NeuroImmune pharmacology and therapeutics最新文献

Objectives: Anti-retroviral therapy (ART) drastically improves human immunodeficiency virus type 1 (HIV-1) outcomes, but may induce adverse neurochemical changes. Interactive effects of ART with recreational drugs are unknown. Notably, people living with HIV-1 (PLWH) smoke at twice the rate of the general population and are more prone to tobacco-linked illness. Thus, chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) was employed to investigate potential ART-nicotine co-morbid neuro-metabolomic influence.

Methods: 16 healthy, male, C57BL/6 mice were divided into four groups: vehicle-treatment, ART-treatment, nicotine-treatment, and ART-nicotine co-treatment. CEST-MRI was performed at day 12 following daily treatments to determine effects on neurometabolic profiles. Magnetic resonance spectroscopy (MRS) was used to contextualize metabolic outcomes.

Results: CEST-MRI detected significantly lower 3 ppm contrast in ART, nicotine, and co-treatment groups, suggesting ART- and nicotine-linked glutamate alteration. Co-treatment induced significantly higher hippocampal nuclear Overhauser effects (NOE) compared to ART-treatment, whereas individual treatments lacked effect on NOE, indicating adverse effect on membrane lipids. MRS confirmed CEST findings of membrane turnover, detecting significantly lower hippocampal total choline across all groups compared to controls.

Conclusions: CEST-MRI detects adverse neuro-metabolomic alterations induced by ART- and nicotine-exposure. This warrants investigation with HIV-1-infection to assess potential influences of co-exposure on PLWH cognition.

The 29^th Scientific Conference of the Society on Neuroimmune Pharmacology (SNIP) in Omaha, NE, will occur from June 8^th to 11^th, 2025. This four-day conference showcases world-renowned biomedical research, providing insights into the latest advancements in the intersecting fields of neuroscience, immunology, pharmacology, and virology. Presentation abstracts are organized into sections that include early career development investigators, mouse models, neurodegenerative diseases, therapeutics, substance use disorders, counseling, drug targeting, disease pathobiology, Blood-Brain Barrier integrity, educational opportunities, young investigator talks, and translational medicine. SNIP remains the sole global meeting dedicated to neuroimmune pharmacology. The focus of research centers on how the neuroimmune axis connects drug abuse, inflammation, and brain functional integrity. The conference features several plenary speakers who have made unique and significant contributions to their fields alongside renowned physician-scientists and luminaries. Symposia will include the SNIP Presidential Symposium on Pathobiology and Novel Therapies for Neurodegenerative Diseases, Ultra Long-Acting Medicines, Development and Delivery of Diagnostic and Therapeutic Biomarkers to disease regions, overcoming barriers to treating neurological disorders, neuroinflammation, and reward pathways for addiction, as well as neuron-glia interaction. All presentations are framed within the context of microbial infections, drugs of abuse, and therapeutics. Therapeutics include nanopharmacology and advances in informatics analysis of multi-omics data to decipher the complex cell and molecular interactions that underpin the function of the nervous system. SNIP member symposia and a local series of presentations will highlight outstanding talent from the University of Nebraska. Additional events include lunch with NIH program officials and a NeuroImmune Pharmacology and Therapeutics Journal dinner. The goal is to unite investigators from diverse basic, clinical, and translational fields to discuss and advance our understanding of the multifactorial impact of substance abuse, inflammation, and infections critical to human health. We aim to engage and mentor young investigators in neuroimmune pharmacology and disseminate information presented at the conference to the scientific community, the general public, and healthcare providers. Cultivating the next generation of scientists is vital to our mission. The agenda encompasses early-career investigator presentations, poster sessions, meet-the-mentors luncheons, and a special panel of junior faculty. The conference also provides an enriching environment for scientists and clinicians to share ideas, foster the next generation of scientists, and promote current disease pathobiology and therapeutics trends. Opportunities to visit the Omaha zoo will be available with guest passes. We thank Dr. Carol Swa

Objectives: Early tobacco use (before age 11) is linked to poorer cognition and reduced cortical surface area and volume in young adolescents. This study examined how socioeconomic status (SES) factors - parental education, household income, and economic hardships - influenced these associations.

