Search Results (355)

Rubella is typically a mild viral illness, but it can lead to severe complications when contracted during pregnancy, such as pregnancy loss or developmental defects in the fetus (congenital rubella syndrome). Therefore, it is crucial to develop and maintain protective immunity in women of childbearing age. In this study, we assessed the transcriptional factors associated with rubella-specific immune outcomes (IgG binding antibody and avidity, neutralizing antibody, and memory B cell ELISpot response) following a third MMR vaccine dose in women of reproductive age to identify key factors/signatures impacting the immune response. We identified baseline (Day 0) and differentially expressed (Day 28–Day 0) genes associated with several RV-specific immune outcomes, including the transferrin receptor 2 (TFR2), which is an important factor regulating iron homeostasis and macrophage functional activity, and a close functional homolog of TFR1, the cellular receptor of the New World hemorrhagic fever arenaviruses. We also identified enriched KEGG pathways, “cell adhesion molecules”, “antigen processing and presentation”, “natural killer cell-mediated cytotoxicity”, and “immune network for IgA production”, relevant to immune response priming and immune activation to be associated with RV-specific immune outcomes. This study provides novel insights into potential biomarkers of rubella-specific immunity in women of childbearing age. Full article

Purpose: Per- and polyfluoroalkyl substances (PFAS) comprise a class of man-made compounds widely utilized in manufacturing everyday consumer products. Experimental studies indicate that PFAS may interfere with iron regulation by hindering absorption or inducing oxidative stress. Nonetheless, epidemiological studies examining the association between PFAS exposure and a broad spectrum of iron-related biomarkers remain scarce. Approach and Results: In this study, data from the 2013–2018 National Health and Nutrition Examination Survey (NHANES) were analyzed, which included 5050 adults aged 18 and older. The relationships between six PFAS compounds, oral iron intake, and a comprehensive set of markers of iron homeostasis, including serum iron, unsaturated iron-binding capacity (UIBC), total iron-binding capacity (TIBC), transferrin saturation, ferritin, and transferrin receptor levels, were examined. Our findings revealed a negative association between both individual and total PFAS (sum of six PFAS) levels and oral iron intake. Additionally, serum iron and transferrin saturation levels exhibited significant positive correlations with all PFAS compounds, whereas ferritin was positively correlated with all PFAS compounds except n-perfluorooctanoic acid (n-PFOA). UIBC and transferrin receptor showed significant negative correlations with all PFAS compounds, while TIBC was significantly negatively correlated with n-perfluorooctane sulfonic acid (n-PFOS), perfluoromethylheptane sulfonic acid isomers (sm-PFOS), perfluorohexane sulfonic acid (PFHxS), and the total PFAS. Conclusions: Higher PFAS exposure was associated with altered iron status biomarkers While this cross-sectional study cannot establish causality, the observed associations raise the possibility that PFAS exposure may influence iron absorption. These findings emphasize the need for additional research into the potential impact of PFAS exposure on iron homeostasis. Full article

To explore the potential seed compounds from natural products as anticancer agents against small-cell lung cancer (SCLC), the underground parts of Agapanthus africanus, a plant commonly used for ornamental purposes, were investigated. Three spirostan-type steroidal glycosides (1–3) were isolated and identified by nuclear magnetic resonance spectral analysis. Compounds 1–3 exhibited cytotoxicity against SBC-3 human SCLC cells, with IC₅₀ values of 0.56, 1.4, and 7.4 µM, respectively. Compound 1, also known an agapanthussaponin A, demonstrated the most potent cytotoxicity among the isolated compounds and was evaluated for its apoptosis- and ferroptosis-inducing activities. Compound 1 arrested the cell cycle of SBC-3 cells in the G₂/M phase and induced apoptosis primarily via the mitochondrial pathway, characterized by caspases-3 and -9 activation, loss of mitochondrial membrane potential, and overproduction of reactive oxygen species. Additionally, 1 triggered ferroptosis via a dual mechanism consisting of enhanced cellular iron uptake through upregulation of transferrin and transferrin receptor 1 expression and impaired glutathione synthesis via downregulation of both xCT and glutathione peroxidase 4 expression. Compound 1 induces cell death via the apoptosis and ferroptosis pathways, suggesting its promise as a seed compound for the development of anticancer therapeutics against SCLC. Full article

Background and Purpose: Glioblastoma remains a therapeutic challenge with a poor prognosis despite multimodal treatments. Reporter-based magnetic resonance imaging (MRI) offers a promising approach for tumor visualization, but its efficacy depends on sufficient reporter gene expression. This study aimed to develop a chimeric element-regulated ferritin heavy chain 1 (FTH1) reporter system to enhance MRI-based glioma detection while enabling targeted therapy via transferrin receptor (TfR)-mediated drug delivery. Methods: Using gene cloning techniques, we constructed a chimeric FTH1 expression system comprising tumor-specific PEG3 promoter (transcriptional control), bFGF-2 5′UTR (translational enhancement), and WPRE (mRNA stabilization). Lentiviral vectors delivered constructs to U251 glioblastoma cells and xenografts. FTH1/TfR expression was validated by Western blot and immunofluorescence. Iron accumulation was assessed via Prussian blue staining and TEM. MRI evaluated T2 signal changes. Transferrin-modified doxorubicin liposomes (Tf-LPD) were characterized for size and drug loading and tested for cellular uptake and cytotoxicity in vitro. In vivo therapeutic efficacy was assessed in nude mouse models through tumor volume measurement, MR imaging, and histopathology. Results: The chimeric system increased FTH1 expression significantly over PEG3-only controls (p < 0.01), with an increase of nearly 1.5-fold compared to the negative and blank groups and approximately a two-fold increase relative to the single promoter group, with corresponding TfR upregulation. Enhanced iron accumulation reduced T2 relaxation times significantly (p < 0.01), improving MR contrast. Tf-LPD (115 nm, 70% encapsulation) showed TfR-dependent uptake, inducing obvious apoptosis in high-TfR cells compared with that in controls. In vivo, Tf-LPD reduced tumor growth markedly in chimeric-system xenografts versus controls, with concurrent MR signal attenuation. Conclusions: The chimeric regulatory strategy overcomes limitations of single-element systems, demonstrating significant potential for integrated glioma theranostics. Its modular design may be adaptable to other reporter genes and malignancies. Full article

Plasma non-transferrin-bound iron (NTBI) comprises multiple subspecies, classified by their composition, chemical reactivity, and susceptibility to chelation. The redox-active and chelatable fraction of NTBI is referred to as labile plasma iron (LPI). The pathophysiological significance of NTBI and LPI lies in their ability to enter cells via alternative transport pathways that are not regulated by the transferrin receptor system or by cellular iron levels. Several mechanisms have been proposed for their cellular entry, including the hijacking of divalent metal transporters and passive diffusion. This unregulated uptake can lead to iron accumulation in vulnerable tissues such as the liver and the heart. NTBI and LPI bypassing normal cellular control mechanisms can rapidly exceed the cell’s capacity to safely store excess iron, leading to toxicity. Both NTBI and LPI contribute to oxidative stress by participating in free-radical-generating reactions. However, LPI concentration in the bloodstream may be differentially affected by the mode and extent of iron overload, the presence of residual serum iron-binding activity, and the antioxidant capacity of individual sera. In summary, both NTBI and LPI contribute to iron-mediated toxicity but differ in terms of reactivity, availability, and pathogenic potential depending on the pathophysiological conditions that influence the degree of toxicity. Full article

Background: Lung ischemia reperfusion injury (LIRI) is a severe complication after lung transplantation (LT). Ferroptosis contributes to the pathogenesis of LIRI. Maresin1 (MaR1) is an endogenous pro-resolving lipid mediator that exerts protective effects against multiorgan diseases. However, the role and mechanism of MaR1 in the ferroptosis of LIRI after LT need to be further investigated. Methods: A mouse LT model and a pulmonary vascular endothelial cell line after hypoxia reoxygenation (H/R) culture were established in our study. Histological morphology and inflammatory cytokine levels predicted the severity of LIRI. Cell viability and cell injury were determined by CCK-8 and LDH assays. Ferroptosis biomarkers, including Fe²⁺, MDA, 4-HNE, and GSH, were assessed by relevant assay kits. Transferrin receptor (TFRC) and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) protein levels were examined by western blotting. In vitro, lipid peroxide levels were detected by DCFH-DA staining and flow cytometry analysis. The ultrastructure of mitochondria was imaged using transmission electron microscopy. Furthermore, the potential mechanism by which MaR1 regulates ferroptosis was explored and verified with signaling pathway inhibitors using Western blotting. Results: MaR1 protected mice from LIRI after LTx, which was reversed by the ferroptosis agonist Sorafenib in vivo. MaR1 administration decreased Fe²⁺, MDA, 4-HNE, TFRC, and ACSL4 contents, increased GSH levels, and ameliorated mitochondrial ultrastructural injury after LTx. In vitro, Sorafenib resulted in lower cell viability and worsened cell injury and enhanced the hallmarks of ferroptosis after H/R culture, which was rescued by MaR1 treatment. Mechanistically, the protein kinase A and YAP inhibitors partly blocked the effects of MaR1 on ferroptosis inhibition and LIRI protection. Conclusions: This study revealed that MaR1 alleviates LIRI and represses ischemia reperfusion-induced ferroptosis via the PKA-Hippo-YAP signaling pathway, which may offer a promising theoretical basis for the clinical application of organ protection after LTx. Full article

Glioblastoma is the most prevalent and aggressive form of brain malignancy. Actual treatments face several challenges due to its high aggressiveness and poor prognosis. The chemotherapeutic agent temozolomide (TMZ) has limited therapeutic efficacy, and mutations in the tumour protein p53 gene (TP53) have been associated with treatment resistance. Thus, this study aimed to explore an innovative therapeutic strategy to enhance treatment efficacy of GBM. Previously, our team had developed a WRAP5 cell-penetrating peptide (CPP) functionalized with a transferrin receptor ligand (Tf) for the targeted delivery of TMZ and a p53-encoding plasmid to glioma cells. Our research had elucidated the circadian oscillations of the clock genes in the U87 glioma cells by employing two different computational models and observed that T16 and T8 time points revealed the highest circadian activity for Bmal1 and Per2 genes, respectively. Similar analysis was conducted for the transferrin receptor, which revealed that T7 and T8 were the key time points for its expression. A confocal microscopy study indicated the highest intracellular uptake of complexes and p53 mRNA expression at T8, the time point with the highest Per2 and transferrin receptor expression. Following mRNA analysis, the evaluation of p53 levels confirmed transcriptional changes at the protein level, and that T16 appears to be a favourable time point for enhancing therapeutic efficacy in U87 glioblastoma cells. These findings suggested that synchronizing the complexes’ administration with the biological clock of GBM cells may significantly improve glioblastoma therapeutics. Full article

Feline parvovirus (FPV) causes feline panleukopenia, a highly contagious disease in cats, marked by severe leukopenia, biphasic fever, diarrhea, vomiting, and hemorrhagic enteritis. Recently, FPV infection in giant pandas has increased, causing diarrhea and ultimately fatal outcomes, thereby threatening their survival and reproduction. Here, we investigated the transmission of FPV in giant pandas and its interaction with cellular receptors using an FPV strain (pFPV-sc) isolated from giant panda feces. Recombinant feline transferrin receptor 1 (fTfR1) and the giant panda ortholog (gpTfR1) were expressed in non-susceptible HEK293T and HeLa cells, while viral infection levels were measured to determine the effect of gpTfR1 on pFPV-sc replication. The findings indicated that gpTfR1 overexpression in non-susceptible cells significantly enhanced pFPV-sc replication, particularly influencing the viral attachment and internalization stages. Our data further revealed early-stage colocalization between gpTfR1 expression and virus infection, suggesting that gpTfR1 facilitates early viral infection and replication. Taken together, our study provides the first evidence on the mechanism of FPV cross-species infection in giant pandas and elucidates the interaction between gpTfR1 and FPV, which establishes a theoretical basis for the development of preventive and therapeutic strategies, thereby safeguarding the health and survival of giant panda populations from FPV. Full article

