A critical role for Macrophage-derived Cysteinyl-Leukotrienes in HIV-1 induced neuronal injury.

Macrophages (MΦ) infected with human immunodeficiency virus (HIV)-1 or activated by its envelope protein gp120 exert neurotoxicity. We found previously that signaling via p38 mitogen-activated protein kinase (p38 MAPK) is essential to the neurotoxicity of HIVgp120-stimulated MΦ. However, the associated downstream pathways remained elusive.

Second-Line Pharmaceutical Treatments for Patients with Type 2 Diabetes.

Importance: Assessing the relative effectiveness and safety of additional treatments when metformin monotherapy is insufficient remains a limiting factor in improving treatment choices in type 2 diabetes.

Objective: To determine whether data from electronic health records across the University of California Health system could be used to assess the comparative effectiveness and safety associated with 4 treatments in diabetes when added to metformin monotherapy.

Design, Setting, And Participants: This multicenter, new user, multidimensional propensity score-matched retrospective cohort study with leave-one-medical-center-out (LOMCO) sensitivity analysis used principles of emulating target trial.

CXCL12-induced neurotoxicity critically depends on NMDA receptor-gated and L-type Ca channels upstream of p38 MAPK.

Background: The chemokine receptor CXCR4 (CD184) and its natural ligand CXCL12 contribute to many physiological processes, including decisions about cell death and survival in the central nervous system. In addition, CXCR4 is a co-receptor for human immunodeficiency virus (HIV)-1 and mediates the neurotoxicity of the viral envelope protein gp120. However, we previously observed that CXCL12 also causes toxicity in cerebrocortical neurons but the cellular mechanism remained incompletely defined.

CCR5 knockout prevents neuronal injury and behavioral impairment induced in a transgenic mouse model by a CXCR4-using HIV-1 glycoprotein 120.

The innate immune system has been implicated in several neurodegenerative diseases, including HIV-1-associated dementia. In this study, we show that genetic ablation of CCR5 prevents microglial activation and neuronal damage in a transgenic model of HIV-associated brain injury induced by a CXCR4-using viral envelope gp120. The CCR5 knockout (KO) also rescues spatial learning and memory in gp120-transgenic mice.

Genetic knockouts suggest a critical role for HIV co-receptors in models of HIV gp120-induced brain injury.

Infection with HIV-1 frequently affects the brain and causes NeuroAIDS prior to the development of overt AIDS. The HIV-1 envelope protein gp120 interacts with host CD4 and chemokine co-receptors to initiate infection of macrophages and lymphocytes. In addition, the virus or fragments of it, such as gp120, cause macrophages to produce neurotoxins and trigger neuronal injury and apoptosis.

Mitogen-activated protein kinase p38 in HIV infection and associated brain injury.

Infection with human immunodeficiency virus-1 (HIV-1) often leads to HIV-associated neurocognitive disorders (HAND) prior to the progression to acquired immunodeficiency syndrome (AIDS). At the cellular level, mitogen-activated protein kinases (MAPK) provide a family of signal transducers that regulate many processes in response to extracellular stimuli and environmental stress, such as viral infection. Recently, evidence has accumulated suggesting that p38 MAPK plays crucial roles in various pathological processes associated with HIV infection, ranging from macrophage activation to neurotoxicity and impairment of neurogenesis to lymphocyte apoptosis.

Activation of p38 MAPK is required in monocytic and neuronal cells for HIV glycoprotein 120-induced neurotoxicity.

HIV-1 envelope protein gp120 has been implicated in neurotoxin production by monocytic cells (i.e., macrophages and microglia), as well as in the pathogenesis of HIV-1-associated neurocognitive disorders.