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Abstract We aimed to conduct a proof-of-concept study of INV-001 in visualizing lymphatic vessels and nodes without venous contamination and to determine the optimal dose condition of INV-001 for magnetic resonance lymphangiography (MRL) in healthy beagles. MRL was performed using a 3.0-Tesla (T) whole body clinical magnetic resonance imaging (MRI) scanner. A dose-finding study of INV-001 for MRL in beagles (N = 6) was carried out according to an adaptive optimal dose finding design. For the reproducibility study (N = 6), MRL was conducted at selected INV-001 doses (0.056 and 0.112 mg Fe/kg) with a 15 mM concentration. Additionally, an excretion study (N = 3) of INV-001 was conducted by analyzing T1, T2, and T2* maps of the liver and kidney 48 h post-administration. INV-001 administration at doses of 0.056 and 0.112 mg Fe/kg (concentration: 15 mM) consistently demonstrated the visualization of contrast-enhanced lymphatic vessels and nodes without venous contamination in the beagles. The contrast enhancement effect was highest at 30 min after INV-001 administration, then gradually decreasing. No toxicity-related issues were identified during the study. After 48 h, the T1, T2, and T2* values in the liver and both kidneys were found to be comparable to the pre-administration values, indicating thorough INV-001 excretion. The optimal dosing conditions of INV-001 for MRL for contrast-enhanced visualization of lymphatic vessels and nodes exclusively with no venous contamination in beagles was determined to be 0.056 mg Fe/kg with a 15 mM concentration.

Abstract Due to global climate change, crops are certainly confronted with a lot of abiotic and biotic stress factors during their growth that cause a serious threat to their development and overall productivity. Among different abiotic stresses, salt and drought are considered the most devastating stressors with serious impact on crop’s yield stability. Here, the current study aimed to elucidate how melatonin works in regulating plant biomass, oxidative stress, antioxidant defense system, as well as the expression of genes related to salt and drought stress in rice plants. Eight groups of rice plants (3 replicates, 5 plants each) underwent varied treatments: control, melatonin, salt, drought, salt + drought, salt + melatonin, drought + melatonin, and salt + drought + melatonin. Melatonin (100 µM) was alternately applied a week before stress exposure; salt stress received 100 mM NaCl every 3 days for 3 weeks, and drought stress involved 10% PEG. Young leaves were randomly sampled from each group. The results showed that melatonin treatment markedly reduces salt and drought stress damage by promoting root, shoot length, fresh and dry weight, increasing chlorophyll contents, and inhibiting excessive production of oxidative stress markers. Salt and drought stress significantly decreased the water balance, and damaged cell membrane by reducing relative water contents and increasing electrolyte leakage. However, melatonin treated rice plants showed high relative water contents and low electrolyte leakage. Under salt and drought stress conditions, exogenous application of melatonin boosted the expression level of salt and drought stress responsive genes like OsSOS, OsNHX, OsHSF and OsDREB in rice plants. Taken together, our results reveal that melatonin treatment significantly increases salt and drought tolerance of rice plants, by increasing plant biomass, suppressing ROS accumulation, elevating antioxidants defense efficiency, and up-regulating the expression of salt and drought stress responsive genes.

The gut microbiota plays a crucial role in the health and well-being of wildlife. However, its composition and diversity remain unexplored, particularly in threatened species such as the Siberian musk deer (SMD). This study aimed to elucidate the gut microbiota composition within different wild SMD communities for assessing their health status. We conducted the first comprehensive fecal microbiome analysis of wild SMD inhabiting three distinct locations in Gangwon Province, Republic of Korea (Korea). Fecal samples were collected non-invasively and 16S rRNA gene sequencing was performed for gut microbiota characterization. Consistent with previous research, Firmicutes and Bacteroidetes were the dominant phyla in the gut microbiota of wild SMD. Planctomycetota was a prevalent phylum in wild SMD gut microbiota, warranting further investigation of its ecological significance. While significant differences were observed in the gut microbiota richness among the three groups, no significant disparities were detected in the beta diversity. Additionally, certain genera exhibited distinct relative abundances among the groups, suggesting potential associations with geographic factors, gut disorders, and dietary habits. Our findings provide valuable insights into the gut microbiome of wild SMD and offer a foundation for future microbiome-based conservation efforts for this vulnerable species.

BackgroundThe risks of invasive prenatal tests are reported in previous studies such as miscarriage, fetal anomalies, and bleeding. However, few compare short-term and long-term outcomes between invasive tests. This study aims to investigate obstetric, perinatal, and children’s neurodevelopmental outcomes following chorionic villus sampling (CVS) or amniocentesis in singleton pregnancy.MethodsThis retrospective cohort study included healthy singleton pregnancies underwent transabdominal CVS (gestational age [GA] at 10–13 weeks) or amniocentesis (GA at 15–21 weeks) at a single medical center between 2012 and 2022. Only cases with normal genetic results were eligible. Short-term and long-term neurodevelopmental outcomes were evaluated.ResultsThe study included 200 CVS cases and 498 amniocentesis cases. No significant differences were found in body mass index, parities, previous preterm birth, conception method, and cervical length (CL) before an invasive test between the groups. Rates of preterm labor, preterm premature rupture of the membranes, preterm birth, neonatal survival, neonatal short-term morbidities, and long-term neurodevelopmental delay were similar. However, the CVS group had a higher rate of cervical cerclage due to short CL before 24 weeks (7.0%) compared to the amniocentesis group (2.4%). CVS markedly increased the risk of cervical cerclage due to short CL (adjusted odd ratio [aOR] = 3.17, 95%CI [1.23–8.12], p = 0.016), after considering maternal characteristics.ConclusionPerforming CVS resulted in a higher incidence of cerclage due to short cervix or cervical dilatation compared to amniocentesis in singleton pregnancies. This highlights the importance of cautious selection for CVS and the necessity of informing women about the associated risks beforehand.

Abstract Excessive salinity reduces crop production and negatively impacts agriculture worldwide. We previously isolated endophytic bacterial strains from two halophytic species: Artemisia princeps and Chenopodium ficifolium. We used three bacterial isolates: ART-1 (Lysinibacillus fusiformis), ART-10 (Lysinibacillus sphaericus), and CAL-8 (Brevibacterium pityocampae) to alleviate the impact of salinity stress on rice. The impact of 160 mM NaCl salinity on rice was significantly mitigated following inoculation with these bacterial strains, resulting in increased growth and chlorophyll content. Furthermore, OsNHX1, OsAPX1, OsPIN1 and OsCATA expression was increased, but OsSOS expression was decreased. Inductively coupled plasma mass spectrometry (ICP-MS) revealed reduced K+ and Na+ levels in shoots of bacteria-inoculated plants, whereas that of Mg2+ was increased. Bacterial inoculation reduced the content of total flavonoids in rice leaves. Salinized plants inoculated with bacteria showed reduced levels of endogenous salicylic acid (SA) and abscisic acid (ABA) but increased levels of jasmonic acid (JA). In conclusion, the bacterial isolates ART-1, ART-10, and CAL-8 alleviated the adverse effect of salinity on rice growth, which justifies their use as an eco-friendly agricultural practice.

