Are We the Problem? A Call to Action for Addressing Institutional Challenges to Engaging Community Partners in Research.

Community-engaged research (CEnR) is a potent tool for addressing health inequities and fostering equitable relationships among communities, researchers, and institutions. CEnR involves collaboration throughout the research process, demonstrating improvements in study recruitment and retention, intervention efficacy, program sustainability, capacity building among partners, and enhanced cultural relevance. Despite the increasing demand for CEnR, institutional policies, particularly human participation protection training (HPP), lag behind, creating institutional barriers to community partnerships. Here, we highlight challenges encountered in our ongoing study, Fostering Opportunities in Research through Messaging and Education (FOR ME), focused on promoting shared decision-making around clinical trial participation among Black women diagnosed with breast cancer. Grounded in CEnR methods, FOR ME has a partnership with a community-based organization (CBO) that addresses the needs of Black women with breast cancer. Our CBO partner attempted to obtain HPP training, which was administratively burdensome and time-consuming. As CEnR becomes more prevalent, academic and research institutions, along with researchers, are faced with a call to action to become more responsive to community partner needs. Accordingly, we present a guide to HPP training for community partners, addressing institutional barriers to community partner participation in research. This guide outlines multiple HPP training pathways for community partners, aiming to minimize institutional barriers and enhance their engagement in research with academic partners.

Gordon Holmes Syndrome Model Mice Exhibit Alterations in Microglia, Age, and Sex-Specific Disruptions in Cognitive and Proprioceptive Function.

Gordon Holmes syndrome (GHS) is a neurological disorder associated with neuroendocrine, cognitive, and motor impairments with corresponding neurodegeneration. Mutations in the E3 ubiquitin ligase RNF216 are strongly linked to GHS. Previous studies show that deletion of Rnf216 in mice led to sex-specific neuroendocrine dysfunction due to disruptions in the hypothalamic-pituitary-gonadal axis. To address RNF216 action in cognitive and motor functions, we tested Rnf216 knock-out (KO) mice in a battery of motor and learning tasks for a duration of 1 year. Although male and female KO mice did not demonstrate prominent motor phenotypes, KO females displayed abnormal limb clasping. KO mice also showed age-dependent strategy and associative learning impairments with sex-dependent alterations of microglia in the hippocampus and cortex. Additionally, KO males but not females had more negative resting membrane potentials in the CA1 hippocampus without any changes in miniature excitatory postsynaptic current (mEPSC) frequencies or amplitudes. Our findings show that constitutive deletion of Rnf216 alters microglia and neuronal excitability, which may provide insights into the etiology of sex-specific impairments in GHS.

Calculation of ATP production rates using the Seahorse XF Analyzer.

Oxidative phosphorylation and glycolysis are the dominant ATP-generating pathways in mammalian metabolism. The balance between these two pathways is often shifted to execute cell-specific functions in response to stimuli that promote activation, proliferation, or differentiation. However, measurement of these metabolic switches has remained mostly qualitative, making it difficult to discriminate between healthy, physiological changes in energy transduction or compensatory responses due to metabolic dysfunction. We therefore present a broadly applicable method to calculate ATP production rates from oxidative phosphorylation and glycolysis using Seahorse XF Analyzer data and empirical conversion factors. We quantify the bioenergetic changes observed during macrophage polarization as well as cancer cell adaptation to in vitro culture conditions. Additionally, we detect substantive changes in ATP utilization upon neuronal depolarization and T cell receptor activation that are not evident from steady-state ATP measurements. This method generates a single readout that allows the direct comparison of ATP produced from oxidative phosphorylation and glycolysis in live cells. Additionally, the manuscript provides a framework for tailoring the calculations to specific cell systems or experimental conditions.

The role of facility and patient mix factors on recovery of screening and diagnostic mammography volumes following the initial COVID-19 pandemic wave.

