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Although it has been established that patients with chronic kidney disease and iron deficiency, as indicated by a transferrin saturation of < 20%, are at increased risk of all-cause mortality and cardiovascular events, the optimal management of such patients has not yet been determined. In this post hoc subgroup analysis, we aimed to clarify the effect of ferric citrate hydrate on transferrin saturation in patients with chronic kidney disease and low transferrin saturation (< 20%) undergoing hemodialysis. To accomplish this, we extracted the relevant data on a subset of patients drawn from two previous studies: the ASTRIO study (A Study examining the contribution to Renal anemia treatment with ferric citrate hydrate, Iron-based Oral phosphate binder, UMIN000019176) and a post-marketing surveillance study. The subset of patients used for the present study were those with baseline transferrin saturation < 20%. We found that administration of ferric citrate hydrate increased transferrin saturation and maintained transferrin saturation at approximately 30%. However, because we did not have access to data on all-cause mortality or cardiovascular events, we could not ascertain whether the frequency of these outcomes was reduced in parallel with improvements in transferrin saturation. Further large studies are required.
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Compuestos Férricos , Diálisis Renal , Transferrina , Humanos , Masculino , Femenino , Compuestos Férricos/uso terapéutico , Compuestos Férricos/administración & dosificación , Transferrina/metabolismo , Transferrina/análisis , Anciano , Persona de Mediana Edad , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/sangre , Anemia Ferropénica/tratamiento farmacológico , Anemia Ferropénica/sangreRESUMEN
BACKGROUND: Overweight/obesity and iron deficiency are highly prevalent in women of reproductive age (WRA), impacting on women's health. Obesity is a risk factor for nutritional deficiencies but its association with iron deficiency is unclear. OBJECTIVE: To determine the association between adiposity and markers of iron status and iron deficiency prevalence in WRA. METHODS: This cross-sectional study analyzed the National Diet and Nutrition Survey (NDNS, 2008-2019) data, focusing on women aged 18-49y with BMI ≥18.5 kg/m2. Prevalence of anemia, Iron Deficiency Anemia (IDA), and Iron Deficiency (ID) were analyzed. Ferritin was adjusted for C-reactive protein. Iron status was assessed across high and low BMI, waist circumference (WC), waist-to-height (WHtR), and waist-to-hip ratio (WHR). Chi2, linear and logistic regression were performed adjusting for covariates. RESULTS: Among 1,098 WRA, 496 normal weight and 602 overweight/obesity, prevalence rates were: anemia 9.2% and IDA 6.8%. Anemia was more prevalent in those with higher WHtR and WHR (11.9% vs 5.9% and 16.7% vs 6.5%, both p<0.001). WRA with increased WC, WHtR, and WHR had higher IDA prevalence than those with lower adiposity. (8.5% vs 4.3%, p=0.005; 9.4% vs 3.3%, p<0.001; 12.1% vs 4.9%, p<0.001). ID prevalence was 49.7% (ferritin cut-off 30 µg/L) and 19.6% (ferritin cut-off 15 µg/L), showing similar rates across adiposity groups. ID prevalence defined by soluble transferrin receptor (sTfR) was higher in women with increased WHR (p=0.001). Higher WHR predicted ID categorized by sTfR (aOR 2.104, p=0.004), and WHtR and WHR predicted anemia and IDA (anemia: WHtR aOR 2.006 p=0.036; WHR aOR 4.489 p<0.001; IDA: WHtR: aOR 2.942, p=0.012; WHR aOR 4.142, p<0.001). CONCLUSIONS: At least one in five WRA in the UK are iron deficient, highlighting the need to revise current policies. Greater central adiposity was strongly associated with impaired iron status and the development of anemia, IDA, and ID.
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This study aimed to explore the impact of caffeine (CAF) encapsulated in transferrin-modified, sterically-stabilized liposomes (Tf-SSL) on the physical performance of rats, specifically forelimb grip strength, running, and swimming. The brain-targeted drug delivery system, Tf-SSL, was used for the administration of caffeine. 168 male Sprague-Dawley (SD) rats were randomly assigned to different groups, including swimming, running, running wheel, and strength groups. Each group was further subdivided into high, medium, and low dose free caffeine (HCAF, MCAF, LCAF) and Tf-SSL CAF groups, along with a control group (CON). The strength, swimming, and running groups underwent training for four weeks, three times per week. The running wheel group was placed in rearing cages for a one-week adaptation period. After the final training session, the resistance, swimming, running, and running wheel exercise capacities of the rats were tested. The rats were administered treatment via tail vein injection, while the blank CON group received 0.9 % saline solution without treatment throughout the entire process. The results demonstrated a Tf-SSL CAF group encapsulation rate of 70.58 ± 5.14 %. Increasing the concentration of supplemented caffeine led to enhanced forelimb grip strength in rats, with significant differences observed in HCAF alone group, medium-dose Tf-SSL CAF (MTf-SSL CAF), and high-dose Tf-SSL CAF (HTf-SSL CAF) groups compared to the CON group. In the running and swimming experiments, higher caffeine supplementation concentrations correlated with increased running and swimming time to exhaustion, and the MTf-SSL CAF group showed longer running and swimming time compared to the HCAF alone group. The results of rat striatal dopamine levels indicated that increased caffeine supplementation concentrations led to higher dopamine secretion, with significantly different striatal concentrations in the HCAF group, MTf-SSL CAF group, and HTf-SSL CAF group compared to the CON group. The running wheel experiment revealed that rats in the medium- and high-dose Tf-SSL CAF groups exhibited greater 6-h running distances than the HCAF group and CON group. In conclusion, caffeine supplementation improved the physical performance of rats, with the high concentration CAF group outperforming the low and medium concentration groups. Furthermore, Tf-SSL CAF demonstrated superior physical enhancement compared to caffeine supplementation alone.
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PURPOSE: In the emerging field of antibody treatments for neurodegenerative diseases, reliable tools are needed to evaluate new therapeutics, diagnose and select patients, monitor disease progression, and assess therapy response. Immuno-PET combines the high affinity and exceptional specificity of monoclonal antibodies with the non-invasive imaging technique positron emission tomography (PET). Its application in neurodegenerative disease brain imaging has been limited due to the marginal uptake across the blood-brain barrier (BBB). The emergence of BBB-shuttle antibodies with enhanced uptake across the BBB extended immuno-PET to brain imaging. We recently reported about specific brain uptake of a bispecific aducanumab mTfR antibody in APP/PS1 TG mice using 89Zr-immuno-PET. However, a sufficient target-to-background ratio was reached at a relatively late scanning time point of 7 days post-injection. To investigate if a better target-to-background ratio could be achieved earlier, an aducanumab BBB-shuttle with a mutated Fc region for reduced FcRn affinity was evaluated. PROCEDURES: AduH310A-8D3 and Adu-8D3 were modified with DFO*-NCS and subsequently radiolabeled with 89Zr. The potential influence of the H310A mutation, modification with DFO*-NCS, and subsequent radiolabeling on the in vitro binding to amyloid-beta and mTfR1 was investigated via amyloid-beta peptide ELISA and FACS analysis using mTfR1 transfected CHO-S cells. Blood kinetics, brain uptake, in vivo PET imaging and target engagement of radiolabeled AduH310A-8D3 were evaluated and compared to non-mutated Adu-8D3 in APP/PS1 TG mice and wild-type animals as controls. RESULTS: Radiolabeling was performed with sufficient radiochemical yields and radiochemical purity. In vitro binding to amyloid-beta and mTfR1 showed no impairment. [89Zr]Zr-AduH310A-8D3 showed faster blood clearance and earlier differentiation of amyloid-beta-related brain uptake compared to [89Zr]Zr-Adu-8D3. However, only half of the brain uptake was observed for [89Zr]Zr-AduH310A-8D3. CONCLUSIONS: Although a faster blood clearance of AduH310A-8D3 was observed, it was concluded that no beneficial effects for 89Zr-immuno-PET imaging of brain uptake were obtained.
