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Cigarette smoke induces an inflammatory response in the lungs by recruiting inflammatory cells, leading to lung diseases such as lung cancer, chronic obstructive pulmonary disease, and pulmonary fibrosis. Existing inhalation exposure methods for assessing the adverse effects of cigarette smoke require expensive equipment and are labor‐intensive. Therefore, we attempted to develop a novel method to assess these adverse effects using intratracheal instillation (ITI) of whole cigarette smoke condensate (WCSC). The WCSC (0, 5, 10, or 20 mg/mL) was administered by ITI once daily for 6 or 12 days using an automatic video instillator. Repeated WCSC ITI increased the lung weight, and monocyte chemoattractant protein‐1 (MCP‐1), neutrophil, and lymphocyte levels within bronchoalveolar lavage fluid compared to the control. In the histopathological analysis of the lung tissue, a mild inflammatory response was observed in the 6 and 12 days 20 mg/mL WCSC exposure groups. The genome‐wide RNA‐seq expression patterns revealed that inflammatory and immune response‐related genes, such as the chemokine signaling pathway, Th1/Th2 cell differentiation, and cytokine‐cytokine receptor interaction, were employed following WCSC exposure. In addition, MCP‐1 was time‐dependent and increased in the 10 mg/mL exposure group compared to the control group. These results suggested that the WCSC might induce the potential pulmonary inflammatory response. Furthermore, we proposed that ITI may be a rapid and effective method of evaluating the adverse effects of WCSC within a short exposure period (less than 2 weeks), and it can be used to evaluate cigarette inhalation toxicity studies as an alternative method. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus-1 (HIV-1) transactivator (Tat)-mediated transcription is essential for HIV-1 replication. It is determined by the interaction between Tat and transactivation response (TAR) RNA, a highly conserved process representing a prominent therapeutic target against HIV-1 replication. However, owing to the limitations of current high-throughput screening (HTS) assays, no drug that disrupts the Tat-TAR RNA interaction has been uncovered yet. We designed a homogenous (mix-and-read) time-resolved fluorescence resonance energy transfer (TR-FRET) assay using europium cryptate as a fluorescence donor. It was optimized by evaluating different probing systems for Tat-derived peptides or TAR RNA. The specificity of the optimal assay was validated by mutants of the Tat-derived peptides and TAR RNA fragment, individually and by competitive inhibition with known TAR RNA-binding peptides. The assay generated a constant Tat-TAR RNA interaction signal, discriminating the compounds that disrupted the interaction. Combined with a functional assay, the TR-FRET assay identified two small molecules (460-G06 and 463-H08) capable of inhibiting Tat activity and HIV-1 infection from a large-scale compound library. The simplicity, ease of operation, and rapidity of our assay render it suitable for HTS to identify Tat-TAR RNA interaction inhibitors. The identified compounds may also act as potent molecular scaffolds for developing a new HIV-1 drug class. [ABSTRACT FROM AUTHOR]

The ongoing COVID‐19 has not only caused millions of deaths worldwide, but it has also led to economic recession and the collapse of public health systems. The vaccines and antivirals developed in response to the pandemic have improved the situation markedly; however, the pandemic is still not under control with recurring surges. Thus, it is still necessary to develop therapeutic agents. In our previous studies, we designed and synthesized a series of novel 2‐anilinoquinazolin‐4(3H)‐one derivatives, and demonstrated inhibitory activity against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and MERS‐CoV in vitro. We then conducted in vivo studies using modified compounds that are suitable for oral administration. These compounds demonstrated no toxicity in rats and inhibited viral entry. Here, we investigated the in vivo efficacy of these drug candidates against SARS‐CoV‐2. Three candidate drugs, 7‐chloro‐2‐((3,5‐dichlorophenyl)amino)quinazolin‐4(3H)‐one (1), N‐(7‐chloro‐4‐oxo‐3,4‐dihydroquinazolin‐2‐yl)‐N‐(3,5‐dichlorophenyl)acetamide (2), and N‐(7‐chloro‐4‐oxo‐3,4‐dihydroquinazolin‐2‐yl)‐N‐(3,5‐difluorophenyl)acetamide (3) were administered orally to hACE2 transgenic mice at a dose of 100 mg/kg. All three drugs improved survival rate and reduced the viral load in the lungs. These results show that the derivatives possess in vivo antiviral efficacy similar to that of molnupiravir, which is currently being used to treat COVID‐19. Overall, our data suggest that 2‐anilinoquinazolin‐4(3H)‐one derivatives are promising as potential oral antiviral drug candidates against SARS‐CoV‐2 infection. [ABSTRACT FROM AUTHOR]