INTRODUCTION: The goal of this study was to understand the extent to which mammography facilities were able to recover monthly screening and diagnostic mammography volumes to their prepandemic levels and to determine what facility and patient mix factors were associated with recovery. METHOD: Facilities, located in and adjacent to Cook County, Illinois, were eligible. In all, 58 screening and 30 diagnostic mammogram facilities submitted mammogram volumes by month with a cross-listing of patient ZIP codes by screening volumes. Monthly screening and diagnostic volumes for the 6-month immediate postpandemic period (July-December 2020) and for the subsequent postpandemic period (January-June 2021) were compared with the same months in 2019. ZIP code distributions were used to define patient mix characteristics related to disadvantage. RESULTS: Compared with the prepandemic period, Breast Imaging Centers of Excellence conducted roughly 50 fewer monthly screening mammograms (95% CI: -91, -9) but 50 more diagnostic mammograms (95% CI: 24, 82) on average in the immediate postpandemic period. Facilities serving a predominantly Black population conducted roughly 50 fewer monthly screens (95% CI: -93, -13) without any increase in monthly diagnostics. CONCLUSION: Highly accredited (and typically higher volume) facilities appeared to actively triage diagnostics, whereas lower resource facilities appeared to struggle to recover to prepandemic volumes without triage to diagnostics. The pandemic disproportionally impacted minority populations already affected by differential access to and utilization of high-quality mammography. Potential explanations are discussed. Policies should be strengthened to facilitate triaging of services during times of stress to the healthcare system.

Fibromyalgia and centralized pain in the rheumatoid arthritis patient.

PURPOSE OF REVIEW: Individuals with rheumatoid arthritis (RA) have traditionally been characterized as having nociceptive pain, leading to the assumption that effective immunosuppression should be enough to provide effective pain management. However, despite therapeutic advancements providing excellent control of inflammation, patients continue to have significant pain and fatigue. The presence of concurrent fibromyalgia, driven by augmented central nervous system processing and largely unresponsive to peripheral therapies, may contribute to this pain persistence. This review provides updates on fibromyalgia and RA as relevant for the clinician. RECENT FINDINGS: Patients with RA have high levels of concomitant fibromyalgia and nociplastic pain. The presence of fibromyalgia can lead to higher scores on disease measures, erroneously indicating that worse disease is presently leading to the increased use of immunosuppressives and opioids. Disease scores that provide a comparison between patient-reported and provider-reported and clinical factors may be helpful to indicate centralized pain. IL-6 and Janus kinase inhibitors, in addition to targeting peripheral inflammation, may provide pain relief by acting on peripheral and central pain pathways. SUMMARY: Central pain mechanisms that may be contributing to pain in RA are common and should be distinguished from pain directly arising from peripheral inflammation.

Identifying and Managing Nociplastic Pain in Individuals With Rheumatic Diseases: A Narrative Review.

Chronic pain is a burdensome and prevalent symptom in individuals with rheumatic disease. The International Association for the Study of Pain classifies pain into 3 descriptive categories: nociceptive, neuropathic, and nociplastic. These categories are intended to provide information about the mechanisms underlying the pain, which can then serve as targets for drug or non-drug treatments. This review describes the 3 types of pain as they relate to patients seen by rheumatology health care providers. The focus is on identifying individuals with nociplastic pain, which can either occur in isolation as in fibromyalgia, or as a comorbidity in individuals with primary autoimmune conditions, such as rheumatoid arthritis and systemic lupus erythematosus. Practical information about how rheumatology health care providers can approach and manage chronic pain is also provided.

Alteration in tyrosine phosphorylation of cardiac proteome and EGFR pathway contribute to hypertrophic cardiomyopathy.

