Dexrazoxane inhibits the growth of esophageal squamous cell carcinoma by attenuating SDCBP/MDA-9/syntenin-mediated EGFR-PI3K-Akt pathway activation.

Syndecan-binding protein (SDCBP) was reported to stimulate the advancement of esophageal squamous cell carcinoma (ESCC) and could potentially be a target for ESCC treatment. There is a growing corpus of research on the anti-tumor effects of iron chelators; however, very few studies have addressed the involvement of dexrazoxane in cancer. In this study, structure-based virtual screening was employed to select drugs targeting SDCBP from the Food and Drug Administration (FDA)-approved drug databases. The sepharose 4B beads pull-down assay revealed that dexrazoxane targeted SDCBP by interacting with its PDZ1 domain. Additionally, dexrazoxane inhibited ESCC cell proliferation and anchorage-independent colony formation via SDCBP. ESCC cell apoptosis and G2 phase arrest were induced as measured by the flow cytometry assay. Subsequent research revealed that dexrazoxane attenuated the binding ability between SDCBP and EGFR in an immunoprecipitation assay. Furthermore, dexrazoxane impaired EGFR membrane localization and inactivated the EGFR/PI3K/Akt pathway. In vivo, xenograft mouse experiments indicated that dexrazoxane suppressed ESCC tumor growth. These data indicate that dexrazoxane might be established as a potential anti-cancer agent in ESCC by targeting SDCBP.

Long Noncoding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 Promotes HIV-1 Replication through Modulating microRNAs in Macrophages.

Macrophages can serve as a reservoir for human immunodeficiency-1 (HIV-1) virus in host cells, constituting a barrier to eradication, even in patients who are receiving antiretroviral therapy. Although many noncoding RNAs have been characterized as regulators in HIV-1/AIDS-induced immune response and pathogenesis, only a few long noncoding RNAs (lncRNAs) have demonstrated a close association with HIV-1 replication, and the molecular mechanisms remain unknown. In this study, we investigated how lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), related microRNAs, and key inflammatory genes alter HIV-1 replication in macrophages. Our data show that HIV-1 infection modulates the expression of miR-155 and miR-150-5p in a time-dependent manner, which is regulated by MALAT1. MALAT1 induced suppressor of cytokine signaling 1 (SOCS1) expression by sponging miR-150-5p in HIV-1-infected macrophages and stimulated inflammatory mediators triggering receptor expressed on myeloid cells/cold inducible RNA binding protein (TREM 1/CIRP) ligand/receptor. The RNA immunoprecipitation (RIP) assay validated the direct interaction within the MALAT1/miR-150-5p/SOCS1 axis. HIV-1 infection-mediated upregulation of MALAT1, SOCS1, and HIV-1 Gag was attenuated by SN50 (an NF-кB p50 inhibitor). MALAT1 antisense oligonucleotides (ASOs) suppressed HIV-1 p24 production and HIV-1 Gag gene expression and decreased expression of miR-155 and SOCS1, as well as the production of proinflammatory cytokines by HIV-1-infected macrophages. In conclusion, HIV-1 infection induces MALAT1, which attenuates miR-150-5p expression and increases SOCS1 expression, promoting HIV-1 replication and reactivation. These data provide new insights into how MALAT1 alters the macrophage microenvironment and subsequently promotes viral replication and suggest a potential role for targeting MALAT1 as a therapeutic approach to eliminate HIV-1 reservoirs. IMPORTANCE Viral reservoirs constitute an obstacle to curing HIV-1 diseases, despite antiretroviral therapy. Macrophages serve as viral reservoirs in HIV infection by promoting long-term replication and latency. Recent studies have shown that lncRNAs can modulate virus-host interactions, but the underlying mechanisms are not fully understood. In this study, we demonstrate how lncRNA MALAT1 contributes to HIV-1 replication through modulation of the miR-150/SOCS1 axis in human macrophages. Our findings have the potential to identify new therapies for eliminating HIV-1 reservoirs in immune cells.

Bioinformatics and experimental validation of an AURKA/TPX2 axis as a potential target in esophageal squamous cell carcinoma.

Aurora kinase A (AURKA), a serine/threonine kinase that regulates mitotic processes, has garnered significant interest given its association with the development of several types of cancer. In the present study, it was shown that AURKA expression was significantly upregulated in esophageal squamous cell carcinoma (ESCC) and could serve as a diagnostic and prognostic indicator based on data obtained from The Cancer Genome Atlas (TCGA) and immunohistochemical analysis. In addition, AURKA was functionally associated with ESCC cell proliferation and colony formation in vitro and knockdown of AURKA inhibited ESCC tumor growth in vivo. Both bioinformatics analysis and pull­down assays demonstrated that TPX2 interacted with AURKA, and their expression was correlated. AURKA cooperated with TPX2 to regulate ESCC progression via the PI3K/Akt pathway. Furthermore, AURKA or TPX2 expression levels were negatively associated with the infiltration of cytotoxic cells, CD8+ T cells and mast cells, but positively associated with Th2 cells. The present study provided a relatively comprehensive understanding of the oncogenic roles of AURKA in ESCC based on data obtained from TCGA combined with experimental analysis.

Long Non-coding RNA LINC01426 Contributes to the Malignant Behaviors of NSCLC Via Acting As a Sponge for miR-143-3p.

Recently, long non-coding RNA (lncRNA) is proved to play critical roles in non-small cell lung cancer (NSCLC) progression. However, the detailed effects of LINC01426 in NSCLC and its functional mechanism remain unknown. The expression of LINC01426, microRNA-143-3p (miR-143-3p), and Ubiquitin-specific peptidase 28 (USP28) was assessed by quantitative real-time polymerase chain reaction (RT-qPCR). The colony-forming ability was determined by colony-forming assay. 5-ethynyl-2'-deoxyuridine (EdU) staining assay was performed to evaluate cell proliferation. The migrated and invaded abilities of cells were measured by transwell assays. Flow cytometry was used to examine cell apoptosis. The protein expression was analyzed by Western blot analysis. The glycolysis ability was analyzed by commercial kits. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA pull-down assay were used to confirm relationship among LINC01426, miR-143-3p, and USP28. A xenograft experiment was conducted to explore the effects of LINC01426 inhibition in vivo. Our results confirmed that LINC01426 and USP28 expression were increased, while miR-143-3p expression was decreased in NSCLC tissues and cells. Further functional experiments demonstrated that LINC01426 inhibition markedly impaired cell proliferation, migration, invasion, autophagy, and glycolysis while induced apoptosis in NSCLC cells, and LINC01426 derived malignant behaviors of NSCLC cells by sponging miR-143-3p. Additionally, LINC01426 regulated USP28 expression by sponging miR-143-3p. USP28 overexpression partly overturned the inhibitory effect of miR-143-3p on NSCLC progression. Consistently, silencing of LINC01426 significantly inhibited the growth of NSCLC tumor in vivo. LINC01426 accelerated the malignant progression of NSCLC. Mechanistically, LINC01426 acted as a competing endogenous RNA (ceRNA) for miR-143-3p to upregulate USP28 expression.

LncRNA PTPRG-AS1 facilitates glycolysis and stemness properties of esophageal squamous cell carcinoma cells through miR-599/PDK1 axis.