Background Although polymyxin has been used as a last-resort antibiotic against resistant bacteria, its use is restricted due to nephrotoxicity and neurotoxicity. While the present antibiotic resistance issue compels clinicians to reconsider polymyxin use in severe illness cases, polymyxin-resistant microorganisms exert an effect. Objectives To address the issue of antibiotic resistance, the cycle of developing new antibiotics to counteract emerging resistance must be discontinued. Here we tried to develop novel therapies that do not rely on direct antimicrobial activity and thus do not promote antibiotic resistance. Methods By a high-throughout screening system based on bacterial respiration, chemical compounds accelerating the antimicrobial effects of polymyxin B were screened. In vitro and in vivo tests were performed to validate adjuvanticity. In addition, membrane depolarization and total transcriptome analysis were used to determine molecular mechanisms. Results PA108, a newly discovered chemical compound, was used to eradicate polymyxin-resistant A. baumannii and three other species in the presence of polymyxin B at concentrations less than the MIC. Since this molecule lacks self-bactericidal action, we hypothesized that PA108 acts as an antibiotic adjuvant, enhancing the antimicrobial activity of polymyxin B against resistant bacteria. At working concentrations, no toxicity was observed in cell lines or mice, although co-treatment with PA108 and polymyxin B increased survival of infected mouse and decreased bacterial loads in organs. Conclusions Boosting antibiotic efficiency through the use of antibiotic adjuvants holds significant promise for tackling the rise in bacterial antibiotic resistance. [ABSTRACT FROM AUTHOR]

The Far Eastern sea cucumber, Stichopus japonicus, is a favored food in Eastern Asia, including Korea, Japan, and China. Aquaculture production of this species has increased because of recent declines in natural stocks and government-operated stock release programs are ongoing. Therefore, the analyses of genetic structure in wild and hatchery populations are necessary to maintain the genetic diversity of this valuable marine resource. In addition, given that sea cucumber color affects market price, with the rare, possibly reproductively isolated, red type being the most valuable, an understanding of the genetic structure and diversity in color variation of green and red types is necessary. We analyzed the genetic structure of wild and hatchery-produced green type S. japonicus from Korea and China, and wild red type from Korea using 9 microsatellite makers. The number of alleles per locus ranged from 11 to 29 across all populations. The mean allele numbers of the green types from Korea (10.6) and China (10.1) were similar, but differed slightly from that of the red type (9.1). Pairwise multilocus FST and genetic distance estimations showed no significant differences between the green types from Korea and China, whereas the differences between the green and red types were significant. This was clearly illustrated by a UPGMA dendrogram, in which the two close subclusters of green types were completely separated from the red type. In addition, the allele frequencies of the green and red types were significantly different. Assignment tests correctly assigned 100% (quality index 99.97%) of individuals to their original color types and demonstrated the feasibility of microsatellite analysis for discrimination between color types.

The heterocyclic indole structure has been shown to be one of the most promising scaffolds, offering various medicinal advantages from its wide range of biological activity. Nonetheless, the significance of 3-oxindole has been less known. In this study, a series of novel 3-oxindole-2-carboxylates were synthesized and their antiviral activity against human immunodeficiency virus-1 (HIV-1) infection was evaluated. Among these, methyl (E)-2-(3-chloroallyl)-4,6-dimethyl-one (6f) exhibited the most potent inhibitory effect on HIV-1 infection, with a half-maximal inhibitory concentration (IC50) of 0.4578 μM but without severe cytotoxicity (selectivity index (SI) = 111.37). The inhibitory effect of these compounds on HIV-1 infection was concordant with their inhibitory effect on the viral replication cycle. Mode-of-action studies have shown that these prominent derivatives specifically inhibited the Tat-mediated viral transcription on the HIV-1 LTR promoter instead of reverse transcription or integration. Overall, our findings indicate that 3-oxindole derivatives could be useful as a potent scaffold for the development of a new class of anti-HIV-1 agents. [ABSTRACT FROM AUTHOR]

We previously reported the potent antiviral effect of the 2-aminoquinazolin-4-(3H)-one 1, which shows significant activity (IC50 = 0.23 μM) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with no cytotoxicity. However, it is necessary to improve the in vivo pharmacokinetics of compound 1 because its area under the curve (AUC) and maximum plasma concentration are low. Here, we designed and synthesized N-substituted quinazolinone derivatives that had good pharmacokinetics and that retained their inhibitory activity against SARS-CoV-2. These compounds were conveniently prepared on a large scale through a one-pot reaction using Dimroth rearrangement as a key step. The synthesized compounds showed potent inhibitory activity, low binding to hERG channels, and good microsomal stability. In vivo pharmacokinetic studies showed that compound 2b had the highest exposure (AUC24h = 41.57 μg∙h/mL) of the synthesized compounds. An in vivo single-dose toxicity evaluation of compound 2b at 250 and 500 mg/kg in rats resulted in no deaths and an approximate lethal dose greater than 500 mg/kg. This study shows that N-acetyl 2-aminoquinazolin-4-(3H)-one 2b is a promising lead compound for developing anti-SARS-CoV-2 agents. [ABSTRACT FROM AUTHOR]

Background: Obesity is becoming prevalent in Korean children. Because body image is becoming increasingly important, it is likely that obesity-induced stress has a significant effect on childhood depression. Aims: To examine the correlation between obesity-induced stress and depressive symptoms in Korean elementary school students. Methods: The study participants were 2,305 elementary school children and their parents in the districts of Jeju-si, Seogwipo-si, Namjeju-gun and Bukjeju-gun on Jeju Island, Korea, who completed questionnaires involving demographic information, an obesity-induced stress scale and the Korean form of Kovacs' Children's Depression Inventory (CDI) from September to December 2006. Results: After controlling for significant independent variables that are wellknown correlates of depressive symptoms in children (e.g. age, gender, residence, family monthly income, obesity status of both parents, family history of chronic illness, and time spent with mother), obesity-induced stress had an odds ratio of 1.128 (95% CI 1.111-1.146). Conclusions: Reducing the prevalence of depressive symptoms in elementary school children in Jeju Island will require special attention, particularly the development of coping strategies to resolve obesity-induced stress in various areas including school, family and society. Key words: Children's Depression Inventory (CDI), depressive symptoms, obesity, obesity-induced stress, odds ratio

Cigarette smoke (CS) substances are known to induce diverse ailments such as cancer, decreased immunity, and lung diseases. Although some studies have been actively conducted to evaluate cigarette toxicity, the current animal exposure methods, that is, exposure of 28‐ or 90‐days, require considerable research cost and lead to obscure results of the CS effects. In a previous study, we compared the effects of CS in a rat model of bleomycin (BLM) and lipopolysaccharide (LPS) induced lung disease. We determined that compared to the LPS‐induced rat model, the BLM‐induced rat model was more sensitive to alterations in secreting cytokines and total cell number. In the current study, we further confirmed the time‐point of effective inhalation exposure by CS in the BLM‐induced lung injury rat model. Using an automatic video instillator, rats were administered a single dose of 2.5 mg/kg BLM (day 1), and subsequently exposed to CS via inhalation (nose‐only) 4 h/day, for 1, 2, 3, and 4 weeks. The bronchoalveolar lavage fluid (BALF) was obtained from the right lung lobes, total cell numbers were counted, and chemokine and cytokine expressions were evaluated using Enzyme‐Linked Immunosorbent Assay. For the 1‐week exposure, we observed a greater increase of neutrophils in the BLM + CS 300 μg/L group than in the BLM or CS 300 μg/L groups. Exposure of CS in the BLM‐induced lung injury rat model enhanced the secretions of chemokines and cytokines, such as CCL2/MCP‐1, CXCL2/MIP‐2 and TNF‐α, at 1 week. Immunohistochemistry and Hematoxylin and Eosin staining of lungs at 1–2 weeks after exposure clearly confirmed this tendency in the increased levels of CCL2/MCP‐1 and TNF‐α. Taken together, these results indicate that the rat model of BLM‐induced lung injury is more sensitive to CS exposure than other rat models, and may be an appropriate model to evaluate the effect of CS exposure at 1–2 weeks. [ABSTRACT FROM AUTHOR]

Despite the continuing global crisis caused by coronavirus disease 2019 (COVID‐19), there is still no effective treatment. Therefore, we designed and synthesized a novel series of 2‐benzylaminoquinazolin‐4(3H)‐one derivatives and demonstrated that they are effective against SARS‐CoV‐2. Among the synthesized derivatives, 7‐chloro‐2‐(((4‐chlorophenyl)(phenyl)methyl)amino)quinazolin‐4(3H)‐one (Compound 39) showed highest anti‐SARS‐CoV‐2 activity, with a half‐maximal inhibitory concentration value greater than that of remdesivir (IC50 = 4.2 μM vs. 7.6 μM, respectively), which gained urgent approval from the U.S. Food and Drug Administration. In addition, Compound 39 showed good results in various assays measuring metabolic stability, human ether a‐go‐go, Cytochromes P450 (CYPs) inhibition, and plasma protein binding (PPB), and showed better solubility and pharmacokinetics than our previous work. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the pancreatic beta cell protective and glucose uptake enhancing effect of the water extract of Tinospora cordifolia stem (TCSE) by using rat insulinoma (RIN)-m5F cells and 3 T3-L1 adipocytes. RIN-m5F cells were stimulated with interleukin-1β and interferon-γ, and the effect of TCSE on insulin secretion and cytokine-induced toxicity was measured by ELISA and MTT assay, respectively. The glucose uptake and protein expression were measured by fluorometry and western blotting. Antidiabetic effect of TCSE was measured using streptozotocin-induced diabetic rats. TCSE dose dependently increased cell viability and insulin secretion in RIN-m5F cells. In addition, TCSE increased both the glucose uptake and glucose transporter 4 translocation in 3 T3-L1 adipocytes via PI3K pathway. Finally, TCSE significantly lowered blood glucose and diet intake and increased body weight in streptozotocin-induced diabetic rats. The level of serum insulin and hepatic glycogen was increased, whereas the level of serum triglyceride, total cholesterol, dipeptidyl peptidase-4, and thiobarbituric acid reactive substances was decreased in TCSE-administered rats. TCSE also increased glucose transporter 4 protein expression in the adipose tissue and liver of TCSE-fed diabetic rats. Our results suggested that TCSE preserved RIN-m5F cells from cytokine-induced toxicity and enhanced glucose uptake in 3 T3-L1 adipocytes, which may regulate glucose metabolism in diabetic rats. [ABSTRACT FROM AUTHOR]

A highly enantioselective asymmetric iodocyclization of gama-hydroxy-cis-alkenes is developed by unprecedented use of the catalyst system derived from (R,R)-salen-Co(II) complex and NCS to obtain 90 percent ee 2-substituted tetrahydrofurans. The method involves catalytic enantioselective intramolecular iodoetherification using salen-Co complexes.

We screened a variety of natural products against MERS-CoV as an attempt of developing I anti i -MERS-CoV drugs, and many flavonoids showed I anti i -MERS activities. Total 12 compounds of bavachinin derivatives in four core structures were evaluated to figure out their I anti i -MERS-CoV activity and cell-cytotoxicity by cellular phenotypic screening method as shown in Table. B 2a b was prepared by hydrogenations of external double bonds of B 1a b , which showed the best I anti i -MERS activities regardless of their I O i -substituents. The I anti i -MERS activity of B 6a b was a little decreased compared to B 1a b , however, the I anti i -MERS activities of its derivatives were conserved. [Extracted from the article]

In a previous study, we showed that several octahydroindene derivatives are potent protease activated receptor 1 (PAR1) antagonists. In the current study, we prepared a series of trans‐fused 5,5‐difulorooctahydroindenes which do not have a C5 stereogenic center, and evaluated their biological activities and metabolic stabilities. Compound 19 in this series, containing a spirooxazolidinone moiety at C2, showed excellent efficacy in both PAR1 binding (IC50 = 70 nM) and human platelet rich plasma (PRP) aggregation (IC50 = 0.19 μM), along with good metabolic stability (R50 = 345.8, 337.2, and 43.4 min in human, rat, and monkey liver microsomes, each), which is comparable to that of vorapaxar. Four stereoisomers of 19 were prepared and evaluated. (1S,2R,3aR,7aR)‐5,5‐Difluoro‐1‐[(E)‐2‐[5‐(3‐fluorophenyl)pyridin‐2‐yl]vinyl]octahydrospiro(indene‐2,5′‐oxazolidin)‐2′‐one (31) was found to be the most active (IC50 = 21 nM) stereoisomer as PAR1 antagonist. Compound 31 exhibited good in vivo oral PK profiles and significant ex vivo antithrombotic efficacy in cynomolgus monkeys upon oral administration. When the plasma concentration of 31 was maintained above 200 ng/mL, platelet aggregation induced by haTRAP was completely inhibited. [ABSTRACT FROM AUTHOR]

Cisplatin (CDDP) and doxorubicin (DOX) are chemotherapeutic drugs that trigger apoptosis by inducing DNA-damage. A previous study using breast cancer cells demonstrated the negative feedback modulation of the epidermal growth factor receptor (EGFR) and receptor tyrosine-protein kinase erbB-2 (ErbB2) via extracellular signal-regulated kinase (ERK)-mediated phosphorylation of conserved Thr-669 and Thr-677 residues, respectively, in the juxtamembrane domain. In addition, CDDP has been identified to cause negative feedback inhibition of activated EGFR in lung cancer cells. In the present study, the role of phosphorylation in the feedback control of the ErbB2/ErbB3 heterodimer in human breast and gastric cancer cells was investigated. Phosphorylation of ErbB2 at Thr-677 was induced by CDDP and DOX, which in turn reduced tyrosine autophosphorylation of ErbB2 and ErbB3. Treatment with trametinib, a mitogen-activated protein kinase inhibitor that blocks ERK-mediated Thr-677 phosphorylation, and substitution of Thr-677 to alanine, blocked the feedback inhibition of ErbB2 and ErbB3. In addition, these agents caused the degradation of ErbB proteins through the activation of p38 mitogen-activated protein kinase (p38) and ERK. These results demonstrate that chemotherapeutic agents trigger ERK- and p38-mediated post-translational downregulation of ErbB receptors. [ABSTRACT FROM AUTHOR]