Alterations of serine/threonine phosphorylation of the cardiac proteome are a hallmark of heart failure. However, the contribution of tyrosine phosphorylation (pTyr) to the pathogenesis of cardiac hypertrophy remains unclear. We use global mapping to discover and quantify site-specific pTyr in two cardiac hypertrophic mouse models, i.e., cardiac overexpression of ErbB2 (TgErbB2) and α myosin heavy chain R403Q (R403Q-αMyHC Tg), compared to control hearts. From this, there are significant phosphoproteomic alterations in TgErbB2 mice in right ventricular cardiomyopathy, hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM) pathways. On the other hand, R403Q-αMyHC Tg mice indicated that the EGFR1 pathway is central for cardiac hypertrophy, along with angiopoietin, ErbB, growth hormone, and chemokine signaling pathways activation. Surprisingly, most myofilament proteins have downregulation of pTyr rather than upregulation. Kinase-substrate enrichment analysis (KSEA) shows a marked downregulation of MAPK pathway activity downstream of k-Ras in TgErbB2 mice and activation of EGFR, focal adhesion, PDGFR, and actin cytoskeleton pathways. In vivo ErbB2 inhibition by AG-825 decreases cardiomyocyte disarray. Serine/threonine and tyrosine phosphoproteome confirm the above-described pathways and the effectiveness of AG-825 Treatment. Thus, altered pTyr may play a regulatory role in cardiac hypertrophic models.

Sex differences in the amygdaloid projections to the ventrolateral periaqueductal gray and their activation during inflammatory pain in the rat.

Preclinical and clinical studies have reported sex differences in pain and analgesia. These differences may be linked to anatomical structures of the central nervous system pain modulatory circuitry, and/or hormonal milieu. The midbrain periaqueductal gray (PAG) is a critical brain region for descending inhibition of pain. The PAG projects to the rostral ventromedial medulla (RVM), which projects bilaterally to the spinal cord to inhibit pain. In addition to pain, this descending circuit (or pathway) can be engaged by endogenous opioids (i.e., endorphins) or exogenous opioids (i.e., morphine), and we have previously reported sex differences in the activation of this circuit during pain and analgesia. Forebrain structures, including the amygdala, project to and engage the PAG-RVM circuit during persistent inflammatory pain. However, there are limited studies in females detailing this amygdalar-PAG pathway and its involvement during persistent inflammatory pain. The objective of the present study was to delineate the neural projections from the amygdala to the PAG in male and female rats to determine if they are sexually distinct in their anatomical organization. We also examined the activation of this pathway by inflammatory pain and the co-localization of receptors for estrogen. Injection of the retrograde tracer fluorogold (FG) into the ventrolateral PAG (vlPAG) resulted in dense retrograde labeling in both the central amygdala (CeA) and medial amygdala (MeA). While the number of CeA-vlPAG neurons were comparable between the sexes, there were more MeA-vlPAG neurons in females. Inflammatory pain resulted in greater activation of the amygdala in males; however, females displayed higher Fos expression within CeA-vlPAG projection neurons. Females expressed higher ERα in the MeA and CeA and the same was true of the projection neurons. Together, these data indicate that although the MeA-vlPAG projections are denser in females, inflammatory pain does not significantly activate these projections. In contrast, inflammatory pain resulted in a greater activation of the CeA-vlPAG pathway in females. As females experience a greater number of chronic pain syndromes, the CeA-vlPAG pathway may play a facilitatory (and not inhibitory) role in pain modulation.

NaCT/SLC13A5 facilitates citrate import and metabolism under nutrient-limited conditions.

Citrate lies at a critical node of metabolism, linking tricarboxylic acid metabolism and lipogenesis via acetyl-coenzyme A. Recent studies have observed that deficiency of the sodium-dependent citrate transporter (NaCT), encoded by SLC13A5, dysregulates hepatic metabolism and drives pediatric epilepsy. To examine how NaCT contributes to citrate metabolism in cells relevant to the pathophysiology of these diseases, we apply 13C isotope tracing to SLC13A5-deficient hepatocellular carcinoma (HCC) cells and primary rat cortical neurons. Exogenous citrate appreciably contributes to intermediary metabolism only under hypoxic conditions. In the absence of glutamine, citrate supplementation increases de novo lipogenesis and growth of HCC cells. Knockout of SLC13A5 in Huh7 cells compromises citrate uptake and catabolism. Citrate supplementation rescues Huh7 cell viability in response to glutamine deprivation or Zn2+ treatment, and NaCT deficiency mitigates these effects. Collectively, these findings demonstrate that NaCT-mediated citrate uptake is metabolically important under nutrient-limited conditions and may facilitate resistance to metal toxicity.

