Senrebotase

BACKGROUNDCannabidiol (CBD) is increasingly used for pain management, including in transplant recipients with limited analgesic options. Its immunomodulatory effects in humans are not well defined at a single-cell level at CBD steady state with concomitant tacrolimus treatment.METHODSIn a phase I ex vivo study, peripheral blood mononuclear cells from 23 participants who received oral CBD (Epidiolex) up to 5 mg/kg twice daily for 11 days were collected before CBD (pre-CBD) and at steady state (post-CBD). Lymphocytes were isolated and stimulated with anti-CD3/CD28 antibodies, with or without tacrolimus (5 ng/mL). Pharmacodynamic responses were assessed using CellTiter-Glo proliferation, single-cell and single-nucleus RNA sequencing, cytokine assays, and flow cytometry. Steady-state plasma concentrations of CBD were quantified via tandem mass spectrometry.RESULTSWe identified an increased proportion of T effector memory (TEM) cells post-CBD (22% increase), which correlated with CBD plasma concentrations (R = 0.77, P = 0.01). CBD reduced proliferation of T (37% decrease) and CD70hi B (17% decrease) lymphocytes with additive immunosuppressive effects to tacrolimus. Single-cell RNA sequencing revealed reduced IL2 and TNF signaling and altered receptor-ligand networks in TEM cells. Post-CBD cytokine assays revealed elevated proinflammatory IL-6 protein levels and antiinflammatory IL-10 levels, with reduced TNF-α, LTA, and IL-2. In flow cytometry, the proportion of TEM and TEMRA cells increased post-CBD with tacrolimus.CONCLUSIONCBD exerts mixed immunomodulatory effects in humans, combining antiproliferative and pro- and antiinflammatory responses. Understanding the clinical safety of CBD use is important given the paucity of pain control options available for immunocompromised transplant populations.TRIAL REGISTRATIONClinicalTrials.gov NCT05490511FUNDINGNIH/National Center for Complementary and Integrative Health (R01AT011463); NIH/National Institute of General Medical Sciences (NIGMS) (R35GM145383); Intramural Research Program of the NIH; NIH/NIGMS (T32GM008425).

The-state-of-the-art literature is eagerly searching for protective strategies of chemotherapy-induced retinal neurotoxicity, driven by oxidative stress, ER stress, mitochondrial dysfunction, and autophagy impairment. We investigated the neuroprotective effects of tempol, a stable nitroxide antioxidant, capable of crossing biological barriers and mitigating cisplatin-induced cytomolecular insult. Forty-eight Wistar rats were divided into control, cisplatin-treated, tempol-treated, and CIS + TEM-cotreated groups. Retinal tissues were analyzed through histological, immunohistochemical, and biomolecular oxidative profile and NGF expression techniques. Autophagy, ER stress markers, and ultrastructural changes were evaluated. Cisplatin induced severe retinal degeneration, characterized by photoreceptor disorganization, mitochondrial damage, impaired redox path-ways, impaired autophagy (LC3↓, p62↑), downregulated NGF, and ER stress activation (CHOP↑, JNK↑, XBP1↑, BiP↑). Tempol pre- and co-treatment restored the high baseline level of retinal autophagy as proved by immunohistochemical and mRNA upregulation of LC3 and downregulation of p62 in ganglion cell, inner nuclear, and outer nuclear layers as well as Beclin 1 gene expression restoration. Furthermore, tempol alleviated ER stress and preserved mitochondrial ultrastructure driven by NGF upregulation and restored redox sensitive pathways, leading to improved retinal ganglion and RPE cell architecture and neuroprotection. This study provides critical insights into the molecular mechanisms of cisplatin-induced retinopathy, emphasizing oxidative stress, ER stress, autophagy inhibition, and apoptosis. It highlights tempol's therapeutic potential as a neuroprotective agent targeting oxidative-apoptotic pathways and restoring ER-mitochondrial-autophagy-neurotrophic retinal homeostasis.