-
International Journal of Pharmaceutics Jun 2024Felodipine has proven to be effective as an atherosclerosis therapy because it increases blood flow to the vessel wall. However, the poor solubility, low...
Felodipine has proven to be effective as an atherosclerosis therapy because it increases blood flow to the vessel wall. However, the poor solubility, low bioavailability, and hepatic first-pass metabolism of oral felodipine compromise its therapeutic effectiveness. The study's goal is to create a nasal pH-sensitive hydrogel of felodipine-loaded invasomes (IPHFI) that will improve felodipine's release, permeation, bioavailability, and efficacy as a potential diabetes-associated atherosclerosis therapy. According to the pre-formulation study, the felodipine-loaded invasomes formulation composed of phospholipid (3%w/v), cholesterol (0.16%w/v), ethanol (3%v/v) and cineole (1%v/v) was chosen as the optimum formulation. The optimum formulation was characterized in vitro and then mixed with a mixture of chitosan and glyceryl monooleate to make the IPHFI formulation. The IPHFI formulation enhanced the release and permeation of felodipine by 2.99 and 3-fold, respectively. To assess the efficacy and bioavailability of the IPHFI formulation, it was studied in vivo using an experimental atherosclerosis rat model. Compared to oral free felodipine, the nasal administration of the IPHFI formulation increased the bioavailability by 3.37-fold and decreased the serum cholesterol, triglycerides, LDL, and calcification score by 1.56, 1.53, 1.80, and 1.18 ratios, respectively. Thus, nasal IPHFI formulation may represent a promising diabetes-associated atherosclerosis therapy.
PubMed: 38945465
DOI: 10.1016/j.ijpharm.2024.124395 -
American Journal of Epidemiology Jun 2024We aimed at examining the shared and unique associations of metabolites with multiple cardiometabolic diseases (CMD), i.e. type 2 diabetes (T2D), coronary heart disease...
We aimed at examining the shared and unique associations of metabolites with multiple cardiometabolic diseases (CMD), i.e. type 2 diabetes (T2D), coronary heart disease (CHD) and stroke. In this study, a total of 168 plasma metabolites were measured by targeted high-throughput nuclear magnetic resonance spectroscopy among 98,162 participants free of T2D, CHD, and stroke at baseline. Cox proportional hazard models estimated hazard ratios for one SD increase in metabolite concentration levels, and false discovery rate (at 10%) was used to correct for multiple comparisons. Over 12.1 years of follow-up on average, 3,463 T2D, 6,186 CHD, and 1,892 stroke events were recorded. Most lipoprotein metabolites were associated with risks of T2D and CHD but not with the risk of stroke, with stronger associations for T2D than for CHD. Phospholipids within intermediate-density lipoprotein or large low-density lipoprotein particles showed positive associations with CHD and inverse associations with T2D. Metabolites indicating very small very low-density lipoprotein, histidine, creatinine, albumin, and glycoprotein acetyls were associated with risks of all three conditions. This large-scale metabolomics study revealed common and distinct metabolic biomarkers for T2D, CHD and stroke, providing instrumental information to possibly implement precision medicine for preventing and treating these conditions.
PubMed: 38944759
DOI: 10.1093/aje/kwae167 -
Journal of Hepatology Jun 2024Regression of cirrhosis has been observed in patients with viral and non-viral etiologies of liver disease in whom the underlying cause of liver injury was effectively...
BACKGROUND & AIMS
Regression of cirrhosis has been observed in patients with viral and non-viral etiologies of liver disease in whom the underlying cause of liver injury was effectively suppressed. However, the understanding of the factors contributing to reversibility of fibrosis and cirrhosis is limited. Our aims were to assess clinical factors, perform genotyping of known variants, and comprehensive metabolic phenotyping to characterize the regression of fibrosis in patients with compensated advanced chronic liver disease (cACLD).
METHODS
In a case-control pilot study with 81 cACLD patients, we compared individuals exhibiting histological or clinical evidence of cACLD regression ("regressors"; n=44) with those showing no improvement ("non-regressors"; n=37) after a minimum of 24 months of successful therapy of the cause of liver disease. Data were validated using an external validation cohort (n=30).
RESULTS
Regardless of the cause of cACLD, the presence of obesity (OR 0.267 95%CI:0.072-0.882; P=0.049), high liver stiffness (OR 0.960, 95%CI:0.925-0.995; P=0.032), and carriage of GCKR variant rs1260326 (OR 0.148, 95%CI:0.030-0.773; P=0.019) are associated with a reduced likelihood of fibrosis regression in a subgroup of 60 ACLD patients genotyped for known genetic variants. Using liver tissue transcriptomics, we identified metabolic pathways differentiating regressors from non-regressors, with top pathways associated to lipid metabolism -especially fatty acids, bile acids, phospholipids, triacylglycerides (biosynthesis), and the carnitine shuttle. In the entire discovery cohort, we further measured metabolites within the defined pathways, which led to identifying 33 circulating markers differentiating regressors from non-regressors after etiological therapy. The validation cohort confirmed 14 of the differentially expressed markers.