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Lipid nanoparticles (LNPs) are promising delivery systems with the ability to deliver small interfering RNA (siRNA) and messenger RNA (mRNA) in diseased tissues and intracellular sites of action. However, delivery to non-hepatic tissues via systemic administration remains challenging. Antibody modification of LNPs is a hopeful approach for improving their selectivity to target tissues. The conventional method of antibody modification via thiol-maleimide linkage is concerned with reduced recognition efficiency of the disease-related target molecules owing to variations in antibody orientation on the surface of the LNPs. In this study, we developed a novel adapter lipopeptide for antibody modification of LNPs via the Fc-region. Here, we selected RI7-217, an anti-transferrin receptor antibody, as the ligand. Through optimization of spacer peptides, we found a FcBP-EKGG-lipid exhibits high water-dispersibility for post-insertion method to LNPs. We prepared RI7-217-modified LNPs by modifying LNPs with FcBP-EKGG-lipids and mixing the antibodies. We found that the luciferase protein expression of RI7-217-modified LNPs was significantly enhanced in an antibody-specific manner against transferrin receptor-expressing U-87 MG cells. This information would be valuable in the development of antibody-modified LNPs for cell-selective targeting.
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Iron deficiency is a common and independent predictor of adverse outcomes in patients with heart failure. The implications of iron deficiency in patients implanted with a left ventricular assist device (LVAD) are less established. This review recaps data on the prevalence, characteristics and impact of Iron deficiency in the LVAD population. A systematic search yielded eight studies involving 517 LVAD patients, with iron deficiency prevalence ranging from 40% to 82%. IV iron repletion was not associated with adverse events and effectively resolved iron deficiency in most patients. However, the effects of iron deficiency and iron repletion on post-implant survival and exercise capacity remain unknown. Although iron deficiency is highly prevalent in LVAD patients, its true prevalence and adverse effects may be misestimated due to inexact diagnostic criteria. Future randomised controlled trials on IV iron treatment in LVAD patients are warranted to clarify the significance of this common comorbidity.
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Iron is essential for numerous physiological processes and its deficiency often leads to anemia. Iron deficiency (ID) is a global problem, primarily affecting reproductive-age women and children, especially in developing countries. Diagnosis uses classical biomarkers like ferritin or transferrin saturation. Recent advancements include using soluble transferrin receptor (sTfR) or hepcidin for improved detection and classification of absolute and functional iron deficiencies, though mostly used in research. ID without anemia may present symptoms like asthenia and fatigue, even without relevant clinical consequences. ID impacts not only red-blood cells but also immune system cells, highlighting its importance in global health and immune-related comorbidities. Managing ID, requires addressing its cause and selecting appropriate iron supplementation. Various improved oral and intravenous products are available, but further research is needed to refine treatment strategies. This review updates on absolute and functional iron deficiencies, their relationships with the immune system and advancements in diagnosis and therapies.
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BACKGROUND: The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance. OBJECTIVE: This research explored the effectiveness of integrating anlotinib (a broad-spectrum tyrosine kinase inhibitor) with programmed death-1 (PD-1) blockade and offers mechanistic insights into more effective strategies for treating HCC. METHODS: Using patient-derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD-1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time-of-flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples. RESULTS: The combination of anlotinib with an anti-PD-1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF-1α signaling axis. CD8+ T-cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8+ T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti-PD-1 therapy in patients with HCC. CONCLUSIONS: Our findings highlight anlotinib's potential to augment the efficacy of anti-PD-1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14-mediated CD8+ T-cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology. HIGHLIGHTS: Synergistic effects of anlotinib and anti-PD-1 immunotherapy demonstrated in HCC preclinical models. Anlotinib inhibits TFRC expression via the VEGFR2/AKT/HIF-1α pathway. CXCL14 upregulation via TFRC suppression boosts CD8+ T-cell recruitment. TFRC emerges as a potential biomarker for evaluating prognosis and predicting response to anti-PD-1-based therapies in advanced HCC patients.
