RESUMEN
Covering: 2015 to 2020The ent-kaurane diterpenoids are integral parts of tetracyclic natural products that are widely distributed in terrestrial plants. These compounds have been found to possess interesting bioactivities, ranging from antitumor, antifungal and antibacterial to anti-inflammatory activities. Structurally, the different tetracyclic moieties of ent-kauranes can be seen as the results of intramolecular cyclizations, oxidations, C-C bond cleavages, degradation, or rearrangements, starting from their parent skeleton. During the past decade, great efforts have been made to develop novel strategies for synthesizing these natural products. The purpose of this review is to describe the recent advances in the total synthesis of ent-kaurane diterpenoids covering the period from 2015 to date.
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Diterpenos de Tipo Kaurano/síntesis química , Diterpenos/síntesis química , Técnicas de Química Sintética/métodosRESUMEN
BACKGROUNDChimeric antigen receptor (CAR) T cells have emerged as an approach to treat malignant tumors. This strategy has also been proposed for the treatment of HIV-1 infection. We have developed a broadly neutralizing antibody-derived (bNAb-derived) CAR T cell therapy that can exert specific cytotoxic activity against HIV-1-infected cells.METHODSWe conducted an open-label trial of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of bNAb-derived CAR T cell therapy in individuals infected with HIV-1 who were undergoing analytical interruption of antiretroviral therapy (ART).RESULTSA total of 14 participants completed only a single administration of bNAb-derived CAR T cells. CAR T cell therapy administration was safe and well tolerated. Six participants discontinued ART, and viremia rebound occurred in all of them, with a 5.3-week median time. Notably, the cell-associated viral RNA and intact proviruses decreased significantly after CAR T cell treatment. Analyses of HIV-1 variants before or after CAR T cell administration suggested that CAR T cells exerted pressure on rebound viruses, resulting in a selection of viruses with less diversity and mutations against CAR T cell-mediated cytotoxicity.CONCLUSIONNo safety concerns were identified with adoptive transfer of bNAb-derived CAR T cells. They reduced viral reservoir. All the rebounds were due to preexisting or emergence of viral escape mutations.TRIAL REGISTRATIONClinicalTrials.gov (NCT03240328).FUNDINGMinistry of Science and Technology of China, National Natural Science Foundation of China, and Department of Science and Technology of Guangdong Province.
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Anticuerpos ampliamente neutralizantes/inmunología , Infecciones por VIH/terapia , VIH-1/inmunología , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos/inmunología , Carga Viral , Adulto , Linfocitos T CD4-Positivos/inmunología , Células HEK293 , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Current combined antiretroviral therapy (cART) mainly targets 3 of the 15 HIV proteins leaving many potential viral vulnerabilities unexploited. To purge the HIV-1 latent reservoir, various strategies including "shock and kill" have been developed. A key question is how to restore impaired immune surveillance. HIV-1 protein Nef has long been known to mediate the downregulation of cell-surface MHC-I and assist HIV-1 to evade the immune system. Through high throughput screening of Food and Drug Administration (FDA) approved drugs, we identified lovastatin, a statin drug, to significantly antagonize Nef to downregulate MHC-I, CD4, and SERINC5, and inhibit the intrinsic infectivity of virions. In addition, lovastatin boosted autologous CTLs to eradicate the infected cells and effectively inhibit the subsequent viral rebound in CD4+ T-lymphocytes isolated from HIV-1-infected individuals receiving suppressive cART. Furthermore, we found that lovastatin inhibits Nef-induced MHC-I downregulation by directly binding with Nef and disrupting the Nef-AP-1 complex. These results demonstrate that lovastatin is a promising agent for counteracting Nef-mediated downregulation of MHC-I, CD4, and SERINC5. Lovastatin could potentially be used in the clinic to enhance anti-HIV-1 immune surveillance.
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Infecciones por VIH/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Lovastatina/farmacología , Antígenos CD4/inmunología , Células Cultivadas , Técnicas de Cocultivo , Regulación hacia Abajo , VIH-1 , Humanos , Proteínas de la Membrana/inmunología , Linfocitos T/inmunología , Factor de Transcripción AP-1/inmunología , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
The inhibitory receptors PD-1, Tim-3, and Lag-3 are highly expressed on tumor-infiltrating lymphocytes and compromise their antitumor activity. For efficient cancer immunotherapy, it is important to prevent chimeric antigen receptor T (CAR-T)-cell exhaustion. Here we downregulate these three checkpoint receptors simultaneously on CAR-T cells and that show the resulting PTL-CAR-T cells undergo epigenetic modifications and better control tumor growth. Furthermore, we unexpectedly find increased tumor infiltration by PTL-CAR-T cells and their clustering between the living and necrotic tumor tissue. Mechanistically, PTL-CAR-T cells upregulate CD56 (NCAM), which is essential for their effector function. The homophilic interaction between intercellular CD56 molecules correlates with enhanced infiltration of CAR-T cells, increased secretion of interferon-γ, and the prolonged survival of CAR-T cells. Ectopically expressed CD56 promotes CAR-T cell survival and antitumor response. Our findings demonstrate that genetic blockade of three checkpoint inhibitory receptors and the resulting high expression of CD56 on CAR-T cells enhances the inhibition of tumor growth.
