ABSTRACT
Diospyros lotus has been traditionally used in Asia for medicinal purposes, exhibiting a broad spectrum of pharmacological effects including antioxidant, neuroprotective and antiinflammatory properties. While the antiitch effect of D. lotus leaves has been reported, studies on the detailed mechanism of action in microglia and astrocytes, which are members of the central nervous system, have yet to be revealed. The present study aimed to investigate effects of D. lotus leaf extract (DLE) and its main component myricitrin (MC) on itchrelated cytokines and signaling pathways in lipopolysaccharide (LPS)stimulated microglia. The effect of DLE and MC on activation of astrocyte stimulated by microglia was also examined. Cytokine production was evaluated through reverse transcription PCR and western blot analysis. Signaling pathway was analyzed by performing western blotting and immunofluorescence staining. The effect of microglia on astrocytes activation was evaluated via western blotting for receptors, signaling molecules and itch mediators and confirmed through gene silencing using short interfering RNA. DLE and MC suppressed the production of itchrelated cytokine IL6 and IL31 in LPSstimulated microglia. These inhibitory effects were mediated through the blockade of NFκB, MAPK and JAK/STAT pathways. In astrocytes, stimulation by microglia promoted the expression of itchrelated molecules such as oncostatin M receptor, interleukin 31 receptor a, inositol 1,4,5trisphosphate receptor 1, lipocalin2 (LCN2), STAT3 and glial fibrillary acidic protein. However, DLE and MC significantly inhibited these receptors. Additionally, astrocytes stimulated by microglia with IL6, IL31, or both genes silenced did not show activation of LCN2 or STAT3. The findings of the present study demonstrated that DLE and MC could suppress pruritic activity in astrocytes induced by microgliaderived IL6 and IL31. This suggested the potential of DLE and MC as functional materials capable of alleviating pruritus.
Subject(s)
Astrocytes , Diospyros , Flavonoids , Interleukin-6 , Microglia , Plant Extracts , Plant Leaves , Pruritus , Astrocytes/drug effects , Astrocytes/metabolism , Microglia/drug effects , Microglia/metabolism , Plant Extracts/pharmacology , Plant Extracts/chemistry , Animals , Flavonoids/pharmacology , Flavonoids/chemistry , Mice , Interleukin-6/metabolism , Interleukin-6/genetics , Plant Leaves/chemistry , Pruritus/drug therapy , Pruritus/metabolism , Diospyros/chemistry , Lipopolysaccharides , Signal Transduction/drug effects , Inflammation/metabolism , Inflammation/drug therapy , InterleukinsABSTRACT
With the advancement in information and communication technology, modern society has relied on various computing systems in areas closely related to human life. However, cyberattacks are also becoming more diverse and intelligent, with personal information and human lives being threatened. The moving target defense (MTD) strategy was designed to protect mission-critical systems from cyberattacks. The MTD strategy shifted the paradigm from passive to active system defense. However, there is a lack of indicators that can be used as a reference when deriving general system components, making it difficult to configure a systematic MTD strategy. Additionally, even when selecting system components, a method to confirm whether the systematic components are selected to respond to actual cyberattacks is needed. Therefore, in this study, we surveyed and analyzed existing cyberattack information and MTD strategy research results to configure a component dataset. Next, we found the correlation between the cyberattack information and MTD strategy component datasets and used this to design and implement the MTD-Diorama data visualization engine to configure a systematic MTD strategy. Through this, researchers can conveniently identify the attack surface contained in cyberattack information and the MTD strategies that can respond to each attack surface. Furthermore, it will allow researchers to configure more systematic MTD strategies that can be used universally without being limited to specific computing systems.
Subject(s)
Computer Security , Humans , AlgorithmsABSTRACT
The amyloid cascade hypothesis suggests that amyloid beta (Aß) contributes to initiating subsequent tau pathology in Alzheimer's disease (AD). However, the underlying mechanisms through which Aß contributes to tau uptake and propagation remain poorly understood. Here, we show that preexisting amyloid pathology accelerates the uptake of extracellular tau into neurons. Using quantitative proteomic analysis of endocytic vesicles, we reveal that Aß induces the internalization of fibroblast growth factor receptor 3 (FGFR3). Extracellular tau binds to the extracellular domain of FGFR3 and is internalized by the FGFR3 ligand, fibroblast growth factor 2 (FGF2). Aß accelerates FGF2 secretion from neurons, thereby inducing the internalization of tau-attached FGFR3. Knockdown of FGFR3 in the hippocampus reduces tau aggregation by decreasing tau uptake and improving memory function in AD model mice. These data suggest FGFR3 in neurons as a novel tau receptor and a key mediator of Aß-induced tau uptake in AD.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Neurons , Receptor, Fibroblast Growth Factor, Type 3 , tau Proteins , tau Proteins/metabolism , Animals , Receptor, Fibroblast Growth Factor, Type 3/metabolism , Receptor, Fibroblast Growth Factor, Type 3/genetics , Amyloid beta-Peptides/metabolism , Mice , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/etiology , Humans , Neurons/metabolism , Hippocampus/metabolism , Fibroblast Growth Factor 2/metabolism , Disease Models, Animal , Protein BindingABSTRACT
OBJECTIVES: To evaluate the cost-effectiveness of the 20-valent pneumococcal conjugate vaccine (PCV20) compared to 13-valent pneumococcal conjugate vaccine (PCV13) for the pediatric population in Korea, where the four-dose vaccine coverage rate is over 97%. METHODS: We constructed a Markov model to calculate the cost and quality-adjusted life-years (QALYs) over 10 years. The health states were susceptible states; disease states, which included invasive pneumococcal diseases such as meningitis, bacteremia, pneumonia, and acute otitis media; and death attributable to pneumococcal disease. The annual incidence and mortality due to pneumococcal diseases were estimated based on the serotypes covered by PCV13 and PCV20, vaccine coverage rate, vaccine effectiveness, and population size. Vaccine, administration, and disease costs were included in the model. RESULTS: In the total population (n = 51,431,305), PCV20 prevented more pneumococcal diseases and deaths, resulting in a gain of 74,855 QALY over PCV13. Meanwhile, the PCV20 group spent $275,136,631 less than the PCV13 group. As PCV20 gained more QALYs but spent less on total medical costs than PCV13, PCV20 was dominant over PCV13. CONCLUSIONS: In the Korean population, PCV20 is a cost-effective and dominant option over PCV13. Our findings provide evidence for decision-making regarding the introduction of PCV20 in countries with high vaccine coverage.
ABSTRACT
Liver cancer stands as the fifth leading cause of cancer-related deaths globally. Hepatocellular carcinoma (HCC) comprises approximately 85%-90% of all primary liver malignancies. However, only 20-30% of HCC patients qualify for curative therapy, primarily due to the absence of reliable tools for early detection and prognosis of HCC. This underscores the critical need for molecular biomarkers for HCC management. Since proteins reflect disease status directly, proteomics has been utilized in biomarker developments for HCC. In particular, proteomics coupled with liquid chromatography-mass spectrometer (LC-MS) methods facilitate the process of discovering biomarker candidates for diagnosis, prognosis, and therapeutic strategies. In this work, we investigated LC-MS-based proteomics methods through recent reference reviews, with a particular focus on sample preparation and LC-MS methods appropriate for the discovery of HCC biomarkers and their clinical applications. We classified proteomics studies of HCC according to sample types, and we examined the coverage of protein biomarker candidates based on LC-MS methods in relation to study scales and goals. Comprehensively, we proposed protein biomarker candidates categorized by sample types and biomarker types for appropriate clinical use. In this review, we summarized recent LC-MS-based proteomics studies on HCC and proposed potential protein biomarkers. Our findings are expected to expand the understanding of HCC pathogenesis and enhance the efficiency of HCC diagnosis and prognosis, thereby contributing to improved patient outcomes.
