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Antiretroviral drugs have made significant progress in treating HIV-1 and improving the quality of HIV-1-infected individuals. However, due to their limited permeability into the brain HIV-1 replication persists in brain reservoirs such as perivascular macrophages and microglia, which cause HIV-1-associated neurocognitive disorders. Therefore, it is highly desirable to find a novel therapy that can cross the blood-brain barrier (BBB) and target HIV-1 pathogenesis in brain reservoirs. A recently developed 2-amino-3-methylpentanoic acid [2-morpholin-4-yl-ethyl]-amide (LM11A-31), which is a p75 neutrotrophin receptor (p75NTR) modulator, can cross the BBB. In this study, we examined whether LM11A-31 treatment can suppress HIV-1 replication, oxidative stress, cytotoxicity, and inflammatory response in macrophages. Our results showed that LM11A-31 (100 nM) alone and/or in combination with positive control darunavir (5.5 µM) significantly suppresses viral replication and reduces cytotoxicity. Moreover, the HIV-1 suppression by LM11A-31 was comparable to the HIV-1 suppression by darunavir. Although p75NTR was upregulated in HIV-1-infected macrophages compared to uninfected macrophages, LM11A-31 did not significantly reduce the p75NTR expression in macrophages. Furthermore, our study illustrated that LM11A-31 alone and/or in combination with darunavir significantly suppress pro-inflammatory cytokines including IL-1β, IL-8, IL-18, and TNF-α and chemokines MCP-1 in HIV-induced macrophages. The suppression of these cytokines and chemokines by LM11A-31 was comparable to darunavir. In contrast, LM11A-31 did not significantly alter oxidative stress, expression of antioxidant enzymes, or autophagy marker proteins in U1 macrophages. The results suggest that LM11A-31, which can cross the BBB, has therapeutic potential in suppressing HIV-1 and inflammatory response in brain reservoirs, especially in macrophages.

Abstract Bibliometric analysis explores large volume of scientific data, revealing trends and insights in a specific research field. Consistently, a bibliometric analysis of 30 years (1990–2020) was performed within the US corn (Zea mays L.) production using the Scopus database and VOSviewer. Search query was performed within the article title, abstract, and keywords indicative of management practices in corn. Exclusion criterion based on subject area and journals generated a total of 7468 publications. The data analysis revealed contributions from 7327 authors and 47 organizations documented in 69 journals. The top five organizations leading the investigation were United States Department of Agriculture – Agricultural Research Service, Iowa State University, University of Nebraska, University of Illinois, and Purdue University. The most prolific authors were Dr. Rattan Lal (Ohio State University, Columbus, OH), Dr. Douglas L. Karlen (USDA‐ARS, Ames, IA), Dr. Kenneth G. Cassman (University of Nebraska, Lincoln, NE), Dr. Lajpat Rai Ahuja (USDA‐ARS, Ft. Collins, CO), and Dr. John Walsh Doran (USDA‐ARS, Lincoln, NE). Journals with most publications were Agronomy Journal; Soil Science Society of America Journal; Soil and Tillage Research; Crop Science; and Agriculture, Ecosystems & Environment. Furthermore, author keywords differed from queried keywords, and no‐till, nitrogen, cover crop, soybean, irrigation, phosphorus, conservation tillage, yield, and water quality were most prominent. Moreover, there was an evident shift in keywords and an observed trend between 1998 and 2020. Overall, these findings allow researchers to explore network maps via the hyperlinks present in papers, identifying research gaps and advancing original studies to bridge gaps in the literature.

Abstract In this study, we investigated the potential of using curcumin (CUR) as an adjuvant to enhance the delivery of antiretroviral drug elvitegravir (EVG) across the BBB, and alleviate oxidative stress and inflammatory response, which are the major hallmark of HIV neuropathogenesis. In a mouse model, we compared the biodistribution of EVG alone and in combination with CUR using intraperitoneal (IP) and intranasal (IN) routes. IN administration showed a significantly higher accumulation of EVG in the brain, while both IP and IN routes led to increased EVG levels in the lungs and liver. The addition of CUR further enhanced EVG brain delivery, especially when administered via the IN route. The expression of neural marker proteins, synaptophysin, L1CAM, NeuN, and GFAP was not significantly altered by EVG or CUR alone or their combination, indicating preserved neural homeostasis. After establishing improved brain concentration and safety of CUR-adjuvanted EVG in mice in acute treatment, we studied the effect of this treatment in HIV-infected U1 macrophages. In U1 macrophages, we also observed that the addition of CUR enhanced the intracellular concentration of EVG. The total area under the curve (AUCtot) for EVG was significantly higher in the presence of CUR. We also evaluated the effects of CUR on oxidative stress and antioxidant capacity in EVG-treated U1 macrophages. CUR reduced oxidative stress, as evidenced by decreased reactive oxygen species (ROS) levels and elevated antioxidant enzyme expression. Furthermore, the combination of CUR and EVG exhibited a significant reduction in proinflammatory cytokines (TNFα, IL-1β, IL-18) and chemokines (RANTES, MCP-1) in U1 macrophages. Additionally, western blot analysis confirmed the decreased expression of IL-1β and TNF-α in EVG + CUR-treated cells. These findings suggest the potential of CUR to enhance EVG permeability to the brain and subsequent efficacy of EVG, including HIV neuropathogenesis.