Ferritin is important for cellular iron storage and metabolism. It consists of 24 ferritin heavy- or light-chain subunits surrounding an iron-containing core, but it is also released as an extracellular molecule that shows increased systemic levels during acute-phase reactions. Furthermore, acute myeloid leukemia (AML) is an aggressive bone marrow malignancy that can be associated with increased ferritin levels both at the time of first diagnosis but also during/following anti-AML treatment due to an iron overload. Such high systemic ferritin levels at diagnosis or later allogeneic stem cell transplantation are associated with decreased long-term survival. Extracellular ferritin binds to several receptors expressed by AML cells (e.g., the transferrin receptor and CXCR4 chemokine receptor) and AML-supporting non-leukemic bone marrow cells (e.g., endothelial, mesenchymal or immunocompetent cells). Ferritin can thereby affect the AML cells directly as well as indirectly via AML-supporting neighboring cells. Finally, ferritin should be regarded as a regulator of the dysfunctional iron metabolism that causes increased iron levels in AML cells, and it is important for cell survival through its function during the initial steps of ferroptosis. Thus, ferritin is not only an adverse prognostic biomarker, but also an important regulator of AML cell proliferation, survival and chemosensitivity and the targeting of iron metabolism/ferroptosis is, therefore, a possible strategy in AML therapy. Full article

Background/Objectives: Glioblastoma represents a particularly aggressive and fatal type of brain tumor. Peptide-drug conjugates, which offer the promise of traversing the blood-brain barrier to selectively accumulate in tumor tissues and precisely target cancer cells, are an active area of research. We present the synthesis and characterization of the T7 peptide (HAIYPRH) as a targeting ligand for the transferrin receptor, which is highly expressed on both the blood-brain barrier and glioma cells. Methods: Using the T7 peptide, the synthesis, characterization, and biological evaluation of a transferrin receptor-targeted, combination SN-38 and rucaparib peptide drug conjugate (T7-SN-38-rucaparib) are described. Results: The T7 peptide drug conjugate readily cleaved in the presence of exogenous cathepsin B, releasing the active drug payloads. In vitro experiments demonstrated potent cytotoxic effects of the T7 peptide drug conjugate on glioblastoma cells (IC₅₀ = 22.27 nM), with reduced toxicity to non-cancerous HEK 293 cells (IC₅₀ = 115.78 nM), indicating selective toxicity toward cancer cells. Further investigations revealed that blocking transferrin receptors with drug-free T7 peptide significantly reduced the conjugate’s cytotoxicity, an effect that could be reversed by introducing exogenous cathepsin B to the cells. Conclusions: These findings highlight the potential of glioblastoma-targeted delivery of SN-38 and rucaparib based on specific recognition of the transferrin receptor for transport across the blood-brain barrier, offering the prospect of reduced toxicity and selective killing of cancer cells. Additionally, since rucaparib does not cross the blood-brain barrier, this work is significant to facilitate the use of rucaparib for the treatment of brain tumors. Full article

Aging leads to ovarian degeneration in poultry, reducing egg production and quality. Ellagic acid (EA), a natural plant-derived compound, may help delay ovarian aging, though its precise mechanisms remain unclear. This study investigated the effects of EA on ovarian aging of low-yield laying chickens and explored its underlying mechanism. EA supplementation (100 and 500 mg/kg) significantly increased ovarian weight as well as the number and proportion of small yellow follicles in aging chickens. EA administration elevated serum antioxidant levels and upregulated the expression of glutathione peroxidase 4 (GPX4) expression to reduce oxidative stress. Importantly, EA treatment suppressed the mRNA and protein expression of ferroptosis markers transferrin receptor protein 1 (TFRC) and solute carrier family 7 member 11 (SLC7A11), increased Proliferating Cell Nuclear Antigen (PCNA) expression, and alleviated G1 phase arrest in granulosa cells (GCs), promoting cell proliferation, which improves egg quality and production. Furthermore, in vitro experiments demonstrated that EA treatment decreased reactive oxygen species production, improved mitochondrial function, inhibited ferroptosis, and attenuated GCs aging. In conclusion, this study reveals the critical role of ferroptosis in chicken ovarian aging and suggests that EA may provide a promising approach for delaying ovarian aging and enhancing productivity in low-yield poultry. Full article