Background: Vitamin D deficiency is common in pregnant women. Some studies have linked vitamin D deficiency to obstetric complications such as gestational hypertension, gestational diabetes, and preterm birth. Therefore, the objective of this study is to investigate the potential impact of vitamin D deficiency during pregnancy on both perinatal and long-term outcomes. Methods: In this retrospective study, conducted between 2017 and 2021, we analyzed the data of 1079 singleton pregnant women with no medical or surgical complications prior to pregnancy. We evaluated obstetric and perinatal outcomes, as well as neurodevelopmental outcomes using Bayley-III tests, Gross Motor Function Measure, or chart review. Results: The maternal serum vitamin D level in the first trimester was 18.2 ± 9.0 ng/mL. Vitamin D deficiency (

Chemical exchange saturation transfer with glutamate (GluCEST) imaging is a novel technique for the non-invasive detection and quantification of cerebral Glu levels in neuromolecular processes. Here we used GluCEST imaging and 1H magnetic resonance spectroscopy (1H MRS) to assess in vivo changes in Glu signals within the hippocampus in a rat model of depression induced by a forced swim test. The forced swimming test (FST) group exhibited markedly reduced GluCEST-weighted levels and Glu concentrations when examined using 1H MRS in the hippocampal region compared to the control group (GluCEST-weighted levels: 3.67 ± 0.81% vs. 5.02 ± 0.44%, p < 0.001; and Glu concentrations: 6.560 ± 0.292 μmol/g vs. 7.133 ± 0.397 μmol/g, p = 0.001). Our results indicate that GluCEST imaging is a distinctive approach to detecting and monitoring Glu levels in a rat model of depression. Furthermore, the application of GluCEST imaging may provide a deeper insight into the neurochemical involvement of glutamate in various psychiatric disorders.

Abstract The extracellular activity of Plasminogen activator inhibitor-1 (PAI-1) is well described, acting as an inhibitor of tissue plasminogen activator and urokinase-type plasminogen activator, impacting fibrinolysis. Recent studies have revealed a pro-tumorigenic role of PAI-1 in human cancers, via the regulation of angiogenesis and tumor cell survival. In this study, immunohistochemical staining of 939 human bladder cancer specimens showed that PAI-1 expression levels correlated with tumor grade, tumor stage and overall survival. The typical subcellular localization of PAI-1 is cytoplasmic, but in approximately a quarter of the cases, PAI-1 was observed to be localized to both the tumor cell cytoplasm and the nucleus. To investigate the potential function of nuclear PAI-1 in tumor biology we applied chromatin immunoprecipitation (ChIP)-sequencing, gene expression profiling, and rapid immunoprecipitation mass spectrometry to a pair of bladder cancer cell lines. ChIP-sequencing revealed that PAI-1 can bind DNA at distal intergenic regions, suggesting a role as a transcriptional coregulator. The downregulation of PAI-1 in bladder cancer cell lines caused the upregulation of numerous genes, and the integration of ChIP-sequence and RNA-sequence data identified 57 candidate genes subject to PAI-1 regulation. Taken together, the data suggest that nuclear PAI-1 can influence gene expression programs and support malignancy.

Although the use of incision-free endoscopy for foreign body (FB) removal in dogs and cats has been extensively documented, its application in birds remains limited. Thus, we present the endoscopic removal of gastrointestinal (GI) FBs from psittacine birds, employing different patient positioning and anesthesia methods. Two blue-and-yellow macaws (Ara ararauna) and a Triton cockatoo (Cacatua galerita triton) were examined. X-ray imaging revealed FBs situated in the proventriculus in each case. The FBs, all identified as feeding tubes, were safely removed using grasping forceps during the endoscopic procedure, and no severe complications occurred. Based on the outcomes of each operation, the most suitable patient position may be ventral recumbency rather than dorsal recumbency, with the use of a mask or endotracheal intubation, depending on the anticipated operation time. However, a larger number of cases would be necessary to confirm the optimal patient positioning and anesthesia method.

Target identification is a crucial process in drug development, aiming to identify key proteins, genes, and signal pathways involved in disease progression and their relevance in potential therapeutic interventions. While C-C chemokine receptor 8 (CCR8) has been investigated as a candidate anti-cancer target, comprehensive multi-omics analyzes across various indications are limited. In this study, we conducted an extensive bioinformatics analysis integrating genomics, proteomics, and transcriptomics data to establish CCR8 as a promising anti-cancer drug target. Our approach encompassed data collection from diverse knowledge resources, gene function analysis, differential gene expression profiling, immune cell infiltration assessment, and strategic prioritization of target indications. Our findings revealed strong correlations between CCR8 and specific cancers, notably Breast Invasive Carcinoma (BRCA), Colon Adenocarcinoma (COAD), Head and Neck Squamous Cell Carcinoma (HNSC), Rectum adenocarcinoma (READ), Stomach adenocarcinoma (STAD), and Thyroid carcinoma (THCA). This research advances our understanding of CCR8 as a potential target for anti-cancer drug development, bridging the gap between molecular insights and creating opportunities for personalized treatment of solid tumors.

This paper proposes two concepts, emotional alienation and spatialized emotion, to theorize the emotional geographies of later-life care. The concepts build on spatiality in Marx's alienation theory, Agamben's concept of bare life and Massey's politics of space. These new concepts are created and adopted in four steps: (1) a literature review on care, emotion, affect, eldercare, and Parkinson's disease patients' mental health in diverse disciplines; (2) theoretical analysis on the political economic status of ailing elderly and care workers; (3) spatial analysis interviews with a Parkinson's disease patient and caregiver as an application of the proposed theories; and (4) a discussion of the expanded theoretical frame centered on the micro-spatial scales of the interior spaces of home. Alienation theory and the concept of bare life have limitations in explaining daily lived experiences in micro-scaled places. Because lived experience, and its emotional dimensions, has a specific geography, this paper argues that a spatialized approach is needed to identify and effectively intervene in the problems of contemporary eldercare. This paper is part of a larger human geography study examining the daily emotions of people living with Parkinson's Disease and care workers in the home that aims to identify where interventions are needed to build a later-life care environment that offers sustainable and dignified later-life care.

