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.

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.

Objectives:HIV suppression in brain viral reservoirs, especially macrophages, and microglia is critical to suppress HIV neuropathogenesis and subsequently HIV-associated neurocognitive disorders (HAND). Since most antiretroviral therapy (ART) drugs do not achieve optimal therapeutic concentrations in the brain and can cause neurotoxicity, an alternative/adjuvant therapy is needed to suppress HIV neuropathogenesis. In this study, our objectives were to examine the anti-HIV, antioxidant, and anti-inflammatory potential of resveratrol (RES) and its synthetic analogs 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) and 4-(E)-{(4-hydroxyphenylimino)-methylbenzene,1,2-diol} (HPIMBD) in HIV-infected macrophages.Methods:We used HIV replication (viral load), oxidative stress (reactive oxygen species and antioxidant enzymes), and inflammatory response (pro- and anti-inflammatory cytokines/chemokines) assays to achieve the objectives of the study.Results:Our results showed that RES and its analogs HPIMBD and TIMBD at 25 µM concentration significantly decrease HIV replication in both primary monocyte-derived macrophages and U1-differentiated macrophages. Moreover, RES and its analogs do not induce any cytotoxicity for up to 3 days in these cells. Further, treatment with RES and TIMBD (25 µM) also reduced the levels of reactive oxygen species without affecting the expression of antioxidant enzymes, SOD1, and catalase in U1 macrophages. Besides, RES and HPIMBD treatment inhibited the proinflammatory cytokines and chemokines in U1 macrophages, which was associated with decreased levels of anti-inflammatory cytokines. Importantly, our western blot experiments show that RES also decreases cellular proinflammatory cytokine IL-1β, which is usually elevated in both myeloid and neuronal cells upon HIV infection.Conclusions:Taken together, our results suggest that RES and/or its analogs are important adjuvants that may be used not only to suppress HIV but also oxidative stress and inflammation in brain viral reservoirs.

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.

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.

Spectinamides are a novel series of spectinomycin analogs being developed for the treatment of tuberculosis. The preclinical lead spectinamide 1599 is an antituberculosis drug that possesses robust in vivo efficacy, good pharmacokinetic properties, and excellent safety profiles in rodents. In individuals infected with Mycobacterium tuberculosis or Mycobacterium bovis, causative agents of tuberculosis, the host immune system is capable of restraining these mycobacteria within granulomatous lesions. The harsh microenvironmental conditions of these granuloma lead to phenotypic transformation of mycobacteria. Phenotypically transformed bacteria display suboptimal growth, or complete growth arrest and are frequently associated with drug tolerance. Here we quantified the effect of spectinamide 1599 on log-phase and phenotypically tolerant isoforms of Mycobacterium bovis BCG using various in vitro approaches as a first indicator of spectinamide 1599 activity against various mycobacterial isoforms. We also used the hollow fiber infection model to establish time-kill curves and deployed pharmacokinetic/pharmacodynamic modeling to characterize the activity differences of spectinamide 1599 towards the different phenotypic subpopulations. Our results indicate that spectinamide 1599 is more efficacious against log phase bacteria when compared to its activity against other phenotypically tolerant forms such as acid phase bacteria and hypoxic phase bacteria, a behavior similar to the established antituberculosis drug isoniazid.

The blood brain barrier (BBB) maintains the homeostasis of the central nervous system (CNS) and protects the brain from toxic substances present in the circulating blood. However, the impermeability of the BBB to drugs is a hurdle for CNS drug development, which hinders the distribution of the most therapeutic molecules into the brain. Therefore, scientists have been striving to develop safe and effective technologies to advance drug penetration into the CNS with higher targeting properties and lower off-targeting side effects. This review will discuss the limitation of artificial nanomedicine in CNS drug delivery and the use of natural extracellular vesicles (EVs), as therapeutic vehicles to achieve targeted delivery to the CNS. Information on clinical trials regarding CNS targeted drug delivery using EVs is very limited. Thus, this review will also briefly highlight the recent clinical studies on targeted drug delivery in the peripheral nervous system to shed light on potential strategies for CNS drug delivery. Different technologies engaged in pre- and post-isolation have been implemented to further utilize and optimize the natural property of EVs. EVs from various sources have also been applied in the engineering of EVs for CNS targeted drug delivery in vitro and in vivo. Here, the future feasibility of those studies in clinic will be discussed.

