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Heliyon Jun 2024Exserolides are isocoumarin derivatives containing lactone moiety. Recently, some isocoumarins have been demonstrated to ameliorate hyperlipidemia, a major factor for...
Exserolides are isocoumarin derivatives containing lactone moiety. Recently, some isocoumarins have been demonstrated to ameliorate hyperlipidemia, a major factor for inducing cardiovascular diseases. However, the effects and mechanisms of action of exserolides on hyperlipidemia are not known. The aim of this study is to investigate whether the marine fungus sp.-derived exserolides (compounds I, J, E, and F) exert lipid-lowering effects via improving reverse cholesterol transport (RCT) . RAW264.7 macrophages and HepG2 cells were used to establish lipid-laden models, and the levels of intracellular lipids and RCT-related proteins were determined by assay kits and Western blotting, respectively. We observed that exserolides (at a 5 μM concentration) significantly decreased intracellular cholesterol and triglyceride levels in oxidized low-density lipoprotein-laden RAW264.7 cells and markedly improved [H]-cholesterol efflux. Among the four tested compounds, exserolide J increased the protein levels of ATP-binding cassette transporter A1, peroxisome proliferator-activated receptor α (PPARα), and liver X receptor α (LXRα). Furthermore, treatment with exserolides significantly decreased oleic acid-laden lipid accumulation in HepG2 hepatocytes. Mechanistically, exserolides enhance PPARα protein levels; furthermore, compound J increases cholesterol 7 alpha-hydroxylase A1 and LXRα protein levels. Molecular docking revealed that exserolides, particularly compound J, can interact with PPARα and LXRα proteins. These data suggest that the terminal carboxyl group of compound J plays a key role in lowering lipid levels by stimulating LXRα and PPARα proteins. In conclusion, compound J exhibits powerful lipid-lowering effects . However, its hypolipidemic effects should be investigated in the future.
PubMed: 38947487
DOI: 10.1016/j.heliyon.2024.e31861 -
Frontiers in Medicine 2024This scoping review prepared by endocrinology and nephrology experts aimed to address the significance of finerenone, as a novel therapeutic option, in diabetic kidney... (Review)
Review
The significance of finerenone as a novel therapeutic option in diabetic kidney disease: a scoping review with emphasis on cardiorenal outcomes of the finerenone phase 3 trials.
This scoping review prepared by endocrinology and nephrology experts aimed to address the significance of finerenone, as a novel therapeutic option, in diabetic kidney disease (DKD), based on the biological prospect of cardiorenal benefit due to non-steroidal mineralocorticoid receptor antagonist (MRA) properties, and the recent evidence from the finerenone phase 3 program clinical trials. The importance of finerenone in slowing DKD progression was critically reviewed in relation to the role of MR overactivation in the pathogenesis of cardiorenal disease and unmet needs in the current practice patterns. The efficacy and safety outcomes of finerenone phase III study program including FIDELIO-DKD, FIGARO-DKD and FIDELITY were presented. Specifically, perspectives on inclusion of patients with preserved estimated glomerular filtration rate (eGFR) or high albuminuria, concomitant use of sodium-glucose co-transporter-2 inhibitor (SGLT2i) or glucagon-like peptide 1 receptor agonist (GLP-1 RA), baseline glycated hemoglobin (HbA1c) level and insulin treatment, clinically meaningful heart failure outcomes and treatment-induced hyperkalemia were addressed. Finerenone has emerged as a new therapeutic agent that slows DKD progression, reduces albuminuria and risk of cardiovascular complications, regardless of the baseline HbA1c levels and concomitant treatments (SGLT2i, GLP-1 RA, or insulin) and with a favorable benefit-risk profile. The evolving data on the benefit of SGLT2is and non-steroidal MRAs in slowing or reducing cardiorenal risk seem to provide the opportunity to use these pillars of therapy in the management of DKD, after a long-period of treatment scarcity in this field. Along with recognition of the albuminuria as a powerful marker to detect those patients at high risk of cardiorenal disease, these important developments would likely to impact standard-of-care options in the setting of DKD.
PubMed: 38947237
DOI: 10.3389/fmed.2024.1384454 -
Research Square Jun 2024Here, we evaluated whether a synthetic lipoxin mimetic, designated AT-01-KG, would improve the course of influenza A infection in a murine model.
OBJECTIVE AND DESIGN
Here, we evaluated whether a synthetic lipoxin mimetic, designated AT-01-KG, would improve the course of influenza A infection in a murine model.
