Apigenin improves cytotoxicity of antiretroviral drugs against HTLV-1 infected cells through the modulation of AhR signaling.

Objectives: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neuroinflammatory autoimmune disease characterized by high levels of infected immortalized T cells in circulation, which makes it difficult for antiretroviral (ART) drugs to work effectively. In previous studies, we established that Apigenin, a flavonoid, can exert immunomodulatory effects to reduce neuroinflammation. Flavonoids are natural ligands for the aryl hydrocarbon receptor (AhR), which is a ligand activated endogenous receptor involved in the xenobiotic response.

Regulation of human T-cell leukemia virus type 1 antisense promoter by myocyte enhancer factor-2C in the context of adult T-cell leukemia and lymphoma.

Adult T-cell leukemia and lymphoma (ATLL) is an intractable T-cell neoplasia caused by a retrovirus, namely human T-cell leukemia virus type 1 (HTLV-1). Patients suffering from ATLL present a poor prognosis and have a dearth of treatment options. In contrast to the sporadic expression of viral transactivator protein Tax present at the 5' promoter region long terminal repeats (LTR), HTLV-1 bZIP gene (HBZ) is encoded by 3'LTR (the antisense promoter) and maintains its constant expression in ATLL cells and patients.

Can Soluble Immune Checkpoint Molecules on Exosomes Mediate Inflammation?

Immune checkpoints (ICPs) are major co-signaling pathways that trigger effector functions in immune cells, with isoforms that are either membrane bound, engaging in direct cell to cell activation locally, or soluble, acting at distant sites by circulating freely or potentially via extracellular vesicles (EVs). Exosomes are small EVs secreted by a variety of cells carrying various proteins and nucleic acids. They are distributed extensively through biological fluids and have major impacts on infectious diseases, cancer, and neuroinflammation.

Apigenin Modulates Dendritic Cell Activities and Curbs Inflammation Via RelB Inhibition in the Context of Neuroinflammatory Diseases.

Neuroinflammation leads to tissue injury causing many of the clinical symptoms of Multiple Sclerosis, an autoimmune disorder of the central nervous system (CNS). While T cells, specifically T1 and T17 cells, are the ultimate effectors of this disease, dendritic cells (DCs) mediate T cell polarization, activation, etc. In our previous study, Apigenin, a natural flavonoid, has been shown to reduce EAE disease severity through amelioration of demyelination in the CNS as well as the sequestering of DCs and other myeloid cells in the periphery.

MEF-2 isoforms' (A-D) roles in development and tumorigenesis.

Myocyte enhancer factor (MEF)-2 plays a critical role in proliferation, differentiation, and development of various cell types in a tissue specific manner. Four isoforms of MEF-2 (A-D) differentially participate in controlling the cell fate during the developmental phases of cardiac, muscle, vascular, immune and skeletal systems. Through their associations with various cellular factors MEF-2 isoforms can trigger alterations in complex protein networks and modulate various stages of cellular differentiation, proliferation, survival and apoptosis.

Potential Role of Flavonoids in Treating Chronic Inflammatory Diseases with a Special Focus on the Anti-Inflammatory Activity of Apigenin.

Inflammation has been reported to be intimately linked to the development or worsening of several non-infectious diseases. A number of chronic conditions such as cancer, diabetes, cardiovascular disorders, autoimmune diseases, and neurodegenerative disorders emerge as a result of tissue injury and genomic changes induced by constant low-grade inflammation in and around the affected tissue or organ. The existing therapies for most of these chronic conditions sometimes leave more debilitating effects than the disease itself, warranting the advent of safer, less toxic, and more cost-effective therapeutic alternatives for the patients.

Human T cell leukemia virus type 1 and Zika virus: tale of two reemerging viruses with neuropathological sequelae of public health concern.

Human T cell leukemia virus type 1 (HTLV-1) and Zika virus (ZIKV) have been considered neglected viruses of low public health concern until recently when incidences of HTLV-1 and ZIKV were observed to be linked to serious immune-related disease and neurological complications. This review will discuss the epidemiology, genomic evolution, virus-host interactions, virulence factors, neuropathological sequelae, and current perspectives of these reemerging viruses. There are no FDA-approved therapeutics or vaccines against these viruses, and as such, it is important for clinical trials to focus on developing vaccines that can induce cell-mediated immune response to confer long-term protective immunity.

Diminished TLR2-TLR9 mediated CD4+ T cell responses are associated with increased inflammation in intraocular tuberculosis.