Methods: Using baseline (N=11,876) and year 3 (N=10,414) datasets from the Adolescent Brain Cognitive Development study, we assessed the impact of baseline tobacco/nicotine use initiation on cognitive scores, cortical volume, thickness, and surface area across the entire cohort and in propensity-matched subgroups. Linear mixed effects models controlled for SES and other covariates, with multiple comparison correction. Analyses were cross-sectional at baseline and longitudinal with both timepoints.

Results: Compared to non-users (N=11,240), early users (N=110) had more advanced pubertal development (p=0.003) and economic hardships (p<0.001), but fewer girls (p=0.04), Hispanics (p=0.02), parents with graduate degrees (p<0.001) and high-income families >$100 K (p=p<0.001). Relative to non-users, early users had poorer cognitive scores (Cohen's d: -0.69 to -0.24), smaller surface areas (Cohen's d: -2.28 to -0.22), similar cortical thickness at both timepoints, and by year 3, smaller cortical volumes (Cohen's d: -1.06 to -1.24). However, SES-adjustments eliminated cognitive scores and volumes differences and reduced cortical surface area effects at both timepoints (Cohen's d: -1.92 to -0.51). After propensity score matching, early users and non-users showed no cognitive or brain differences, regardless of SES adjustments.

Conclusions: Adjusting for SES eliminated the negative impact of early tobacco/nicotine use on cognition and reduced its effect on brain surface area, underscoring the importance of SES in morphometry studies.

Objectives: Chronic cannabis use is linked to anti-inflammatory effects, and cocaine exhibits context-dependent immunomodulation; their distinct impacts on monocyte subsets and systemic inflammation are not fully understood. Systemic microbial translocation contributes to monocyte differentiation, but the levels in chronic cocaine and cannabis users in humans in vivo are lacking.

Methods: Peripheral blood mononuclear cells (PBMCs) and plasma samples were collected from chronic cocaine users, cannabis users, and non-drug users. The route of drug administration was via smoking or snorting. Monocyte subsets were analyzed using flow cytometry; plasma levels of cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) and lipopolysaccharide (LPS, a marker of microbial translocation) were measured using a Meso Scale immunoassay and Limulus amoebocyte lysate assay, respectively.

Results: Cannabis use was associated with increased total monocyte counts, increased percentages of a classical subset (CD14++CD16-), and decreased percentages of a non-classical subset (CD14+CD16++) in CD14+ monocytes compared to cocaine users and/or healthy controls. Similar levels were observed in the percentages of intermediate monocytes (CD14++CD16+) and plasma levels of six cytokines and LPS among the three study groups. Cocaine users exhibited similar frequencies of monocyte subsets, cytokine levels, and LPS levels compared to controls.

Conclusions: Chronic use of cannabis, but not cocaine, is associated with shifts in non-activated monocyte subset distribution, characterized by increased classical and decreased non-classical monocyte subsets, without concurrent systemic cytokine dysregulation or LPS translocation. These findings highlight substance-specific immune effects, potentially affecting long-term immune function.

Objectives: Amyloid-β (Aβ) plaque deposition in the brain is a principal pathological feature of both Alzheimer's disease (AD) and progressive human immunodeficiency virus type one (HIV-1) infection. Both enable Aβ assembly and Aβ protein aggregation. The potential link between HIV-1 and AD remains uncertain, supporting the need for a reliable animal model. HIV-1 is tropic and pathogenic for humans. It does not replicate in mice. The restricted species tropism has slowed progress in basic research activities. The current study seeks to correct animal model limitations.

Methods: We created an AD mouse to address the need to develop an small animal model that allows studies of viral infection by making a knock-in (KI) with the human amyloid precursor protein (APP)^KM670,671NL Swedish mutation to the mouse genome. The resulting founder mice were crossed with immunodeficient NOG (NOD. Cg-Prkdc ^scid Il2rg ^tm1Sug Tg(CMV-IL-34)1/Jic) to generate NOG/APP^KM670,671NL/IL-34 (NAIL) mice. The mice were reconstituted with human hematopoietic stem cells to generate NAIL mice with functional adaptive and innate human immune systems. Four-month-old, humanized NAIL mice were infected with HIV-1_ADA, a macrophage-tropic viral strain then evaluated for viral infection and AD pathology.

