Transferrin receptor 2 is emerging as a major player in the control of iron metabolism

Abstract Our knowledge of mammalian iron metabolism has advanced dramatically over recent years. Iron is an essential element for virtually all living organisms. Its intestinal absorption and accurate cellular regulation is strictly required to ensure the coordinated synthesis of the numerous iron-containing proteins involved in key metabolic processes, while avoiding the uptake of excess iron that can lead to organ damage. A range of different proteins exist to ensure this fine control within the various tissues of the body. Among these proteins, transferrin receptor (TFR2) seems to play a key role in the regulation of iron homeostasis. Disabling mutations in TFR2 are responsible for type 3 hereditary hemochromatosis (Type 3 HH). This review describes the biological properties of this membrane receptor, with a particular emphasis paid to the structure, function and cellular localization. Although much information has been garnered on TFR2, further efforts are needed to elucidate its function in the context of the iron regulatory network

Dynamic Rheological Analysis of MLVs and Lamellar Phases in the System C12E4 / D2O

AbstractThe mechanical properties of the lamellar phase, La, of the system C12E4/D2O were studied along an isoplethal path (30 wt% C12E4) in the temperature range 10 - 60°C. A dynamic analysis was determined by small strain oscillatory rheometry. The multilamellar vesicles ("MLVs") ("onions") were transformed by shearing the lamellar phase. The micellar phase was investigated by steady and dynamic rheological experiments. The micellar aggregate size increases slightly upon heating and the transition from micelles to lamellae appears to be a first order transition. The mechanical spectra of the lamellar phase show a strong dependence of the moduli on the frequency. This is typical of defective lamellar phases. They are different from MLVs mechanical spectra. The MLVs viscous and storage moduli are almost independent from the frequency and they exhibit the characteristics of a strong gel. The temperature of formation of the MLVs phase influences the mechanical properties of the MLVs. Three different packing states of the MLVs phase were observed in the temperature range 25 - 55°C

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Mechanical properties of PAN-based gel electrolytes: small-amplitude oscillatory shear study

Polymer electrolytes with ionic conductivities on the order of mS cm -1 at room temperature were prepared from the gelification of LiClO4/ethylene carbonate-propylene carbonate (EC-PC) solutions into a poly(acrylonitrile) (PAN) matrix. Oscillating rheological experiments were performed on gels prepared at different solvent/salt molar ratios in order to investigate their mechanical properties. Temperature sweep tests (25-120°C) showed changes in the rheological behaviour that was related to structural transitions. A strong-weak gel transition takes place at about 80°C, independent of salt concentration hence assignable only to the polymeric matrix, This transition is completely reversible during cooling ramps and represents a necessary mechanical property from a processing standpoint. A gel-sol transition was observed at ca. 110°C where both viscoelastic moduli reduce themselves by a factor 100, reporting the formation of a fluid system with G″>G'

Regulation of transferrin receptor 2 in human cancer cell lines.

In a recent study we have explored TfR2 expression in a panel of cancer cell lines and we observed that about 40% of these cell lines clearly express TfR2. Taking advantage of this observation and considering the frequent overexpression of c-Myc in cancer cells we have explored the existence of a possible relationship between c-Myc and TfR2 in these cell lines. Our results provided evidence that TfR2(+) cell lines express low c-Myc levels and low TfR1 levels, while TfR2(-) cell lines express high c-Myc and TfR1 levels. Using the erythroleukemic K562 TfR2(+) cells as a model, we observed that agents that enhance c-Myc expression, such as iron, determine a decrease of TfR2 expression, while molecules that induce a decreased c-Myc expression, such as the iron chelator desferoxamine or the kinase inhibitor ST 1571, induce an enhanced TfR2 expression. On the other hand, we have evaluated a possible effect of hypoxia and nitric oxide on TfR2 expression in erythroleukemia K526 and hepatoma HepG2 cells, providing evidence that: (i) agents inducing cellular hypoxia, such as CoCl(2), elicited a marked upmodulation of TfR1, but a downmodulation of TfR2 expression; (ii) NO(+) donors, such as sodium nitroprusside (SNP), induced a moderate decrease of TfR1, associated with a marked decline of TfR2 expression; (iii) NO donors, such as S-Nitroso-N-Acetylpenicillamine (SNAP), induced a clear increase of TfR1, associated with a moderate upmodulation of TfR2 expression. The ensemble of these observations suggests that in cancer cell lines TfR2 expression can be modulated through stimuli similar to those known to act on TfR1 and these findings may have important implications for our understanding of the role of TfR2 in the regulation of iron homeostasis

Cross talk among Notch3, pre-TCR, and Tal1 in T-cell development and leukemogenesis.

Integrated pathways are believed to determine hematopoietic cell fate and/or neoplastic transformation. Notch signaling has been shown to regulate T-cell differentiation and leukemogenesis. However, specific target genes and molecular partners are not fully elucidated. We show that Notch3 activation sustains aberrant SCL/Tal1 overexpression and phosphorylation in mature thymocytes. Furthermore, we define the role of SCL/Tal1 as a component of an activator complex, including phosphorylated Tal1 and Sp1, that specifically enhances cyclin D1 expression and demonstrate that Tal1/Sp1 specifically co-occupy the D1 promoter in vivo, only in the presence of pre-T-cell receptor (TCR). We therefore conclude not only that cyclin D1 is a target of the Tal1/Sp1 complex, but also that Notch3-dependent activation of pre-TCR/ERK signaling regulates SCL/Tal1 function

Emergency department performances during overcrowding: the experience of the health protection agency of Brianza

Background: Hospital emergency departments (ED) can contribute to improve health outcomes and reduce costs of health care system. This study evaluated ED admissions during a twelve months period, analyzing characteristics of patients who underwent to emergency care in order to understand factors involved in ED overcrowding and promote adequate management. Methods: This retrospective study analyzed a twelve months window, with in-depth focus on December/January when almost all EDs reported overcrowding. All ED admissions were recorded in electronic schedules including: demographic characteristics, time/date of the access, incoming triage code, diagnosis, performed procedures, discharge, time/date of discharge. A backward multivariable logistic regression model was used to estimate relationships between investigated variables and ED pattern mortality. Results: A total of 416,299 ED admissions were analyzed. During the overcrowded period there was an increase in patients admissions (+32 patients per day, p = 0.0079) with a statistically significant rise of critical patients (+1.7% yellow codes and +0.7% red codes, p < 0.001) and older subjects (+1.4% patients aged 75 or more years, p < 0.001). Moreover, there were statistically significant increases in waiting times and in length of visits, a higher percentage of patients who were hospitalized (13.3% vs. 12.2%, p < 0.001), left ED (4.46% vs. 4.15%, p < 0.001) and died (0.27% vs. 0.17%, p < 0.0001). This latter result maintained a marginal statistical significance (OR = 1.16, 95% CI = 0.98–1.38, p = 0.075) after adjustment for confounding. Conclusion: Our study highlights that ED crowding can determine measurable worsening in ED services and patient outcomes as mortality, waiting times, lengths of stay, percentage of abandonment without being seen and, probably, costs. Thus, address ED crowding has to be considered an important public health priority requiring policymakers involvement