Research Article Details
| Article ID: | A50193 |
| PMID: | 35483638 |
| Source: | J Control Release |
| Title: | Celastrol-loaded lactosylated albumin nanoparticles attenuate hepatic steatosis in non-alcoholic fatty liver disease. |
| Abstract: | Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease with several liver-associated pathologic characteristics such as aberrant lipid accumulation, persistent chronic inflammation and hyperactive endoplasmic reticulum (ER) stress. Plant-derived celastrol (CEL) appeared to be a promising anti-inflammatory and anti-obesity drug but the clinical application was delayed by low oral bioavailability. The present study was designed for developing biodegradable albumin-based nanoparticles to deliver CEL to the liver for treating NAFLD. CEL was entrapped into lactosylated bovine serum albumin (Lac-BSA) by high pressure homogenization to generate CEL-loaded Lac-BSA nanoparticles (CEL-Lac-BSA). CEL-Lac-BSA displayed spherical morphology, narrow size distribution at 158.6 ± 3.4 nm and reasonable drug-loading efficiency at 13.62 ± 0.13%. CEL-Lac-BSA not only showed better hepatocyte uptake and hepatic deposition than free CEL, but also outperformed in reducing lipid deposition, ameliorating liver function and enhancing insulin sensitivity in a mouse model of diet-induced NAFLD. Mechanistic studies indicated that CEL-Lac-BSA more effectively downregulated the mRNA levels of genes for lipogenesis and lipid transporter while upregulated the mRNA levels of lipolysis mediators. Western blot analysis confirmed the outperformance of CEL-Lac-BSA in enhancing the activation of AMP-activated protein kinase (AMPK) and silent information regulation 2 homolog (SIRT1) and the protein levels of fatty acid synthase (FASN) and sterol regulatory element-binding protein-1c (SREBP1c) in NAFLD mice. Taken together, CEL-Lac-BSA showed better potential in the treatment of diet-induced NAFLD. Lactose-coating of albumin-based nanoparticles effectively facilitated the liver-targeting release of hydrophobic drug CEL for ameliorating hepatic steatosis. Therefore, CEL-Lac-BSA may be translated into a potential clinical therapy against obesity and NAFLD. |
| DOI: | 10.1016/j.jconrel.2022.04.034 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| S07 | Anti-lipogenesis | de novo lipogenesis; de novo lipogenesis; DNL; anti-lipogenic mechanisms; adipogenesis; anti-obesity | stearoyl-CoA desaturase 1 (SCD-1); Acetyl-coenzyme carboxylase; acyl-CoA carboxylase inhibitor (ACC inhibitor); stearoyl Coenzyme A desaturase inhibitor (SCD inhibitor); THR-beta selective agonist; DGAT2 inhibitor; FASN inhibitor | Aramchol; Firsocostat (GS-0976); VK-2809; ION 224 | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T01 | 5'-AMP-activated protein kinase subunit beta-1 | PRKAB1 | activator | Kinase | Q9Y478 | AAKB1_HUMAN | Details |
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T20 | Fatty acid synthase | FASN | inhibitor | Enzyme | P49327 | FAS_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D545 | Pig placenta extract | Biological extract | -- | -- | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |