Discovery of new acetamide derivatives of 5-indole-1,3,4-oxadiazol-2-thiol as inhibitors of HIV-1 Tat-mediated viral transcription.

Human immunodeficiency virus-1 (HIV-1) encodes a transcriptional factor called Tat, which is critical for viral transcription. Tat-mediated transcription is highly ordered apart from the cellular manner; therefore, it is considered a target for developing anti-HIV-1 drugs. However, drugs targeting Tat-mediated viral transcription are not yet available.

A Novel Time-Resolved Fluorescence Resonance Energy Transfer Assay for the Discovery of Small-Molecule Inhibitors of HIV-1 Tat-Regulated Transcription.

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.

Identification of 3-Oxindole Derivatives as Small Molecule HIV-1 Inhibitors Targeting Tat-Mediated Viral Transcription.

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.

An Overview of Human Immunodeficiency Virus-1 Antiretroviral Drugs: General Principles and Current Status.

Treatment with highly active antiretroviral therapy (HAART) can prolong a patient's life-span by disrupting pivotal steps in the replication cycle of the human immunodeficiency virus-1 (HIV-1). However, drug resistance is emerging as a major problem worldwide due to the prolonged period of treatment undergone by HIV-1 patients. Since the approval of zidovudine in 1987, over thirty antiretroviral drugs have been categorized into the following six distinct classes based on their biological function and resistance profiles: (1) nucleoside analog reverse-transcriptase inhibitors; (2) non-nucleoside reverse transcriptase inhibitors; (3) integrase strand transferase inhibitors; (4) protease inhibitors; (5) fusion inhibitors; and (6) co-receptor antagonists.

Identification of Aristolactam Derivatives That Act as Inhibitors of Human Immunodeficiency Virus Type 1 Infection and Replication by Targeting Tat-Mediated Viral Transcription.

Despite the success of antiretroviral therapy (ART), efforts to develop new classes of antiviral agents have been hampered by the emergence of drug resistance. Dibenzo-indole-bearing aristolactams are compounds that have been isolated from various plants species and which show several clinically relevant effects, including anti-inflammatory, antiplatelet, and anti-mycobacterial actions. However, the effect of these compounds on human immunodeficiency virus type 1 (HIV-1) infection has not yet been studied.

Identification of novel compounds against Tat-mediated human immunodeficiency virus-1 transcription by high-throughput functional screening assay.

Trans-activator (Tat)-mediated human immunodeficiency virus type 1 (HIV-1) transcription is essential for the replication of HIV-1 and is considered a potent therapeutic target for HIV-1 inhibition. In this study, the Library of Pharmacologically Active Compounds (LOPAC) was screened using our dual-reporter screening system for repositioning as Tat-inhibitory compounds. Consequently, two compounds were found to be potent, with low cytotoxicity.

Epidemiological characteristics of HIV infected Korean: Korea HIV/AIDS Cohort Study.

Objectives: To manage evidence-based diseases, it is important to identify the characteristics of patients in each country.

Methods: The Korea HIV/AIDS Cohort Study seeks to identify the epidemiological characteristics of 1,442 Korean individuals with human immunodeficiency virus (HIV) infection (12% of Korean individuals with HIV infection in 2017) who visited 21 university hospitals nationwide. The descriptive statistics were presented using the Korea HIV/AIDS cohort data (2006-2016).

Development of a dual reporter screening assay for distinguishing the inhibition of HIV Tat-mediated transcription from off-target effects.

Human immunodeficiency virus (HIV) encodes a transcription trans-activator (Tat) with an essential role in the transcriptional elongation of viral RNA based on the viral promoter long terminal repeat (LTR). Tat-mediated transcription is conserved and can be distinguished from host transcription, so it is a therapeutic target for combating HIV replication. Traditional screening assays for Tat-mediated transcriptional inhibitors are based on the biochemical properties of Tat and transactivation-responsive RNA.

Activated protein C prevents methylglyoxal-induced endoplasmic reticulum stress and cardiomyocyte apoptosis via regulation of the AMP-activated protein kinase signaling pathway.

Previous epidemiological studies have shown that methylglyoxal (MGO) levels are highly regulated in diabetic cardiovascular diseases. We have also previously reported that MGO mediates ER stress and apoptosis in cardiomyocytes. Furthermore, activated protein C (APC) has recently been shown to play a protective role against ER stress, as well as a cardioprotective role against ischemia and reperfusion injury by augmenting the AMP-activated protein kinase (AMPK) signaling pathway.

Highly activated p53 contributes to selectively increased apoptosis of latently HIV-1 infected cells upon treatment of anticancer drugs.