BACKGROUND AND AIM: Esophageal squamous cell carcinoma (ESCC) is the most significant subtype of esophageal cancer featured with high occurrence. Long noncoding RNAs (lncRNAs) have been proved to modulate the biological properties of cancer cells, including cell proliferation, invasion, migration, and apoptosis. LncRNA protein tyrosine phosphatase receptor type G-antisense RNA 1 (PTPRG-AS1) has been reported to play as an oncogene in diverse cancers. However, the detailed function PTPRG-AS1 may exert in ESCC is unclear. METHODS: PTPRG-AS1 expression in ESCC cells was investigated via quantitative reverse transcription real-time polymerase chain reaction (RT-qPCR). The effects of PTPRG-AS1 on ESCC cell proliferation, migration, glycolysis, and stemness were verified through functional assays. Mechanism assays including RIP assay, RNA pull down assay, and luciferase reporter assays were performed to verify the molecular mechanism of PTPRG-AS1. RESULTS: PTPRG-AS1 silencing hindered the proliferation, migration, glycolysis and stemness of ESCC cells. PTPRG-AS1 regulated pyruvate dehydrogenase kinase 1 (PDK1) expression via sponging miR-599. The PTPRG-AS1/miR-599/PDK1 axis was further verified to aggravate the progression of ESCC cells. CONCLUSION: PTPRG-AS1 sponged miR-599 to up-regulate PDK1 expression, thereby promoting the proliferation and migration as well as glycolysis and stemness properties of ESCC cells.

GFI1 promotes the proliferation and migration of esophageal squamous cell carcinoma cells through the inhibition of SOCS1 expression.

Growth factor­independent 1 (GFI1) has been reported to serve a vital role in hematopoietic development. However, the function and molecular mechanism of GFI1 in esophageal squamous cell carcinoma (ESCC) remains unknown. In the present study, the biological functions and the molecular mechanism of the effects of GFI1 in ESCC were analyzed. The results demonstrated that GFI1 expression levels were significantly upregulated in ESCC compared with those in normal esophageal tissues. Knockdown of GFI1 using small interfering RNA suppressed ESCC cell proliferation and migration. Furthermore, GFI1 enhanced STAT3 and NF­κB signaling by inhibiting the expression of suppressor of cytokine signaling 1 (SOCS1) in ESCC cells. Taken together, the results of the present study demonstrated that GFI1 promoted the proliferation and migration of ESCC cells via inhibition of SOCS1 expression. These results suggested that GFI1 may be a valuable target for ESCC therapy.

Interaction between Phonological and Semantic Processes in Visual Word Recognition using Electrophysiology.

Controversies have always existed in research related to reading abilities; on whether printed words are perceived in a feedforward manner based on orthographic information after which, other representations, such as phonology and semantics are activated, or whether these are fully interactive and high-level semantic information affects early processing. An interference paradigm was implemented in the presented protocol of phonological and semantic judgment tasks that utilized the same precede-target pairs to explore the relative order of phonological and semantic activation. The high- and low-frequency target words were preceded with three conditions: semantically related, phonological-related (homophones), or unrelated. The results showed that the induced P200 component of low-frequency word pairs was significantly greater than high-frequency words in both the semantic and phonological tasks. In addition, both the homophones in the semantic task and the semantically related pairs in the phonological task caused reduction in N400 when compared to the the control condition, word frequency-independently. It is worth noting that for the low-frequency pairs in the phonological judgment task, the P200 released by the semantically related word pairs was significantly larger than that in the control condition. Overall, semantic processing in phonological tasks and phonological processing in semantic tasks were found in both high- and low-frequency words, suggesting that the interaction between semantics and phonology may operate in a task-independent manner. However, the specific time this interaction occurred may have been affected by the task and frequency.

Delving Into the Working Mechanism of Prediction in Sentence Comprehension: An ERP Study.

The present study aims to delineate the working mechanism of prediction in sentence comprehension, by disentangling the influence of the facilitated general memory retrieval from the coexistent influence of the predicted language-specific semantic and/or syntactic information for the first time. The results support that prediction might influence the downstream cognitive processing in two aspects: (1) the pre-activated information facilitates the retrieval of a matched input in memory and, (2) the pre-activated information interacts with higher-level semantic/syntactic processing. More importantly, the present findings suggest that these two types of influences seem to occur at different stages of sentence comprehension: the facilitated memory retrieval of the input modulates N400 amplitude and the latency of post-N400 late central-parietal positivity/P600, while the predicted semantic/syntactic information and/or their interactions modulate the amplitude of the late positivity. The present findings would be helpful for interpreting the underlying mechanism of observed effects in prediction studies.