Obesity is a complex disease associated with various metabolic abnormalities, cardiovascular diseases, and low-grade chronic inflammation. Inflammation associated with T helper 1 (Th1) immune cells is dominant in adipose tissue (AT) and exerts metabolically deleterious impacts. The precise mechanism of alteration in AT immune system and its effect on metabolic homeostasis remains unclear. In this study, we investigated how a high-fat diet (HFD) alters the AT immune response and influences inflammation during obesity. HFD consumption amends the metabolic parameters, including body weight, glucose, and insulin levels. We observed increased infiltration of Th17 cells, a subset of dendritic cells (CD103+), and M1 macrophages in AT of mice fed HFD compared to those fed a normal diet (ND). In mice that were fed HFD, we also observed a reduction in regulatory T cells (Tregs) relative to the numbers of these cells in mice fed ND. Corresponding with this, mice in the HFD group exhibited higher levels of proinflammatory cytokines and chemokines than those in the ND group. We also observed alterations in signaling pathways, including increased protein expression of IRF3, TGFβ1, and mRNA expression of IL-6, KLF4, and STAT3 in the AT of the mice fed HFD as compared to those fed ND. Further, HFD-fed mice exhibited decreased protein expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) compared to mice fed ND, suggesting that PPAR-γ functions as a negative regulator of Th17 cell differentiation. These results suggest that HFD induces increased levels of inflammatory cytokines and key immune cells, including Th17, M1 macrophages, and CD103+ dendritic cells, and reduces levels of PPAR-γ and Tregs to sustain AT inflammation. This study supports the notion that dysregulation of Th17/Tregs, which polarizes macrophages towards M1 phenotypes in part through TGFβ1-IRF3-STAT3 and negatively regulates PPAR-γ mediated pathways, results in AT inflammation during obesity.

People living with HIV/AIDS (PLWHA) are at an increased risk of severe and critical COVID-19 infection. There is a steady increase in neurological complications associated with COVID-19 infection, exacerbating HIV-associated neurocognitive disorders (HAND) in PLWHA. Nutraceuticals, such as phytochemicals from medicinal plants and dietary supplements, have been used as adjunct therapies for many disease conditions, including viral infections. Appropriate use of these adjunct therapies with antiviral proprieties may be beneficial in treating and/or prophylaxis of neurological complications associated with these co-infections. However, most of these nutraceuticals have poor bioavailability and cannot cross the blood–brain barrier (BBB). To overcome this challenge, extracellular vesicles (EVs), biological nanovesicles, can be used. Due to their intrinsic features of biocompatibility, stability, and their ability to cross BBB, as well as inherent homing capabilities, EVs hold immense promise for therapeutic drug delivery to the brain. Therefore, in this review, we summarize the potential role of different nutraceuticals in reducing HIV- and COVID-19-associated neurological complications and the use of EVs as nutraceutical/drug delivery vehicles to treat HIV, COVID-19, and other brain disorders.

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.

PURPOSE:Computerised prescriber (or physician) order entry (CPOE) implementation is one of the strategies to reduce medication errors. The extent to which CPOE influences the incidence of chemotherapy-related medication errors (CMEs) was not previously collated and systematically reviewed. Hence, this study was designed to collect, collate, and systematically review studies to evaluate the effect of CPOE on the incidence of CMEs.METHODS:A search was performed of four databases from 1 January 1995 until 1 August 2019. English-language studies evaluating the effect of CPOE on CMEs were selected as per inclusion and exclusion criteria. The total CMEs normalised to total prescriptions pre- and post-CPOE were extracted and collated to perform a meta-analysis using the 'meta' package in R. The systematic review was registered with PROSPERO CRD42018104220.RESULTS:The database search identified 1621 studies. After screening, 19 studies were selected for full-text review, of which 11 studies fulfilled the selection criteria. The meta-analysis of eight studies with a random effects model showed a risk ratio of 0.19 (95% confidence interval: 0.08-0.44) favouring CPOE (I2 = 99%).CONCLUSION:The studies have shown consistent reduction in CMEs after CPOE implementation, except one study that showed an increase in CMEs. The random effects model in the meta-analysis of eight studies showed that CPOE implementation reduced CMEs by 81%.

The infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and resultant coronavirus diseases-19 (COVID-19) disproportionally affects minorities, especially African Americans (AA) compared to the Caucasian population. The AA population is disproportionally affected by COVID-19, in part, because they have high prevalence of underlying conditions such as obesity, diabetes, and hypertension, which are known to exacerbate not only kidney diseases, but also COVID-19. Further, a decreased adherence to COVID-19 guidelines among tobacco smokers could result in increased infection, inflammation, reduced immune response, and lungs damage, leading to more severe form of COVID-19. As a result of high prevalence of underlying conditions that cause kidney diseases in the AA population coupled with tobacco smoking make the AA population vulnerable to severe form of both COVID-19 and kidney diseases. In this review, we describe how tobacco smoking interact with SARS-CoV-2 and exacerbates SARS-CoV-2-induced kidney diseases including renal failure, especially in the AA population. We also explore the role of extracellular vesicles (EVs) in COVID-19 patients who smoke tobacco. EVs, which play important role in tobacco-mediated pathogenesis in infectious diseases, have also shown to be important in COVID-19 pathogenesis and organ injuries including kidney. Further, we explore the potential role of EVs in biomarker discovery and therapeutics, which may help to develop early diagnosis and treatment of tobacco-induced renal injury in COVID-19 patients, respectively.

Biomaterials have been the subject of numerous studies to pursue potential therapeutic interventions for a wide variety of disorders and diseases. The physical and chemical properties of various materials have been explored to develop natural, synthetic, or semi-synthetic materials with distinct advantages for use as drug delivery systems for the central nervous system (CNS) and non-CNS diseases. In this review, an overview of popular biomaterials as drug delivery systems for neurogenerative diseases is provided, balancing the potential and challenges associated with the CNS drug delivery. As an effective drug delivery system, desired properties of biomaterials are discussed, addressing the persistent challenges such as targeted drug delivery, stimuli responsiveness, and controlled drug release in vivo. Finally, we discuss the prospects and limitations of incorporating extracellular vesicles (EVs) as a drug delivery system and their use for biocompatible, stable, and targeted delivery with limited immunogenicity, as well as their ability to be delivered via a non-invasive approach for the treatment of neurodegenerative diseases.

Over the last two decades, the United States (U.S.) has experienced an opioid crisis that has had a significant negative societal and economic impact. Due to the high utilization of opioids in Persons Living with HIV and AIDS (PLWHA), there is a need for a qualitative literature review that presents opioid-use related problems in this population. This study aims to present and identify a thematic overview of the qualitative manuscripts on PLWHA who take opioid medications in the U.S., with a focus on perceptions surrounding medication assisted therapy. The systematic literature search was performed in December 2019. Four databases were searched: PubMed/MEDLINE, Scopus, Web of Science, and Cumulative Index to Nursing & Allied Health Literature (CINAHL). A total of 5348 results were exported from databases into EndNote x9, and duplicates were removed for a total of 3039 unique abstracts to screen. The records were imported into Rayyan, an online platform designed to expedite the screening process. Three authors screened titles and abstracts and determined 19 articles that would be screened in full text. On 9 April 2020, it was determined that eight articles would be included for review. The analysis of the eight manuscripts that fit the inclusion and exclusion criteria revealed barriers and facilitators to medication assisted therapy (MAT) in PLWHA. This review communicates or describes the story of PLWHA who might have delayed access to HIV healthcare providers and the commencement of antiretroviral therapy. In the literature, several studies have focused on the role of physicians in prescribing and addressing the medication regimens but none of the studies examined the role of pharmacists in access to care in this population. Therefore, further research is needed for a better understanding of the social aspects of taking opioid medications in PLWHA and the role of pharmacists within the continuum of care.