TREATMENT
Mice were infected with influenza A/H1N1 and treated with AT-01-KG (1.7 mg/kg/day, i.p.) at day 3 post-infection. Methods Mortality rate was assessed up to day 21 and inflammatory parameters were assessed at days 5 and 7. Results AT-01-KG attenuated mortality, reducing leukocyte infiltration and lung damage at day 5 and day 7 post-infection. AT-01-KG is a Formyl Peptide Receptor 2 (designated FPR2/3 in mice) agonist, and the protective responses were not observed in FPR2/3 animals. In mice treated with LXA (50mg/kg/day, i.p., days 3-6 post-infection), at day 7, macrophage reprogramming was observed, as seen by a decrease in classically activated macrophages and an increase in alternatively activated macrophages in the lungs. Furthermore, the number of apoptotic cells and cells undergoing efferocytosis was increased in the lavage of treated mice. Treatment also modulated the adaptive immune response, increasing the number of anti-inflammatory T cells (Th2) and regulatory T (Tregs) cells in the lungs of the treated mice. Conclusions Therefore, treatment with a lipoxin A analog was beneficial in a model of influenza A infection in mice. The drug decreased inflammation and promoted resolution and beneficial immune responses, suggesting it may be useful in patients with severe influenza.
PubMed: 38947034
DOI: 10.21203/rs.3.rs-4491036/v1 -
World Journal of Gastroenterology Jun 2024Metabolic dysfunction-associated fatty liver disease (MAFLD) is a hepatic manifestation of the metabolic syndrome. It is one of the most common liver diseases worldwide... (Review)
Review
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a hepatic manifestation of the metabolic syndrome. It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries. MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma. Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis. The mechanisms involved in maintaining gut-liver axis homeostasis are complex. One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gut-liver axis functionality. An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis. Moreover, alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of drugs developed for the treatment of type 2 diabetes mellitus. They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis. The mechanisms reported to be involved in this effect include an improved regulation of glycemia, reduced lipid synthesis, β-oxidation of free fatty acids, and induction of autophagy in hepatic cells. Recently, multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment. A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD. This review presents the current understanding of the role of the gut-liver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.
Topics: Humans; Glucagon-Like Peptide-1 Receptor; Gastrointestinal Microbiome; Liver; Non-alcoholic Fatty Liver Disease; Animals; Metabolic Syndrome; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Incretins; Intestinal Mucosa; Glucagon-Like Peptide-1 Receptor Agonists
PubMed: 38946874
DOI: 10.3748/wjg.v30.i23.2964 -
World Journal of Gastrointestinal... Jun 2024Glucagon-like peptide receptor agonists (GLP-1RA) are used to treat type 2 diabetes mellitus and, more recently, have garnered attention for their effectiveness in...
Glucagon-like peptide receptor agonists (GLP-1RA) are used to treat type 2 diabetes mellitus and, more recently, have garnered attention for their effectiveness in promoting weight loss. They have been associated with several gastrointestinal adverse effects, including nausea and vomiting. These side effects are presumed to be due to increased residual gastric contents. Given the potential risk of aspiration and based on limited data, the American Society of Anesthesiologists updated the guidelines concerning the preoperative management of patients on GLP-1RA in 2023. They included the duration of mandated cessation of GLP-1RA before sedation and usage of "full stomach" precautions if these medications were not appropriately held before the procedure. This has led to additional challenges, such as extended waiting time, higher costs, and increased risk for patients. In this editorial, we review the current societal guidelines, clinical practice, and future directions regarding the usage of GLP-1RA in patients undergoing an endoscopic procedure.
PubMed: 38946857
DOI: 10.4253/wjge.v16.i6.292 -
Journal of Cell Communication and... Jun 2024The morbidity and death rates of calcified aortic valves|calcific aortic valve (CAV) disease (CAVD) remain high for its limited therapeutic choices. Here, we...