Deuterium-Stabilized (R)-Pioglitazone (PXL065) Is Responsible for Pioglitazone Efficacy in NASH yet Exhibits Little to No PPARγ Activity.

The antidiabetic drug pioglitazone is, to date, the most efficacious oral drug recommended off-label for the treatment of nondiabetic or diabetic patients with biopsy-proven nonalcoholic steatohepatitis (NASH). However, weight gain and edema side effects have limited its use for NASH. Pioglitazone is a mixture of two stereoisomers ((R)-pioglitazone and (S)-pioglitazone) that interconvert in vitro and in vivo. We aimed to characterize their individual pharmacology to develop a safer and potentially more potent drug for NASH. We stabilized the stereoisomers of pioglitazone with deuterium at the chiral center. Preclinical studies with deuterium-stabilized (R)-pioglitazone (PXL065) and (S)-pioglitazone demonstrated that (R)-pioglitazone retains the efficacy of pioglitazone in NASH, including reduced hepatic triglycerides, free fatty acids, cholesterol, steatosis, inflammation, hepatocyte enlargement, and fibrosis. Although both stereoisomers inhibit the mitochondrial pyruvate carrier, PXL065 shows limited to no peroxisome proliferator-activated receptor gamma (PPARγ) activity, whereas (S)-pioglitazone appears responsible for the PPARγ activity and associated weight gain. Nonetheless, in preclinical models, both stereoisomers reduce plasma glucose and hepatic fibrosis to the same extent as pioglitazone, suggesting that these benefits may also be mediated by altered mitochondrial metabolism. In a phase 1a clinical study, we demonstrated safety and tolerability of single 7.5-mg, 22.5-mg, and 30-mg doses of PXL065 as well as preferential exposure to the (R)-stereoisomer in comparison to 45-mg pioglitazone. Conclusion: PXL065 at a dose lower than 22.5 mg is predicted to exhibit efficacy for NASH equal to, or greater than, 45-mg pioglitazone without the potentially detrimental weight gain and edema. The development of PXL065 for NASH represents a unique opportunity to leverage the therapeutic benefits of pioglitazone, while reducing or eliminating PPARγ-related side effects.

Perm1 promotes cardiomyocyte mitochondrial biogenesis and protects against hypoxia/reoxygenation-induced damage in mice.

Normal contractile function of the heart depends on a constant and reliable production of ATP by cardiomyocytes. Dysregulation of cardiac energy metabolism can result in immature heart development and disrupt the ability of the adult myocardium to adapt to stress, potentially leading to heart failure. Further, restoration of abnormal mitochondrial function can have beneficial effects on cardiac dysfunction. Previously, we identified a novel protein termed Perm1 (PGC-1 and estrogen-related receptor (ERR)-induced regulator, muscle 1) that is enriched in skeletal and cardiac-muscle mitochondria and transcriptionally regulated by PGC-1 (peroxisome proliferator-activated receptor gamma coactivator 1) and ERR. The role of Perm1 in the heart is poorly understood and is studied here. We utilized cell culture, mouse models, and human tissue, to study its expression and transcriptional control, as well as its role in transcription of other factors. Critically, we tested Perm1's role in cardiomyocyte mitochondrial function and its ability to protect myocytes from stress-induced damage. Our studies show that Perm1 expression increases throughout mouse cardiogenesis, demonstrate that Perm1 interacts with PGC-1α and enhances activation of PGC-1 and ERR, increases mitochondrial DNA copy number, and augments oxidative capacity in cultured neonatal mouse cardiomyocytes. Moreover, we found that Perm1 reduced cellular damage produced as a result of hypoxia and reoxygenation-induced stress and mitigated cell death of cardiomyocytes. Taken together, our results show that Perm1 promotes mitochondrial biogenesis in mouse cardiomyocytes. Future studies can assess the potential of Perm1 to be used as a novel therapeutic to restore cardiac dysfunction induced by ischemic injury.

