Partial agonist

Altered cholesterol, oxysterol, sphingolipid, and fatty acid concentrations are reported in blood, cerebrospinal fluid, and brain tissue of people with relapsing remitting multiple sclerosis (RRMS) and are linked to disease progression and treatment responses. CD4+ T cells are pathogenic in RRMS, and defective T cell function could be mediated in part by liver X receptors (LXRs) - nuclear receptors that regulate lipid homeostasis and immunity. RNA-sequencing and pathway analysis identified that genes within the 'lipid metabolism' and 'signalling of nuclear receptors' pathways were dysregulated in CD4+ T cells isolated from RRMS patients compared with healthy donors...

BACKGROUND: Major Depressive Disorder (MDD) is a prevalent and debilitating condition, necessitating novel therapeutic strategies due to the limited efficacy and adverse effects of current treatments. We explored how galanin receptor 2 (GALR2) and Neuropeptide Y1 Receptor (NPYY1R) agonists, working together, can boost brain cell growth and increase antidepressant-like effects in rats. This suggests new ways to treat Major Depressive Disorder (MDD). RESEARCH DESIGN AND METHODS: In a controlled laboratory setting, adult naive Sprague-Dawley rats were administered directly into the brain's ventricles, a method known as intracerebroventricular (ICV) administration, with GALR2 agonist (M1145), NPYY1R agonist, both, or in combination with a GALR2 antagonist (M871)...

Piezo1 and Piezo2 are novel mechanosensory ion channels that transduce mechanical stimuli from the environment into intracellular biochemical signals in various tissues and organ systems. Here, we showed that Piezo1 and Piezo2 displayed a robust expression during jawbone development. Deletion of Piezo1 in neural crest cells caused jawbone malformations in a small but significant number of mice. We further demonstrated that disruption of Piezo1 and Piezo2 in neural crest cells caused more striking defects in jawbone development than any single knockout, suggesting essential but partially redundant roles of Piezo1 and Piezo2...

Osteosarcoma is a highly malignant, painful cancer with poor treatment opportunities and a bad prognosis. Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors are non-selective cation channels that have been of great interest in cancer, as their expression is increased in some malignancies. In our study we aim to characterize the expression and functionality of the TRPA1 and TRPV1 channels in human and mouse osteosarcoma tissues and in a mouse cell line. TRPA1/Trpa1 and TRPV1/Trpv1 mRNA expressions were demonstrated by PCR gel electrophoresis and RNAscope in situ hybridization...

OBJECTIVE: The Krebs cycle enzyme Aconitate Decarboxylase 1 (ACOD1) mediates itaconate synthesis in myeloid cells.. Previously, we reported that administration of 4-octyl itaconate abrogated lupus phenotype in mice. Here, we explore the role of the endogenous ACOD1/itaconate pathway in the development of murine lupus as well as their relevance in premature cardiovascular damage in SLE. METHODS: We characterized Acod1 protein expression in bone marrow-derived macrophages and human monocyte-derived macrophages, following a TLR7 agonist (imiquimod, IMQ)...

The alpha7 nicotinic acetylcholine receptor (α7-nAChR) has has long been considered a promising therapeutic target for addressing cognitive impairments associated with a spectrum of neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia. However, despite this potential, clinical trials employing α7-nAChR (partial) agonists such as TC-5619 and encenicline (EVP-6124) have fallen short in demonstrating sufficient efficacy. We here investigate the target engagement of TC-5619 and encenicline in the pig brain by use of the α7-nAChR radioligand 11 C-NS14492 to characterize binding both with in vitro autoradiography and in vivo occupancy using positron emission tomography (PET)...

The spontaneous firing activity of nigral dopaminergic neurons is associated with some important roles including modulation of dopamine release, expression of tyrosine hydroxylase (TH), as well as neuronal survival. The decreased neuroactivity of nigral dopaminergic neurons has been revealed in Parkinson's disease. Central glucagon-like peptide-1 (GLP-1) functions as a neurotransmitter or neuromodulator to exert multiple brain functions. Although morphological studies revealed the expression of GLP-1 receptors (GLP-1Rs) in the substantia nigra pars compacta, the possible modulation of GLP-1 on spontaneous firing activity of nigral dopaminergic neurons is unknown...

PURPOSE: The ROCK inhibitor ripasudil hydrochloride hydrate was shown to have axonal protective effects in TNF-induced optic nerve degeneration. The α2-adrenoreceptor agonist brimonidine was also shown to exert axonal protection. The current study aimed to elucidate whether additive axonal protection was achieved by the simultaneous injection of ripasudil and brimonidine and examine the association with AMPK activation. METHODS: Intravitreal administration was performed in the following groups: PBS, TNF, or TNF with ripasudil, with brimonidine, or with a combination of ripasudil and brimonidine...

β-blockers are a heterogeneous class, with individual agents distinguished by selectivity for β1 - vs. β2 - and α-adrenoceptors, presence or absence of partial agonist activity at one of more β-receptor subtype, presence or absence of additional vasodilatory properties, and lipophilicity, which determines the ease of entry the drug into the central nervous system. Cardioselectivity (β1 -adrenoceptor selectivity) helps to reduce the potential for adverse effects mediated by blockade of β2 -adrenoceptors outside the myocardium, such as cold extremities, erectile dysfunction, or exacerbation of asthma or chronic obstructive pulmonary disease...