Results: Productive HIV-1 infection was confirmed by plasma HIV-1 RNA levels in infected NAIL mice. The viral load increased by tenfold between day 10 and day 25 post-infection. By day 25, viral DNA confirmed the establishment of HIV-1 reservoirs in CD45+ cells from the immune tissues of infected NAIL mice. Additionally, p24 measurements in lymphoid and brain tissues of NAIL mice validated productive HIV-1 infection. Amyloid burden from infected NAIL mice was increased. Immunofluorescence staining revealed co-localization of Aβ fibrils and HLA-DR⁺ microglia in infected NAIL mice.

Conclusions: These results highlight the AD-HIV model's unique pathobiological and infectious features where the viral and immune responses can now be measured.

Objectives: HIV-1 enters the central nervous system (CNS) early in infection, and a significant proportion of people with HIV experience CNS complications despite anti-retroviral therapy. Chronic immune dysfunction, inflammatory cytokines and chemokines, and viral proteins like Tat and gp120 released by HIV-1-infected immune cells are implicated in the pathogenesis of HIV-1-associated neurocognitive disorders (HAND).

Methods: To elucidate the contribution of non-viral factors to CNS complications in people with HIV-1, a comparative analysis of neurovirulent subtype B (HIV-1_ADA) and non-neurovirulent subtype C (HIV-1_Indie-C1) isolates was performed. Culture supernatants from HIV-1-infected PBMCs, either with or without immunodepletion of Tat and gp120, were used to treat SH-SY5Y neuroblastoma cells.

Results: HIV-1_ADA-infected PBMC media showed significantly higher neurotoxicity than HIV-1_IndieC1-infected PBMC media, notwithstanding the depletion of Tat and gp120, highlighting the role of non-viral factors (e.g., cytokines) contributing to neurotoxicity. A comparison of inflammatory profiles revealed that HIV-1_ADA media contained elevated levels of cytokines (IL-1α, IL-1β, IL-6 and TNFα) and chemokines (CCL2, CCL3, CCL4 and IP-10). Given the involvement of Tat in upregulating immune mediators, we tested the role of purified Tat proteins from HIV-1 subtypes B and C in inducing an inflammatory phenotype in PBMCs. PBMCs from healthy subjects were treated with recombinant purified Tat from subtype B or C. Subtype B Tat induced a stronger inflammatory response than subtype C Tat.

Conclusions: These results confirm that both viral and non-viral immune factors mediate neuronal damage in people with HIV.

Objectives: A significant clinical concern in the era of Pre-Exposure Prophylaxis (PrEP) is the increased incidence of HIV Anti-Retroviral Drug Resistance Mutations (ARV-DRM). Previous research has indicated that there is an association between substance use and failed viral suppression, which can lead to ARV-DRM. The goal of this retrospective study was to investigate whether substance use as determined by at least one positive urinalysis screen is associated with increased/decreased odds of having a ARV-DRM.

Methods: This study used firth logistic regression analyses of data retrieved from the National NeuroAIDS Tissue Consortium Data Coordinating Center to examine the relationship between substance use and ARV-DRM. The dataset analyzed 614 participants with the following criteria: HIV+ status, at least one paired plasma and cerebrospinal fluid (CSF) viral load measurement, at least one urinalysis of substance use, at least 18 years of age, and analysis of DRM in CSF/Plasma.

Results: Cannabis use was a significant predictor of ARV-DRM and was associated with a lower odds of having ARV-DRM (odds ratio=0.189), after accounting for demographic variables and the interaction between polysubstance use and cannabis use. A significant negative relationship was observed between a cannabis positive test and high viremia (>1,000 copies/mL) but not between a cannabis positive test and CSF Escape (viral load CSF>viral load plasma).

Conclusions: The above results may suggest an immunomodulatory role for cannabis that impacts the propensity for ARV-DRM. These findings could incentivize future research to further investigate effects of cannabis use on the development of HIV ARV-DRM.

Objectives: During physical and psychosocial development, many adolescents engage in binge alcohol drinking. Ethanol (EtOH) is the key chemical in alcoholic beverages. EtOH intoxication impairs locomotor behaviors. We previously found that binge treatment with EtOH (BE) causes spleen atrophy, leading to immune dysregulation. With these premises, we hypothesized that BE-induced spleen atrophy is correlated with compromised locomotion and behaviors in adolescence.

Methods: We exposed F344 rats to either 3 days of BE (mimicking college drinking) or water following pubertal onset. 24 h following the last BE, we assessed behaviors using ANY-Maze, focusing on locomotor activity, freezing, and thigmotaxis, before spleen collection. Correlation analysis and Linear Regression analysis quantified BE's effects on behavior. In parallel, we used GEO2R to obtain differentially expressed genes (DEGs) from public dataset GSE49028 (B6129Sf2/J mice were given BE) and identified signaling pathways in the prefrontal cortex (PFC) involved in BE compromising locomotion and increasing anxiety.

Results: BE significantly decreased spleen size. Interestingly, we found that BE exposure had a gender-dependent impact, affecting males more than females. Furthermore, functional analysis of the dataset identified several targets of interest including the downregulation of BDNF as a critical regulator of behavioral deficit following BE treatment.

Conclusions: Using data-driven discovery and hypothesis-testing investigation to integrate these two studies, we provide an understanding of the underlying biological mechanism of BE-induced spleen atrophy-associated behavioral impairments through the genetic alterations in the PFC. Our findings will help develop a potent, powerful cocktail of reagents to treat behavioral impairment in those who binge drink.

A major barrier to cure HIV is the early generation of viral reservoirs in tissues. These viral reservoirs can contain intact or defective proviruses, but both generates low levels of viral proteins contribute to chronic bystander damage even in the ART era. Most viral reservoir detection techniques are limited to blood-based, reactivation, and sequencing assays that lack spatial properties to examine the contribution of the host's microenvironment to latency and cure efforts. Currently, little is known about the contribution of the microenvironment to viral reservoir survival, residual viral expression, and associated inflammation. Only a few spatiotemporal techniques are available, and fewer integrate spatial genomics, transcriptomics, and proteomics into the analysis of the viral reservoir microenvironment-all essential components to cure HIV. During the development of these spatial techniques, many considerations need to be included in the analysis to avoid misinterpretation. This manuscript tries to clarify some critical concepts in viral reservoir detection by spatial techniques and the upcoming opportunities for cure efforts.

Obesity, by any standard, is a global health crisis. Both genetic and dietary contributions to the development and maintenance of obesity were integral factors of our experimental design. As mutations of the melanocortin 4 receptors (MC4R) are the leading monogenetic cause of obesity, MC4R haploinsufficient rats were fed a range of dietary fat (0-12 %) in a longitudinal design. Physiological and motivational assessments were performed using a locomotor task, a 5-choice sucrose preference task, an operant task with fixed and progressive ratios, as well as a distraction operant task. Dendritic spine morphology of medium spiny neurons (MSNs) of the nucleus accumbens (NAc), cells with ample D1 and D2 receptors, was also assessed. The percentage of lipid deposits in the liver of each rat was also analyzed using the Area Fraction Fractionator probe for stereological measurements. MC4R haploinsufficiency resulted in a phenotypic resemblance for adult-onset obesity that was exacerbated by the consumption of a high-fat diet. Results from the operant tasks indicate that motivational deficits due to MC4R haploinsufficiency were apparent prior to the onset of obesity and exacerbated by dietary fat consumption after obesity was well established. Moreover, MSN morphology shifted to longer spines with smaller head diameters for the MC4R+/- animals under the high-fat diet, suggesting a potential mechanism for the dysregulation of motivation to work for food. Increasing our knowledge of the neural circuitry/mechanisms responsible for the rewarding properties of food has significant implications for understanding energy balance and the development of obesity.