Deficiencies in erythrocyte metabolic enzymes are associated with hereditary hemolytic anemia. Here, we report the development of a novel multiplex enzyme assay for six major enzymes, namely glucose-6-phosphate dehydrogenase, pyruvate kinase, pyrimidine 5′-nucleotidase, hexokinase, triosephosphate isomerase, and adenosine deaminase, deficiencies in which are implicated in erythrocyte enzymopathies. To overcome the drawbacks of traditional spectrophotometric enzyme assays, the present assay was based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS). The products of the six enzymes were directly measured by using ion pairing UPLC–MS/MS, and the precision, linearity, ion suppression, optimal sample amounts, and incubation times were evaluated. Eighty-three normal individuals and 13 patients with suspected enzymopathy were analyzed. The UPLC running time was within 5 min. No ion suppression was observed at the retention time for the products or internal standards. We selected an optimal dilution factor and incubation time for each enzyme system. The intra- and inter-assay imprecision values (CVs) were 2.5–12.1% and 2.9–14.3%, respectively. The linearity of each system was good, with R 2 values > 0.97. Patient samples showed consistently lower enzyme activities than those from normal individuals. The present ion paring UPLC–MS/MS assay enables facile and reproducible multiplex evaluation of the activity of enzymes implicated in enzymopathy-associated hemolytic anemia. [ABSTRACT FROM AUTHOR]

Maternal embryonic leucine zipper kinase ( MELK) has been implicated in various cellular processes and is highly upregulated in diverse cancers, then it is thought to be a promising anticancer target. 3-Anilino-1 H-pyrazolo[3,4- b]pyridine scaffold was identified as a novel scaffold for MELK kinase inhibitors in high throughput screening ( HTS). From exploration for structure-activity relationship ( SAR) studies mainly by the modification of the 3 (C3), and 5-positions (C5), 4-(4-methylpiperazin-1-yl)- N-{5-[1-(piperidin-4-yl)-1 H-pyrazol-4-yl]-1 H-pyrazolo[3,4- b]pyridin-3-yl}benzamide ( 21a) was found to exhibit good activity (IC50 = 0.15 μM) on MELK as a lead in early state. [ABSTRACT FROM AUTHOR]

Sodium dichloroisocyanurate-96% (NaDCC) is commonly used to treat drinking water, industrial water, and wastewater. However, exposure to NaDCC by inhalation can have toxic pulmonary effects in humans. In the present study, we evaluated the potential toxicity of NaDCC following a 90-day inhalation toxicity study in Sprague-Dawley/Crl:CD (SD) rats. The animals were exposed to 0.4, 2.0, or 10.0 mg/m3 NaDCC for 90 days. In addition, male and female rats from the 10.0 mg/m3 group were set up as the recovery group for 14 days. The bronchoalveolar lavage fluid showed a concentration-dependent increase in the total cell count, with a significant increase in neutrophils in both the sexes in the 10.0 mg/m3 group compared to the negative control group. In the 10.0 mg/m3 group, lung organ weight was significantly increased among the female rats. Histopathological examination showed eosinophilic droplets in the olfactory/respiratory epithelium, mucous cell hyperplasia, atrophy/degeneration of the tracheal branches, and wall thickening of the alveolar ducts in the nasal cavity of both sexes in the 10.0 mg/m3 group. The adverse effects of NaDCC exposure were observed to decrease during the 14-day recovery period in both sexes. Based on pathological observations, the "no observed adverse effect concentration (NOAEC)" of inhaled NaDCC was 2.0 mg/m3 for both sexes. These results are expected to provide a scientific basis for inhalation toxicity data of NaDCC. [Display omitted] • The total cell number in BALF increased in a concentration-dependent manner. • The histological changes showed in nasal cavity and bronchi of 10.0 mg/m3 group. • In the alveolar duct, the adverse effect of wall thickening by NaDCC was observed. • The adverse effect was observed to decrease during the recovery period. • The no-observed adverse effect concentration of NaDCC was 2.0 mg/m3 for both sexes. [ABSTRACT FROM AUTHOR]