An ERP Study on the Role of Phonological Processing in Reading Two-Character Compound Chinese Words of High and Low Frequency.

Unlike in English, the role of phonology in word recognition in Chinese is unclear. In this event-related potential experiment, we investigated the role of phonology in reading both high- and low-frequency two-character compound Chinese words. Participants executed semantic and homophone judgment tasks of the same precede-target pairs. Each pair of either high- or low-frequency words were either unrelated (control condition) or related semantically or phonologically (homophones). The induced P200 component was greater for low- than for high-frequency word-pairs both in semantic and phonological tasks. Homophones in the semantic judgment task and semantically-related words in the phonology task both elicited a smaller N400 than the control condition, word frequency-independently. However, for low-frequency words in the phonological judgment task, it was found that the semantically related pairs released a significantly larger P200 than the control condition. Thus, the semantic activation of both high- and low-frequency words may be no later than phonological activation.

Endoscopic resection versus esophagectomy for early esophageal cancer: a meta-analysis.

BACKGROUND: Esophagectomy is the standard treatment for early-stage esophageal cancer but is associated with high morbidity and mortality. Thus, endoscopic resection is increasingly used as an alternative option. However, the literature is inconsistent regarding the efficacy of these treatments. This meta-analysis aimed to compare the efficacy and safety of these two treatments. METHODS: A systematic electronic search of PubMed, EMBASE, and the Cochrane Library was performed for studies comparing endoscopic resection and surgery for early-stage esophageal cancer. The overall survival, tumor recurrence, major adverse events, procedure-related mortality, and R0 resection rates were investigated. Forest plots were constructed based on the random-effects model. RESULTS: We found 15 studies involving 2,467 and 2,264 patients who underwent endoscopic resection and surgery, respectively. The meta-analysis showed that patients undergoing endoscopic resection had significantly fewer major adverse events (relative risk, 0.46; 95% confidence interval, 0.33-0.64) and a lower procedure-related mortality rate (relative risk, 0.27; 95% confidence interval, 0.10-0.73) than those undergoing surgery. The number of postprocedural stricture events did not significantly differ between the two treatments (relative risk, 0.89; 95% confidence interval, 0.53-1.49). Endoscopic resection was associated with higher recurrence rates (relative risk, 1.69; 95% confidence interval, 0.99-2.89) and lower R0 resection rates (relative risk, 0.92; 95% confidence interval, 0.86-0.98) than surgery. There may be some advantage conferred by esophagectomy in the long-term survival outcomes (hazard ratio, 1.21; 95% confidence interval, 1.02-1.43). DISCUSSION: Endoscopic resection is a minimally invasive and safe treatment for early-stage esophageal cancer. However, esophagectomy may be associated with better long-term survival.

Urban airborne PM2.5-activated microglia mediate neurotoxicity through glutaminase-containing extracellular vesicles in olfactory bulb.

Emerging evidence has showed that exposure to airborne particulate matter (PM) with an aerodynamic diameter less than 2.5 µm (PM2.5) is associated with neurodegeneration. Our previous studies in vitro found that PM2.5 exposure causes primary neurons damage through activating microglia. However, the molecular mechanism of microglia-mediated neurotoxicity remains to elucidate. In this study, five groups (N = 13 or 10) of six-week-old male C57BL/6 mice were daily exposed to PM2.5 (0.1 or 1 mg/kg/day body weight), Chelex-treated PM2.5 (1 mg/kg/day body weight), PM2.5 (1 mg/kg/day body weight) plus CB-839 (glutaminase inhibitor), or deionized water by intranasal instillation for 28 days, respectively. Compared with the control groups, We found that PM2.5 triggered reactive oxygen species (ROS) generation and microglia activation evidenced by significant increase of ionized calcium binding adaptor molecule-1 (IBa-1) staining in the mouse olfactory bulbs (OB). Data from transmission electron microscope (TEM) images and Western blot analysis showed that PM2.5 significantly increased extracellular vesicles (EVs) release from OB or murine microglial line BV2 cells, and glutaminase C (GAC) expression and glutamate generation in isolated OB and BV2 cells. However, treatment with N-acetylcysteine (NAC) or CB-839 significantly diminished the number of EVs and the expression of GAC and abolished PM2.5-induced neurotoxicity. These findings provide new insights that PM2.5 induces oxidative stress and microglia activation through its metal contents and glutaminase-containing EVs in OBs, which may serve as a potential pathway/mechanism of excessive glutamate generation in PM2.5-induced neurotoxicity.