The morbidity and death rates of calcified aortic valves|calcific aortic valve (CAV) disease (CAVD) remain high for its limited therapeutic choices. Here, we investigated the function, therapeutic potential, and putative mechanisms of Enoyl coenzyme A hydratase 1 (ECH1) in CAVD by various in vitro and in vivo experiments. Single-cell sequencing revealed that ECH1 was predominantly expressed in valve interstitial cells and was significantly reduced in CAVs. Overexpression of ECH1 reduced aortic valve calcification in ApoE mice treated with high cholesterol diet, while ECH1 silencing had the reverse effect. We also identified Wnt5a, a noncanonical Wnt ligand, was also altered when ECH1 expression was modulated. Mechanistically, we found that ECH1 exerted anti-calcific actions through suppressing Wnt signaling, since CHIR99021, a Wnt agonist, may significantly lessen the protective impact of ECH1 overexpression on the development of valve calcification. ChIP and luciferase assays all showed that ECH1 overexpression prevented Runx2 binding to its downstream gene promoters (osteopontin and osteocalcin), while CHIR99021 neutralized this protective effect. Collectively, our findings reveal a previously unrecognized mechanism of ECH1-Wnt5a/Ca regulation in CAVD, implying that targeting ECH1 may be a potential therapeutic strategy to prevent CAVD development.
PubMed: 38946717
DOI: 10.1002/ccs3.12038 -
Stroke Jul 2024GPR65 (G protein-coupled receptor 65) can sense extracellular acidic environment to regulate pathophysiological processes. Pretreatment with the GPR65 agonist BTB09089...
BACKGROUND
GPR65 (G protein-coupled receptor 65) can sense extracellular acidic environment to regulate pathophysiological processes. Pretreatment with the GPR65 agonist BTB09089 has been proven to produce neuroprotection in acute ischemic stroke. However, whether delayed BTB09089 treatment and neuronal GPR65 activation promote neurorestoration remains unknown.
METHODS
Ischemic stroke was induced in wild-type (WT) or GPR65 knockout (GPR65) mice by photothrombotic ischemia. Male mice were injected intraperitoneally with BTB09089 every other day at days 3, 7, or 14 poststroke. AAV-Syn-GPR65 (adenoassociated virus-synapsin-GPR65) was utilized to overexpress GPR65 in the peri-infarct cortical neurons of GPR65 and WT mice. Motor function was monitored by grid-walk and cylinder tests. The neurorestorative effects of BTB09089 were observed by immunohistochemistry, Golgi-Cox staining, and Western blotting.
RESULTS
BTB09089 significantly promoted motor outcomes in WT but not in GPR65 mice, even when BTB09089 was delayed for 3 to 7 days. BTB09089 inhibited the activation of microglia and glial scar progression in WT but not in GPR65 mice. Meanwhile, BTB09089 reduced the decrease in neuronal density in WT mice, but this benefit was abolished in GPR65 mice and reemerged by overexpressing GPR65 in peri-infarct cortical neurons. Furthermore, BTB09089 increased the GAP43 (growth-associated protein-43) and synaptophysin puncta density, dendritic spine density, dendritic branch length, and dendritic complexity by overexpressing GPR65 in the peri-infarct cortical neurons of GPR65 mice, which was accompanied by increased levels of p-CREB (phosphorylated cAMP-responsive element-binding protein). In addition, the therapeutic window of BTB09089 was extended to day 14 by overexpressing GPR65 in the peri-infarct cortical neurons of WT mice.
CONCLUSIONS
Our findings indicated that delayed BTB09089 treatment improved neurological functional recovery and brain tissue repair poststroke through activating neuronal GRP65. GPR65 overexpression may be a potential strategy to expand the therapeutic time window of GPR65 agonists for neurorehabilitation after ischemic stroke.
PubMed: 38946544
DOI: 10.1161/STROKEAHA.124.046954 -
Expert Review of Clinical Pharmacology Jun 2024Medications for opioid use disorder (MOUD) include opioid agonist therapies (OAT) (buprenorphine and methadone), and opioid antagonists (extended-release naltrexone).... (Review)
Review
INTRODUCTION
Medications for opioid use disorder (MOUD) include opioid agonist therapies (OAT) (buprenorphine and methadone), and opioid antagonists (extended-release naltrexone). All forms of MOUD improve opioid use disorder (OUD) and HIV outcomes. However, the integration of services for HIV and OUD remains inadequate. Persistent barriers to accessing MOUD underscore the immediate necessity of addressing pharmacoequity in the treatment of OUD in persons with HIV (PWH).
AREAS COVERED
In this review article, we specifically focus on OAT among PWH as it is the most commonly utilized form of MOUD. Specifically, we delineate the intersection of HIV and OUD services, emphasizing their integration into the United States Ending the HIV Epidemic (EHE) plan by offering comprehensive screening, testing, and treatment for both HIV and OUD. We identify potential drug interactions of OAT with antiretroviral therapy (ART), address disparities in OAT access, and present the practical benefits of long-acting formulations of buprenorphine, ART, and pre-exposure prophylaxis for improving HIV prevention and treatment, and OUD management.