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Linfocitos T CD8-positivos , Carcinoma Hepatocelular , Inmunoterapia , Indoles , Neoplasias Hepáticas , Quinolinas , Receptores de Transferrina , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Quinolinas/farmacología , Quinolinas/uso terapéutico , Quinolinas/administración & dosificación , Animales , Ratones , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Indoles/farmacología , Indoles/uso terapéutico , Humanos , Inmunoterapia/métodos , Receptores de Transferrina/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
Hydroxychloroquine sulfate (HCQ) is currently being repurposed for cancer treatment. The antitumor mechanism of HCQ is inhibition of cellular autophagy, but its therapeutic potential is severely limited by poor solubility, lack of tumor targeting and lower cellular uptake. Therefore, utilization of human H-chain apoferritin (HFn) composed only of heavy subunits is an attractive approach for tumor targeting drug delivery. This study focused on pH-triggered encapsulation of HCQ within the inner cavity of HFn to form HFn@HCQ nanoparticles for tumor-targeted drug delivery. Characterization using a range of techniques has been used to confirm the successful establishment of HFn@HCQ. HFn@HCQ exhibited pH-responsive release behavior, with almost no drug release at pH 7.4, but 80% release at pH 5.0. Owing to its intrinsic binding to transferrin receptor 1 (TfR1), HFn@HCQ was significantly internalized through TfR1-mediated endocytosis, with a 4.4-fold difference of internalization amount across cell lines. Additionally, HFn@HCQ enhanced the antitumor effect against four different cancer cell lines when compared against HCQ alone, especially in TfR1 high-expressing cells, where the inhibitory effect was 3-fold higher than free HCQ. The autophagy inhibition of HFn@HCQ has been demonstrated, which is a major pathway to induce cancer cell death. According to current findings, HFn based drug delivery is a promising strategy to target and kill TfR1 overexpressing tumor cells.
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The clinical utility of raloxifene (RLX), a selective estrogen receptor modulator (SERM), has been compromised by severe side effects and unfavorable drug properties. To address these, a transferrin (Tf) conjugated graphene oxide nanoribbon (GONR) platform was tried for RLX. The stability of GONRs in biological media was improved by surface modification with 1, 2-Distearoyl-sn-glycero-3 phosphoethanolamine-Poly (ethylene glycol) (DSPE-PEG). The Tf molecule was covalently attached to DSPE-PEG (DPT) using EDC-NHS chemistry. The surface of GONR was then modified with DSPE-PEG (DP) or DPT and loaded with RLX (GDP-RLX and GDPT-RLX). The final formulations were characterized for drug loading and stability. The anticancer activities of pure RLX, GDP-RLX, and GDPT-RLX were evaluated and compared in all the in vitro and in vivo studies. In vitro cell line studies showed that GDPT-RLX have significantly high cytotoxicity, cellular uptake, apoptosis induction, G2/M phase arrest, anti-migration properties, and apoptotic protein expression, followed by GDP-RLX and RLX. Pharmacokinetics and tumor biodistribution were also found to be excellent with GDPT-RLX. The in vivo tumor therapy and tumor evaluation outcomes were also consistent with the in vitro data. The Tf conjugated GDPT-RLX represents a promising approach for targeted and sustained delivery of RLX with enhanced therapeutic efficacy.