This study aimed to investigate the impact of yeast hydrolysate (YH) on lipogenesis, elucidate its mechanistic action, and identify the active compounds responsible for its anti-adipogenic effects. YH (2 mg/mL) significantly reduced Oil Red O-stained lipids. YH (2 mg/mL) also downregulated C/EBPβ and upregulated KLF2, both of which are early adipogenic factors. Moreover, YH (2 mg/mL) decreased C/EBPα, PPARγ, FABP4, FAS, ACC, and HMGCR mRNA expression. Additionally, YH significantly downregulated SEBP1c and SREBP2 and their target genes, which govern fatty acid and cholesterol metabolism; however, 2 mg/mL YH had a greater suppressive effect on SREBP1c than on SREBP2. YH (2 mg/mL) also significantly reduced the mRNA level of G6PD and malic enzyme, which are enzymes that synthesize NADPH for lipid synthesis, compared with the control. Furthermore, 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (MTCA) was identified as the active compound with anti-adipogenic effects using solvent fractionation and chromatographic analysis of YH, and 1.1 μg/mL MTCA significantly downregulated SREBP1c/SREBP2 mRNAs by 47.8% and 69.2%, respectively, along with the target genes FAS, ACC, and HMGCR by 79.0%, 77.0%, and 40.9%, respectively. Collectively, YH effectively suppressed adipogenic lipid storage by downregulating SREBP- and NADPH-synthesizing genes. These findings suggest that YH containing MTCA has the potential to act as an anti-obesity agent.

The number of corn cultivars that have been improved using genetically modified technology continues to increase. However, concerns about the unintentional release of living-modified organisms (LMOs) into the environment still exist. Specifically, there are cases where LMO crops grown as fodder are released into the environment and form a volunteer plant community, which raises concerns about their safety. In this study, we analyzed the possibility of weediness and volunteer plants’ occurrence when GMO fodder corn grains distributed in Korea are unintentionally released into the environment. Volunteer plants’ occurrence was investigated by directly sowing grains in an untreated field. The results showed that the germination rate was extremely low, and even if a corn seed germinated, it could not grow into an adult plant and would die due to weed competition. In addition, the germination rate of edible and fodder grains was affected by temperature (it was high at 20 °C and 30 °C but low at 40 °C and extremely low at 10 °C), and it was higher in the former than in the latter. And the germination rate was higher in Daehakchal (edible corn grains) than in Gwangpyeongok (fodder corn grains). The environmental risk assessment data obtained in this study can be used for future evaluations of the weediness potential of crops and the development of volunteer plant suppression technology in response to unintentional GMO release.

The expression of the placental growth factor (PGF) in cancer cells and the tumor microenvironment can contribute to the induction of angiogenesis, supporting cancer cell metabolism by ensuring an adequate blood supply. Angiogenesis is a key component of cancer metabolism as it facilitates the delivery of nutrients and oxygen to rapidly growing tumor cells. PGF is recognized as a novel target for anti-cancer treatment due to its ability to overcome resistance to existing angiogenesis inhibitors and its impact on the tumor microenvironment. We aimed to integrate bioinformatics evidence using various data sources and analytic tools for target-indication identification of the PGF target and prioritize the indication across various cancer types as an initial step of drug development. The data analysis included PGF gene function, molecular pathway, protein interaction, gene expression and mutation across cancer type, survival prognosis and tumor immune infiltration association with PGF. The overall evaluation was conducted given the totality of evidence, to target the PGF gene to treat the cancer where the PGF level was highly expressed in a certain tumor type with poor survival prognosis as well as possibly associated with poor tumor infiltration level. PGF showed a significant impact on overall survival in several cancers through univariate or multivariate survival analysis. The cancers considered as target diseases for PGF inhibitors, due to their potential effects on PGF, are adrenocortical carcinoma, kidney cancers, liver hepatocellular carcinoma, stomach adenocarcinoma, and uveal melanoma.

While ion channels and transporters involved in excitation-contraction coupling have been linked and constructed as comprehensive computational models, validation of whether each individual component of a model can be reused has not been previously attempted. Here we address this issue while using a novel modular modeling approach to investigate the underlying mechanism for the differences between left ventricle (LV) and right ventricle (RV). Our model was developed from modules constructed using the module assembly principles of the CellML model markup language. The components of three existing separate models of cardiac function were disassembled as to create smaller modules, validated individually, and then the component parts were combined into a new integrative model of a rat ventricular myocyte. The model was implemented in OpenCOR using the CellML standard in order to ensure reproducibility. Simulated action potential (AP), Ca2+ transient, and tension were in close agreement with our experimental measurements: LV AP showed a prolonged duration and a more prominent plateau compared with RV AP; Ca2+ transient showed prolonged duration and slow decay in LV compared to RV; the peak value and relaxation of tension were larger and slower, respectively, in LV compared to RV. Our novel approach of module-based mathematical modeling has established that the ionic mechanisms underlying the APs and Ca2+ handling play a role in the variation in force production between ventricles. This simulation process also provides a useful way to reuse and elaborate upon existing models in order to develop a new model.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of anti-cancer drugs. The main symptoms often include sensory disturbances and neuropathic pain, and currently there is no effective treatment for this condition. This study aimed to investigate the suppressive effects of magnolin, an extracellular signal-regulated kinase (ERK) inhibitor substance derived from a 95% EtOH extract of the seeds of Magnolia denudata, on the symptoms of CIPN. A taxol-based anti-cancer drug paclitaxel (PTX) was repeatedly injected (2 mg/kg/day, total 8 mg/kg) into mice to induce CIPN. A neuropathic pain symptom was assessed using a cold allodynia test that scores behaviors of licking and shaking paw after plantar administration of acetone drop. Magnolin was administered intraperitoneally (0.1, 1, or 10 mg/kg) and behavioral changes to acetone drop were measured. The effect of magnolin administration on ERK expression in the dorsal root ganglion (DRG) was investigated using western blot analysis. The results showed that the repeated injections of PTX induced cold allodynia in mice. Magnolin administration exerted an analgesic effect on the PTX-induced cold allodynia and inhibited the ERK phosphorylation in the DRG. These results suggest that magnolin could be developed as an alternative treatment to suppress paclitaxel-induced neuropathic pain symptoms.

Abstract Background Accumulating evidence suggests that plasminogen activator inhibitor-1 (PAI-1) plays an important role in bladder tumorigenesis by regulating cell cycle. However, it remains unclear whether and how inhibition of PAI-1 suppresses bladder tumorigenesis. Methods To elucidate the therapeutic effect of PAI-1 inhibition, we tested its tumorigenicity in PAI-1 knockout (KO) mice exposed to a known bladder carcinogen. Results PAI-1 deficiency did not inhibit carcinogen-induced bladder cancer in mice although carcinogen-exposed wild type mice significantly increased PAI-1 levels in bladder tissue, plasma and urine. We found that PAI-1 KO mice exposed to carcinogen tended to upregulate protein C inhibitor (PAI-3), urokinase-type plasminogen activator (uPA) and tissue-type PA (tPA), and significantly increased PAI-2, suggesting a potential compensatory function of these molecules when PAI-1 is abrogated. Subsequent studies employing gene expression microarray using mouse bladder tissues followed by post hoc bioinformatics analysis and validation experiments by qPCR and IHC demonstrated that SERPING1 is further downregulated in PAI-1 KO mice exposed to BBN, suggesting that SERPING1 as a potential missing factor that regulate PAI-2 overexpression (compensation pathway). Conclusions These results indicate that serpin compensation pathway, specifically PAI-2 overexpression in this model, supports bladder cancer development when oncoprotein PAI-1 is deleted. Further investigations into PAI-1 are necessary in order to identify true potential targets for bladder cancer therapy.

Abstract Chemotherapy‐induced peripheral neuropathy (CIPN) frequently occurs in cancer patients. This side effect lowers the quality of life of patients and may cause the patients to abandon chemotherapy. Several medications (e.g., duloxetine and gabapentin) are recommended as remedies to treat CIPN; however, usage of these drugs is limited because of low efficacy or side effects such as dizziness, nausea, somnolence, and vomiting. From ancient East Asia, the decoction of medicinal herbal formulas or single herbs have been used to treat pain and could serve as alternative therapeutic option. Recently, the analgesic potency of medicinal plants and their phytochemicals on CIPN has been reported, and a majority of their effects have been shown to be mediated by glial modulation. In this review, we summarize the analgesic efficacy of medicinal plants and their phytochemicals, and discuss their possible mechanisms focusing on glial modulation in animal studies.

Abiotic stresses, such as salt and heat stress, coexist in some regions of the world and can have a significant impact on agricultural plant biomass and production. Rice is a valuable crop that is susceptible to salt and high temperatures. Here, we studied the role of flavanol 3-hydroxylase in response to combined salt and heat stress with the aim of better understanding the defensive mechanism of rice. We found that, compared with wild-type plants, the growth and development of transgenic plants were improved due to higher biosynthesis of kaempferol and quercetin. Furthermore, we observed that oxidative stress was decreased in transgenic plants compared with that in wild-type plants due to the reactive oxygen species scavenging activity of kaempferol and quercetin as well as the modulation of glutathione peroxidase and lipid peroxidase activity. The expression of high-affinity potassium transporter (HKT) and salt overly sensitive (SOS) genes was significantly increased in transgenic plants compared with in control plants after 12 and 24 h, whereas sodium-hydrogen exchanger (NHX) gene expression was significantly reduced in transgenic plants compared with in control plants. The expression of heat stress transcription factors (HSFs) and heat shock proteins (HSPs) in the transgenic line increased significantly after 6 and 12 h, although our understanding of the mechanisms by which the F3H gene regulates HKT, SOS, NHX, HSF, and HSP genes is limited. In addition, transgenic plants showed higher levels of abscisic acid (ABA) and lower levels of salicylic acid (SA) than were found in control plants. However, antagonistic cross talk was identified between these hormones when the duration of stress increased; SA accumulation increased, whereas ABA levels decreased. Although transgenic lines showed significantly increased Na+ ion accumulation, K+ ion accumulation was similar in transgenic and control plants, suggesting that increased flavonoid accumulation is crucial for balancing Na+/K+ ions. Overall, this study suggests that flavonoid accumulation increases the tolerance of rice plants to combined salt and heat stress by regulating physiological, biochemical, and molecular mechanisms.

Critical determinants of synaptic functions include subcellular locations, input sources, and specific molecular characteristics. However, there is not yet a reliable and efficient method that can detect synapses. Electron microscopy is a gold-standard method to detect synapses due to its exceedingly high spatial resolution. However, it requires laborious and time-consuming sample preparation and lengthy imaging time with limited labeling methods. Recent advances in various fluorescence microscopy methods have highlighted fluorescence microscopy as a substitute for electron microscopy in reliable synapse detection in a large volume of neural circuits. In particular, array tomography has been verified as a useful tool for neural circuit reconstruction. To further improve array tomography, we developed a novel imaging method, called “structured illumination microscopy on the putative region of interest on ultrathin sections”, which enables efficient and accurate detection of synapses-of-interest. Briefly, based on low-magnification conventional fluorescence microscopy images, synapse candidacy was determined. Subsequently, the coordinates of the regions with candidate synapses were imaged using super-resolution structured illumination microscopy. Using this system, synapses from the high-order thalamic nucleus, the posterior medial nucleus in the barrel cortex were rapidly and accurately imaged.

Abstract Background We set out to determine if the administration of subcutaneous (SQ) ALT-803 was non-inferior to standard intravesical BCG treatment in a carcinogen induced mouse (C57BL/6J) bladder cancer model. Methods Using this well-established carcinogen induced mouse model, we studied the effects of various dosing schemas of ALT-803 (SQ alone, SQ with intravesical BCG, intravesical alone, intravesical with intravesical BCG) compared to intravesical BCG alone (positive control) and PBS (negative control). The non-inferiority margin for the difference in bladder weight, as a surrogate for tumor mass, was defined as 7%. Results All treatment groups (i.e., ALT-803 SQ alone, ALT-803 SQ with intravesical BCG, ALT-803 intravesical alone, ALT-803 intravesical with intravesical BCG and intravesical BCG alone) demonstrated a significant reduction in tumor burden as evident by bladder weights and H&E stain (p

Soil salinity is a major abiotic stress that causes disastrous losses in crop yields. To identify favorable alleles that enhance the salinity resistance of rice (Oryza sativa L.) crops, a set of 120 Cheongcheong Nagdong double haploid (CNDH) lines derived from a cross between the Indica variety Cheongcheong and the Japonica variety Nagdong were used. A total of 23 QTLs for 8 different traits related to salinity resistance on chromosomes 1–3 and 5–12 were identified at the seedling stage. A QTL related to the salt injury score (SIS), qSIS-3b, had an LOD score of six within the interval RM3525–RM15904 on chromosome 3, and a phenotypic variation of 31% was further examined for the candidate genes. Among all the CNDH populations, five resistant lines (CNDH 27, CNDH 34-1, CNDH 64, CNDH 78, and CNDH 112), five susceptible lines (CNDH 52-1, CNDH 67, CNDH 69, CNDH 109, and CNDH 110), and the parent lines Cheongcheong and Nagdong were selected for relative gene expression analysis. Among all the genes, two candidate genes were highly upregulated in resistant lines, including the auxin-responsive protein IAA13 (Os03g0742900) and the calmodulin-like protein 4 (Os03g0743500-1). The calmodulin-like protein 4 (Os03g0743500-1) showed a higher expression in all the resistant lines than in the susceptible lines and a high similarity with other species in sequence alignment and phylogenetic tree, and it also showed a protein–protein interaction with other important proteins. The genes identified in our study will provide new genetic resources for improving salt resistance in rice using molecular breeding strategies in the future.

