfolded protein response (UPR). ER stress is usually maintained at higher levels in cancer cells as compared to normal cells due to altered metabolism in cancer. Here, we investigated whether curcumin is ER stress-mediated apoptosis in cervical cancer cells, and ROS increased by curcumin are involved in the process as an upstream contributor. Curcumin inhibited proliferation of cervical cancer cells (C33A, CaSki, HeLa, and ME180) and induced apoptotic cell death. Curcumin activated ER-resident UPR sensors, such as PERK, IRE-1α, and ATF6, and their downstream-signaling proteins in cervical cancer cells, but not in normal epithelial cells and peripheral blood mononuclear cells (PBMCs). CHOP, a key factor involved in ER stress-mediated apoptosis, was also activated by curcumin. CHOP decreased the ratio of anti-apoptotic protein Bcl-2 to pro-apoptotic protein Bax expression, and subsequently increased the apoptotic population of cervical cancer cells. Furthermore, curcumin elevated levels of intracellular reactive oxygen species (ROS) in cervical cancer cells, but not in normal epithelial cells. Scavenging ROS resulted in inhibition of ER stress and partially restored cell viability in curcumin-treated cancer cells. Collectively, these observations show that curcumin promotes ER stress-mediated apoptosis in cervical cancer cells through increase of cell type-specific ROS generation. Therefore, modulation of these differential responses to curcumin between normal and cervical cancer cells could be an effective therapeutic strategy without adverse effects on normal cells.
Subject(s)
Antineoplastic Agents/pharmacology , Curcumin/pharmacology , Endoplasmic Reticulum Stress/drug effects , Reactive Oxygen Species/metabolism , Uterine Cervical Neoplasms/metabolism , Apoptosis , Cell Line, Tumor , Cell Survival/drug effects , Female , Gene Expression Regulation, Neoplastic/drug effects , HeLa Cells , Humans , Unfolded Protein Response/drug effectsABSTRACT
The activation of transcriptional coactivators YAP and its paralog TAZ has been shown to promote resistance to anti-cancer therapies. YAP/TAZ activity is tightly coupled to actin cytoskeleton architecture. However, the influence of actin remodeling on cancer drug resistance remains largely unexplored. Here, we report a pivotal role of actin remodeling in YAP/TAZ-dependent BRAF inhibitor resistance in BRAF V600E mutant melanoma cells. Melanoma cells resistant to the BRAF inhibitor PLX4032 exhibit an increase in actin stress fiber formation, which appears to promote the nuclear accumulation of YAP/TAZ. Knockdown of YAP/TAZ reduces the viability of resistant melanoma cells, whereas overexpression of constitutively active YAP induces resistance. Moreover, inhibition of actin polymerization and actomyosin tension in melanoma cells suppresses both YAP/TAZ activation and PLX4032 resistance. Our siRNA library screening identifies actin dynamics regulator TESK1 as a novel vulnerable point of the YAP/TAZ-dependent resistance pathway. These results suggest that inhibition of actin remodeling is a potential strategy to suppress resistance in BRAF inhibitor therapies.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Drug Resistance, Neoplasm , Indoles/pharmacology , Intracellular Signaling Peptides and Proteins/metabolism , Melanoma/metabolism , Phosphoproteins/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Sulfonamides/pharmacology , Actin Cytoskeleton/drug effects , Actins , Adaptor Proteins, Signal Transducing/genetics , Cell Line, Tumor , Cell Shape/drug effects , Cell Survival/drug effects , Gene Expression Profiling , Gene Knockdown Techniques , Humans , Melanoma/genetics , Mutation , Oligonucleotide Array Sequence Analysis , Phosphoproteins/genetics , Proto-Oncogene Proteins B-raf/genetics , RNA/genetics , Trans-Activators , Transcription Factors , Transcriptional Coactivator with PDZ-Binding Motif Proteins , Vemurafenib , YAP-Signaling ProteinsABSTRACT
While acute treatment with beetroot juice (BRJ) containing nitrate (NO3 (-)) can lower systolic blood pressure (SBP), afterload, and myocardial O2 demand during submaximal exercise, effects of chronic supplementation with BRJ (containing a relatively low dose of NO3 (-), 400 mg) on cardiac output (CO), SBP, total peripheral resistance (TPR), and the work of the heart in response to dynamic exercise are not known. Thus, in 14 healthy males (22 ± 1 yr), we compared effects of 15 days of both BRJ and nitrate-depleted beetroot juice (NDBRJ) supplementation on plasma concentrations of NOx (NO3 (-)/NO2 (-)), SBP, diastolic blood pressure (DBP), mean arterial pressure (MAP), CO, TPR, and rate pressure product (RPP) at rest and during progressive cycling exercise. Endothelial function was also assessed via flow-mediated dilation (FMD). BRJ supplementation increased plasma NOx from 83.8 ± 13.8 to 167.6 ± 13.2 µM. Compared with NDBRJ, BRJ reduced SBP, DBP, MAP, and TPR at rest and during exercise (P < 0.05). In addition, RPP was decreased during exercise, while CO was increased, but only at rest and the 30% workload (P < 0.05). BRJ enhanced FMD-induced increases in brachial artery diameter (pre: 12.3 ± 1.6%; post: 17.8 ± 1.9%). We conclude that 1) chronic supplementation with BRJ lowers blood pressure and vascular resistance at rest and during exercise and attenuates RPP during exercise and 2) these effects may be due, in part, to enhanced endothelium-induced vasodilation in contracting skeletal muscle. Findings suggest that BRJ can act as a dietary nutraceutical capable of enhancing O2 delivery and reducing work of the heart, such that exercise can be performed at a given workload for a longer period of time before the onset of fatigue.
Subject(s)
Beta vulgaris , Diet , Dietary Supplements , Endothelium, Vascular/physiology , Exercise , Fruit and Vegetable Juices , Hemodynamics , Muscle, Skeletal/blood supply , Nitrates/administration & dosage , Arterial Pressure , Bicycling , Cross-Over Studies , Double-Blind Method , Heart Rate , Humans , Male , Muscle Contraction , Muscle Fatigue , Plant Roots , Time Factors , Vascular Resistance , Young AdultABSTRACT
BACKGROUND: We conducted a genome-wide linkage analysis to identify quantitative trait loci (QTL) that influence meat quality-related traits in a large F2 intercross between Landrace and Korean native pigs. Thirteen meat quality-related traits of the m. longissimus lumborum et thoracis were measured in more than 830 F2 progeny. All these animals were genotyped with 173 microsatellite markers located throughout the pig genome, and the GridQTL program based on the least squares regression model was used to perform the QTL analysis. RESULTS: We identified 23 genome-wide significant QTL in eight chromosome regions (SSC1, 2, 6, 7, 9, 12, 13, and 16) (SSC for Sus Scrofa) and detected 51 suggestive QTL in the 17 chromosome regions. QTL that affect 10 meat quality traits were detected on SSC12 and were highly significant at the genome-wide level. In particular, the QTL with the largest effect affected crude fat percentage and explained 22.5% of the phenotypic variance (F-ratio = 278.0 under the additive model, nominal P = 5.5 × 10(-55)). Interestingly, the QTL on SSC12 that influenced meat quality traits showed an obvious trend for co-localization. CONCLUSIONS: Our results confirm several previously reported QTL. In addition, we identified novel QTL for meat quality traits, which together with the associated positional candidate genes improve the knowledge on the genetic structure that underlies genetic variation for meat quality traits in pigs.