Background: Despite the successful inhibition of human immunodeficiency virus type 1 (HIV-1) replication by combination antiretroviral therapy, cells latently infected with HIV-1 remaining in patients are a major obstacle for eradication of HIV-1 infection. The tumor suppressor factor p53 is activated by HIV-1 infection, and restricts HIV-1 replication. However, a therapeutic strategy based on p53 activity has not been considered for elimination of latently infected cells.

Functional characteristics of the natural polymorphisms of HIV-1 gp41 in HIV-1 isolates from enfuvirtide-naïve Korean patients.

HIV-1 gp41 plays a key role in viral entry. The insertion of Thr at position 4 and Met/Val/Phe substitutions at position 7 are frequently observed in the fusion peptide (FP) motif of gp41 without major enfuvirtide resistance associated with mutation in heptad repeats 1/2 (HR1/2) of HIV-1 isolates from Korean patients. Here, the influence of these mutations on their biological function was evaluated by employing HIV-1 variants with mutant FPs as shown previously and with recombinant HIV-1 using the env genes of 20 HIV-1 isolates from Korean patients.

Impaired IL-2 expression in latent HIV-1 infection.

Regarding the T cell function in HIV-1 infection, activation of T cells is enhanced in acutely HIV-1-infected T cells upon stimuli. However, T cell immune responses underlying the activation of T cell receptor (TCR) signaling molecules and interleukin (IL)-2 production in latently HIV-1-infected cells are poorly understood. The expression and activation of TCR components and its downstream molecules in acutely and latently HIV-1-infected T cells were compared using quantitative reverse transcription polymerase chain reaction (RT-PCR) for mRNA expression and enzyme-linked immunosorbent assay (ELISA) for levels of IL-2 in phytohemagglutinin M (PHA-M).

Interferon-inducible protein 10 (IP-10) is associated with viremia of early HIV-1 infection in Korean patients.

Cytokines/chemokines play key roles in modulating disease progression in human immunodeficiency virus (HIV) infection. Although it is known that early HIV-1 infection is associated with increased production of proinflammatory cytokines, the relationship between cytokine levels and HIV-1 pathogenesis is not clear. The concentrations of 18 cytokines/chemokines in 30 HIV-1 negative and 208 HIV-1 positive plasma samples from Korean patients were measured by the Luminex system.

Mutation of a positively charged cytoplasmic motif within CD1d results in multiple defects in antigen presentation to NKT cells.

CD1d is an MHC class I-like molecule that presents glycolipid Ags to types I and II NKT cells. The YxxI motif in the cytoplasmic tail of CD1d contributes to its intracellular localization to the endolysosomal compartment and is important for Ag presentation to type I NKT cells. In this study, we identified the (327-329)RRR motif in CD1d and showed that it is critical for the control of CD1d intracellular trafficking and Ag presentation.

Functional microscopy tip fabrication by an electric conductive nanowire.

The functional microscopy tip was fabricated by an electric conductive nanowire (NW). Single crystalline nickel silicide (NiSi) NW grown by plasma-enhanced chemical vapor deposition has an excellent electrical conductivity. On behalf of the advantages in tiny size and conductivity of NiSi NW, it was utilized as a nanoscale probe.

Blockade of airway inflammation and hyperresponsiveness by inhibition of BLT2, a low-affinity leukotriene B4 receptor.

BLT2 is a low-affinity receptor for leukotriene B(4) (LTB(4)), a potent lipid mediator of inflammation generated from arachidonic acid via the 5-lipoxygenase pathway. Unlike BLT1, a high-affinity receptor for LTB(4), no clear physiological function has yet been identified for BLT2, especially with regard to the pathogenesis of asthma. The aim of this study was to investigate whether BLT2 plays a role in the pathogenesis of asthma.

A nickel silicide nanowire microscopy tip obtains nanoscale information.

An electric conductive Ni silicide nanowire (NiSi NW) embedding electric force microscopy (EFM) tip was fabricated by the dielectrophoretic method and was used to obtain electric information. Due to the geometric and electric excellence, the NiSi NW provides advantages in imaging and fabrication of the microscopy tip. A lead zirconate titanate (PZT) ferroelectric thin film was positively and negatively polarized, and the polarities were obtained by probing of the NiSi NW EFM tip to give distinctive charging information of the PZT film.

PMA-induced up-regulation of MMP-9 is regulated by a PKCalpha-NF-kappaB cascade in human lung epithelial cells.

Expression of matrix metalloproteinase-9 (MMP-9) is associated with airway remodeling and tissue injury in asthma. However, little is known about how MMP-9 is up-regulated in airway epithelial cells. In this study, we show that phorbol myristate acetate (PMA) induces MMP-9 expression via a protein kinase Calpha (PKCalpha)-dependent signaling cascade in BEAS-2B human lung epithelial cells.