Chronic myelomonocytic leukemia (CMML) presents as a complex hematologic malignancy with myelodysplastic and myeloproliferative features. Our case report explores the rare coexistence of CMML with immune thrombocytopenic purpura (ITP) in a 63-year-old female patient. CMML diagnosis followed World Health Organization criteria, and the patient was classified as having high-risk myelodysplastic syndrome (MDS)-CMML stage 2. Initial treatment with subcutaneous azacytidine for CMML proved partially effective, highlighting persistent severe thrombocytopenia...

INTRODUCTION: Definitions of moderate asthma exacerbation have been inconsistent, making their economic burden difficult to assess. An algorithm to accurately identify moderate exacerbations from claims data is needed. METHODS: A retrospective cohort study of Reliant Medical Group patients aged ≥18 years, with ≥1 prescription claim for inhaled corticosteroid/long-acting β2 -agonist, and ≥1 medical claim with a diagnosis code for asthma was conducted...

Nalmefene hydrochloride was first discovered as an opioid antagonist derivative of naltrexone in 1975. It is among the most potent opioid antagonists currently on the market and is differentiated from naloxone and naltrexone by its partial agonist activity at the kappa-opioid receptor which may benefit in the treatment of alcohol use disorder. Oral nalmefene has been approved in the European Union for treatment of alcohol use disorder since 2013. As of 2023, nalmefene is available in the United States as an intranasal spray for reversal of opioid overdose but is not approved for alcohol or opioid use disorder as a maintenance treatment...

Chronic psychostimulant use causes long-lasting changes to neural and cognitive function that persist after long periods of abstinence. As cocaine users transition from drug use to abstinence, a parallel transition from hyperactivity to hypoactivity has been found in orbitofrontal-striatal glucose metabolism and striatal D2 /D3 -receptor activity. Targeting these changes pharmacologically, using highly selective dopamine D3 -receptor (D3 R) antagonists and partial agonists, has shown promise in reducing drug-taking, and attenuating relapse in animal models of cocaine and opioid use disorder...

AIM OF THE STUDY: The past twenty years have seen a rise in cocaine-related statistics in France, including cocaine use in the general population, emergency ward presentations of acute cocaine intoxication, cocaine use disorders related outpatient appointments and cocaine-related deaths. This study's objectives were to describe trends in patients' admission for specific cocaine detoxification as well as changes in patients' characteristics in the Assistance publique-Hôpitaux de Paris (AP-HP) hospitals group located in Paris region, France...

Epitestosterone is a stereoisomer of the active androgen testosterone and its circulating concentrations are similar to those of testosterone in women and children. However, its biological function and pathways of metabolism remain unknown. The structural similarity to testosterone suggests a potential function in the modulation of androgen receptor signalling. It is well established that the conversion of testosterone to 5α-dihydrotestosterone enhances local androgen receptor signalling. In this study, we show that epitestosterone is metabolized to 5α-dihydroepitestosterone by both human steroid 5α-reductase isoforms, SRD5A1 and SRD5A2...

BACKGROUND: The relationship between opioid craving and opioid use is unclear. We sought to determine to what extent craving mediated the relationship between opioid agonist therapy and changes in opioid use. METHODS: Data came from a pragmatic, 24-week, pan-Canadian, multi-centric, open-label, randomized controlled trial comparing flexible buprenorphine/naloxone take-home doses to standard supervised methadone models of care for the treatment of prescription-type opioid use disorder...

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have shown efficacy in the treatment of metabolic disease-related complications, partially attributable to their anti-inflammatory properties. However, the specific cell types and pathways involved in these effects were not fully understood. A recent study by Wong et al. demonstrated the importance of the brain GLP-1R in mediating the anti-inflammatory effects of GLP-1RAs in Toll-like receptor and sepsis-mediated inflammation. In this discussion, we review the existing literature on the action of GLP-1RAs in inflammation and explore the implications of these recent findings...

Osteoarthritis (OA) is the most prevalent degenerative joint disease, and PPARs are involved in its pathogenesis; however, the specific mechanisms by which changes in PPARδ impact the OA pathogenesis yet to be discovered. The purpose of this study was to ascertain how PPARδ affects the onset and development of OA. In vitro , we found that PPARδ activation ameliorated apoptosis and extracellular matrix (ECM) degradation in OA chondrocytes stimulated by IL-1β. In addition, PPARδ activation may modulate AKT/mTOR signaling to partially regulate chondrocyte autophagy and apoptosis...

BACKGROUND: Ovarian cancer (OVCA) stands as one of the most fatal gynecological malignancies. Honokiol (HNK) has been substantiated by numerous studies for its anti-tumor activity against malignancies including OVCA. Consequently, this work was designed to elucidate the impact of HNK-mediated modulation of the YAP/TAZ pathway on the biological functions of OVCA cells. METHODS: OVCA cells were subjected to treatment with varying concentrations (0, 25, 50, 75, and 100 μM) of HNK, concomitant with the administration of YAP agonist (XMU)...

This study evaluates the antiallodynic and antihyperalgesic effects of LMH-2, a new haloperidol (HAL) analog that acts as sigma-1 receptor (σ1 R) antagonist, in diabetic mice using a model of neuropathic pain induced by chronic hyperglycemia. Additionally, we compared its effects with those of HAL. Hyperglycemia was induced in mice by nicotinamide-streptozotocin administration (NA-STZ, 50-130 mg/kg). Four weeks later, mechanical allodynia was assessed using the up-down method, and hyperalgesia was evoked with formalin 0...