Drought and ultraviolet radiation (UV radiation) are the coexisting environmental factors that negatively affect plant growth and development via oxidative damage. Flavonoids are reactive, scavenging oxygen species (ROS) and UV radiation-absorbing compounds generated under stress conditions. We investigated the biosynthesis of kaempferol and quercetin in wild and flavanone 3-hydroxylase (F3H) overexpresser rice plants when drought and UV radiation stress were imposed individually and together. Phenotypic variation indicated that both kinds of stress highly reduced rice plant growth parameters in wild plants as compared to transgenic plants. When combined, the stressors adversely affected rice plant growth parameters more than when they were imposed individually. Overaccumulation of kaempferol and quercetin in transgenic plants demonstrated that both flavonoids were crucial for enhanced tolerance to such stresses. Oxidative activity assays showed that kaempferol and quercetin overaccumulation with strong non-enzymatic antioxidant activity mitigated the accumulation of ROS under drought and UV radiation stress. Lower contents of salicylic acid (SA) in transgenic plants indicated that flavonoid accumulation reduced stress, which led to the accumulation of low levels of SA. Transcriptional regulation of the dehydrin (DHN) and ultraviolet-B resistance 8 (UVR8) genes showed significant increases in transgenic plants compared to wild plants under stress. Taken together, these results confirm the usefulness of kaempferol and quercetin in enhancing tolerance to both drought and UV radiation stress.

Background/Aims: Chronic atrophic gastritis (AG) and intestinal metaplasia (IM) of the stomach are premalignant lesions. The present study aimed to examine the associations between obesity and these lesions. Methods: A total of 2,997 patients, who underwent gastroscopy, participated in this study, excluding those who had been diagnosed with gastric cancer. Participants were divided into four groups based on their body mass index (BMI). The risk of AG and IM with increasing BMI was analyzed in men and women, separately. Results: The association between BMI and AG was not significant. After adjusting for age, smoking, alcohol, and AG, the odds ratios for IM in the overweight, obesity, and severe obesity groups were 2.25 (95% confidence interval [CI], 1.50-3.37), 2.32 (95% CI, 1.58-3.42), and 4.86 (95% CI, 2.04-11.5) in men, and 2.66 (95% CI, 1.29-5.47), 4.46 (95% CI, 2.28-8.75), and 9.57 (95% CI, 3.26-28.12) in women, compared with the normal BMI group. Conclusions: Gastric IM was significantly associated with increased BMI.

Various drought indices have been used for agricultural drought monitoring, such as Standardized Precipitation Index (SPI), Standardized Precipitation Evapotranspiration Index (SPEI), Palmer Drought Severity Index (PDSI), Soil Water Deficit Index (SWDI), Normalized Difference Vegetation Index (NDVI), Vegetation Health Index (VHI), Vegetation Drought Response Index (VegDRI), and Scaled Drought Condition Index (SDCI). They incorporate such factors as rainfall, land surface temperature (LST), potential evapotranspiration (PET), soil moisture content (SM), and vegetation index to express the meteorological and agricultural aspects of drought. However, these five factors should be combined more comprehensively and reasonably to explain better the dryness/wetness of land surface and the association with crop yield. This study aims to develop the Integrated Crop Drought Index (ICDI) by combining the weather factors (rainfall and LST), hydrological factors (PET and SM), and a vegetation factor (enhanced vegetation index (EVI)) to better express the wet/dry state of land surface and healthy/unhealthy state of vegetation together. The study area was the State of Illinois, a key region of the U.S. Corn Belt, and the quantification and analysis of the droughts were conducted on a county scale for 2004–2019. The performance of the ICDI was evaluated through the comparisons with SDCI and VegDRI, which are the representative drought index in terms of the composite of the dryness and vegetation elements. The ICDI properly expressed both the dry and wet trend of the land surface and described the state of the agricultural drought accompanied by yield damage. The ICDI had higher positive correlations with the corn yields than SDCI and VegDRI during the crucial growth period from June to August for 2004–2019, which means that the ICDI could reflect the agricultural drought well in terms of the dryness/wetness of land surface and the association with crop yield. Future work should examine the other factors for ICDI, such as locality, crop type, and the anthropogenic impacts, on drought. It is expected that the ICDI can be a viable option for agricultural drought monitoring and yield management.

Aging is associated with mitochondrial dysfunction, which leads to a decline in cellular function and the development of age-related diseases. Reduced skeletal muscle mass with aging appears to promote a decrease in mitochondrial quality and quantity. Moreover, mitochondrial dysfunction adversely affects the quality and quantity of skeletal muscle. During aging, physical exercise can cause beneficial adaptations to cellular energy metabolism in skeletal muscle, including alterations to mitochondrial content, protein, and biogenesis. Here, we briefly summarize current findings on the association between the aging process and impairment of mitochondrial function, including mitochondrial biogenesis and reactive oxygen species in skeletal muscle. We also discuss the potential role of exercise in the improvement of aging-driven mitochondrial dysfunctions.

Heart failure (HF) is a multifactorial disease brought about by numerous, and oftentimes complex, etiological mechanisms. Although well studied, HF continues to affect millions of people worldwide and current treatments can only prevent further progression of HF. Mitochondria undoubtedly play an important role in the progression of HF, and numerous studies have highlighted mitochondrial components that contribute to HF. This review presents an overview of the role of mitochondrial biogenesis, mitochondrial oxidative stress, and mitochondrial permeability transition pore in HF, discusses ongoing studies that attempt to address the disease through mitochondrial targeting, and provides an insight on how these studies can affect future research on HF treatment.

Hepatitis C virus (HCV) nonstructural 5A (NS5A) protein is a critical factor for HCV RNA replication. Here the authors show that SCOTIN, an interferon beta-inducible host protein, functions to limit HCV replication by targeting viral protein NS5A for autophagosomal degradation.