The "Sweet Spot" Revisited: Optimal Recall Rates for Cancer Detection With 2D and 3D Digital Screening Mammography in the Metro Chicago Breast Cancer Registry.

OBJECTIVE. One central question pertaining to mammography quality relates to discerning the optimal recall rate to maximize cancer detection while minimizing unnecessary downstream diagnostic imaging and breast biopsies. We examined the trade-offs for higher recall rates in terms of biopsy recommendations and cancer detection in a single large health care organization. MATERIALS AND METHODS. We included 2D analog, 2D digital, and 3D digital (tomosynthesis) screening mammography examinations among women 40-79 years old performed between January 1, 2005, and December 31, 2017, with cancer follow-up through 2018. There were 36, 67, and 38 radiologists who read at least 1000 2D analog examinations, 2D digital examinations, and 3D tomosynthesis examinations, respectively, who were included in these analyses. Using logistic regression with marginal standardization, we estimated radiologist-specific mean recall (abnormal interpretations/1000 mammograms), biopsy recommendation, cancer detection (screening-detected in situ and invasive cancers/1000 mammograms), and minimally invasive cancer detection rates while adjusting for differences in patient characteristics. RESULTS. Among 1,060,655 screening mammograms, the mean recall rate was 10.7%, the cancer detection rate was 4.0/1000 mammograms, and the biopsy recommendation rate was 1.60%. Recall rates between 7% and 9% appeared to maximize cancer detection while minimizing unnecessary biopsies. CONCLUSION. The results of this investigation are in contrast to those of a recent study suggesting appropriateness of higher recall rates. The "sweet spot" for optimal cancer detection appears to be in the recall rate range of 7-9% for both 2D digital mammography and 3D tomosynthesis. Too many women are being called back for diagnostic imaging, and new benchmarks could be set to reduce this burden.

Trends in Attaining Mammography Quality Benchmarks With Repeated Participation in a Quality Measurement Program: Going Beyond the Mammography Quality Standards Act to Address Breast Cancer Disparities.

PURPOSE: The Mammography Quality Standards Act requires that mammography facilities conduct audits, but there are no specifications on the metrics to be measured. In a previous mammography quality improvement project, the authors examined whether breast cancer screening facilities could collect the data necessary to show that they met certain quality benchmarks. Here the authors present trends from the first 5 years of data collection to examine whether continued participation in this quality improvement program was associated with an increase in the number of benchmarks met for breast cancer screening. METHODS: Participating facilities across the state of Illinois (n = 114) with at least two time points of data collected (2006, 2009, 2010, 2011, and/or 2013) were included. Facilities provided aggregate data on screening mammographic examinations and corresponding diagnostic follow-up information, which was used to estimate 13 measures and corresponding benchmarks for patient tracking, callback, cancer detection, loss to follow-up, and timeliness of care. RESULTS: The number of facilities able to show that they met specific benchmarks increased with length of participation for many but not all measures. Trends toward meeting more benchmarks were apparent for cancer detection, timely imaging, not lost at biopsy, known minimal status (P < .01 for all), and proportion of screening-detected cancers that were minimal and early stage (P < .001 for both). CONCLUSIONS: Participation in the quality improvement program seemed to lead to improvements in patient tracking, callback and detection, and timeliness benchmarks.

Tenofovir disoproxil fumarate induces peripheral neuropathy and alters inflammation and mitochondrial biogenesis in the brains of mice.

