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Activation of spinal microglia contributes to aberrant pain responses associated with neuropathic pain states. Endocannabinoids (ECs) are present in the spinal cord, and inhibit nociceptive processing; levels of ECs may be altered by microglia which modulate the turnover of endocannabinoids in vitro. Here, we investigate the effect of minocycline, an inhibitor of activated microglia, on levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG), and the related compound N-palmitoylethanolamine (PEA), in neuropathic spinal cord. Selective spinal nerve ligation (SNL) in rats resulted in mechanical allodynia and the presence of activated microglia in the ipsilateral spinal cord. Chronic daily treatment with minocycline (30 mg/kg, ip for 14 days) significantly reduced the development of mechanical allodynia at days 5, 10 and 14 post-SNL surgery, compared to vehicle-treated SNL rats (P < 0.001). Minocycline treatment also significantly attenuated OX-42 immunoreactivity, a marker of activated microglia, in the ipsilateral (P < 0.001) and contralateral (P < 0.01) spinal cord of SNL rats, compared to vehicle controls. Minocycline treatment significantly (P < 0.01) decreased levels of 2-AG and significantly (P < 0.01) increased levels of PEA in the ipsilateral spinal cord of SNL rats, compared to the contralateral spinal cord. Thus, activation of microglia affects spinal levels of endocannabinoids and related compounds in neuropathic pain states.

Background:Dysfunction of dopaminergic, GABAergic, and glutamatergic function underlies many core symptoms of schizophrenia. Combined neonatal injection of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP), and post-weaning social isolation of rats produces a behavioral syndrome with translational relevance to several core symptoms of schizophrenia. This study uses DNA microarray to characterize alterations in hippocampal neurotransmitter-related gene expression and examines the ability of the sodium channel blocker, lamotrigine, to reverse behavioral changes in this model.Methods:Fifty-four male Lister-hooded rat pups either received phencyclidine (PCP, 10mg/kg, s.c.) on post-natal days (PND) 7, 9, and 11 before being weaned on PND 23 into separate cages (isolation; PCP-SI; n = 31) or received vehicle injection and group-housing (2–4 per cage; V-GH; n = 23) from weaning. The effect of lamotrigine on locomotor activity, novel object recognition, and prepulse inhibition of acoustic startle was examined (PND 60–75) and drug-free hippocampal gene expression on PND 70.Results:Acute lamotrigine (10–15mg/kg i.p.) reversed the hyperactivity and novel object recognition impairment induced by PCP-SI but had no effect on the prepulse inhibition deficit. Microarray revealed small but significant down-regulation of hippocampal genes involved in glutamate metabolism, dopamine neurotransmission, and GABA receptor signaling and in specific schizophrenia-linked genes, including parvalbumin (PVALB) and GAD67, in PCP-SI rats, which resemble changes reported in schizophrenia.Conclusions:Findings indicate that alterations in dopamine neurotransmission, glutamate metabolism, and GABA signaling may contribute to some of the behavioral deficits observed following PCP-SI, and that lamotrigine may have some utility as an adjunctive therapy to improve certain cognitive deficits symptoms in schizophrenia.

Background Oleamide (ODA) is a fatty acid primary amide first identified in the cerebrospinal fluid of sleep-deprived cats, which exerts effects on vascular and neuronal tissues, with a variety of molecular targets including cannabinoid receptors and gap junctions. It has recently been reported to exert a hypolipidemic effect in hamsters. Here, we have investigated the nuclear receptor family of peroxisome proliferator-activated receptors (PPARs) as potential targets for ODA action. Results Activation of PPARα, PPARβ and PPARγ was assessed using recombinant expression in Chinese hamster ovary cells with a luciferase reporter gene assay. Direct binding of ODA to the ligand binding domain of each of the three PPARs was monitored in a cell-free fluorescent ligand competition assay. A well-established assay of PPARγ activity, the differentiation of 3T3-L1 murine fibroblasts into adipocytes, was assessed using an Oil Red O uptake-based assay. ODA, at 10 and 50 μM, was able to transactivate PPARα, PPARβ and PPARγ receptors. ODA bound to the ligand binding domain of all three PPARs, although complete displacement of fluorescent ligand was only evident for PPARγ, at which an IC 50 value of 38 μM was estimated. In 3T3-L1 cells, ODA, at 10 and 20 μM, induced adipogenesis. Conclusions We have, therefore, identified a novel site of action of ODA through PPAR nuclear receptors and shown how ODA should be considered as a weak PPARγ ligand in vitro .