ABSTRACT
The aberrant assembly of amyloid-ß (Aß) is implicated in Alzheimer's disease (AD). Recent clinical outcomes of Aß-targeted immunotherapy reinforce the notion that clearing Aß burden is a potential therapeutic approach for AD. Herein, to develop drug candidates for chemically driven clearance of Aß aggregates, we synthesized 51 novel polyfunctionalized furo[2,3-b:4,5-b']dipyridine-chalcone hybrid compounds. After conducting two types of cell-free anti-Aß functional assays, Aß aggregation prevention and Aß aggregate clearance, we selected YIAD-0336, (E)-8-((1H-pyrrol-2-yl)methylene)-10-(4-chlorophenyl)-2,4-dimethyl-7,8-dihydropyrido[3',2':4,5]furo[3,2-b]quinolin-9(6H)-one, for further in vivo investigations. As YIAD-0336 exhibited a low blood-brain barrier penetration profile, it was injected along with aggregated Aß directly into the intracerebroventricular region of ICR mice and ameliorated spatial memory in Y-maze tests. Next, YIAD-0336 was orally administered to 5XFAD transgenic mice with intravenous injections of mannitol, and YIAD-0336 significantly removed Aß plaques from the brains of 5XFAD mice. Collectively, YIAD-0336 dissociated toxic aggregates in the mouse brain and hence alleviated cognitive deterioration. Our findings indicate that chemically driven clearance of Aß aggregates is a promising therapeutic approach for AD.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Disease Models, Animal , Mice, Transgenic , Animals , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Mice , Amyloid beta-Peptides/metabolism , Chalcone/chemistry , Chalcone/pharmacology , Chalcone/analogs & derivatives , Chalcones/chemistry , Chalcones/pharmacology , Chalcones/administration & dosage , Male , Brain/drug effects , Brain/metabolism , Humans , Memory/drug effects , Protein Aggregates/drug effects , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/drug effects , Maze Learning/drug effects , Pyridines/chemistry , Pyridines/pharmacology , Pyridines/administration & dosageABSTRACT
N,N-dimethyltryptamine (DMT) is a serotonergic psychedelic that is being investigated clinically for the treatment of psychiatric disorders. Although the neurophysiological effects of DMT in humans are well-characterized, similar studies in animal models as well as data on the neurochemical effects of DMT are generally lacking, which are critical for mechanistic understanding. In the current study, we combined behavioral analysis, high-density (32-channel) electroencephalography, and ultra-high-performance liquid chromatography-tandem mass spectrometry to simultaneously quantify changes in behavior, cortical neural dynamics, and levels of 17 neurochemicals in medial prefrontal and somatosensory cortices before, during, and after intravenous administration of three different doses of DMT (0.75 mg/kg, 3.75 mg/kg, 7.5 mg/kg) in male and female adult rats. All three doses of DMT produced head twitch response with most twitches observed after the low dose. DMT caused dose-dependent increases in serotonin and dopamine levels in both cortical sites along with a reduction in EEG spectral power in theta (4-10 Hz) and low gamma (25-55 Hz), and increase in power in delta (1-4 Hz), medium gamma (65-115), and high gamma (125-155 Hz) bands. Functional connectivity decreased in the delta band and increased across the gamma bands. In addition, we provide the first measurements of endogenous DMT in these cortical sites at levels comparable to serotonin and dopamine, which together with a previous study in occipital cortex, suggests a physiological role for endogenous DMT. This study represents one of the most comprehensive characterizations of psychedelic drug action in rats and the first to be conducted with DMT.
ABSTRACT
A new approach for the preparation of amides was developed using C-C bond cleavage that initiates C- to N-acyl transfer, employing activated ketones as acylation reagents and amine nucleophiles. The reaction was operational under the coupling reagent system that is commonly utilized for peptide bond formations. The method enables practical preparation of amides using linear and cyclic ketone substrates under mild conditions.