Activation of LXRß Signaling in the Amygdala Confers Anxiolytic Effects Through Rebalancing Excitatory and Inhibitory Neurotransmission upon Acute Stress.

The balance of major excitatory (glutamate, Glu) and inhibitory (γ-aminobutyric acid, GABA), named as E/I neurotransmission, is critical for proper information processing. Anxiety-like responses upon stress are accompanied by abnormal alterations in the formation and function of synapses, resulting in the imbalance of E/I neurotransmission in the amygdala. Liver X receptors (LXRs), including LXRα and LXRß isoforms, are nuclear receptors responsible for regulating central nervous system (CNS) functions besides maintaining metabolic homeostasis. However, little is known about the contribution of LXRs in E/I balance in regulating anxiety-related behaviors induced by stress. In this study, we found stress-induced anxiety led to the expression reduction of LXRß not LXRα in mice amygdala. GW3965, a dual agonist for both LXRα and LXRß, alleviated anxiety-like behaviors of stressed mice through activation of LXRß, confirmed by the knockdown of LXRß mediated by lentiviral shRNAs in the basolateral amygdala (BLA). This was paralleled by correcting the disequilibrium of E/I neurotransmission in the stressed BLA. Importantly, GW3965 exerted anxiolytic effects by correcting the promoted amplitude and frequency of miniature excitatory postsynaptic current (mEPSC), and augmenting the decreased that of miniature inhibitory postsynaptic current (mIPSC) in the stressed BLA. This suggests that stress-induced anxiety-like behaviors can largely be ascribed to the deficit of LXRß signaling in E/I neurotransmission in BLA. These findings highlight the deficiency of LXRß signaling in the amygdala linked to anxiety disorder, and LXRß activation may represent a potential novel target for anxiety treatment with an alteration in synaptic transmission in the amygdala.

Glutaminase 1 Regulates Neuroinflammation After Cerebral Ischemia Through Enhancing Microglial Activation and Pro-Inflammatory Exosome Release.

Cerebral ischemia induces a robust neuroinflammatory response that is largely mediated by the activation of CNS resident microglia. Activated microglia produce pro-inflammatory molecules to cause neuronal damage. Identifying regulators of microglial activation bears great potential in discovering promising candidates for neuroprotection post cerebral ischemia. Previous studies demonstrate abnormal elevation of glutaminase 1 (GLS1) in microglia in chronic CNS disorders including Alzheimer's disease and HIV-associated neurocognitive disorders. Ectopic expression of GLS1 induced microglia polarization into pro-inflammatory phenotype and exosome release in vitro. However, whether GLS1 is involved in neuroinflammation in acute brain injury remains unknown. Here, we observed activation of microglia, elevation of GLS1 expression, and accumulation of pro-inflammatory exosomes in rat brains 72 h post focal cerebral ischemia. Treatment with CB839, a glutaminase inhibitor, reversed ischemia-induced microglial activation, inflammatory response, and exosome release. Furthermore, we found that the application of exosome secretion inhibitor, GW4869, displayed similar anti-inflammatory effects to that of CB839, suggesting GLS1-mediated exosome release may play an important role in the formation of neuroinflammatory microenvironment. Therefore, GLS1 may serve as a key mediator and promising target of neuroinflammatory response in cerebral ischemia.

miR-106b regulates the proliferation and differentiation of neural stem/progenitor cells through Tp53inp1-Tp53-Cdkn1a axis.