CONCLUSIONS
We identified and validated a group of lipid biomarkers associated with regression of fibrosis that could be used as non-invasive biomarker for detecting regression of fibrosis in cACLD.
PubMed: 38944391
DOI: 10.1016/j.jhep.2024.06.028 -
Journal of Molecular Biology Jun 2024Autophagy is a cellular degradation pathway where double-membrane autophagosomes form de novo to engulf cytoplasmic material destined for lysosomal degradation. This... (Review)
Review
Autophagy is a cellular degradation pathway where double-membrane autophagosomes form de novo to engulf cytoplasmic material destined for lysosomal degradation. This process requires regulated membrane remodeling, beginning with the initial autophagosomal precursor and progressing to its elongation and maturation into a fully enclosed, fusion-capable vesicle. While the core protein machinery involved in autophagosome formation has been extensively studied over the past two decades, the role of phospholipids in this process has only recently been studied. This review focuses on the phospholipid composition of the phagophore membrane and the mechanisms that supply lipids to expand this unique organelle.
PubMed: 38944336
DOI: 10.1016/j.jmb.2024.168691 -
Neoplasia (New York, N.Y.) Jun 2024
PubMed: 38943994
DOI: 10.1016/j.neo.2024.101018 -
Food Chemistry Jun 2024Liposomes (LIP) loaded with natural active ingredients have significant potential in the food industry. However, their low loading efficiency (LE) hampers the...
Liposomes (LIP) loaded with natural active ingredients have significant potential in the food industry. However, their low loading efficiency (LE) hampers the advancement of liposomal products. To improve the loading capacity of functional compounds, bionic oleosomes (BOLE) with a monolayer of phospholipid membranes and a glyceryl tricaprylate/caprate (GTCC) oil core have first been engineered by high-pressure homogenization. TEM revealed that the core of BOLE consists of GTCC instead of water, thereby extending the hydrophobic space. Steady-state fluorescence and active loading experiments confirmed that cholesterol (CH) detached from the phospholipid membrane and entered the oil core, where it repelled cannabidiol (CBD). Based on the extending hydrophobic space, CBD-BOLE was prepared and its LE was 3.13 times higher than CBD-LIP. The CBD-phospholipid ratio (CPR) of CBD-BOLE significantly improved at least 7.8 times. Meanwhile, the free radical scavenging activity of CBD was increased and cytotoxicity was reduced.
PubMed: 38943919
DOI: 10.1016/j.foodchem.2024.140181 -
Cell Reports Jun 2024Platelet-activating factor (PAF) is a potent phospholipid mediator crucial in multiple inflammatory and immune responses through binding and activating the PAF receptor...
Platelet-activating factor (PAF) is a potent phospholipid mediator crucial in multiple inflammatory and immune responses through binding and activating the PAF receptor (PAFR). However, drug development targeting the PAFR has been limited, partly due to an incomplete understanding of its activation mechanism. Here, we present a 2.9-Å structure of the PAF-bound PAFR-G complex. Structural and mutagenesis analyses unveil a specific binding mode of PAF, with the choline head forming cation-π interactions within PAFR hydrophobic pocket, while the alkyl tail penetrates deeply into an aromatic cleft between TM4 and TM5. Binding of PAF modulates conformational changes in key motifs of PAFR, triggering the outward movement of TM6, TM7, and helix 8 for G protein coupling. Molecular dynamics simulation suggests a membrane-side pathway for PAF entry into PAFR via the TM4-TM5 cavity. By providing molecular insights into PAFR signaling, this work contributes a foundation for developing therapeutic interventions targeting PAF signal axis.
PubMed: 38943642
DOI: 10.1016/j.celrep.2024.114422 -
Pigment Cell & Melanoma Research Jun 2024Most melanomas progress from radial to vertical growth phase before spreading locoregionally and distally. Much is still unknown about the metabolic changes in the tumor...
Most melanomas progress from radial to vertical growth phase before spreading locoregionally and distally. Much is still unknown about the metabolic changes in the tumor cells and their microenvironment during this metastatic progression. We aimed to gain new insight into the molecular characteristics of melanoma in regard to spatial lipidomics to deliver new knowledge regarding tumor metastatic progression. We included 10 fresh tumor samples from 10 patients including two in situ melanomas, two invasive primary melanomas, and six metastatic melanomas (four in-transit metastases and two distant metastases). In addition, we analyzed four healthy skin controls from the same patients. Time-of-flight imaging secondary ion mass spectrometry (ToF-SIMS) enabled detailed spatial-lipidomics that could be directly correlated with conventional histopathological analysis of consecutive H&E-stained tissue sections. Significant differences in the lipid profiles were found in primary compared to metastatic melanomas, notably an increase in phosphatidylethanolamine lipids relative to phosphatidylinositol lipids and an increase in GM3 gangliosides in the metastatic samples. Furthermore, analysis of the data from in transit versus distant metastases samples highlighted that specific phospholipids, and a difference in the long versus shorter chain GM3 gangliosides, discriminated the metastatic routes. Further studies are warranted to verify these preliminary findings. Lipidomic changes could serve as a novel biomarker for tumor progression and even serve as a target for novel treatments. Furthermore, analyzing the lipid profiles could help to differentiate between primary and metastatic melanomas in challenging cases.