Background The endocannabinoid system (ECS) is a ubiquitously expressed signalling system, with involvement in lipid metabolism and obesity. There are reported changes in obesity of blood concentrations of the endocannabinoids anandamide (AEA) and 2-arachidonoylglcyerol (2-AG), and of adipose tissue expression levels of the two key catabolic enzymes of the ECS, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). Surprisingly, however, the activities of these enzymes have not been assayed in conditions of increasing adiposity. The aim of the current study was to investigate whether FAAH and MGL activities in human subcutaneous adipocytes are affected by body mass index (BMI), or other markers of adiposity and metabolism. Methods Subcutaneous abdominal mature adipocytes, fasting blood samples and anthropometric measurements were obtained from 28 metabolically healthy subjects representing a range of BMIs. FAAH and MGL activities were assayed in mature adipocytes using radiolabelled substrates. Serum glucose, insulin and adipokines were determined using ELISAs. Results MGL activity showed no relationship with BMI or other adiposity indices, metabolic markers (fasting serum insulin or glucose) or serum adipokine levels (adiponectin, leptin or resistin). In contrast, FAAH activity in subcutaneous adipocytes correlated positively with BMI and waist circumference, but not with skinfold thickness, metabolic markers or serum adipokine levels. Conclusions In this study, novel evidence is provided that FAAH activity in subcutaneous mature adipocytes increases with BMI, whereas MGL activity does not. These findings support the hypothesis that some components of the ECS are upregulated with increasing adiposity in humans, and that AEA and 2-AG may be regulated differently.

Rationale Schizophrenia is a debilitating disorder comprising positive, negative and cognitive deficits with a poorly defined neurobiological aetiology; therefore, animal models with greater translational reliability are essential to develop improved therapies. Objectives This study combines two developmental challenges in rats, neonatal phencyclidine (PCP) injection and subsequent rearing in social isolation from weaning, to attempt to produce more robust behavioural deficits with greater translational relevance to schizophrenia than either challenge alone. Methods Forty-two male Lister-hooded rat pups received the N -methyl- d -aspartate (NMDA) receptor antagonist, phencyclidine (PCP, 10 mg/kg, s.c.), or vehicle on post-natal day (PND) 7, 9 and 11 and were weaned on PND 23 into group housing (saline-treated n  = 11 or PCP-treated n  = 10) or isolation (saline n  = 10 or PCP n  = 11). Six weeks post-weaning, novelty- and PCP-induced (3.2 mg/kg) locomotor activity, novel object discrimination, prepulse inhibition of acoustic startle and contextual memory in a conditioned emotion response (CER) were recorded. Results Isolation rearing alone significantly elevated baseline locomotor activity and induced visual recognition memory impairment in novel object discrimination. Neonatal PCP treatment did not induce locomotor sensitisation to a subsequent acute PCP injection, but it impaired prepulse inhibition when combined with isolation rearing. CER freezing behaviour was significantly reduced by isolation rearing but an even greater effect occurred when combined with neonatal PCP treatment. Conclusions Neonatal PCP and isolation rearing both produce behavioural deficits in adult rats, but combined treatment caused a wider range of more severe cognitive impairments, providing a more comprehensive preclinical model to determine the neurobiological aetiology of schizophrenia than either treatment alone.

Background Circulating endocannabinoid levels are increased in obesity and diabetes. We have shown that fatty acid amide hydrolase (FAAH, an endocannabinoid hydrolysing enzyme) in subcutaneous adipose tissue positively correlates with BMI in healthy volunteers. The aim of the present study was to investigate whether the hydrolytic enzymes of the endocannabinoid system are affected by diabetes or metabolic syndrome in obesity. Methods Using radiolabelled substrates, FAAH and monoacylglycerol lipase (MGL) activities were assessed in adipocytes from various adipose depots in Zucker rats (n = 22, subcutaneous abdominal, visceral and epididymal) and bariatric patients (n = 28, subcutaneous abdominal and omental). Results FAAH activity was significantly increased in adipocytes of obese (Zucker Fatty) compared to Zucker lean rats (P < 0.05) but was not raised in the Zucker Diabetic Fatty rats (ZDF). MGL activity was raised in both Zucker Fatty (P < 0.001-0.01) and ZDF rats (P < 0.05) and was positively correlated with body weight and plasma glucose levels (P < 0.01). In bariatric patients (BMI range 37–58 kg.m 2 ), there was a trend for MGL activity to correlate positively with BMI, reaching significance when type 2 diabetic patients were removed. FAAH and MGL activities in obese humans were not correlated with blood pressure, skinfold thicknesses, fasting glucose, insulin, HbA1c, triglycerides or cholesterol levels. Conclusions FAAH in adipocytes is differentially altered in animal models of obesity and diabetes, while MGL activity is increased by both. However, in obese humans, FAAH or MGL activity in adipocytes is not affected by diabetes, dyslipidaemia or other markers of metabolic dysfunction. This suggests increased circulating levels of endocannabinoids are not a result of altered degradation in adipose tissue.