Mounting evidence suggests that antiretroviral therapy (ART) drugs may contribute to the prevalence of HIV-associated neurological dysfunction. The HIV envelope glycoprotein (gp120) is neurotoxic and has been linked to alterations in mitochondrial function and increased inflammatory gene expression, which are common neuropathological findings in HIV+ cases on ART with neurological disorders. Tenofovir disproxil fumarate (TDF) has been shown to affect neurogenesis in brains of mice and mitochondria in neurons. In this study, we hypothesized that TDF contributes to neurotoxicity by modulating mitochondrial biogenesis and inflammatory pathways. TDF administered to wild-type (wt) and GFAP-gp120 transgenic (tg) mice caused peripheral neuropathy, as indicated by nerve conduction slowing and thermal hyperalgesia. Conversely TDF protected gp120-tg mice from cognitive dysfunction. In the brains of wt and gp120-tg mice, TDF decreased expression of mitochondrial transcription factor A (TFAM). However, double immunolabelling revealed that TFAM was reduced in neurons and increased in astroglia in the hippocampi of TDF-treated wt and gp120-tg mice. TDF also increased expression of GFAP and decreased expression of IBA1 in the wt and gp120-tg mice. TDF increased tumor necrosis factor (TNF) α in wt mice. However, TDF reduced interleukin (IL) 1ß and TNFα mRNA in gp120-tg mouse brains. Primary human astroglia were exposed to increasing doses of TDF for 24 hours and then analyzed for mitochondrial alterations and inflammatory gene expression. In astroglia, TDF caused a dose-dependent increase in oxygen consumption rate, extracellular acidification rate and spare respiratory capacity, changes consistent with increased metabolism. TDF also reduced IL-1ß-mediated increases in IL-1ß and TNFα mRNA. These data demonstrate that TDF causes peripheral neuropathy in mice and alterations in inflammatory signaling and mitochondrial activity in the brain.

Knockdown of Ant2 Reduces Adipocyte Hypoxia And Improves Insulin Resistance in Obesity.

Decreased adipose tissue oxygen tension and increased HIF-1α expression can trigger adipose tissue inflammation and dysfunction in obesity. Our current understanding of obesity-associated decreased adipose tissue oxygen tension is mainly focused on changes in oxygen supply and angiogenesis. Here, we demonstrate that increased adipocyte O2 demand, mediated by ANT2 activity, is the dominant cause of adipocyte hypoxia. Deletion of adipocyte Ant2 improves obesity-induced intracellular adipocyte hypoxia by decreasing obesity-induced adipocyte oxygen demand, without effects on mitochondrial number or mass, or oligomycin-sensitive respiration. This led to decreased adipose tissue HIF-1α expression and inflammation with improved glucose tolerance and insulin resistance in both a preventative or therapeutic setting. Our results suggest that ANT2 may be a target for the development of insulin sensitizing drugs and that ANT2 inhibition might have clinical utility.

Mitochondria supply ATP to the ER through a mechanism antagonized by cytosolic Ca2.

The endoplasmic reticulum (ER) imports ATP and uses energy from ATP hydrolysis for protein folding and trafficking. However, little is known about how this vital ATP transport occurs across the ER membrane. Here, using three commonly used cell lines (CHO, INS1 and HeLa), we report that ATP enters the ER lumen through a cytosolic Ca2+-antagonized mechanism, or CaATiER (Ca2+-Antagonized Transport into ER). Significantly, we show that mitochondria supply ATP to the ER and a SERCA-dependent Ca2+ gradient across the ER membrane is necessary for ATP transport into the ER, through SLC35B1/AXER. We propose that under physiological conditions, increases in cytosolic Ca2+ inhibit ATP import into the ER lumen to limit ER ATP consumption. Furthermore, the ATP level in the ER is readily depleted by oxidative phosphorylation (OxPhos) inhibitors and that ER protein misfolding increases ATP uptake from mitochondria into the ER. These findings suggest that ATP usage in the ER may increase mitochondrial OxPhos while decreasing glycolysis, i.e. an 'anti-Warburg' effect.