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BACKGROUND: Ferroptosis is a cell death caused by iron-dependent accumulation of lipid peroxidation. Transferrin receptor (TFR) is a ferroptosis-related protein responsible for iron transport. The detailed biologic role of TFR in intrahepatic cholangiocarcinoma (ICC) is not fully elucidated. METHODS: The study enrolled 92 ICC patients who had undergone hepatic resection. Immunohistochemistry (IHC) assays were performed for TFR protein expression. The regulation of malignant activity and the effect on sensitivity to the ferroptosis-inducer artesunate by TFR were investigated in vitro. RESULTS: Using IHC staining, 23 patients were categorized as TFR-positive. The TFR-positive group had a significantly larger tumor size and more microscopic vascular invasion. In the multivariate analysis, TFR positivity was an independent poor prognostic factor. In vitro TFR-knockdown (KD) significantly decreased the intracellular iron levels and the cell proliferation, migration, and invasion rates. Artesunate treatment significantly decreased cell viability, whereas cisplatin promoted ferroptosis. When iron transport into cells was inhibited by TFR-KD, ferroptosis was significantly suppressed. Expression of PD-L1 was induced by cisplatin, with a further increase observed when artesunate and cisplatin were used in combination. CONCLUSIONS: Transferrin receptor is a poor prognostic factor for ICC and contributes to sensitivity to ferroptosis.
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After the discovery of cis-platin, the first metal-based anticancer drugs, budotitane, and titanocene dichloride entered clinical trials. These two classes of complexes were effective against those cell lines that are resistant to cisplatin and other platinum-based drugs. However, the main limitation of these complexes is their low hydrolytic stability. After these two classes, a third generation titanium based complex, i.e. diaminebis(phenolato)bisalkoxo, was invented, which showed more hydrolytic stability and high cytotoxicity than budotitane and titanocene dichloride. The Hydrolytic stability of complexes plays an important role in cytotoxicity. Earlier research showed that hydrolytically less stable complexes decompose rapidly into non-bioavailable moiety and become inactive. The mechanism of Ti(IV) complexes of diaminebis(phenolato)bisalkoxo is under investigation and is presumed to involve Endoplasmic Reticulum (ER) stress, which leads to apoptosis. The proposed mechanism involves the removal of ligands from the titanium complex and the binding of the Ti center to transferrin protein and its release inside the cell. Also, the structure of the ligand plays a key role in the cytotoxicity of complexes; as the bulkiness of the ligand increased, the cytotoxic nature of complexes decreased.
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Aim and background: Sepsis is a major global health affecting millions worldwide, hence understanding its contributing factors becomes paramount. This cross-sectional study at a tertiary care center explores the relationship between iron profile, vitamin D levels, and outcomes in sepsis and septic shock patients. The primary objective was to explore the prevalence of iron profile and vitamin D parameters during early intensive care unit (ICU) admission and their association with 28-day mortality. Materials and methods: Spanning 18 months, the study enrolled adult patients meeting sepsis or septic shock criteria at the ICU. Data collection included demographic information, clinical characteristics, and blood samples for iron profile and vitamin D levels at admission. Disease severity was assessed using sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation II (APACHE II) scores, and treatment was administered as per surviving sepsis-3 guidelines. Results: The research involved 142 participants, uncovering prevalent organisms such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Noteworthy connections to mortality were identified for factors including vasopressor support, ICU stay duration, SOFA score, and APACHE-II score. Interestingly, age, gender, and vitamin D levels showed no significant associations. However, the study did reveal a significant association between iron, ferritin, and transferrin saturation levels with increased 28-day mortality. Conclusion: Our study concluded that low Iron, elevated ferritin, and decreased transferrin saturation levels maintained associations with the outcome of interest. While no such relationship was established with vitamin D levels. These results suggest potential implications for patient management and prognosis, warranting further exploration in future research. How to cite this article: Bairwa M, Jatteppanavar B, Kant R, Singh M, Choudhury A. Impact of Iron Profile and Vitamin D Levels on Clinical Outcomes in Patients with Sepsis and Septic Shock: A Cross-sectional Analysis at a Tertiary Care Center. Indian J Crit Care Med 2024;28(6):569-574.