IntroductionObstructive sleep apnoea (OSA) and type 2 diabetes mellitus (T2DM) often occur concurrently, and untreated OSA may potentially amplify the high risk of cardiovascular disease in T2DM. Compliance with continuous positive airway pressure (CPAP), the conventional treatment for OSA, can be poor and considering weight loss is the most effective treatment for OSA. This trial examines whether the glucagon-like peptide-1 receptor agonist liraglutide, a glucose-lowering therapy associated with significant weight loss used in T2DM, can improve the severity and symptoms of OSA.Methods and analysisThis is an outpatient, single-centred, open-labelled, prospective, phase IV randomised controlled trial in a two-by-two factorial design. One hundred and thirty-two patients with newly diagnosed OSA (apnoea–hypopnoea index (AHI) ≥15 events/hour), and existing obesity and T2DM (glycated haemoglobin (HbA1c) ≥47 mmol/mol), will be recruited from diabetes and sleep medicine outpatient clinics in primary and secondary care settings across Liverpool. Patients will be allocated equally, using computer-generated random, permuted blocks of unequal sizes, to each of the four treatment arms for 26 weeks: (i) liraglutide (1.8 mg once per day) alone, (ii) liraglutide 1.8 mg once per day with CPAP, (iii) CPAP alone (conventional care) or (iv) no treatment (control). The primary outcome measure is change in OSA severity, determined by AHI. Secondary outcome measures include effects on glycaemic control (glycated haemoglobin (HbA1c)), body weight and quality of life measures. Exploratory measures include measures of physical activity, MRI-derived measures of regional body composition including fat mass (abdominal subcutaneous, visceral, neck and liver fat) and skeletal muscle mass (cross-sectional analysis of thigh), indices of cardiac function (using transthoracic echocardiography) and endothelial function.Ethical approvalThe study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1019) and it is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.Trial registration numbersISRCTN16250774. EUDRACT No. 2014-000988-41. UTN U1111-1139-0677.

The phase 3 CARES-310 trial showed significant improvements in progression-free survival (primary analysis) and overall survival (interim analysis) with the anti-PD-1 antibody camrelizumab plus the oral vascular endothelial growth factor receptor 2 inhibitor rivoceranib versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Here, we present the final analysis of overall survival, and updated data on progression-free survival, secondary efficacy endpoints, and safety. This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions. Eligible patients were aged 18 years or older, with unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Participants were randomly assigned (1:1) using a centralised interactive response system to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. The study is complete and was registered with ClinicalTrials.gov, NCT03764293. Between June 28, 2019, and March 24, 2021, 543 patients (457 [84%] males; 450 [83%] were Asian) were randomly assigned to receive camrelizumab–rivoceranib (n=272) or sorafenib (n=271). At final analysis on June 14, 2023, the median follow-up was 22·1 months (IQR 11·9–30·3) in the camrelizumab–rivoceranib group and 14·9 months (7·2–28·3) in the sorafenib group. Median overall survival was 23·8 months (95% CI 20·6–27·2) with camrelizumab–rivoceranib and 15·2 months (13·2–18·5) with sorafenib (hazard ratio [HR] 0·64 [95% CI 0·52–0·79]; one-sided p<0·0001). Median progression-free survival was 5·6 months (95% CI 5·5–7·4) with camrelizumab–rivoceranib and 3·7 months (3·1–3·7) with sorafenib (HR 0·54 [0·44–0·67]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (104 [38%] of 272 patients in the camrelizumab–rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 42 [16%]), increased aspartate aminotransferase (47 [17%] vs 14 [5%]), and increased alanine aminotransferase (38 [14%] vs eight [3%]). Treatment-related serious adverse events were reported in 69 (25%) of 272 patients in the camrelizumab–rivoceranib group and 18 (7%) of 269 patients in the sorafenib group. Treatment-related deaths occurred in one patient each in the camrelizumab–rivoceranib group (multiple organ dysfunction syndrome) and sorafenib group (respiratory failure and circulatory collapse). At final analysis, camrelizumab plus rivoceranib continued to show clinically meaningful survival improvement compared with sorafenib, with manageable safety. The extended follow-up further confirmed the benefit-to-risk profile of camrelizumab plus rivoceranib, supporting the combination as a new first-line treatment option for unresectable hepatocellular carcinoma. Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.