ABSTRACT
Antiretroviral therapy-naive people living with HIV possess less fat than people without HIV. Previously, we found that HIV-1 transactivator of transcription (TAT) decreases fat in ob/ob mice. The TAT38 (a.a. 20-57) is important in the inhibition of adipogenesis and contains three functional domains: Cys-ZF domain (a.a. 20-35 TACTNCYCAKCCFQVC), core-domain (a.a. 36-46, FITKALGISYG), and protein transduction domain (PTD)(a.a. 47-57, RAKRRQRRR). Interestingly, the TAT38 region interacts with the Cyclin T1 of the P-TEFb complex, of which expression increases during adipogenesis. The X-ray crystallographic structure of the complex showed that the Cys-ZF and the core domain bind to the Cyclin T1 via hydrophobic interactions. To prepare TAT38 mimics with structural and functional similarities to TAT38, we replaced the core domain with a hydrophobic aliphatic amino acid (from carbon numbers 5 to 8). The TAT38 mimics with 6-hexanoic amino acid (TAT38 Ahx (C6)) and 7-heptanoic amino acid (TAT38 Ahp (C7)) inhibited adipogenesis of 3T3-L1 potently, reduced cellular triglyceride content, and decreased body weight of diet-induced obese (DIO) mice by 10.4-11 % in two weeks. The TAT38 and the TAT38 mimics potently repressed the adipogenic transcription factors genes, C/EBPα, PPARγ, and SREBP1. Also, they inhibit the phosphorylation of PPARγ. The TAT peptides may be promising candidates for development into a drug against obesity or diabetes.
Subject(s)
Adipogenesis , PPAR gamma , Sterol Regulatory Element Binding Protein 1 , tat Gene Products, Human Immunodeficiency Virus , Animals , PPAR gamma/metabolism , Adipogenesis/drug effects , Mice , Sterol Regulatory Element Binding Protein 1/metabolism , Sterol Regulatory Element Binding Protein 1/genetics , tat Gene Products, Human Immunodeficiency Virus/metabolism , tat Gene Products, Human Immunodeficiency Virus/genetics , CCAAT-Enhancer-Binding Protein-alpha/metabolism , CCAAT-Enhancer-Binding Protein-alpha/genetics , 3T3-L1 Cells , Humans , Gene Expression Regulation , Mice, Obese , Male , Cyclin T/metabolism , Obesity/metabolism , Adipocytes/metabolism , Mice, Inbred C57BL , CCAAT-Enhancer-Binding ProteinsABSTRACT
BACKGROUND: Peucedanum japonicum Thunb. (PJ) is a vegetable widely consumed in East Asia and is known to have anticancer and anti-inflammatory effects. However, the effect of PJ on muscle atrophy remains elusive. PURPOSE: This study aimed to investigate the effect of PJ and its active compound on dexamethasone (DEX)-induced muscle atrophy. METHODS: We performed qualitative and quantitative analysis of PJ using ultra-performance liquid chromatography-mass spectrometry tandem mass spectrometry (UPLC-MS/MS) and high-performance liquid chromatography (HPLC), respectively. The efficacy of PJ and its main compound 4-caffeoylquinic acid (CQA) on muscle atrophy was evaluated in DEX-induced myotube atrophy and DEX-induced muscle atrophy in mouse myoblasts (C2C12) and C57BL/6 mice, in vitro and in vivo, respectively. RESULTS: The UPLC-MS/MS and HPLC data showed that the concentration of 4-CQA in PJ was 18.845 mg/g. PJ and 4-CQA treatments significantly inhibited DEX-induced myotube atrophy by decreasing protein synthesis and glucocorticoid translocation to the nucleus in C2C12 myotubes. In addition, PJ enhanced myogenesis by upregulating myogenin and myogenic differentiation 1 in C2C12 cells. PJ supplementation effectively increased muscle function and mass, downregulated atrogenes, and decreased proteasome activity in C57BL/6 mice. Additionally, PJ effectively decreased the nuclear translocation of forkhead transcription factor 3 alpha by inhibiting glucocorticoid receptor. CONCLUSION: Overall, PJ and its active compound 4-CQA alleviated skeletal muscle atrophy by inhibiting protein degradation. Hence, our findings present PJ as a potential novel pharmaceutical candidate for the treatment of muscle atrophy.
Subject(s)
Apiaceae , Dexamethasone , Mice, Inbred C57BL , Muscular Atrophy , Plant Extracts , Quinic Acid/analogs & derivatives , Animals , Muscular Atrophy/chemically induced , Muscular Atrophy/drug therapy , Dexamethasone/pharmacology , Mice , Plant Extracts/pharmacology , Plant Extracts/chemistry , Apiaceae/chemistry , Male , Cell Line , Tandem Mass Spectrometry , Muscle Fibers, Skeletal/drug effects , Quinic Acid/pharmacology , Chromatography, High Pressure Liquid , Myogenin/metabolismABSTRACT
Background: Melanocortin 1 receptor (MC1R), a receptor of α-melanocyte-stimulating hormone (α-MSH), is exclusively present in melanocytes where α-MSH/MC1R stimulate melanin pigmentation through microphthalmia-associated transcription factor M (MITF-M). Toll-like receptor 4 (TLR4), a receptor of endotoxin lipopolysaccharide (LPS), is distributed in immune and other cell types including melanocytes where LPS/TLR4 activate transcriptional activity of nuclear factor (NF)-κB to express cytokines in innate immunity. LPS/TLR4 also up-regulate MITF-M-target melanogenic genes in melanocytes. Here, we propose a molecular target of antimelanogenic activity through elucidating inhibitory mechanism on α-MSH-induced melanogenic programs by benzimidazole-2-butanol (BI2B), an inhibitor of LPS/TLR4-activated transcriptional activity of NF-κB. Methods: Ultraviolet B (UV-B)-irradiated skins of HRM-2 hairless mice and α-MSH-activated melanocyte cultures were employed to examine melanogenic programs. Results: Topical treatment with BI2B ameliorated UV-B-irradiated skin hyperpigmentation in mice. BI2B suppressed the protein or mRNA levels of melanogenic markers, such as tyrosinase (TYR), MITF-M and proopiomelanocortin (POMC), in UV-B-exposed and pigmented skin tissues. Moreover, BI2B inhibited melanin pigmentation in UV-B-irradiated co-cultures of keratinocyte and melanocyte cells and that in α-MSH-activated melanocyte cultures. Mechanistically, BI2B inhibited the activation of cAMP response element-binding protein (CREB) in α-MSH-induced melanogenic programs and suppressed the expression of MITF-M at the promoter level. As a molecular target, BI2B primarily inhibited mitogen-activated protein kinase (MAPK) kinase 3 (MKK3)-catalyzed kinase activity on p38MAPK. Subsequently, BI2B interrupted downstream pathway of p38MAPK-mitogen and stress-activated protein kinase-1 (MSK1)-CREB-MITF-M, and suppressed MITF-M-target melanogenic genes, encoding enzymes TYR, TYR-related protein-1 (TRP-1) and dopachrome tautomerase (DCT) in melanin biosynthesis, and encoding proteins PMEL17 and Rab27A in the transfer of pigmented melanosomes to the overlaying keratinocytes in the skin. Conclusion: Targeting the MKK3-p38MAPK-MSK1-CREB-MITF-M pathway was suggested as a rationale to inhibit UV-B- or α-MSH-induced facultative melanogenesis and as a strategy to prevent acquired pigmentary disorders in the skin.
Subject(s)
Cyclic AMP Response Element-Binding Protein , Hyperpigmentation , Animals , Mice , Cyclic AMP Response Element-Binding Protein/metabolism , Melanins/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , alpha-MSH/pharmacology , alpha-MSH/metabolism , Microphthalmia-Associated Transcription Factor/genetics , Microphthalmia-Associated Transcription Factor/metabolism , Lipopolysaccharides/toxicity , Melanocytes/metabolism , Hyperpigmentation/drug therapy , Hyperpigmentation/metabolism , Monophenol Monooxygenase/metabolism , Cell Line, TumorABSTRACT
Chronic gut inflammation promotes the development of metabolic diseases such as obesity. There is growing evidence which suggests that dysbiosis in gut microbiota and metabolites disrupt the integrity of the intestinal barrier and significantly impact the level of inflammation in various tissues, including the liver and adipose tissues. Moreover, dietary sources are connected to the development of leaky gut syndrome through their interaction with the gut microbiota. This review examines the effects of these factors on intestinal microorganisms and the communication pathways between the gut-liver and gut-brain axis. The consumption of diets rich in fats and carbohydrates has been found to weaken the adherence of tight junction proteins in the gastrointestinal tract. Consequently, this allows endotoxins, such as lipopolysaccharides produced by detrimental bacteria, to permeate through portal veins, leading to metabolic endotoxemia and alterations in the gut microbiome composition with reduced production of metabolites, such as short-chain fatty acids. However, the precise correlation between gut microbiota and alternative sweeteners remains uncertain, necessitating further investigation. This study highlights the significance of exploring the impact of diet on gut microbiota and the underlying mechanisms in the gut-liver and gut-brain axis. Nevertheless, limited research on the gut-liver axis poses challenges in comprehending the intricate connections between diet and the gut-brain axis. This underscores the need for comprehensive studies to elucidate the intricate gut-brain mechanisms underlying intestinal health and microbiota.
Subject(s)
Diet , Dysbiosis , Gastrointestinal Microbiome , Humans , Bacteria/classification , Bacteria/metabolism , Brain-Gut Axis/physiology , Diet/adverse effects , Dysbiosis/microbiology , Gastrointestinal Microbiome/physiology , Gastrointestinal Tract/microbiology , Inflammation , Liver/metabolismABSTRACT
Amyloid-ß (Aß) oligomers are implicated in the onset of Alzheimer's disease (AD). Herein, quinoline-derived half-curcumin-dioxaborine (Q-OB) fluorescent probe was designed for detecting Aß oligomers by finely tailoring the hydrophobicity of the biannulate donor motifs in donor-π-acceptor structure. Q-OB shows a great sensing potency in dynamically monitoring oligomerization of Aß during amyloid fibrillogenesis in vitro. In addition, we applied this strategy to fluorometrically analyze Aß self-assembly kinetics in the cerebrospinal fluids (CSF) of AD patients. The fluorescence intensity of Q-OB in AD patients' CSF revealed a marked change of log (I/I0) value of 0.34 ± 0.13 (cognitive normal), 0.15 ± 0.12 (mild cognitive impairment), and 0.14 ± 0.10 (AD dementia), guiding to distinguish a state of AD continuum for early diagnosis of AD. These studies demonstrate the potential of our approach can expand the currently available preclinical diagnostic platform for the early stages of AD, aiding in the disruption of pathological progression and the development of appropriate treatment strategies.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Humans , Alzheimer Disease/diagnosis , Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Amyloidogenic Proteins , tau Proteins/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluidABSTRACT
Black ginseng (BG) is processed ginseng traditionally made in Korea via the steaming and drying of ginseng root through three or more cycles, leading to changes in its appearance due to the Maillard reaction on its surface, resulting in a dark coloration. In this study, we explored markers for differentiating processed ginseng by analyzing the chemical characteristics of BG. We elucidated a new method for the structural identification of ginsenoside metabolites and described the features of processed ginseng using UPLC-QTOF-MS in the positive ion mode. We confirmed that maltose, glucose, and fructose, along with L-arginine, L-histidine, and L-lysine, were the key compounds responsible for the changes in the external quality of BG. These compounds can serve as important metabolic markers for distinguishing BG from conventionally processed ginseng. The major characteristics of white ginseng, red ginseng, and BG can be distinguished based on their high-polarity and low-polarity ginsenosides, and a precise method for the structural elucidation of ginsenosides in the positive ion mode is presented.