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Glioblastoma (GBM) represents a formidable challenge in oncology, characterized by aggressive proliferation and poor prognosis. Iron metabolism plays a critical player in GBM progression, with dysregulated iron uptake and utilization contributing to tumor growth and therapeutic resistance. Iron's pivotal role in DNA synthesis, oxidative stress, and angiogenesis underscores its significance in GBM pathogenesis. Elevated expression of iron transporters, such as transferrin receptor 1 (TfR1), highlights the tumor's reliance on iron for survival. Innovative treatment strategies targeting iron dysregulation hold promise for overcoming therapeutic challenges in GBM management. Approaches such as iron chelation therapies, induction of ferroptosis to nanoparticle-based drug delivery systems exploit iron-dependent vulnerabilities, offering avenues for enhance treatment efficacy and improve patient outcomes. As research advances, understanding the complexities of iron-mediated carcinogenesis provides a foundation for developing precision medicine approaches tailored to combat GBM effectively. This review explores the intricate relationship between iron metabolism and GBM, elucidating its multifaceted implications and therapeutic opportunities. By consolidating the latest insights into iron metabolism in GBM, this review underscores its potential as a therapeutic target for improving patient care in combination with the standard of care approach.
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BACKGROUND: Cardiac iron overload and ferroptosis greatly contribute to the poor prognosis of myocardial infarction (MI). Iron chelator is one of the most promising strategies for scavenging excessive iron and alleviating cardiac dysfunction post MI. However, various side effects of existing chemical iron chelators restrict their clinical application, which calls for a more viable and safer approach to protect against iron injury in ischemic hearts. RESULTS: In this study, we isolated macrophage-derived extracellular vesicles (EVs) and identified macrophage-derived EVs as a novel endogenous biological chelator for iron. The administration of macrophage-derived EVs effectively reduced iron overload in hypoxia-treated cardiomyocytes and hearts post MI. Moreover, the oxidative stress and ferroptosis induced by excessive iron were considerably suppressed by application of macrophage-derived EVs. Mechanistically, transferrin receptor (TfR), which was inherited from macrophage to the surface of EVs, endowed EVs with the ability to bind to transferrin and remove excess protein-bound iron. EVs with TfR deficiency exhibited a loss of function in preventing MI-induced iron overload and protecting the heart from MI injury. Furthermore, the iron-chelating EVs were ultimately captured and processed by macrophages in the liver. CONCLUSIONS: These results highlight the potential of macrophage-derived EVs as a powerful endogenous candidate for iron chelation therapy, offering a novel and promising therapeutic approach to protect against iron overload-induced injury in MI and other cardiovascular diseases.
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Vesículas Extracelulares , Quelantes del Hierro , Sobrecarga de Hierro , Macrófagos , Ratones Endogámicos C57BL , Infarto del Miocardio , Receptores de Transferrina , Infarto del Miocardio/metabolismo , Animales , Vesículas Extracelulares/metabolismo , Sobrecarga de Hierro/metabolismo , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Ratones , Quelantes del Hierro/farmacología , Quelantes del Hierro/uso terapéutico , Receptores de Transferrina/metabolismo , Masculino , Hierro/metabolismo , Miocitos Cardíacos/metabolismo , Ferroptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Transferrina/metabolismo , HumanosRESUMEN
New strategies for enhancing drug delivery to the blood-brain barrier (BBB) represent a major challenge in treating cerebral diseases. Nanoemulsion-based nanocarriers represent an ideal candidate to improve drug delivery thanks to their versatility in functionalization and cargo protection. In this work, a paclitaxel-loaded nano-emulsion has been firstly functionalized and stabilized with two layers constituted of chitosan and hyaluronic acid, and, secondly, the latter has been conjugated to the CRT peptide. CRT is a bioactive peptide that selectively recognizes bEnd.3 cells, a model of the BBB, thanks to its interactions with transferrin (Tf) and its receptor (TfR). Cytotoxic results showed a 41.5% higher uptake of CRT functionalized nano-emulsion than the negative control, demonstrating the ability of this novel tool to be accumulated in brain endothelium tissue. Based upon these results, our approach can be fully generalizable to the design of multifunctional nanocarriers for delivery of therapeutic agents to the central nervous systems.
