Diospyros lotus leaf extract and its main component myricitrin inhibit itch­related IL­6 and IL­31 by suppressing microglial inflammation and microglial­mediated astrocyte activation.

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.

MTD-Diorama: Moving Target Defense Visualization Engine for Systematic Cybersecurity Strategy Orchestration.

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.

FGFR3 drives Aß-induced tau uptake.

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.

High-throughput Proteomics-Guided Biomarker Discovery of Hepatocellular Carcinoma.

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.

Cost-effectiveness analysis of the 20-valent pneumococcal conjugate vaccine for the pediatric population in South Korea.

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.

Chemically Driven Clearance of Amyloid Aggregates by Polyfunctionalized Furo[2,3-b:4,5-b']dipyridine-Chalcone Hybrids to Ameliorate Memory in an Alzheimer Mouse Model.

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.

Neurochemical and Neurophysiological Effects of Intravenous Administration of N,N-dimethyltryptamine in Rats.

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.

C-C Bond Cleavage-Induced C- to N-Acyl Transfer for Synthesis of Amides.

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.

TAT38 and TAT38 mimics potently inhibit adipogenesis by repressing C/EBPα, PPARγ, Pi-PPARγ, and SREBP1 expression.

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.

Interruption of p38MAPK-MSK1-CREB-MITF-M pathway to prevent hyperpigmentation in the skin.

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.

Identification of Peucedanum japonicum Thunb. extract components and their protective effects against dexamethasone-induced muscle atrophy.

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.

Early onset diagnosis in Alzheimer's disease patients via amyloid-ß oligomers-sensing probe in cerebrospinal fluid.

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.

Diet-Induced Gut Dysbiosis and Leaky Gut Syndrome.

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.

Structural Identification of Ginsenoside Based on UPLC-QTOF-MS of Black Ginseng (Panax Ginseng C.A. Mayer).

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.

The United Nation's Civil Assistance Command in Korea's (UNCACK) Public Health Measures on Koje Island during the Korean War.

This study focuses on the health and sanitation projects carried out on Koje Island by the United Nations Civil Assistance Command in Korea (UNCACK). Koje Island was unique as it served as a destination for dispersed refugees and as an area for housing prisoners of war. Unlike in other regions, UNCACK was actively involved in the implementation of health and sanitation projects on Koje Island. Their infectious disease control projects on Koje Island serve as a valuable example for studying infectious disease prevention initiatives and local medical projects in modern and contemporary Korea. In this study, I examine the documents produced by UNCACK to assess the status of infectious disease control and vaccination plans. Additionally, I analyze the disease prevention initiatives implemented among the residents of Koje Island, including isolation, treatment, and improvement of living conditions. Finally, I explore the characteristics of the Koje Island preventive measures and assess the efforts and limitations of both UNCACK and the Korean government in addressing health issues during the Korean War. Despite the presence of refugees and POWs, Koje Island managed to implement systematic public health initiatives in a controlled environment, widely regarded as highly successful. The public health initiatives on Koje Island, led by UNCACK, provided an opportunity to utilize limited resources, manpower, and Korean health professionals, cultivating the skills necessary to manage infectious diseases effectively. Moreover, these initiatives on Koje Island, although modest, continued into the postwar period, influencing medical missionary activities, the demand for health services among residents, the establishment of independent medical institutions, and the implementation of local health projects.

Temperature change in pig rib bone during implant site preparation by low-speed drilling

OBJECTIVES: The purpose of this study was to evaluate the temperature change during low-speed drilling using infrared thermography. MATERIAL AND METHODS: Pig ribs were used to provide cortical bone of a similar quality to human mandible. Heat production by three implant drill systems (two conventional drilling systems and one low-speed drilling system) was evaluated by measuring the bone temperature using infrared thermography. Each system had two different bur sizes. The drill systems used were twist drill (2.0 mm/2.5 mm), which establishes the direction of the implant, and finally a 3.0 mm-pilot drill. Thermal images were recorded using the IRI1001 system (Infrared Integrated Systems Ltd.). Baseline temperature was 31±1ºC. Measurements were repeated 10 times, and a static load of 10 kg was applied while drilling. Data were analyzed using descriptive statistics. Statistical analysis was conducted with two-way ANOVA. RESULTS AND CONCLUSIONS: Mean values (n=10 drill sequences) for maximum recorded temperature (Max TºC), change in temperature (ΔTºC) from baseline were as follows. The changes in temperature (ΔTºC) were 1.57ºC and 2.46ºC for the lowest and the highest values, respectively. Drilling at 50 rpm without irrigation did not produce overheating. There was no significant difference in heat production between the 3 implant drill systems (p>0.05). No implant drill system produced heat exceeding 47ºC, which is the critical temperature for bone necrosis during low-speed drilling. Low-speed drilling without irrigation could be used during implant site preparation.