IntroductionObeticholic acid (OCA) is a potent, selective FXR agonist approved for the treatment of PBC based upon biochemical improvements predicted to improve transplant-free survival. An optional liver biopsy substudy was conducted in a subset of patients from the Phase 3 POISE trial to determine the impact of OCA treatment on progression of liver fibrosis. Results, using standard histologic grading, showed that the majority of patients treated with OCA either improved or had no worsening of fibrosis over 3 years. New technologies, such as second harmonic generation (SHG) microscopy, allow quantitative measurement of the molecular features of fibrosis using high-resolution stain-free imaging of collagen 1 and 3. This post-hoc analysis assessed the impact of OCA treatment on collagen morphometry using biopsy samples from the POISE substudy.MethodsPatients included in this analysis had an inadequate response or intolerance of UDCA, biopsies ≤1 year from double-blind baseline and after ∼3 years of OCA treatment. Unstained slides were used to quantify collagen using SHG and 2-photon microscopy. Stained biopsy samples were masked, randomized and scored by consensus of 2 blinded pathologists utilizing Nakanuma Staging for histologic evaluation. Two cohorts were identified: an All Biopsy Cohort, defined as all adequate biopsy samples (determined by the pathologists) with collagen data, and a Paired Biopsy Cohort, defined as patients with both a baseline and follow-up biopsy and collagen data.ResultsThe All Biopsy Cohort was composed of 31 patients (46 samples total, mean age 56 years, 90% female, 97% received UDCA), and the Paired Biopsy Cohort was composed of 16 patients (59 years, 94% female, 100% received UDCA). In the All Biopsy Cohort, trends were observed between increasing median Collagen Area Ratio (CAR) (fig A), Collagen Fiber Density (CFD), and Collagen Reticulation Index (CRI) and increasing Nakanuma Fibrosis Stage. In the Paired Biopsy Cohort, the majority of patients (12/16) had a reduction in CAR after 3 years of OCA treatment (fig B). The median (Q1,Q3) change and percent change from baseline was CAR -2.1 (-4.6,-0.3) and -31.1% (-46.1,-11.4), CFD -0.8 (-2.5,0.0) and -35.3% (-57.0,-2.5), and CRI -0.1 (-0.3,0.0) and -7.4% (-20.8,-1.1).Abstract ATU-09 Figure 1ConclusionsIn this analysis, 3 years of OCA treatment resulted in a reduction in CAR, CFD and CRI, supporting the overall trend of improvement or no progression in the histologic components of PBC.

IntroductionObeticholic Acid (OCA) is a potent and selective farnesoid X receptor agonist approved for the treatment of primary biliary cholangitis (PBC). PBC is a chronic liver disease characterized by the immune mediated destruction of bile ducts resulting in cholestasis, cirrhosis and liver failure. The POISE study was a randomized, placebo-controlled phase 3 study investigating daily OCA 5–10 mg in PBC patients with an ongoing open label extension (OLE). The purpose of this analysis was to assess the long-term effects of OCA on key markers of liver damage and inflammation.MethodsPatients enrolled in the double-blind phase had an inadequate response to UDCA or were intolerant of UDCA. Patients were randomized to placebo, OCA 5–10 mg, or OCA 10 mg. Upon completion of the 12-month double-blind phase, 198 patients enrolled in the OLE and received OCA. For this analysis, patients were pooled and assessed from the time of first dose of OCA. Data are shown through 48 months of OCA exposure, for patients randomized to placebo in the double-blind phase, only 36 months of data are included.ResultsAt baseline (N=198), patients were 92% female, mean age was 55 years, PBC disease duration was 9 years, and 93% received UDCA (mean dose: 16 mg/kg/day). As observed in the table, there were sustained and significant reductions in immunoglobulins (Ig) A, G and M throughout 48 months of OCA treatment. In addition, significant reductions were observed in tumor necrosis factor (TNF)-α, c-reactive protein (CRP), and cleaved cytokeratin (CK)-18 throughout the duration of the OLE. No clinically meaningful changes were observed with transforming growth factor (TGF)-β and interleukin (IL)-12, both remained within the normal range.Abstract PTU-009 Table 1Median change from Baseline in Key immune, apoptotic and inflammatory markers*p<0.05; **p<0.01; ***p<0.0001. p-values for the comparisons to baseline were obtained using a Wilcoxon signed rank test. Normal ranges: CRP 0-3 mg/L, TNF-α 8.1 pg/ml, TGF-β 18.3-63.4 ng/ml, Ck-18 80 U/L, IL-12 34-246 pg/mL, IgA 0.7-4 g/L, IgG 7-16 g/L, IgM 0.4-2.3 g/LConclusionsThese results demonstrate that OCA has a durable anti-inflammatory effect in patients with PBC as observed by reductions on key markers of apoptosis (TNF-α and CK-18) and inflammation (CRP). Furthermore, a sustained reduction is observed in IgM, which is classically elevated in PBC patients. The clinical significance of OCA mediated reductions in IgA and IgG continues to remain unknown.