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We report a successful formulation of Artemisone (ATM) in transferrin (Tf)-conjugated nanostructured lipid carriers (NLCs), achieving nearly a five-times increase in cell toxicity. The escalating cost of new drug discoveries led to the repurposing of approved drugs for new indications. This study incorporated Artemisone, an antimalarial drug, into a nanostructured lipid carrier (NLC) and tested for possible anticancer effects. The aim was to develop NLCs, and transferrin-conjugated NLCs (NLC-Tf) encapsulating Artemisone to enhance its delivery and anticancer activity. NLC formulations were prepared using high-pressure homogenization followed by ultrasonication and were characterized by particle size, zeta potential, and PDI. The conjugation of (Tf) to (NLC) was confirmed using IR, and the anticancer activity was tested using MTS assay. All formulations were in the nanometer size range (140-167 nm) with different zeta potential values. IR spectroscopy confirmed the successful conjugation of transferrin to NLC. Upon testing the formulations on melanoma cell lines using MTS assay, there was a significant decrease in viability and an increase in the encapsulated ATM-Tf toxicity compared to positive control ATM. The NLCs presented a promising potential carrier for delivering ATM to melanoma cells, and further conjugation with Tf significantly improved the ATM cytotoxicity.
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Artemisininas , Portadores de Fármacos , Lípidos , Melanoma , Nanoestructuras , Transferrina , Transferrina/química , Transferrina/farmacología , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/metabolismo , Portadores de Fármacos/química , Artemisininas/química , Artemisininas/farmacología , Línea Celular Tumoral , Lípidos/química , Nanoestructuras/química , Supervivencia Celular/efectos de los fármacos , Tamaño de la Partícula , Antineoplásicos/farmacología , Antineoplásicos/química , Sistemas de Liberación de Medicamentos , Nanopartículas/químicaRESUMEN
BACKGROUND: Evidence on the link between iron status markers and insulin resistance (IR) is limited. We aimed to explore the relationship between iron status and IR among U.S. adults. METHODS: This study involved 2993 participants from the National Health and Nutrition Examination Survey (NHANES) 2003-2006, 2017-2020. IR is characterized by a HOMA-IR value of ≥2.5. Weighted linear and multivariable logistic regression analyses were used to examine the linear relationships between iron status and IR. Furthermore, restricted cubic splines (RCS) were used to identify the non-linear dose-response associations. Stratified analyses by age, sex, BMI and PA were also performed. Last, ROC curve was used to evaluate the predictive value of iron status in IR. RESULTS: In weighted linear analyses, serum iron (SI) exhibited a negative correlation with HOMA-IR (ß (95% CI) = -0.03(-0.05, -0.01), P = 0.01). In weighted multivariate logistic analyses, iron intake and serum transferrin receptor (sTfR) were positively correlated with IR (OR =1.02; 95% CI=1.00-1.04, P = 0.04; OR =1.07; 95% CI=1.02-1.13, P = 0.01). Also, SI and transferrin saturation (TSAT) were negatively correlated with IR (OR =0.96; 95% CI=0.94-0.98, P <0.0001; OR =0.98; 95% CI=0.97-0.99, P <0.001) after adjusting for confounding factors. RCS depicted a nonlinear dose-response relationship between sTfR and TSAT and IR. This correlation remained consistent across various population subgroups. ROC curve showed that TSAT performed better than iron intake, SI, sTfR and TSAT in ROC analyses for IR prediction. CONCLUSION: All biomarkers demonstrated significantly lower risk of IR with increasing iron levels, which will contribute to a more comprehensive and in-depth understanding of the relationship between the two and provide a solid foundation for future exploration of the mechanisms underlying their relationship.