Intraocular tuberculosis (IOTB) is amongst the leading causes of uveitis in tropical countries. Despite reports on involvement of proinflammatory cytokines, studies on innate immune responses in disease pathogenesis are lacking. Reports from animal models and patients with pulmonary tuberculosis indicate that defects in toll like receptor (TLR)2 and TLR9 signalling predispose them to tuberculosis.

In vivo and in vitro immunogenicity of novel MHC class I presented epitopes to confer protective immunity against chronic HTLV-1 infection.

Human T-cell leukemia virus type 1 (HTLV-1) has infected as many as 10 million people worldwide. While 90% are asymptomatic, 5% develop severe diseases including adult T-cell leukemia/lymphoka (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). No vaccine against HTLV-1 exists, and screening programs are not universal.

FDC:TFH Interactions within Cervical Lymph Nodes of SIV-Infected Rhesus Macaques.

Cerebrospinal fluid (CSF) drains via the lymphatic drainage pathway. This lymphatic pathway connects the central nervous system (CNS) to the cervical lymph node (CLN). As the CSF drains to CLN via the dural and nasal lymphatics, T cells and antigen presenting cells pass along the channels from the subarachnoid space through the cribriform plate.

Antibody blockade of CLEC12A delays EAE onset and attenuates disease severity by impairing myeloid cell CNS infiltration and restoring positive immunity.

The mechanism of dendritic cells (DCs) recruitment across the blood brain barrier (BBB) during neuroinflammation has been the least explored amongst all leukocytes. For cells of myeloid origin, while integrins function at the level of adhesion, the importance of lectins remains unknown. Here, we identified functions of one C-type lectin receptor, CLEC12A, in facilitating DC binding and transmigration across the BBB in response to CCL2 chemotaxis.

HTLV-1 Infection and Neuropathogenesis in the Context of Rag1γc (RAG1-Hu) and BLT Mice.

To date, the lack of a suitable small animal model has hindered our understanding of Human T-cell lymphotropic virus (HTLV)-1 chronic infection and associated neuropathogenesis defined as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The host immune response plays a critical role in the outcome of HTLV-1 infection, which could be better tested in the context of humanized (hu) mice. Thus, we employ here the Balb/c-Rag1γc or Rag1 as well as Bone marrow-Liver-Thymic (BLT) mouse models for engraftment of human CD34 hematopoietic stem cells.

Short Communication: Inhibition of DC-SIGN-Mediated HIV-1 Infection by Complementary Actions of Dendritic Cell Receptor Antagonists and Env-Targeting Virus Inactivators.

The DC-SIGN receptor on human dendritic cells interacts with HIV gp120 to promote both infection of antigen-presenting cells and transinfection of T cells. We hypothesized that in DC-SIGN-expressing cells, both DC-SIGN ligands such as dextrans and gp120 antagonists such as peptide triazoles would inhibit HIV infection with potential complementary antagonist effects. To test this hypothesis, we evaluated the effects of dextran (D66), isomaltooligosaccharides (D06), and several peptide triazoles (HNG156, K13, and UM15) on HIV infection of B-THP-1/DC-SIGN cells.

IFN-α-Induced Downregulation of miR-221 in Dendritic Cells: Implications for HCV Pathogenesis and Treatment.

Although interferon (IFN)-α is known to exert immunomodulatory and antiproliferative effects on dendritic cells (DCs) through induction of protein-coding IFN-stimulated genes (ISGs), little is known about IFN-α-regulated miRNAs in DCs. Since several miRNAs are involved in regulating DC functions, it is important to investigate whether IFN-α's effects on DCs are mediated through miRNAs as well. In this study, we examined miRNA expression patterns in myeloid DCs (mDCs) and plasmacytoid DCs after exposing them to IFN-α.

Apigenin, a Natural Flavonoid, Attenuates EAE Severity Through the Modulation of Dendritic Cell and Other Immune Cell Functions.

Apigenin, a natural flavonoid, found in several plants, fruits, vegetables, herbs, and spices, is known to have anti-oxidant and anti-inflammatory properties that are evident in the use of these substances for centuries as medicinal approaches to treat asthma, insomnia, Parkinson's disease, neuralgia, and shingles. However, there is a considerable dearth of information regarding its effect on immune cells, especially dendritic cells (DC) that maintain the critical balance between an immunogenic and tolerogenic immune response, in an immunospecialized location like the central nervous system (CNS). In this paper we looked at the anti-inflammatory properties of Apigenin in restoration of immune function and the resultant decrease in neuroinflammation.