Abstract We have recently demonstrated that long-term exposure of cigarette smoke condensate (CSC) to HIV-uninfected (U937) and -infected (U1) macrophages induce packaging of pro-inflammatory molecules, particularly IL-1β, in extracellular vesicles (EVs). Therefore, we hypothesize that exposure of EVs derived from CSC-treated macrophages to CNS cells can increase their IL-1β levels contributing to neuroinflammation. To test this hypothesis, we treated the U937 and U1 differentiated macrophages once daily with CSC (10 µg/ml) for 7 days. Then, we isolated EVs from these macrophages and treated these EVs with human astrocytic (SVGA) and neuronal (SH-SY5Y) cells in the absence and presence of CSC. We then examined the protein expression of IL-1β and oxidative stress related proteins, cytochrome P450 2A6 (CYP2A6), superoxide dismutase-1 (SOD1), catalase (CAT). We observed that the U937 cells have lower expression of IL-1β compared to their respective EVs, confirming that most of the produced IL-1β are packaged into EVs. Further, EVs isolated from HIV-infected and uninfected cells, both in the absence and presence of CSC, were treated to SVGA and SH-SY5Y cells. These treatments showed a significant increase in the levels of IL-1β in both SVGA and SH-SY5Y cells. However, under the same conditions, the levels of CYP2A6, SOD1, and catalase were only markedly altered. These findings suggest that the macrophages communicate with astrocytes and neuronal cells via EVs-containing IL-1β in both HIV and non-HIV setting and could contribute to neuroinflammation.

Although antiretroviral therapy (ART) can suppress peripheral HIV, patients still suffer from neuroHIV due to insufficient levels of ART drugs in the brain. Hence, this study focuses on developing a poly lactic-co-glycolic acid (PLGA) nanoparticle-based ART drug delivery system for darunavir (DRV) using an intranasal route that can overcome the limitation of drug metabolic stability and blood–brain barrier (BBB) permeability. The physicochemical properties of PLGA-DRV were characterized. The results indicated that PLGA-DRV formulation inhibits HIV replication in U1 macrophages directly and in the presence of the BBB without inducing cytotoxicity. However, the PLGA-DRV did not inhibit HIV replication more than DRV alone. Notably, the total antioxidant capacity remained unchanged upon treatment with both DRV or PLGA-DRV in U1 cells. Compared to DRV alone, PLGA-DRV further decreased reactive oxygen species, suggesting a decrease in oxidative stress by the formulation. Oxidative stress is generally increased by HIV infection, leading to increased inflammation. Although the PLGA-DRV formulation did not further reduce the inflammatory response, the formulation did not provoke an inflammatory response in HIV-infected U1 macrophages. As expected, in vitro experiments showed higher DRV permeability by PLGA-DRV than DRV alone to U1 macrophages. Importantly, in vivo experiments, especially using intranasal administration of PLGA-DRV in wild-type mice, demonstrated a significant increase in the brain-to-plasma ratio of DRV compared to the free DRV. Overall, findings from this study attest to the potential of the PLGA-DRV nanoformulation in reducing HIV pathogenesis in macrophages and enhancing drug delivery to the brain, offering a promising avenue for treating HIV-related neurological disorders.

Despite the availability of combined antiretroviral therapy (cART), which reduces the HIV replication in chronically HIV-infected patients, HIV associated neurocognitive disorders (HAND) persists in the brain. The blood-brain barrier (BBB) is the major barrier for the penetration of drugs including antiretrovirals, limiting the drug penetration to the brain. In the present study, we have shown improved brain drug concentration in mice for darunavir (DRV), an FDA-approved drug, using an intranasal (IN) delivery method that bypasses the BBB. Here, we compared the time-dependent biodistribution of DRV at two different concentrations, high (25 mg/kg) and low (2.5 mg/kg), using two administration routes intravenous (IV) and intranasal (IN) in brain, liver, lungs, and plasma. Compared with IV administration, IN administration demonstrated a significantly improved DRV penetration in the brain at both low and high DRV concentrations (IV vs IN: at 2.5 mg/kg: 6.91 ± 1.69 ng/g vs 12.08 ± 2.91 ng/g, at 25 mg/kg: 12.84 ± 2.88 ng/g vs 19.74 ± 1.80 ng/g). As expected, IN administration showed significantly lower DRV concentrations in plasma (IV vs IN: at 2.5 mg/kg: 81.37 ± 22.04 ng/g vs 19.91 ± 12.65 ng/g, at 25 mg/kg: 899.12 ± 136.93 ng/g vs 320.56 ± 40.04 ng/g) and liver (IV vs IN: at 2.5 mg/kg: 118.39 ± 28.13 ng/g vs 29.27 ± 4.17 ng/g at 25 mg/kg: 1085.18 ± 255.0 ng/g vs 833.83 ± 242.4 ng/g). The IN administration did not show significant change in lungs compared to the IV administration. As a result, these findings suggest that the IN route can increase the DRV level in the brain, suppressing HIV in the brain reservoirs. Additionally, it could also reduce off-target effects, especially in peripheral organs.

Background Benzo(a)pyrene (BaP), an important polycyclic aromatic hydrocarbons (PAH) component of cigarette/tobacco smoking, is known to cause adverse health effects and is responsible for various life-threatening conditions including cancer. However, it is not yet clear whether BaP contributes to the macrophage- and astrocyte-mediated inflammatory response. Methods We examined the acute (up to 72 h) effects of BaP on the expression of antioxidant enzymes (AOEs), cytokines/chemokines, and cytochromes P450 (CYP) enzymes in astrocytic cell lines, SVGA, and chronically HIV-infected U1 macrophage. The treated cells were examined for mRNA, protein levels of CYPs, AOEs superoxide dismutase-1 (SOD1) and catalase (CAT), cytokines/chemokines, using Western blot, multiplex ELISA, and reactive oxygen species (ROS) by flow cytometry analysis. Results Upon acute exposure, BaP (1 μM) showed a significant increase in the mRNA levels of CYPs (CYP1A1 and CYP1B1), and pro-inflammatory cytokine IL-1β in SVGA cells following BaP for 24, 48, and 72h. In addition, we observed a significant increase in the mRNA levels of SOD1 and CAT at 24h of BaP treatment. In contrast, BaP did not exert any change in the protein expression of AOEs and CYP enzymes. In U1 cells, however, we noticed an interesting increase in the levels of MCP-1 as well as a modest increase in TNFα, IL-8 and IL-1β levels observed at 72 h of BaP treatment but could not reach to statistically significant level. Conclusions Overall, these results suggest that BaP contributes in part to macrophage and astrocyte-mediated neuroinflammation by mainly inducing IL-1β and MCP-1 production, which is likely to occur with the involvement of CYP and/or oxidative stress pathways.

The ubiquitin proteasome system (UPS) is critically important for cellular homeostasis and affects virtually all key functions in normal and neoplastic cells. Currently, a comprehensive review of the role of the UPS in ependymoma (EPN) brain tumors is lacking but may provide valuable new information on cellular networks specific to different EPN subtypes and reveal future therapeutic targets. We have reviewed publicly available EPN gene transcription datasets encoding components of the UPS pathway. Reactome analysis of these data revealed genes and pathways that were able to distinguish different EPN subtypes with high significance. We identified differential transcription of several genes encoding ubiquitin E2 conjugases associated with EPN subtypes. The expression of the E2 conjugase genes UBE2C, UBE2S, and UBE2I was elevated in the ST_EPN_RELA subtype. The UBE2C and UBE2S enzymes are associated with the ubiquitin ligase anaphase promoting complex (APC/c), which regulates the degradation of substrates associated with cell cycle progression, whereas UBE2I is a Sumo-conjugating enzyme. Additionally, elevated in ST_EPN_RELA were genes for the E3 ligase and histone deacetylase HDAC4 and the F-box cullin ring ligase adaptor FBX031. Cluster analysis demonstrated several genes encoding E3 ligases and their substrate adaptors as EPN subtype specific genetic markers. The most significant Reactome Pathways associated with differentially expressed genes for E3 ligases and their adaptors included antigen presentation, neddylation, sumoylation, and the APC/c complex. Our analysis provides several UPS associated factors that may be attractive markers and future therapeutic targets for the subtype-specific treatment of EPN patients.