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Understanding the role of iron in ethanol-derived hepatic stress could help elucidate the efficacy of dietary or clinical interventions designed to minimize liver damage from chronic alcohol consumption. We hypothesized that normal levels of iron are involved in ethanol-derived liver damage and reduced dietary iron intake would lower the damage caused by ethanol. We used a pair-fed mouse model utilizing basal Lieber-DeCarli liquid diets for 22 weeks to test this hypothesis. In our mouse model, chronic ethanol exposure led to mild hepatic stress possibly characteristic of early-stage alcoholic liver disease, seen as increases in liver-to-body weight ratios. Dietary iron restriction caused a slight decrease in non-heme iron and ferritin (FeRL) expression while it increased transferrin receptor 1 (TfR1) expression without changing ferroportin 1 (FPN1) expression. It also elevated protein lysine acetylation to a more significant level than in ethanol-fed mice under normal dietary iron conditions. Interestingly, iron restriction led to an additional reduction in nicotinamide adenine dinucleotide (NAD+) and NADH levels. Consistent with this observation, the major mitochondrial NAD+-dependent deacetylase, NAD-dependent deacetylase sirtuin-3 (SIRT3), expression was significantly reduced causing increased protein lysine acetylation in ethanol-fed mice at normal and low-iron conditions. In addition, the detection of superoxide dismutase 1 and 2 levels (SOD1 and SOD2) and oxidative phosphorylation (OXPHOS) complex activities allowed us to evaluate the changes in antioxidant and energy metabolism regulated by ethanol consumption at normal and low-iron conditions. We observed that the ethanol-fed mice had mild liver damage associated with reduced energy and antioxidant metabolism. On the other hand, iron restriction may exacerbate certain activities of ethanol further, such as increased protein lysine acetylation and reduced antioxidant metabolism. This metabolic change may prove a barrier to the effectiveness of dietary reduction of iron intake as a preventative measure in chronic alcohol consumption.
Asunto(s)
Antioxidantes , Metabolismo Energético , Etanol , Animales , Ratones , Acetilación/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Antioxidantes/metabolismo , Masculino , Hierro/metabolismo , Superóxido Dismutasa-1/metabolismo , Superóxido Dismutasa-1/genética , Superóxido Dismutasa/metabolismo , Lisina/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Receptores de Transferrina/metabolismo , Sirtuina 3/metabolismo , Sirtuina 3/genética , NAD/metabolismo , Ferritinas/metabolismo , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/genética , Estrés Oxidativo/efectos de los fármacos , Ratones Endogámicos C57BL , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/patología , Hepatopatías Alcohólicas/etiologíaRESUMEN
The human transmembrane protein Transferrin Receptor-1 is regarded as a promising target for the systemic delivery of therapeutic agents, particularly of nucleic acid therapeutics, such as short double stranded RNAs. This ubiquitous receptor is involved in cellular iron uptake, keeping intracellular homeostasis. It is overexpressed in multiple cancer cell types and is internalized via clathrin-mediated endocytosis. In previous studies, a human transferrin receptor-1 RNA aptamer, identified as TR14 ST1-3, was shown to be capable of effectively internalizing into cells in culture and to deliver small, double stranded RNAs in vitro and in vivo, via systemic administration. To understand, at the molecular level, the aptamer binding to the receptor and the impact of conjugation with the therapeutic RNA, a multi-level in silico protocol was employed, including protein-aptamer docking, molecular dynamics simulations and free energy calculations. The competition for the binding pocket, between the aptamer and the natural ligand human Transferrin, was also evaluated. The results show that the aptamer binds to the same region as Transferrin, with residues from the helical domain showing a critical role. Moreover, the conjugation to the therapeutic RNA, was shown not to affect aptamer binding. Overall, this study provides an atomic-level understanding of aptamer association to human Transferrin Receptor-1 and of its conjugation with a short model-therapeutic RNA, providing also important clues for futures studies aiming to deliver other oligonucleotide-based therapeutics via Transferrin Receptor.