Evapotranspiration (ET) is an important component of the Earth’s energy and water cycle via the interaction between the atmosphere and the land surface. The reference evapotranspiration (ET0) is particularly important in the croplands because it is a convenient and reasonable method for calculating the actual evapotranspiration (AET) that represents the loss of water in the croplands through the soil evaporation and vegetation transpiration. To date, many efforts have been made to retrieve ET0 on a spatially continuous grid. In particular, the Moderate Resolution Imaging Spectroradiometer (MODIS) product is provided with a reasonable spatial resolution of 500 m and a temporal resolution of 8 days. However, the applicability to the local-scale variabilities due to complex and heterogeneous land surfaces in countries like South Korea is not sufficiently validated. Meanwhile, the AI approaches showed a useful functionality for the ET0 retrieval on the local scale but have rarely demonstrated a substantial product for a spatially continuous grid. This paper presented a retrieval of the daily reference evapotranspiration (ET0) over a 500 m grid for croplands in South Korea using machine learning (ML) with satellite images and numerical weather prediction data. In a blind test for 2013–2019, the ML-based ET0 model produced the accuracy statistics with a root mean square error of 1.038 mm/day and a correlation coefficient of 0.870. The results of the blind test were stable irrespective of location, year, and month. This outcome is presumably because the input data of the ML-based ET0 model were suitably arranged spatially and temporally, and the optimization of the model was appropriate. We found that the relative humidity and land surface temperature were the most influential variables for the ML-based ET0 model, but the variables with lower importance were also necessary to consider the nonlinearity between the variables. Using the daily ET0 data produced over the 500 m grid, we conducted a case study to examine agrometeorological characteristics of the croplands in South Korea during the period when heatwave and drought events occurred. Through the experiments, the feasibility of the ML-based ET0 retrieval was validated, especially for local agrometeorological applications in regions with heterogeneous land surfaces, such as South Korea.

This paper describes the development of an optimized corn yield prediction model under extreme weather conditions for the Midwestern United States (US). We tested six different artificial intelligence (AI) models using satellite images and meteorological data for the dominant growth period. To examine the effects of extreme weather events, we defined the drought and heatwave by considering the characteristics of corn growth and selected the cases for sensitivity tests from a historical database. In particular, we conducted an optimization for the hyperparameters of the deep neural network (DNN) model to ensure the best configuration for accuracy improvement. The result for drought cases showed that our DNN model was approximately 51–98% more accurate than the other five AI models in terms of root mean square error (RMSE). For the heatwave cases, our DNN model showed approximately 30–77% better accuracy in terms of RMSE. The correlation coefficient was 0.954 for drought cases and 0.887–0.914 for heatwave cases. Moreover, the accuracy of our DNN model was very stable, despite the increases in the duration of the heatwave. It indicates that the optimized DNN model can provide robust predictions for corn yield under conditions of extreme weather and can be extended to other prediction models for various crops in future work.

Three-dimensional (3D) computational aortic models have been established to reproduce aortic diseases such as aortic aneurysm and dissection; however, no such models have been developed to study diabetes mellitus (DM). To characterize biomechanical properties of the human aorta with DM, reconstructed aortic CT images were converted into DICOM format, and imported into the 3D segmentation using Mimics software. This resulted in a 3D reconstruction of the complete aorta, including three branches. We applied a pulsatile blood pressure waveform for the ascending aorta to provide a biomimetic environment using COMSOL Multiphysics software. Hemodynamics were compared between the control and DM models. We observed that mean blood flow velocity, aortic pressure, and von Mises stress values were lower in the DM model than in the control model. Furthermore, the range of aortic movement was lower in the DM model than in the control model, suggesting that the DM aortic wall is more susceptible to rupture. When comparing biomechanical properties in discrete regions of the aorta, all values were higher in the ascending aorta for both control and DM models, corresponding to the location of most aortic lesions. We have developed a compute based that integrates advanced image processing strategies and computational techniques based on finite element method to perform hemodynamics analysis based on CT images. Our study of image-based CFD analysis hopes to provide a better understanding of the relationship between aortic hemodynamic and developing pathophysiology of aortic diseases.

The divalent zinc ion is a cation that plays an indispensable role as a structural constituent of numerous proteins, including enzymes and transcription factors. Recently, it has been suggested that zinc also plays a dynamic role in extracellular and intracellular signaling as well. Ion channels are pore-forming proteins that control the flow of specific ions across the membrane, which is important to maintain ion gradients. In this review, we outline the modulatory effect of zinc on the activities of several ion channels through direct binding of zinc into histidine, cysteine, aspartate, and glutamate moieties of channel proteins. The binding of zinc to ion channels results in the activation or inhibition of the channel due to conformational changes. These novel aspects of ion-channel activity modulation by zinc provide new insights into the physiological regulation of ion channels.

A 46-year-old Korean woman was diagnosed with stage III breast cancer and underwent 8 cycles of neoadjuvant chemotherapy, breast conservation surgery and adjuvant radiotherapy. However, the cancer recurred in the right upper lung (RUL) and the right pulmonary hilum after 8 months. The RUL nodule was removed through a wedge resection, and the pathologic finding was revealed as a metastatic adenocarcinoma. Adjuvant chemotherapy was recommended, but she refused it because she feared adverse reactions to chemotherapy. Instead, Korean Medicine Therapy with intravenous wild ginseng pharmacopuncture (WGP), Cordyceps sinensis pharmacopuncture, Trichosanthes kirilowii pharmacopuncture, Euonymus alatus pharmacopuncture (EAP) and Astragalus membranaceus pharmacopuncture was started. After a month, the disease looked stable, but findings of newly occurring metastatic lymphadenopathies appeared on CT after 6 months. Salvage chemotherapy was recommended, but she also refused it. At this time, Prunella vulgaris pharmacopuncture was started. Finally, a complete resolution was confirmed on PET-CT after 5 months, and she has remained in stable condition for more than 6 months with WGP, EAP, a Soram nebulizer solution inhalation and the oral intake of Soramdan S and Hangamdan S.

Fucoidan is an l-fucose-enriched sulfated polysaccharide isolated from brown algae and marine invertebrates. In this study, we investigated the protective effect of fucoidan from Fucus vesiculosus on alcohol-induced murine liver damage. Liver injury was induced by oral administration of 25% alcohol with or without fucoidan (30 mg/kg or 60 mg/kg) for seven days. Alcohol administration increased serum aspartate aminotransferase and alanine aminotransferase levels, but these increases were suppressed by the treatment of fucoidan. Transforming growth factor beta 1 (TGF-β1), a liver fibrosis-inducing factor, was highly expressed in the alcohol-fed group and human hepatoma HepG2 cell; however, the increase in TGF-β1 expression was reduced following fucoidan administration. Treatment with fucoidan was also found to significantly reduce the production of inflammation-promoting cyclooygenase-2 and nitric oxide, while markedly increasing the expression of the hepatoprotective enzyme, hemeoxygenase-1, on murine liver and HepG2 cells. Taken together, the antifibrotic and anti-inflammatory effects of fucoidan on alcohol-induced liver damage may provide valuable insights into developing new therapeutics or interventions.

The aim of this review was to understand the effects of β-adrenergic stimulation on oxidative stress, structural remodeling, and functional alterations in the heart and cerebral artery. Diverse stimuli activate the sympathetic nervous system, leading to increased levels of catecholamines. Long-term overstimulation of the β-adrenergic receptor (βAR) in response to catecholamines causes cardiovascular diseases, including cardiac hypertrophy, stroke, coronary artery disease, and heart failure. Although catecholamines have identical sites of action in the heart and cerebral artery, the structural and functional modifications differentially activate intracellular signaling cascades. βAR-stimulation can increase oxidative stress in the heart and cerebral artery, but has also been shown to induce different cytoskeletal and functional modifications by modulating various components of the βAR signal transduction pathways. Stimulation of βAR leads to cardiac dysfunction due to an overload of intracellular Ca2+ in cardiomyocytes. However, this stimulation induces vascular dysfunction through disruption of actin cytoskeleton in vascular smooth muscle cells. Many studies have shown that excessive concentrations of catecholamines during stressful conditions can produce coronary spasms or arrhythmias by inducing Ca2+-handling abnormalities and impairing energy production in mitochondria, In this article, we highlight the different fates caused by excessive oxidative stress and disruptions in the cytoskeletal proteome network in the heart and the cerebral artery in responsed to prolonged βAR-stimulation.

Echinochrome A (Ech A) is a natural pigment from sea urchins that has been reported to have antioxidant properties and a cardio protective effect against ischemia reperfusion injury. In this study, we ascertained whether Ech A enhances the mitochondrial biogenesis and oxidative phosphorylation in rat cardio myoblast H9c2 cells. To study the effects of Ech A on mitochondrial biogenesis, we measured mitochondrial mass, level of oxidative phosphorylation, and mitochondrial biogenesis regulatory gene expression. Ech A treatment did not induce cytotoxicity. However, Ech A treatment enhanced oxygen consumption rate and mitochondrial ATP level. Likewise, Ech A treatment increased mitochondrial contents in H9c2 cells. Furthermore, Ech A treatment up-regulated biogenesis of regulatory transcription genes, including proliferator-activated receptor gamma co-activator (PGC)-1α, estrogen-related receptor (ERR)-α, peroxisome proliferator-activator receptor (PPAR)-γ, and nuclear respiratory factor (NRF)-1 and such mitochondrial transcription regulatory genes as mitochondrial transcriptional factor A (TFAM), mitochondrial transcription factor B2 (TFB2M), mitochondrial DNA direct polymerase (POLMRT), single strand binding protein (SSBP) and Tu translation elongation factor (TUFM). In conclusion, these data suggest that Ech A is a potentiated marine drug which enhances mitochondrial biogenesis.

Echinochrome A (EchA) is a dark-red pigment of the polyhydroxynaphthoquinone class isolated from sea urchin Scaphechinus mirabilis. Acetylcholinesterase (AChE) inhibitors are used in the treatment of various neuromuscular disorders, and are considered as strong therapeutic agents for the treatment of Alzheimer’s disease (AD). Although EchA is clinically used to treat ophthalmic diseases and limit infarct formation during ischemia/ reperfusion injury, anti-AChE effect of EchA is still unknown. In this study, we investigated the anti-AChE effect of EchA in vitro. EchA and its exhausted form which lost anti-oxidant capacity did not show any significant cytotoxicy on the H9c2 and A7r5 cells. EchA inhibited AChE with an irreversible and uncompetitive mode. In addition, EchA showed reactive oxygen species scavenging activity, particularly with nitric oxide. These findings indicate new therapeutic potential for EchA in treating reduced acetylcholine-related diseases including AD and provide an insight into developing new AChE inhibitors.

Echinochrome A (Ech A) is a naphthoquinoid pigment from sea urchins that possesses antioxidant, antimicrobial, anti-inflammatory and chelating abilities. Although Ech A is the active substance in the ophthalmic and cardiac drug Histochrome®, its underlying cardioprotective mechanisms are not well understood. In this study, we investigated the protective role of Ech A against toxic agents that induce death of rat cardiac myoblast H9c2 cells and isolated rat cardiomyocytes. We found that the cardiotoxic agents tert-Butyl hydroperoxide (tBHP, organic reactive oxygen species (ROS) inducer), sodium nitroprusside (SNP; anti-hypertension drug), and doxorubicin (anti-cancer drug) caused mitochondrial dysfunction such as increased ROS level and decreased mitochondrial membrane potential. Co-treatment with Ech A, however, prevented this decrease in membrane potential and increase in ROS level. Co-treatment of Ech A also reduced the effects of these cardiotoxic agents on mitochondrial oxidative phosphorylation and adenosine triphosphate level. These findings indicate the therapeutic potential of Ech A for reducing cardiotoxic agent-induced damage.

This paper compares different artificial intelligence (AI) models in order to develop the best crop yield prediction model for the Midwestern United States (US). Through experiments to examine the effects of phenology using three different periods, we selected the July−August (JA) database as the best months to predict corn and soybean yields. Six different AI models for crop yield prediction are tested in this research. Then, a comprehensive and objective comparison is conducted between the AI models. Particularly for the deep neural network (DNN) model, we performed an optimization process to ensure the best configurations for the layer structure, cost function, optimizer, activation function, and drop-out ratio. In terms of mean absolute error (MAE), our DNN model with the JA database was approximately 21−33% and 17−22% more accurate for corn and soybean yields, respectively, than the other five AI models. This indicates that corn and soybean yields for a given year can be forecasted in advance, at the beginning of September, approximately a month or more ahead of harvesting time. A combination of the optimized DNN model and spatial statistical methods should be investigated in future work, to mitigate partly clustered errors in some regions.

A growing body of evidence suggests that exercise may contribute to preventing pathological changes, treating multiple chronic diseases, and reducing mortality and morbidity ratios. Scientific evidence moreover shows that exercise plays a key role in improving health-related physical fitness components and hormone function. Regular exercise training is one of the few strategies that has been strictly adapted in healthy individuals and in athletes. However, time-dependent exercise has different outcomes, based on the exercise type, duration, and hormone adaptation. In the present review, we therefore briefly describe the type, duration, and adaptation of exercise performed in the morning and evening. In addition, we discuss the clinical considerations and indications for exercise training.

Background: Photodynamic therapy (PDT) is a new modality in the treatment of cancer. This study thus aims to examine whether the PDT is effective against in vivo hepatocellular carcinoma. Methods: In vivo efficacy of PDT on hepatocellular carcinoma was tested in xenografted mice with human hepatocellular carcinoma cell lines (Huh7) by utilizing a gold nanoparticles (GNPs) conjugate of new photosensitizer (PS), purpurin-18-N-butylimide-N-methyl-D-glucamine (Pu-18-N-butylimide-NMGA). The conjugate (PS-GNPs) was synthesized from the reaction between Pu-18-N-butylimide-NMGA and chloroauric acid (HAuCl4). Mice were arbitrarily assigned into one of three groups. First group received saline alone, second group received PS-GNPs alone, and the last group received both PS-GNPs and irradiation. PS-GNPs was injected directly into the tumor mass and irradiations were performed 24 hours after injection of PS-GNPs. Results: Tumor volume was significantly smaller in the group which received both PS-GNPs and irradiation compared with other two groups. Western blot and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay revealed that the group which received both PS-GNPs and irradiation showed larger amount of apoptotic protein and DNA fragmentation compared with other two groups. Conclusion: This study suggests that Pu-18-N-butylimide-NMGA-GNP conjugate is an effective agent for PDT in the treatment of hepatocellular carcinoma.

Medicinal tablets have been used for a long time to treat cardiovascular disease. However, mortality rate is steadily increasing partly because of the patients’ sedentary lifestyle and unhealthy diet. By contrast, exercise has been systematically shown to have multiple benefits. Regular exercise training can prevent various diseases in healthy individuals. Combined exercise and cardiac medications may lead to the improvement of heart disease. Numerous exercise training pathways still need further investigations. How exercise can prevent, treat, or attenuate diseases remains somewhat elusive. Thus, this review will discuss cardiac medications in parallel with the mechanism of action of exercise.

We investigated the effects of YC-1, an activator of soluble guanylyl cyclase (sGC), on voltage-dependent K+ (Kv) channels in smooth muscle cells from freshly isolated rabbit coronary arteries by using the whole-cell patch clamp technique. YC-1 inhibited the Kv current in a dose-dependent fashion with an apparent K d of 9.67 μ M. It accelerated the decay rate of Kv channel inactivation without altering the kinetics of current activation. The rate constants of association and dissociation for YC-1 were 0.36 ± 0.01 μ M −1·s−1 and 3.44 ± 0.22 s−1, respectively. YC-1 did not have a significant effect on the steady-state activation and inactivation curves. The recovery time constant from inactivation was decreased in the presence of YC-1, and application of train pulses (1 or 2 Hz) caused a progressive increase in the YC-1 blockade, indicating that YC-1–induced inhibition of Kv currents is use-dependent. Pretreatment with Bay 41-2272 (also a sGC activator), ODQ (a sGC inhibitor), or Rp-8-Br-PET-cGMPs (a protein kinase G inhibitor) did not affect the basal Kv current and also did not significantly alter the inhibitory effect of YC-1. From these results, we suggest that YC-1 directly inhibits the Kv current independently of sGC activation and in a state-, time-, and use-dependent fashion. Keywords:: YC-1, voltage-dependent K+ channel, guanylyl cyclase, coronary artery

The PAF complex (PAFc) participates in various steps of the transcriptional process, from initiation to termination, by interacting with and recruiting various proteins to the proper locus for each step. PAFc is an evolutionarily conserved, multi-protein complex comprising PAF1, CDC73, CTR9, LEO1, yRTF1 and, in humans, hSKI8. These components of PAFc work together, and their protein levels are closely interrelated. In the present study, we investigated the mechanism of PAF1 protein degradation. We found that PAF1 protein levels are negatively regulated by the expression of CNOT4, an ortholog of yNOT4 and a member of the CCR4-NOT complex. CNOT4 specifically controls PAF1 but not other components of PAFc at the protein level by regulating the polyubiquitination of PAF1 and its subsequent degradation by the 26S proteasome. The degradation of PAF1 was found to require nuclear localization, as no PAF1 degradation by CNOT4 and the 26S proteasome was observed with NLS (nucleus localization signal)-deficient PAF1 mutants. However, chromatin binding by PAF1 was not necessary for 26S proteasome- or CNOT4-mediated degradation. Our results suggest that CNOT4 controls the degradation of chromatin-unbound PAF1 via the 26S proteasome.

BACKGROUND AND PURPOSE: Beta adrenergic overstimulation may increase the vascular damage and stroke. However, the underlying mechanisms of beta adrenergic overstimulation in cerebrovascular dysfunctions are not well known. We investigated the possible cerebrovascular dysfunction response to isoproterenol induced beta-adrenergic overstimulation (ISO) in rabbit cerebral arteries (CAs). METHODS: ISO was induced in six weeks aged male New Zealand white rabbit (0.8-1.0 kg) by 7-days isoproterenol injection (300 μg/kg/day). We investigated the alteration of protein expression in ISO treated CAs using 2DE proteomics and western blot analysis. Systemic properties of 2DE proteomics result were analyzed using bioinformatics software. ROS generation and following DNA damage were assessed to evaluate deteriorative effect of ISO on CAs. Intracellular Ca(2+) level change and vascular contractile response to vasoactive drug, angiotensin II (Ang II), were assessed to evaluate functional alteration of ISO treated CAs. Ang II-induced ROS generation was assessed to evaluated involvement of ROS generation in CA contractility. RESULTS: Proteomic analysis revealed remarkably decreased expression of cytoskeleton organizing proteins (e.g. actin related protein 1A and 2, α-actin, capping protein Z beta, and vimentin) and anti-oxidative stress proteins (e.g. heat shock protein 9A and stress-induced-phosphoprotein 1) in ISO-CAs. As a cause of dysregulation of actin-cytoskeleton organization, we found decreased level of RhoA and ROCK1, which are major regulators of actin-cytoskeleton organization. As functional consequences of proteomic alteration, we found the decreased transient Ca(2+) efflux and constriction response to angiotensin II and high K(+) in ISO-CAs. ISO also increased basal ROS generation and induced oxidative damage in CA; however, it decreased the Ang II-induced ROS generation rate. These results indicate that ISO disrupted actin cytoskeleton proteome network through down-regulation of RhoA/ROCK1 proteins and increased oxidative damage, which consequently led to contractile dysfunction in CA.