Host Genetic Factors and Dendritic Cell Responses Associated with the Outcome of Interferon/Ribavirin Treatment in HIV-1/HCV Co-Infected Individuals.

HIV-1/HCV co-infection is a significant health problem. Highly active antiretroviral treatment (HAART) against HIV-1 has proved to be fairly successful. On the other hand, direct acting antiviral drugs against HCV have improved cure rates but high cost and development of drug resistance are important concerns.

Targeting the C-type lectins-mediated host-pathogen interactions with dextran.

Dextran, the α-1,6-linked glucose polymer widely used in biology and medicine, promises new applications. Linear dextran applied as a blood plasma substitute demonstrates a high rate of biocompatibility. Dextran is present in foods, drugs, and vaccines and in most cases is applied as a biologically inert substance.

In vivo immunogenicity of Tax(11-19) epitope in HLA-A2/DTR transgenic mice: implication for dendritic cell-based anti-HTLV-1 vaccine.

Viral oncoprotein Tax plays key roles in transformation of human T-cell leukemia virus (HTLV-1)-infected T cells leading to adult T-cell leukemia (ATL), and is the key antigen recognized during HTLV-associated myelopathy (HAM). In HLA-A2+ asymptomatic carriers as well as ATL and HAM patients, Tax(11-19) epitope exhibits immunodominance. Here, we evaluate CD8 T-cell immune response against this epitope in the presence and absence of dendritic cells (DCs) given the recent encouraging observations made with Phase 1 DC-based vaccine trial for ATL.

Effect of morphine and SIV on dendritic cell trafficking into the central nervous system of rhesus macaques.

Recruitment of immune cells such as monocytes/macrophages and dendritic cells (DCs) across the blood-brain barrier (BBB) has been documented in diseases involving neuroinflammation. Neuroinvasion by HIV leads to neurocognitive diseases and alters the permeability of the BBB. Likewise, many HIV patients use drugs of abuse such as morphine, which can further compromise the BBB.

Lack of recall response to Tax in ATL and HAM/TSP patients but not in asymptomatic carriers of human T-cell leukemia virus type 1.

Purpose & Methods: The immunopathogenic mechanisms responsible for debilitating neurodegenerative and oncologic diseases associated with human T-cell leukemia virus type 1 (HTLV-1) are not fully understood. Quality of cytotoxic T lymphocytes (CTLs) is being increasingly associated with the outcome of persistent HTLV-1 infection. In this respect, a patient cohort (from HTLV-1 endemic region) consisting of seronegative controls (controls), asymptomatic carriers (ACs), and patients with adult T-cell leukemia (ATL) or HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) was analyzed for CD8(+) T cells polyfunctionality in response to the viral antigen Tax.

An altered maturation and adhesion phenotype of dendritic cells in diseased individuals compared to asymptomatic carriers of human T cell leukemia virus type 1.

The immunopathogenic mechanisms underlying human T cell leukemia virus type 1 (HTLV-1)-mediated diseases such as adult T cell leukemia (ATL) and HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are not clearly understood. As critical effectors of antiviral immune response, dendritic cells (DCs) are implicated to play an important role in determining the outcome of HTLV-1 infection. However, a complete understanding of their role in any disease pathogenesis requires extensive assessment of the phenotypic and functional state of DCs.

Dendritic Cells in HIV-1 and HCV Infection: Can They Help Win the Battle?

Persistent infections with human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) are a major cause of morbidity and mortality worldwide. As sentinels of our immune system, dendritic cells (DCs) play a central role in initiating and regulating a potent antiviral immune response. Recent advances in our understanding of the role of DCs during HIV-1 and HCV infection have provided crucial insights into the mechanisms employed by these viruses to impair DC functions in order to evade an effective immune response against them.

Cotranscriptional Chromatin Remodeling by Small RNA Species: An HTLV-1 Perspective.

Cell type specificity of human T cell leukemia virus 1 has been proposed as a possible reason for differential viral outcome in primary target cells versus secondary. Through chromatin remodeling, the HTLV-1 transactivator protein Tax interacts with cellular factors at the chromosomally integrated viral promoter to activate downstream genes and control viral transcription. RNA interference is the host innate defense mechanism mediated by short RNA species (siRNA or miRNA) that regulate gene expression.