Metformin Inhibits Progression of Head and Neck Squamous Cell Carcinoma by Acting Directly on Carcinoma-Initiating Cells.

Metformin may reduce the progression of head and neck squamous cell carcinoma (HNSCC); however, whether metformin acts by altering the host metabolism or targets cancer-initiating cells remains poorly understood. This gap in knowledge has prevented the stratification of patient populations who are most likely to benefit from metformin treatment. Here, we explored whether metformin acts directly on HNSCC cells to inhibit aberrant cell growth. To investigate the tumor cell autonomous effects of metformin, we engineered representative HPV- and HPV+ HNSCC cells harboring typical genetic alternations to express the yeast mitochondrial NADH dehydrogenase (NDI1) protein, which is insensitive to metformin. NDI1 expression rescued the inhibitory effects of metformin on mitochondrial complex I, abolished the ability of metformin to activate AMP-activated protein kinase, and inhibited mTOR signaling both in vitro and in vivo, and was sufficient to render metformin ineffective to prevent HNSCC tumor growth. This experimental system provided an opportunity to identify metformin-regulated transcriptional programs linked to cancer cell growth inhibition in the tumor microenvironment. Remarkably, computational analysis of the metformin-induced transcriptome revealed that metformin downregulated gene expression signatures associated with cancer stemness and epithelial-mesenchymal transition, concomitant with increased expression of squamous differentiation genes. These findings support that metformin may act directly on cancer-initiating cells to prevent their progression to HNSCC, which may inform the selection of patients at risk of developing HNSCC in future early-stage clinical trials. SIGNIFICANCE: Metformin's ability to directly target HNSCC-initiating cells instead of exerting cancer preventive activity based solely on its systemic effects may inform the selection of patients in future precision prevention trials.

Mitochondrial biogenesis is altered in HIV+ brains exposed to ART: Implications for therapeutic targeting of astroglia.

The neuropathogenesis of HIV associated neurocognitive disorders (HAND) involves disruption of mitochondrial homeostasis and increased neuroinflammation. However, it is unknown if alterations in mitochondrial biogenesis in the brain underlie the neuropathogenesis of HAND. In this study, neuropathological and molecular analyses of mitochondrial biogenesis and inflammatory pathways were performed in brain specimens from a well-characterized cohort of HIV+ cases that were on antiretroviral regimens. In vitro investigations using primary human astroglia and neurons were used to probe the underlying mechanisms of mitochondrial alterations. In frontal cortices from HAND brains compared to cognitive normal brains, total levels of transcription factors that regulate mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and transcription factor A, mitochondrial (TFAM) were decreased. Immunohistochemical analyses revealed that TFAM was decreased in neurons and increased in astroglia. These changes were accompanied by decreased total mitochondrial DNA per cell and increased levels of messenger RNA for the proinflammatory cytokine interleukin (IL)-1ß. To determine how IL-1ß affects astroglial bioenergetic processes and mitochondrial activity, human astroglial cultures were exposed to recombinant IL-1ß. IL-1ß induced mitochondrial activity within 30 min of treatment, altered mitochondrial related gene expression, altered mitochondrial morphology, enhanced adenoside triphosphate (ATP) utilization and increased the expression of inflammatory cytokines. WIN55,212-2 (WIN), an aminoalkylindole derivative and cannabinoid receptor agonist, blocked IL-1ß-induced bioenergetic fluctuations and inflammatory gene expression in astroglia independent of cannabinoid receptor (CB)1 and peroxisome proliferator-activated receptor (PPAR) γ. A PPARα antagonist reversed the anti-inflammatory effects of WIN in human astroglia. These results show that mitochondrial biogenesis is differentially regulated in neurons and astroglia in HAND brains and that targeting astroglial bioenergetic processes may be a strategy to modulate neuroinflammation.