BACKGROUND: Recent studies suggested that miR-17~106 family was involved in the regulation of neural stem/progenitor cells (NPCs). However, distinct function of each family member was reported in regulating stem cells within and without the brain. Hence, to investigate the roles of individual miRNAs in miR-17~106 family and mechanisms underlying their effects on neurogenesis is important to extend our understanding in the CNS development. METHODS: Here, we examined the influence of miR-106a/b on the proliferation, differentiation, and survival of embryonic NPCs using specific mimics and inhibitor. The targets of miR-106a/b were identified from miRNA target prediction database and confirmed by luciferase assay. Specific siRNAs were utilized to erase the effects of miR-106a/b on the expression levels of target genes. RESULTS: A positive correlation was observed between the temporal reduction of miR-106a/b expression levels and the decline of NPC pools in vivo and in vitro. The perturbation of miR-106's function approaches revealed that miR-106b, but not miR-106a, facilitated the maintenance of NPCs and repressed the generation of both neuronal and glial cells, without preference to a particular lineage. No effect was observed for miR-106a/b in NPCs' survival. The influence of miR-106b on NPCs' proliferation and differentiation is likely achieved by directly inhibiting the expression of Tp53inp1 and Cdkn1a, key components of Tp53inp1-Tp53-Cdkn1a axis. CONCLUSION: Our study demonstrated a novel axis, miR-106b-Tp53inp1-Tp53-Cdkn1a, in regulating the proliferation and differentiation of NPCs.

Exosomal miRNAs in central nervous system diseases: biomarkers, pathological mediators, protective factors and therapeutic agents.

Exosomes are small bilipid layer-enclosed extracellular vesicles that can be found in tissues and biological fluids. As a key cell-to-cell and distant communication mediator, exosomes are involved in various central nervous system (CNS) diseases, potentially through transferring their contents such as proteins, lipids and nucleic acids to the target cells. Exosomal miRNAs, which are small non-coding RNAs in the exosomes, are known to be more stable than free miRNAs and therefore have lasting effects on disease-related gene expressions. There are distinct profiles of exosomal miRNAs in different types of CNS diseases even before the onset of irreversible neurological damages, indicating that exosomal miRNAs within tissues and biological fluids could serve as promising biomarkers. Emerging evidence has also demonstrated the pathological effects of several exosomal miRNAs in CNS diseases via specific modulation of disease-related factors. Moreover, exosomes carry therapeutically beneficial miRNAs across the blood-brain-barrier, which can be exploited as a powerful drug delivery tool to help alleviating multiple CNS diseases. In this review, we summarize the recent progress made in understanding the biological roles of exosomal miRNAs as potential diagnostic biomarkers, pathological regulators, and therapeutic targets/drugs for CNS diseases. A comprehensive discussion of the main concerns and challenges for the applications of exosomal miRNAs in the clinical setting is also provided.

Exosomes released from neural progenitor cells and induced neural progenitor cells regulate neurogenesis through miR-21a.

Neural stem/progenitor cells (NPCs) are known to have potent therapeutic effects in neurological disorders through secreting exosomes. The limited numbers of NPCs in adult brain and the decline of NPC pool in many neurological disorders restrain the further use of exosomes in treating these diseases. The direct conversion of somatic cells into induced NPCs (iNPCs) provides abundant NPC-like cells to study the therapeutic effects of NPCs-originated exosomes (EXOs). Our recent study demonstrated that iNPCs-derived exosomes (iEXOs) exhibit distinct potential in facilitating the proliferation of NPCs, compared to EXOs, indicating the importance to investigate the effects of EXOs and iEXOs on the differentiation of NPCs, which remains unknown. Here, our results suggest that EXOs, but not iEXOs, promoted neuronal differentiation and neither of them had effect on glial generation. Microarray analysis revealed different miRNA signatures in EXOs and iEXOs, in which miR-21a was highly enriched in EXOs. Perturbation of function assay demonstrated the key roles of miR-21a in the generation of neurons and mediating the neurogenic potential of exosomes. Our data suggest that EXOs and iEXOs may achieve their therapeutic effects in promoting neurogenesis through transferring key miRNAs, which sheds light on the development of highly efficient cell-free therapeutic strategies for treating neurological diseases.