ABSTRACT
Psychiatric evaluation relies on subjective symptoms and behavioral observation, which sometimes leads to misdiagnosis. Despite previous efforts to utilize plasma proteins as objective markers, the depletion method is time-consuming. Therefore, this study aimed to enhance previous quantification methods and construct objective discriminative models for major psychiatric disorders using nondepleted plasma. Multiple reaction monitoring-mass spectrometry (MRM-MS) assays for quantifying 453 peptides in nondepleted plasma from 132 individuals [35 major depressive disorder (MDD), 47 bipolar disorder (BD), 23 schizophrenia (SCZ) patients, and 27 healthy controls (HC)] were developed. Pairwise discriminative models for MDD, BD, and SCZ, and a discriminative model between patients and HC were constructed by machine learning approaches. In addition, the proteins from nondepleted plasma-based discriminative models were compared with previously developed depleted plasma-based discriminative models. Discriminative models for MDD versus BD, BD versus SCZ, MDD versus SCZ, and patients versus HC were constructed with 11 to 13 proteins and showed reasonable performances (AUROC = 0.890-0.955). Most of the shared proteins between nondepleted and depleted plasma models had consistent directions of expression levels and were associated with neural signaling, inflammatory, and lipid metabolism pathways. These results suggest that multiprotein markers from nondepleted plasma have a potential role in psychiatric evaluation.
Subject(s)
Bipolar Disorder , Depressive Disorder, Major , Schizophrenia , Humans , Depressive Disorder, Major/diagnosis , Depressive Disorder, Major/metabolism , Bipolar Disorder/diagnosis , Bipolar Disorder/metabolism , Schizophrenia/diagnosis , Schizophrenia/metabolism , Mass SpectrometryABSTRACT
In many cases of traumatic brain injury (TBI), conspicuous abnormalities, such as scalp wounds and intracranial hemorrhages, abate over time. However, many unnoticeable symptoms, including cognitive, emotional, and behavioral dysfunction, often last from several weeks to years after trauma, even for mild injuries. Moreover, the cause of such persistence of symptoms has not been examined extensively. Recent studies have implicated the dysregulation of the molecular system in the injured brain, necessitating an in-depth analysis of the proteome and signaling pathways that mediate the consequences of TBI. Thus, in this study, the brain proteomes of two TBI models were examined by quantitative proteomics during the recovery period to determine the molecular mechanisms of TBI. Our results show that the proteomes in both TBI models undergo distinct changes. A bioinformatics analysis demonstrated robust activation and inhibition of signaling pathways and core proteins that mediate biological processes after brain injury. These findings can help determine the molecular mechanisms that underlie the persistent effects of TBI and identify novel targets for drug interventions.
Subject(s)
Brain Injuries, Traumatic , Brain Injuries , Animals , Rodentia/metabolism , Proteomics/methods , Proteome/genetics , Proteome/metabolism , Brain Injuries, Traumatic/metabolism , Brain Injuries/metabolismABSTRACT
Some individuals with mild traumatic brain injury (mTBI), also known as concussion, have neuropsychiatric and physical problems that last longer than a few months. Symptoms following mTBI are not only impacted by the kind and severity of the injury but also by the post-injury experience and the individual's responses to it, making the persistence of mTBI particularly difficult to predict. We aimed to identify prognostic blood-based protein biomarkers predicting 6-month outcomes, in light of the clinical course after the injury, in a longitudinal mTBI cohort (N = 42). Among 420 target proteins quantified by multiple-reaction monitoring-mass spectrometry assays of blood samples, 31, 43, and 15 proteins were significantly associated with the poor recovery of neuropsychological symptoms at < 72 h, 1 week, and 1 month after the injury, respectively. Sequential associations among clinical assessments (depressive symptoms and cognitive function) affecting the 6-month outcomes were evaluated. Then, candidate biomarker proteins indirectly affecting the outcome via neuropsychological symptoms were identified. Using the identified proteins, prognostic models that can predict the 6-month outcome of mTBI were developed. These protein biomarkers established in the context of the clinical course of mTBI may have potential for clinical application.