PubMed: 38943376
DOI: 10.1111/pcmr.13182 -
Lipids in Health and Disease Jun 2024Malignant bone tumors, including primary bone cancer and metastatic bone tumors, are a significant clinical challenge due to their high frequency of presentation, poor... (Review)
Review
Malignant bone tumors, including primary bone cancer and metastatic bone tumors, are a significant clinical challenge due to their high frequency of presentation, poor prognosis and lack of effective treatments and therapies. Bone tumors are often accompanied by skeletal complications such as bone destruction and cancer-induced bone pain. However, the mechanisms involved in bone cancer progression, bone metastasis and skeletal complications remain unclear. Lysophosphatidic acid (LPA), an intercellular lipid signaling molecule that exerts a wide range of biological effects mainly through specifically binding to LPA receptors (LPARs), has been found to be present at high levels in the ascites of bone tumor patients. Numerous studies have suggested that LPA plays a role in primary malignant bone tumors, bone metastasis, and skeletal complications. In this review, we summarize the role of LPA signaling in primary bone cancer, bone metastasis and skeletal complications. Modulating LPA signaling may represent a novel avenue for future therapeutic treatments for bone cancer, potentially improving patient prognosis and quality of life.
Topics: Humans; Lysophospholipids; Bone Neoplasms; Signal Transduction; Receptors, Lysophosphatidic Acid; Animals
PubMed: 38943207
DOI: 10.1186/s12944-024-02196-9 -
Journal of Orthopaedic Surgery and... Jun 2024Tendon stem/progenitor cell (TSPC) senescence contributes to tendon degeneration and impaired tendon repair, resulting in age-related tendon disorders. Ferroptosis, a...
Platelet-derived exosomes alleviate tendon stem/progenitor cell senescence and ferroptosis by regulating AMPK/Nrf2/GPX4 signaling and improve tendon-bone junction regeneration in rats.
BACKGROUND
Tendon stem/progenitor cell (TSPC) senescence contributes to tendon degeneration and impaired tendon repair, resulting in age-related tendon disorders. Ferroptosis, a unique iron-dependent form of programmed cell death, might participate in the process of senescence. However, whether ferroptosis plays a role in TSPC senescence and tendon regeneration remains unclear. Recent studies reported that Platelet-derived exosomes (PL-Exos) might provide significant advantages in musculoskeletal regeneration and inflammation regulation. The effects and mechanism of PL-Exos on TSPC senescence and tendon regeneration are worthy of further study.
METHODS
Herein, we examined the role of ferroptosis in the pathogenesis of TSPC senescence. PL-Exos were isolated and determined by TEM, particle size analysis, western blot and mass spectrometry identification. We investigated the function and underlying mechanisms of PL-Exos in TSPC senescence and ferroptosis via western blot, real-time quantitative polymerase chain reaction, and immunofluorescence analysis in vitro. Tendon regeneration was evaluated by HE staining, Safranin-O staining, and biomechanical tests in a rotator cuff tear model in rats.
RESULTS
We discovered that ferroptosis was involved in senescent TSPCs. Furthermore, PL-Exos mitigated the aging phenotypes and ferroptosis of TSPCs induced by t-BHP and preserved their proliferation and tenogenic capacity. The in vivo animal results indicated that PL-Exos improved tendon-bone healing properties and mechanical strength. Mechanistically, PL-Exos activated AMPK phosphorylation and the downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway, leading to the suppression of lipid peroxidation. AMPK inhibition or GPX4 inhibition blocked the protective effect of PL-Exos against t-BHP-induced ferroptosis and senescence.
CONCLUSION
In conclusion, ferroptosis might play a crucial role in TSPC aging. AMPK/Nrf2/GPX4 activation by PL-Exos was found to inhibit ferroptosis, consequently leading to the suppression of senescence in TSPCs. Our results provided new theoretical evidence for the potential application of PL-Exos to restrain tendon degeneration and promote tendon regeneration.
Topics: Animals; Ferroptosis; Exosomes; NF-E2-Related Factor 2; Cellular Senescence; Rats; Signal Transduction; Phospholipid Hydroperoxide Glutathione Peroxidase; Regeneration; AMP-Activated Protein Kinases; Stem Cells; Tendons; Male; Blood Platelets; Rats, Sprague-Dawley; Rotator Cuff Injuries; Disease Models, Animal
PubMed: 38943181
DOI: 10.1186/s13018-024-04869-8