In this study, we investigated whether intravenously self-administered nicotine with menthol and audiovisual cue modulates nicotine-metabolizing CYP2A6, oxidative stress modulators, and cytokines/chemokines in plasma extracellular vesicles (EVs) in rats. We assigned rats to self-administered nicotine with: (a) audiovisual cue (AV), (b) menthol, and (c) menthol and AV cue. We found increased levels of CD9 in plasma EVs after self-administered nicotine with menthol and AV cue. Moreover, expression of CYP2A6 in plasma EVs was significantly increased after self-administered nicotine in response to menthol and AV cue. However, despite an upward trend on SOD1 and catalase, increase was not found to be statistically significant, while total antioxidant capacity was found to be significantly increased in plasma and plasma EVs obtained after self-administered nicotine with menthol and AV cue. Among cytokine and chemokine profiling, we found a significant increase in the levels of MCP-1 after self-administered nicotine with menthol and AV cue and complete packaging of IL-1β in EVs. Taken together, the study provides evidence that nicotine in response to menthol and AV cues can package altered levels of CYP2A6, and cytokines/chemokines in plasma EVs that may contribute to cell-cell communication, nicotine metabolism, and inflammation upon cigarette smoking.

Chemodietary agents are emerging as promising adjuvant therapies in treating various disease conditions. However, there are no adjuvant therapies available to minimize the neurotoxicity of currently existing antiretroviral drugs (ARVs). In this study, we investigated the anti-HIV effect of a chemodietary agent, Cucurbitacin-D (Cur-D), in HIV-infected macrophages using an in-vitro blood–brain barrier (BBB) model. Since tobacco smoking is prevalent in the HIV population, and it exacerbates HIV replication, we also tested the effect of Cur-D against cigarette smoke condensate (CSC)-induced HIV replication. Our results showed that Cur-D treatment reduces the viral load in a dose-dependent (0–1 μM) manner without causing significant toxicity at <1 μM concentration. Further, a daily dose of Cur-D (0.1 μM) not only reduced p24 in control conditions, but also reduced CSC (10 μg/mL)-induced p24 in U1 cells. Similarly, Cur-D (single dose of 0.4 μM) significantly reduced the CSC (single dose of 40 μg/mL)-induced HIV replication across the BBB model. In addition, treatment with Cur-D reduced the level of pro-inflammatory cytokine IL-1β. Therefore, Cur-D, as an adjuvant therapy, may be used not only to suppress HIV in the brain, but also to reduce the CNS toxicity of currently existing ARVs.

Genetic variants influencing the pharmacokinetics and/or pharmacodynamics of the chemotherapeutic drugs used in Acute Lymphoblastic Leukemia (ALL) therapy often contribute to the occurrence of treatment related toxicity (TRT). In this study, we explored the association of candidate genetic variants with early hematological TRT (grade 3–4) occurring within the first 100 days of low-dose methotrexate and 6-mercaptopurine based maintenance therapy (n = 73). Fourteen variants in the following candidate genes were genotyped using allele discrimination assay by real-time PCR: ABCB1, DHFR, GGH, FPGS, MTHFR, RFC1, SLCO1B1, TPMT, and NUDT15. Methotrexate polyglutamate (MTXPG3-5) levels in red blood cells were measured by LC-MS/MS. Early hematological TRT (grade 3–4) was seen in 54.9% of patients. The NUDT15c.415T allele was associated with early TRT occurrence [HR: 3.04 (95% CI: 1.5–6.1); p = 0.007]. Sensitivity of early TRT prediction improved (from 30.7% to 89.7%) by considering FPGS variant (rs1544105’T’) carrier status along with NUDT15c.415T allele [HR = 2.7 (1.5–4.7, p = 0.008)]. None of the considered genetic variants were associated with MTXPG3-5 levels, which in turn were not associated with early TRT. NUDT15c.415T allele carrier status could be used as a stratifying marker for Indian ALL patients to distinguish patients at high or low risk of developing early hematological TRT.

The diagnosis of neurocognitive disorders associated with HIV infection, alcohol, and tobacco using CSF or neuroimaging are invasive or expensive methods, respectively. Therefore, extracellular vesicles (EVs) can serve as reliable noninvasive markers due to their bidirectional transport of cargo from the brain to the systemic circulation. Hence, our objective was to investigate the expression of astrocytic (GFAP) and neuronal (L1CAM) specific proteins in EVs circulated in the plasma of HIV subjects, with and without a history of alcohol consumption and tobacco smoking. The protein expression of GFAP (p < 0.01) was significantly enhanced in plasma EVs obtained from HIV-positive subjects and alcohol users compared to healthy subjects, suggesting enhanced activation of astrocytes in those subjects. The L1CAM expression was found to be significantly elevated in cigarette smokers (p < 0.05). However, its expression was not found to be significant in HIV subjects and alcohol users. Both GFAP and L1CAM levels were not further elevated in HIV-positive alcohol or tobacco users compared to HIV-positive nonsubstance users. Taken together, our data demonstrate that the astrocytic and neuronal-specific markers (GFAP and L1CAM) can be packaged in EVs and circulate in plasma, which is further elevated in the presence of HIV infection, alcohol, and/or tobacco. Thus, the astroglial marker GFAP and neuronal marker L1CAM may represent potential biomarkers targeting neurological dysfunction upon HIV infection and/or alcohol/tobacco consumption.

The coronavirus disease-19 (COVID-19) pandemic has affected individuals of all categories, irrespective of their geographical locations, professions, gender, or race. As a result of full or partial lock-down and stay-at-home orders, the well-being and productivity of individuals were severely affected. Since basic science research requires laboratory experiments, the work-from-home strategy hurt their productivity. In addition, the combination of decreased productivity and staying at home is likely to compromise their well-being by causing stress and anxiety. In this case study, a strategy was developed to engage researchers through listening and learning, motivation, and empowerment, using regular virtual sessions. Through these virtual sessions, research work was prioritized and coordinated, from idea conception to writing research papers and grant proposals. Perceived stress scores (PSS) and COVID-19-related stress (COVID-SS) scores were measured to evaluate general and COVID-19-induced stress, respectively, every month from March to July 2020 during the COVID-19 era. The result showed a significant improvement in both the PSS and the COVID-SS scores of the intervention group compared to the control group. In addition, while there was no/minimal change in PSS and COVID-SS scores from March to subsequent months until July for the control group, the intervention groups showed significant and consistent improvement in both scores in the intervention group. Overall, the intervention strategy showed improved well-being for basic science researchers, which was also consistent with their improved productivity during the COVID-19 era.

In the last two decades, the mortality rate in people living with HIV/AIDS (PLWHA) has decreased significantly, resulting in an almost normal longevity in this population. However, a large portion of this population still endures a poor quality of life, mostly due to an increased inclination for substance abuse, including tobacco smoking. The prevalence of smoking in PLWHA is consistently higher than in HIV negative persons. A predisposition to cigarette smoking in the setting of HIV potentially leads to exacerbated HIV replication and a higher risk for developing neurocognitive and other CNS disorders. Oxidative stress and inflammation have been identified as mechanistic pathways in smoking-mediated HIV pathogenesis and HIV-associated neuropathogenesis. Extracellular vesicles (EVs), packaged with oxidative stress and inflammatory agents, show promise in understanding the underlying mechanisms of smoking-induced HIV pathogenesis via cell-cell interactions. This review focuses on recent advances in the field of EVs with an emphasis on smoking-mediated HIV pathogenesis and HIV-associated neuropathogenesis. This review also provides an overview of the potential applications of EVs in developing novel therapeutic carriers for the treatment of HIV-infected individuals who smoke, and in the discovery of novel biomarkers that are associated with HIV-smoking interactions in the CNS.