Glutaminase C Regulates Microglial Activation and Pro-inflammatory Exosome Release: Relevance to the Pathogenesis of Alzheimer's Disease.

Microglial activation is a key pathogenic process at the onset of Alzheimer's disease (AD). Identifying regulators of microglial activation bears great potential in elucidating causes and mechanisms of AD and determining candidates for early intervention. Previous studies demonstrate abnormal elevation of glutaminase C (GAC) in HIV-infected or immune-activated microglia. However, whether GAC elevation causes microglial activation remains unknown. In this study, we found heightened expression levels of GAC in early AD mouse brain tissues compared with those in control littermates. Investigations on an in vitro neuroinflammation model revealed that GAC is increased in primary mouse microglia following pro-inflammatory stimulation. To model GAC elevation we overexpressed GAC by plasmid transfection and observed that GAC-overexpression shift the microglial phenotype to a pro-inflammatory state. Treatment with BPTES, a glutaminase inhibitor, reversed LPS-induced microglial activation and inflammation. Furthermore, we discovered that GAC overexpression in mouse microglia increased exosome release and changed exosome content, which includes specific packaging of pro-inflammatory miRNAs that activate microglia. Together, our results demonstrate a causal effect of GAC elevation on microglial activation and exosome release, both of which promote the establishment of a pro-inflammatory microenvironment. Therefore, GAC may have important relevance to the pathogenesis of AD.

Small molecule ONC201 inhibits HIV-1 replication in macrophages via FOXO3a and TRAIL.

Despite the success of antiretroviral therapy (ART), eradication of HIV-1 from brain reservoirs remains elusive. HIV-1 brain reservoirs include perivascular macrophages that are behind the blood-brain barrier and difficult to access by ART. Macrophages express transcription factor FOXO3a and the TNF superfamily cytokine TRAIL, which are known to target HIV-1-infected macrophages for viral inhibition. ONC201 is a novel and potent FOXO3a activator capable of inducing TRAIL. It can cross the blood-brain barrier, and has shown antitumor effects in clinical trials. We hypothesized that activation of FOXO3a/TRAIL by ONC201 will inhibit HIV-1 replication in macrophages. Using primary human monocyte-derived macrophages, we demonstrated that ONC201 dose-dependently decreased replication levels of both HIV-1 laboratory strain and primary strains as determined by HIV-1 reverse transcriptase activity assay. Consistent with data on HIV-1 replication, ONC201 also reduced intracellular and extracellular p24, viral RNA, and integrated HIV-1 DNA in infected macrophages. Blocking TRAIL or knockdown of FOXO3a with siRNA reversed ONC201-mediated HIV-1 suppression, suggesting that ONC201 inhibits HIV-1 through FOXO3a and TRAIL. The anti-HIV-1 effect of ONC201 was further validated in vivo in NOD/scid-IL-2Rgcnull mice. After intracranial injection of HIV-1-infected macrophages into the basal ganglia, we treated the mice daily with ONC201 through intraperitoneal injection for six days. ONC201 significantly decreased p24 levels in both the macrophages and the brain tissues, suggesting that ONC201 suppresses HIV-1 in vivo. Therefore, ONC201 can be a promising drug candidate to combat persistent HIV-1 infection in the brain.

Propofol reduces microglia activation and neurotoxicity through inhibition of extracellular vesicle release.

Propofol is an established anesthetic widely used for induction and maintenance of anesthesia. We investigated propofol for its anti-inflammatory effects on microglia and found that propofol treatment is associated with substantial lower levels of extracellular vesicles (EVs) in immune activated microglia. Importantly, EVs collected from immune activated microglia reversed propofol-mediated anti-inflammatory and neuroprotective effects, suggesting that propofol reduces proinflammatory microglia activation and microglia-mediated neurotoxicity through inhibition of EV release. These data shed new insight into a novel molecular mechanism of propofol-mediated neuroprotective and immunomodulatory effects through inhibition of EV release.