Subject(s)
Brain Concussion , Humans , Brain Concussion/diagnosis , Prognosis , Proteomics , Biomarkers , Disease ProgressionABSTRACT
Decreasing hydride-induced embrittlement of zirconium-based cladding is a significant challenge for the successful dry storage of spent nuclear fuel. Herein, to radically minimize hydride-induced embrittlement, we used nanoparticles as sacrificial agents with a greater affinity than zirconium for hydrogen. Corrosion experiments in the presence of gold (Au) and palladium (Pd) nanoparticles under simulated pressurized water reactor (PWR) conditions revealed that the hydrogen content of the zirconium samples was remarkably reduced, with a maximum decrease efficiency of 53.9% using 65 nm Au and 53.8% using 50 nm Pd nanoparticles. This approach provides an effective strategy for preventing hydride-induced embrittlement of zirconium-based cladding.
ABSTRACT
Patulin (PAT) is a natural mycotoxin found in decaying pome fruits. Although some toxicological studies have been conducted on PAT, recent research has highlighted its anticancer and antifungal effects. However, studies have yet to examine the effects and molecular mechanisms of PAT in other metabolic diseases. Obesity is a chronic disease caused by excessive food intake and abnormal lifestyle, leading to low-grade inflammation. Therefore, this study aimed to elucidate the effect of PAT on obesity at the cellular level. PAT treatment reduced lipid accumulation, suppressed glucose and LDL uptake, inhibited lipid deposition and triglyceride synthesis, upregulated fatty acid oxidation-related genes (Pgc1α), and downregulated adipogenic/lipogenic genes (Pparγ and C/ebpα) in hypertrophied 3T3-L1 adipocytes. Additionally, PAT treatment enhanced mitochondrial respiration and mass in differentiated adipocytes and alleviated inflammatory response in activated RAW 264.7 macrophages. Moreover, PAT treatment downregulated pro-inflammatory genes (il-6, Tnf-α, Cox-2, and inos), suppressed lipopolysaccharide (LPS)-induced increase in inflammatory mediators (IL-6, TNF-α, and NO), and restored mitochondrial oxidative function in LPS-stimulated macrophages by improving oxygen consumption and mitochondrial integrity and suppressing ROS generation. Overall, these findings suggest a potential for PAT in the prevention of lipid accumulation and inflammation-related disorders.
ABSTRACT
Chloroplast genomes are valuable for inferring evolutionary relationships. We report the complete chloroplast genomes of 36 Corydalis spp. and one Fumaria species. We compared these genomes with 22 other taxa and investigated the genome structure, gene content, and evolutionary dynamics of the chloroplast genomes of 58 species, explored the structure, size, repeat sequences, and divergent hotspots of these genomes, conducted phylogenetic analysis, and identified nine types of chloroplast genome structures among Corydalis spp. The ndh gene family suffered inversion and rearrangement or was lost or pseudogenized throughout the chloroplast genomes of various Corydalis species. Analysis of five protein-coding genes revealed simple sequence repeats and repetitive sequences that can be potential molecular markers for species identification. Phylogenetic analysis revealed three subgenera in Corydalis. Subgenera Cremnocapnos and Sophorocapnos represented the Type 2 and 3 genome structures, respectively. Subgenus Corydalis included all types except type 3, suggesting that chloroplast genome structural diversity increased during its differentiation. Despite the explosive diversification of this subgenus, most endemic species collected from the Korean Peninsula shared only one type of genome structure, suggesting recent divergence. These findings will greatly improve our understanding of the chloroplast genome of Corydalis and may help develop effective molecular markers.