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Antígeno CD56/metabolismo , Neoplasias/inmunología , Neoplasias/terapia , Ingeniería de Proteínas , Receptores Quiméricos de Antígenos/metabolismo , Animales , Antineoplásicos/uso terapéutico , Apoptosis , Línea Celular Tumoral , Femenino , Células HEK293 , Humanos , Inmunoterapia Adoptiva , Ratones , Neoplasias/tratamiento farmacológico , Receptor ErbB-2/metabolismoRESUMEN
BACKGROUND: MOV10 protein has ATP-dependent 5'-3' RNA helicase activity and belongs to the UPF1p superfamily. It can inhibit human immunodeficiency virus type 1 (HIV-1) replication at multiple stages and interact with apolipoprotein-B-mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G or A3G), a member of the cytidine deaminase family that exerts potent inhibitory effects against HIV-1 infection. However, HIV-1-encoded virion infectivity factor (Vif) protein specifically mediates the degradation of A3G via the ubiquitin-proteasome system (UPS). RESULTS: We demonstrate that MOV10 counteracts Vif-mediated degradation of A3G by inhibiting the assembly of the Vif-CBF-ß-Cullin 5-ElonginB-ElonginC complex. Through interference with UPS, MOV10 enhances the level of A3G in HIV-1-infected cells and virions, and synergistically inhibits the replication and infectivity of HIV-1. In addition, the DEAG-box of MOV10 is required for inhibition of Vif-mediated A3G degradation as the DEAG-box mutant significantly loses this ability. CONCLUSIONS: Our results demonstrate a novel mechanism involved in the anti-HIV-1 function of MOV10. Given that both MOV10 and A3G belong to the interferon antiviral system, their synergistic inhibition of HIV-1 suggests that these proteins may play complicated roles in antiviral functions.
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Desaminasa APOBEC-3G/metabolismo , Infecciones por VIH/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , ARN Helicasas/metabolismo , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/metabolismo , Antivirales/metabolismo , Línea Celular Transformada , Células HEK293 , Infecciones por VIH/enzimología , Infecciones por VIH/virología , Interacciones Huésped-Patógeno/fisiología , Humanos , Mutación , ARN Helicasas/genética , Transducción de Señal , Ubiquitina/metabolismo , Replicación ViralRESUMEN
The discovery of PIWI-interacting RNAs (piRNAs) revealed the complexity of the RNA world. Although piRNAs were first deemed to be germline specific, substantial evidence shows their various roles in somatic cells; however, their function in highly differentiated immune cells remains elusive. In this study, by initially screening with a small RNA deep-sequencing analysis, we found that a piRNA, tRNA-Glu-derived piRNA [td-piR(Glu)], was expressed much more abundantly in human monocytes than in dendritic cells. By regulating the polymerase III activity, IL-4 potently decreased the biogenesis of tRNA-Glu and, subsequently, td-piR(Glu). Further, we revealed that the td-piR(Glu)/PIWIL4 complex recruited SETDB1, SUV39H1, and heterochromatin protein 1ß to the CD1A promoter region and facilitated H3K9 methylation. As a result, the transcription of CD1A was significantly inhibited. Collectively, we demonstrated that a piRNA acted as the signal molecule for a cytokine to regulate the expression of an important membrane protein for lipid Ag presentation.
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Antígenos CD1/genética , Células Dendríticas/inmunología , Interleucina-4/metabolismo , Monocitos/inmunología , ARN Interferente Pequeño/genética , Antígenos CD1/inmunología , Células Cultivadas , Células Dendríticas/metabolismo , Epigenómica , Células HEK293 , Heterocromatina/metabolismo , Humanos , Regiones Promotoras Genéticas , ARN Interferente Pequeño/metabolismo , Análisis de Secuencia de ADN , Transducción de Señal , Activación Transcripcional , Regulación hacia ArribaRESUMEN
PIWI-interacting RNA (piRNA) silences the transposons in germlines or induces epigenetic modifications in the invertebrates. However, its function in the mammalian somatic cells remains unknown. Here we demonstrate that a piRNA derived from Growth Arrest Specific 5, a tumor-suppressive long non-coding RNA, potently upregulates the transcription of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a proapoptotic protein, by inducing H3K4 methylation/H3K27 demethylation. Interestingly, the PIWIL1/4 proteins, which bind with this piRNA, directly interact with WDR5, resulting in a site-specific recruitment of the hCOMPASS-like complexes containing at least MLL3 and UTX (KDM6A). We have indicated a novel pathway for piRNAs to specially activate gene expression. Given that MLL3 or UTX are frequently mutated in various tumors, the piRNA/MLL3/UTX complex mediates the induction of TRAIL, and consequently leads to the inhibition of tumor growth.