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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]

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]

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 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.

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 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]

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]

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]

Red seaweed, known as Rhodophyta, has a long history of use in traditional Asian medicine, including Traditional Chinese Medicine and Ayurveda. It is believed to have cooling and detoxification properties. Red seaweed species, such as Gracilaria, have been used in traditional remedies to address various conditions, such as inflammation, thyroid disorders, and digestive issues. Obesity is a risk factor of hepatic steatosis, a hallmark of non-alcoholic fatty liver disease (NAFLD) that affects nearly 25% of the worldwide population. Gracilaria chorda (GC) contains bioactive peptides that may be applicable in the prevention of metabolic syndrome diseases. This study investigated the effects of GC subcritical water extract at 210 °C (GCSW210) on preventing liver injury and lipid and glucose dysregulation in an oleic acid (OA)-induced hepatic steatosis cell model (HepG2) and high-fat diet (HFD)-induced obese animal model (C57BL/6J mice). Human hepatoma HepG2 cells were exposed to 0.1 mM OA for 24 h to induce hepatic steatosis and C57BL/6J mice were fed a HFD for 13 weeks. For lipid accumulation, triglyceride (TG) content was measured in both models, along with free fatty acid (FFA), plasma glucose, and insulin levels in HFD-fed mice. Protein expression of master regulators of adipogenesis and lipogenesis, as well as cholesterol and mitochondrial biosynthesis, was studied via western blotting in hepatic steatosis-induced in vitro and in vivo models. In addition, protein expression of the insulin signaling cascade in skeletal muscle tissues of HFD-fed mice was studied. GCSW210 significantly decreased lipid accumulation in HepG2 cells exposed to OA and suppressed the expression of lipogenic factors, such as sterol regulatory element-binding protein (SREBP)-1c and fatty acid synthase. In addition, GCSW210 abrogated transcription factors related to cholesterol biosynthesis, such as SREBP-2 and low-density lipoprotein receptor. Similarly, FFA, TG, serum glutamic acid, aspartate transaminase, alanine transferase, plasma glucose, and insulin levels were also significantly reduced in GCSW210-treated HFD-fed mice, which were comparable to the positive control mice treated with Garcinia cambogia extract. Additionally, GCSW210 enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase in the hepatic tissues of HFD-fed mice. Moreover, GCSW210 treatment improved insulin signal transduction by reducing insulin receptor substrate 1 Ser307 phosphorylation and elevated phosphatidylinositol 3-kinase/protein kinase B and glucose transporter type 4 protein expression in muscle tissue. 5-Hdroxymethylfufural (5-HMF) was confirmed to be active substances isolated from GCSW210 through LC-PDA and LC-MS. GCSW210 significantly regulated glucose metabolism, alleviated insulin resistance (IR) induced by high fatty acid synthesis and lipid accumulation, and elevated de novo lipogenesis by activating AMPK phosphorylation in both the liver and muscle tissues of HFD-fed mice. GCSW210 may be a potential functional food for preventing HFD-induced metabolic diseases, such as IR, NAFLD, and type 2 diabetes mellitus. [Display omitted] • GCSW210 alleviated lipid accumulation, fatty acid synthesis, and weight gain. • GCSW210 combat DNL by activating p-AMPK in liver and muscle tissues of HFD-mice. • GCSW210 modulates HFD-induced insulin resistance. • Thus, it improves metabolic diseases such as IR, NAFLD, and T2DM. • The major compound of GCSW210 is 5-HMF. [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]

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]