The rhizome of Dryopteris crassirhizoma Nakai. (Dryopteridaceae) has been used in traditional medicine in East Asia and has recently been reported to have anticancer, anti-inflammation, and antibacterial activity as well as antiviral activity. Natural phloroglucinols from D. crassirhizoma, dryocrassin ABBA and filixic acid ABA were reported to inhibit influenza virus infection with an inhibitory activity on neuraminidase. In this study, we found that dryocrassin ABBA and filixic acid ABA have an inhibitory activity against the main protease of SARS-CoV-2. Therefore, dryocrassin ABBA and filixic acid ABA exhibited inhibitory activity against SARS-CoV-2 infection in Vero cells dose-dependently using the immunofluorescence-based antiviral assays. Moreover, these compounds inhibited SARS-CoV and MERS-CoV infection, suggesting their broad-spectrum anticoronaviral activity. In addition, a 5-day repeated-dose toxicity study of dryocrassin ABBA and filixic acid ABA suggested that an approximately lethal dose of these compounds in mice was >10 mg/kg. Pharmacokinetic studies of dryocrassin ABBA showed good microsomal stability, low hERG inhibition, and low CYP450 inhibition. In vivo pharmacokinetic properties of dryocrassin ABBA showed a long half-life (5.5–12.6 h) and high plasma exposure (AUC 19.3–65 μg·h/mL). Therefore, dryocrassin ABBA has therapeutic potential against emerging coronavirus infections, including COVID-19. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: There is sparse data on apoB dyslipoproteinemia in Asian population. The purpose of this study was to assess apoB dyslipoproteinemia and to compare the LDL-C, non-HDL and apoB for risk assessment with percentile equivalent cut off in Korean population. Methods: With 1193 Korean adult subjects, the prevalence and characteristics of different types of dyslipoproteinemias were analyzed in each age and gender group. The percentile values of direct LDL-C, calculated LDL-C, non HDL-C, HDL-C, apoAI, apoB and apoB/apoAI ratio were estimated. Results: The prevalences of normoapoB–hyperTG, hyperapoB–normoTG and hyperapoB–hyperTG dyslipoproteinemia were 6.9, 8.9 and 10.9% in men and 3.7, 6.4 and 2.8% in women. The 40th percentile of direct LDL-C, calculated LDL-C, non-HDL-C and apo B were 108, 104.2, 126 and 85mg/dl, respectively. The individual above optimal cut off was significantly underestimated with LDL-C than with non-HDL and apoB, in groups with adverse risk factors. Conclusions: This study firstly shows the prevalence of various types of dyslipoproteinemias in Asian population. The percentile values of Korean population were similar to those of NHANES. Integration of lipid markers is needed for making clinical decisions and further research involving various populations and methodologies should be performed. [Copyright &y& Elsevier]

Objective: This study aimed to establish reference intervals for lymphocyte subsets including CD4+CD25highFoxP3+ regulatory T-cells (Tregs) in umbilical cord blood. Methods: Umbilical cord blood was obtained after birth from 120 healthy full-term neonates, who were born between November 2010 and November 2011. Lymphocyte subsets including Tregs were analysed using flow cytometer (Beckman Coulter, Fullerton, CA, USA), and the reference intervals were defined using non-parametrical percentile methods according to the Clinical and Laboratory Standard Institute guideline (C28-A3). Results: The reference intervals for lymphocyte subsets were: helper T-cells (CD3+/CD4+), 15.40-70.06%; cytotoxic T-cells (CD3+/CD8+), 9.65-34.28%; B-cells (CD19+), 4.50-29.59%; and natural killer cells (CD3−/CD16+/CD56+), 1.42-28.03%. The reference interval for Tregs was 0.35-9.07%. Conclusions: This study provides the reference intervals for lymphocyte subsets including Tregs in umbilical cord blood from healthy full-term neonates. These results could be used as fundamental data for clinical laboratory tests as well as future researches. [ABSTRACT FROM AUTHOR]

Abstract: Piperazinyl derivatives of 1-(arylsulfonyl)-2,3-dihydro-1H-quinolin-4-ones have been identified with high binding affinities for 5-HT6 receptor. In particular, 2-methyl-5-(N-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one (8g) exhibits high binding affinity toward 5-HT6 (IC50 =8nM) receptor with good selectivity over other serotonin and dopamine receptors. [ABSTRACT FROM AUTHOR]

