Combination treatment with FAAH inhibitors/URB597 and ferroptosis inducers significantly decreases the growth and metastasis of renal cell carcinoma cells via the PI3K-AKT signaling pathway

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(4)

Published: April 6, 2023

Abstract Ferroptosis, a nonapoptotic form of programmed cell death characterized by significant iron-dependent peroxidation phospholipids, is regulated cellular metabolism, redox homeostasis, and various cancer-related signaling pathways. Recently, considerable progress has been made in demonstrating the critical role lipid metabolism regulating ferroptosis, indicating potential combinational strategies for treating cancer future. In this study, we explored effects compounds ferroptosis inducers on renal carcinoma (RCC) cells. We found potent synergy fatty acid amide hydrolase (FAAH) inhibitor URB597 with inducer (1S, 3R)-RSL3 (RSL3) inhibiting growth metastasis RCC cells both vitro vivo via induction G1 cycle arrest promotion production peroxides, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), cytosolic reactive oxygen species (ROS). addition, inhibition FAAH increased sensitivity to ferroptosis. Genome-wide RNA sequencing indicated that combination RSL3 more regulation expression genes related proliferation, cycle, migration invasion, than either single agent alone. Moreover, treatment modulated phosphatidylinositol 3 kinase (PI3K)-AKT pathway. These data demonstrate dual targeting could be promising strategy RCC.

Language: Английский

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The Impact of Cannabis Use on Cognition in People with HIV: Evidence of Function-Dependent Effects and Mechanisms from Clinical and Preclinical Studies

Current HIV/AIDS Reports, Journal Year: 2024, Volume and Issue: 21(3), P. 87 - 115

Published: April 11, 2024

Language: Английский

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Effects of acute cannabidiol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

Frontiers in Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: March 5, 2024

Background Some evidence suggests that cannabidiol (CBD) has potential to help alleviate HIV symptoms due its antioxidant and anti-inflammatory properties. Here we examined acute CBD effects on various behaviors the endocannabinoid system in Tat transgenic mice. Methods mice (female/male) were injected with (3, 10, 30 mg/kg) assessed for antinociception, activity, coordination, anxiety-like behavior, recognition memory. Brains taken quantify endocannabinoids, cannabinoid receptors, catabolic enzymes. Additionally, metabolite 7-hydroxy-CBD quantified plasma cortex. Results decreased supraspinal-related nociception locomotion. sex had little no any of behavioral measures. For male was associated elevated concentration proinflammatory arachidonic acid CNS regions, including cerebellum also showed higher FAAH expression levels Tat(+) males. GPR55 striatum females compared metabolism altered by expression. Conclusion Findings indicate are not Tat, minimal behavior system.

Language: Английский

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HIV-1 Tat protein alters medial prefrontal cortex neuronal activity and recognition memory

iScience, Journal Year: 2025, Volume and Issue: 28(3), P. 112075 - 112075

Published: Feb. 22, 2025

Despite advancements in combined antiretroviral therapy, human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) continue to affect 40%-50% of people living with HIV. While neuroimaging studies have revealed HIV-1-induced alterations cortical networks and brain macrostructures, it still remains unclear how individual neurons the medial prefrontal cortex (mPFC) are affected during recognition memory. Using vivo calcium imaging an HIV-1 transactivator transcription (Tat) transgenic mouse model, we examined mPFC neuronal activity a novel object memory task. Our findings show that HIV Tat expression reduces overall Tat(+) mice without altering number activated cells. Moreover, distinct subpopulations up- downmodulated both Tat(-) depending on exploration. Importantly, familiarity-driven increases were disrupted by expression. These enhance our understanding HAND may inform future pharmacological strategies aimed at restoring cognitive function.

Language: Английский

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Effects of acute Δ9-tetrahydrocannabinol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

Brain Research, Journal Year: 2023, Volume and Issue: 1822, P. 148638 - 148638

Published: Oct. 17, 2023

Cannabis use is highly prevalent especially among people living with HIV (PLWH). Activation of the anti-inflammatory and neuroprotective endocannabinoid system by phytocannabinoids, i.e. Δ

Language: Английский

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Cannabinoid receptor 1 positive allosteric modulator ZCZ011 shows differential effects on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(6), P. e0305868 - e0305868

Published: June 24, 2024

The cannabinoid receptor type 1 (CB R) is a promising therapeutic target for various neurodegenerative diseases, including HIV-1-associated neurocognitive disorder (HAND). However, the potential of CB R by direct activation limited due to its psychoactive side effects. Therefore, research has focused on indirectly activating utilizing positive allosteric modulators (PAMs). Studies have shown that PAMs (ZCZ011 and GAT211) are effective in mouse models Huntington’s disease neuropathic pain, hence, we assess ZCZ011 well-established model neuroHIV. current study investigates effect chronic treatment (14 days) behavioral paradigms endocannabinoid system HIV-1 Tat transgenic female male mice. Chronic (10 mg/kg) did not alter body mass, locomotor activity, or anxiety-like behavior regardless sex genotype. differential effects were noted hot plate latency, motor coordination, recognition memory mice only, with increasing latency improving coordination memory. Only minor no alterations seen related lipids except cerebellum, where was more pronounced Moreover, AEA PEA levels cerebellum positively correlated improved In summary, these findings indicate antinociception, memory, based expression, making options HAND without