EXPERT OPINION
Optimizing OUD outcomes in PWH necessitates careful attention to diagnosing OUD, initiating OUD treatment, and ensuring medication retention. Innovative approaches to healthcare delivery, such as mobile pharmacies, can integrate both OUD and HIV and reach underserved populations.
PubMed: 38946101
DOI: 10.1080/17512433.2024.2375448 -
ACS Applied Materials & Interfaces Jun 2024Dry eye disease (DED) is a chronic multifactorial ocular surface disease mainly caused by the instability of tear film, characterized by a series of ocular discomforts...
Dry eye disease (DED) is a chronic multifactorial ocular surface disease mainly caused by the instability of tear film, characterized by a series of ocular discomforts and even visual disorders. Oxidative stress has been recognized as an upstream factor in DED development. Diquafosol sodium (DQS) is an agonist of the P2Y receptor to restore the integrity/stability of the tear film. With the ability to alternate between Ce and Ce, cerium oxide nanozymes could scavenge overexpressed reactive oxygen species (ROS). Hence, a DQS-loaded cerium oxide nanozyme was designed to boost the synergistic treatment of DED. Cerium oxide with branched polyethylenimine--poly(ethylene glycol) as nucleating agent and dispersant was fabricated followed with DQS immobilization via a dynamic phenylborate ester bond, obtaining the DQS-loaded cerium oxide nanozyme (defined as Ce@PBD). Because of the ability to mimic the cascade processes of superoxide dismutase and catalase, Ce@PBD could scavenge excessive accumulated ROS, showing strong antioxidant and anti-inflammatory properties. Meanwhile, the P2Y receptors in the conjunctival cells could be stimulated by DQS in Ce@PBD, which can relieve the incompleteness and instability of the tear film. The animal experiments demonstrated that Ce@PBD significantly restored the defect of the corneal epithelium and increased the number of goblet cells, with the promotion of tear secretion, which was the best among commercial DQS ophthalmic solutions.
PubMed: 38946068
DOI: 10.1021/acsami.4c07390 -
Physiological Reports Jul 2024To better understand mechanisms of serotonin- (5-HT) mediated vasorelaxation, isolated lateral saphenous veins from cattle were assessed for vasoactivity using myography...
To better understand mechanisms of serotonin- (5-HT) mediated vasorelaxation, isolated lateral saphenous veins from cattle were assessed for vasoactivity using myography in response to increasing concentrations of 5-HT or selective 5-HT receptor agonists. Vessels were pre-contracted with 1 × 10 M phenylephrine and exposed to increasing concentrations of 5-HT or 5-HT receptor agonists that were selective for 5-HT, 5-HT, 5-HT, and 5-HT. Vasoactive response data were normalized as a percentage of the maximum contractile response induced by the phenylephrine pre-contraction. At 1 × 10 M 5-HT, a relaxation was observed with an 88.7% decrease (p < 0.01) from the phenylephrine maximum. At 1 × 10 M 5-HT, a contraction was observed with a 165% increase (p < 0.01) from the phenylephrine maximum. Increasing concentrations of agonists selective for 5-HT, 5-HT, or 5-HT resulted in a 27%, 92%, or 44% (p < 0.01) decrease from the phenylephrine maximum, respectively. Of these 5-HT receptor agonists, the selective 5-HT receptor agonist resulted in the greatest potency (-log EC) value (6.30) compared with 5-HT and 5-HT receptor agonists (4.21 and 4.66, respectively). To confirm the involvement of 5-HT in 5-HT-mediated vasorelaxation, blood vessels were exposed to either DMSO (solvent control) or a selective 5-HT antagonist (1 × 10 M) for 5-min prior to the phenylephrine pre-contraction and 5-HT additions. Antagonism of the 5-HT receptor attenuated the vasorelaxation caused by 5-HT. Approximately 94% of the vasorelaxation occurring in response to 5-HT could be accounted for through 5-HT, providing strong evidence that 5-HT-mediated vasorelaxation occurs through 5-HT activation in bovine peripheral vasculature.
Topics: Animals; Cattle; Vasodilation; Saphenous Vein; Serotonin; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Phenylephrine; Serotonin Receptor Agonists; Male
PubMed: 38946059
DOI: 10.14814/phy2.16128