Abstract: (Piperazin-1-yl-phenyl)-arylsulfonamides were synthesized and identified to show high affinities for both 5-HT2C and 5-HT6 receptors. Among them, naphthalene-2-sulfonic acid isopropyl-[3-(4-methyl-piperazin-1-yl)-phenyl]-amide (6b) exhibits the highest affinity towards both 5-HT2C (IC50 =4nM) and 5-HT6 receptors (IC50 =3nM) with good selectivity over other serotonin (5-HT1A, 5-HT2A, and 5-HT7) and dopamine (D2–D4) receptor subtypes. In 5-HT2C and 5-HT6 receptor functional assays, this compound showed considerable antagonistic activity for both receptors. [ABSTRACT FROM AUTHOR]

We evaluated the immunomodulatory effects of three different classes of antifungal agents on the human monocytic cell line, THP-1, which had been stimulated in vitro with Aspergillus fumigatus conidia. Cells treated with amphotericin B (AmB), micafungin (MF), and voriconazole (VCZ), at concentrations not affecting cell viability, reduced production of tumor necrosis factor (TNF)-α in response to conidia, with the greatest reduction noted with VCZ. The reduction of TNF-α production correlated with TNF-α gene expression assessed by PCR and nuclear factor κB (NFκB) levels. Co-stimulation with granulocyte-macrophage colony stimulating factor abolished immunomodulatory effects of the drugs. Antifungal agents affect the immune reaction caused by A. fumigatus conidia in stimulated monocytes at clinically relevant drug concentrations. Because drugs with different mechanisms of action produced this effect, this suggests that it is the result of factors mediated by the cells. The impact of these immunomodulatory effects needs assessment. [ABSTRACT FROM AUTHOR]

Cardiotonic steroids are steroid-like natural compounds known to inhibit Na+/K+-ATPase pumps. To develop a broad-spectrum antiviral drug against the emerging coronavirus infection, this study assessed the antiviral properties of these compounds. The activity of seven types of cardiotonic steroids against the MERS-CoV, SARS-CoV, and SARS-CoV-2 coronavirus varieties was analyzed using immunofluorescence antiviral assay in virus-infected cells. Bufalin, cinobufagin, and telocinobufagin showed high anti-MERS-CoV activities (IC50, 0.017~0.027 μM); bufalin showed the most potent anti-SARS-CoV and SARS-CoV-2 activity (IC50, 0.016~0.019 μM); cinobufotalin and resibufogenin showed comparatively low anti-coronavirus activity (IC50, 0.231~1.612 μM). Differentially expressed genes in Calu3 cells treated with cinobufagin, telocinobufagin, or bufalin, which had high antiviral activity during MERS-CoV infection were analyzed using QuantSeq 3′ mRNA-Seq analysis and data showed similar gene expression patterns. Furthermore, the intraperitoneal administration of 10 mg/kg/day bufalin, cinobufagin, or digitoxin induced 100% death after 1, 2, and 4 days in 5-day repeated dose toxicity studies and it indicated that bufalin had the strongest toxicity. Pharmacokinetic studies suggested that telocinobufagin, which had high anti-coronavirus activity and low toxicity, had better microsomal stability, lower CYP inhibition, and better oral bioavailability than cinobufagin. Therefore, telocinobufagin might be the most promising cardiotonic steroid as a therapeutic for emerging coronavirus infections, including COVID-19. [ABSTRACT FROM AUTHOR]

Abstract: A novel series of 1H-indole-3-carboxylic acid pyridine-3-ylamides were synthesized and identified to show high affinity and selectivity for 5-HT2C receptor. Among them, 1H-indole-3-carboxylic acid[6-(2-chloro-pyridin-3-yloxy)-pyridin-3-yl]-amide (15k) exhibits the highest affinity (IC50 =0.5nM) with an excellent selectivity (>2000 times) over other serotonin (5-HT1A, 5-HT2A, and 5-HT6) and dopamine (D2–D4) receptors. [Copyright &y& Elsevier]