Radiation therapy is a standard of care treatment for patients with glioblastoma. However, patients’ survival rate is dismal, with nearly all patients experiencing disease progression after treatment. Enriched iron content associated with increased transferrin receptor (TfR) expression is an indicator of poor glioblastoma patient outcomes; however, the underlying contributions to tumor progression remain elusive. The goal of this present study is to understand how iron metabolism in glioma contributes to radiation-induced glioblastoma cell motility. U251 and a doxycycline-inducible ferritin heavy chain overexpressing U251 (U251 FtH⁺) cell line were used. For in vitro studies, cells were irradiated with 2 Gy using a ³⁷Cs source, and after 72 h, atomic force microscopy (AFM) nanoindentation was employed to assess changes in cell stiffness following irradiation. Cell motility was studied using temporal confocal microscopy. For in vivo studies, U251 cells were grown in the rear flanks of female nude athymic mice, and the tumor was irradiated with five fractions of 2 Gy (10 Gy). The tumors were then imaged using a GE 7T small animal MRI to assess changes in T2* MRI, and colorimetric analysis of labile iron was performed using ferrozine. Following irradiation, a biomechanical shift characterized by decreased cell stiffness along with increased cell motility occurred in U251 cells, which corresponded to increased TfR expression. FtH overexpression completely reversed the enhanced cell motility following irradiation. Irradiation of U251 tumors induced the same iron metabolic shift. Interestingly, the change in labile iron in U251 tumors corresponded with an increase in T2* relaxation times, suggesting that T2* mapping may serve as a surrogate marker for assessing radiation-induced changes in iron metabolism. Full article

Sertoli cell-only (SCO) tubules are a histologic pattern characterized by the absence of germ cells within seminiferous tubules, leading to infertility in both humans and dogs. While its association with testicular tumors has been documented, the role of iron metabolism in SCO tubules remains unclear. This study investigates the immunolabeling of key iron-related proteins (Transferrin Receptor 1, Transferrin Receptor 2, and Ferritin Heavy chain 1) and Proliferating Cell Nuclear Antigen (PCNA) in canine SCO tubules within distinct microenvironments: seminomas, Sertoli cell tumors, and isolated. We confirm the presence and distribution of iron-related proteins in Sertoli cells as a part of a Sertoli cell-only pattern across different microenvironments. Our findings suggest a potential increase in iron uptake in association with tumors, and the cytoplasmic PCNA immunolabeling suggests a preferential activation of cell survival rather than proliferation, potentially facilitating neoplastic transformation. In contrast, Sertoli cells in the isolated Sertoli cell-only pattern exhibit nuclear PCNA immunolabeling, possibly correlated to the state of immaturity of Sertoli cells. These findings highlight the role of iron homeostasis and apoptosis in testicular tumorigenesis. Immunohistochemistry revealed that Sertoli cells in SCO tubules actively uptake iron in all conditions, yet their capacity to utilize it for proliferation appears restricted. Interestingly, PCNA labeling exhibits a pattern dependent on the microenvironment: in tumor-associated SCO tubules, it showed cytoplasmic localization, characteristic of an anti-apoptotic function, whereas isolated SCO tubules showed nuclear PCNA labeling, suggesting a potential role in DNA synthesis and repair. These findings highlight the interplay between iron homeostasis and cellular survival mechanisms, offering novel perspectives on its pathophysiology and implications for testicular cancer development. Full article

Background/Objectives: Iron deficiency anemia in pregnancy poses risks to mothers and infants. This study aimed to correlate maternal iron indices in the second trimester with cord blood indices and pregnancy outcomes. Methods: This prospective cohort study was nested within the RAPIDIRON Trial (Reducing Anaemia in Pregnancy in India) at Jawaharlal Nehru Medical College, Karnataka, India. A total of 292 pregnant women with moderate anemia who received oral iron supplementation were enrolled from April 2021 to May 2023. Maternal iron indices were measured at multiple time points and correlated with cord blood indices and pregnancy outcomes. Results: Increased hemoglobin levels were observed in mothers of preterm and term neonates from 8.92 ± 0.81 vs. 9.02 ± 0.77 g/dL at 12–16 weeks to 11.14 ± 1.31 vs. 10.73 ± 1.24 g/dL at 26–30 weeks. A similar trend was observed in mothers across birth weight groups. Ferritin and TSAT levels significantly increased in all outcome groups (p < 0.001), peaking at 20–24 weeks and then slightly declining at 26–30 weeks. Additionally, maternal sTfR levels significantly improved from the early (7.72 ± 1.33 vs. 7.51 ± 1.61) to late second trimester (5.87 ± 0.81 vs. 5.76 ± 1.11) in mothers of both anemic and non-anemic neonates (p < 0.001). Maternal sTfR in other outcome groups also showed a similar pattern. A negligible correlation was found between maternal and cord blood iron indices. Conclusions: Maternal iron indices increased from the early to mid-second trimester, followed by a slight fall in the late second trimester. Notably, higher iron indices were observed in mothers of preterm and low-birth-weight neonates. Full article