Language: Английский

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The Endocannabinoid System as a Potential Therapeutic Target for HIV-1-Associated Neurocognitive Disorder

Cannabis and Cannabinoid Research, Journal Year: 2023, Volume and Issue: 8(3), P. 445 - 463

Published: Feb. 6, 2023

Background: Despite the successful introduction of combined antiretroviral therapy, prevalence mild to moderate forms HIV-associated neurocognitive disorders (HAND) remains high. It has been demonstrated that neuronal injury caused by HIV is excitotoxic and inflammatory, it correlates with decline in HAND. Endocannabinoid system (ECS) protects body from excitotoxicity neuroinflammation on demand presents a promising therapeutic target for treating Here, we firstly discuss potential pathogenesis We secondly structural functional changes ECS are currently known among HAND patients. thirdly current clinical preclinical findings concerning neuroprotective anti-inflammatory properties Fourth, will interactions between neuroendocrine systems, including hypothalamic-pituitary-adrenocortical (HPA) hypothalamic-pituitary-gonadal (HPG) axes under conditions. Materials Methods: have carried out review literature using PubMed summarize state knowledge association Results: The may be ideally suited modulation pathophysiology. Direct activation presynaptic cannabinoid receptor 1 or reduction metabolism attenuates excitotoxicity. Chronic associated can reduced activating 2 immune cells. sensitivity enhanced increased expression In addition, indirect regulation through hormone-related receptors strategy influence also alleviate progression due reciprocal inhibition HPA HPG axes. Conclusions: Taken together, targeting inflammation neurodegeneration HIV-1 infection. Further studies required clarify role endocannabinoid signaling neurotoxicity. Strategies promoting slow down cognitive proposed.

Language: Английский

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Targeting the endocannabinoid system in HAND

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 539 - 556

Published: Jan. 1, 2024

Language: Английский

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Cannabinoid receptor 1 positive allosteric modulator ZCZ011 shows differential effects on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 10, 2024

Abstract The cannabinoid receptor type 1 (CB R) is a promising therapeutic target for various neurodegenerative diseases, including HIV-1-associated neurocognitive disorder (HAND). However, the potential of CB R by direct activation limited due to its psychoactive side effects. Therefore, research has focused on indirectly activating utilizing positive allosteric modulators (PAMs). Studies have shown that PAMs (ZCZ011 and GAT211) are effective in mouse models Huntington’s disease neuropathic pain, hence, we assess ZCZ011 well-established model neuroHIV. current study investigates effect chronic treatment (14 days) behavioral paradigms endocannabinoid system HIV-1 Tat transgenic female male mice. Chronic (10 mg/kg) did not alter body mass, locomotor activity, or anxiety-like behavior regardless sex genotype. differential effects were noted hot plate latency, motor coordination, recognition memory mice only, with increasing latency improving coordination memory. Only minor no alterations seen related lipids except cerebellum, where was more pronounced Moreover, AEA PEA levels cerebellum positively correlated improved In summary, these findings indicate antinociception, memory, based expression, making options HAND without

Language: Английский

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A helping HAND: therapeutic potential of MAGL inhibition against HIV-1-associated neuroinflammation

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: May 21, 2024

Background Human immunodeficiency virus (HIV) affects nearly 40 million people globally, with roughly 80% of all living HIV receiving antiretroviral therapy. Antiretroviral treatment suppresses viral load in peripheral tissues but does not effectively penetrate the blood-brain barrier. Thus, reservoirs persist central nervous system and continue to produce low levels inflammatory factors early proteins, including transactivator transcription (Tat). Tat is known contribute chronic neuroinflammation synaptodendritic damage, which associated development cognitive, motor, and/or mood problems, collectively as HIV-associated neurocognitive disorders (HAND). Cannabinoid anti-inflammatory effects are well documented, therapeutic utility cannabis remains limited due its psychotropic effects, alterations within brain regions encoding reward processing motivation, such nucleus accumbens. Alternatively, inhibiting monoacylglycerol lipase (MAGL) has demonstrated potential through interactions endocannabinoid system. Methods The present study utilized a reward-related operant behavioral task quantify motivated behavior female transgenic mice treated vehicle or MAGL inhibitor MJN110 (1 mg/kg). Brain tissue was collected assess dendritic injury neuroinflammatory profiles, microtubule-associated protein (MAP2ab) intensity, microglia density, morphology, astrocyte astrocytic interleukin-1ß (IL-1ß) colocalization, various lipid mediators. Results No significant differences were observed; however, protected against Tat-induced by significantly upregulating MAP2ab intensity accumbens infralimbic cortex Tat(+) mice. only minor noted for Iba-1 + density morphology. Further, increased GFAP IL-1ß colocalization accumbens, reducing these measures subjects. Lastly, selected HETE-related mediators striatum downregulated treatment. Conclusions These findings demonstrate neuroprotective properties without cannabimimetic suggest promising alternative managing neuroinflammation.

Language: Английский

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