Iron and zinc are essential micronutrients required for growth and health. Deficiencies of these nutrients are highly prevalent among populations, but can be alleviated by supplementation and food fortification. Cross-sectional studies in humans showed positive association of serum zinc levels with hemoglobin and markers of iron status. Dietary restriction of zinc or intestinal specific conditional knock out of ZIP4 (SLC39A4), an intestinal zinc transporter, in experimental animals demonstrated iron deficiency anemia and tissue iron accumulation. Similarly, increased iron accumulation has been observed in cultured cells exposed to zinc deficient media. These results together suggest a potential role of zinc in modulating intestinal iron absorption and mobilization from tissues. Studies in intestinal cell culture models demonstrate that zinc induces iron uptake and transcellular transport via induction of divalent metal iron transporter-1 (DMT1) and ferroportin (FPN1) expression, respectively. It is interesting to note that intestinal cells are exposed to very high levels of zinc through pancreatic secretions, which is a major route of zinc excretion from the body. Therefore, zinc appears to be modulating the iron metabolism possibly via regulating the DMT1 and FPN1 levels. Herein we critically reviewed the available evidence to hypothesize novel mechanism of Zinc-DMT1/FPN1 axis in regulating intestinal iron absorption and tissue iron accumulation to facilitate future research aimed at understanding the yet elusive mechanisms of iron and zinc interactions.

Background The brain requires iron for a number of processes, including energy production. Inadequate or excessive amounts of iron can be detrimental and lead to a number of neurological disorders. As such, regulation of brain iron uptake is required for proper functioning. Understanding both the movement of iron into the brain and how this process is regulated is crucial to both address dysfunctions with brain iron uptake in disease and successfully use the transferrin receptor uptake system for drug delivery. Methods Using in vivo steady state infusions of apo- and holo-transferrin into the lateral ventricle, we demonstrate the regulatory effects of brain apo- and holo-transferrin ratios on the delivery of radioactive 55Fe bound to transferrin or H-ferritin in male and female mice. In discovering sex differences in the response to apo- and holo-transferrin infusions, ovariectomies were performed on female mice to interrogate the influence of circulating estrogen on regulation of iron uptake. Results Our model reveals that apo- and holo-transferrin significantly regulate iron uptake into the microvasculature and subsequent release into the brain parenchyma and their ability to regulate iron uptake is significantly influenced by both sex and type of iron delivery protein. Furthermore, we show that cells of the microvasculature act as reservoirs of iron and release the iron in response to cues from the interstitial fluid of the brain. Conclusions These findings extend our previous work to demonstrate that the regulation of brain iron uptake is influenced by both the mode in which iron is delivered and sex. These findings further emphasize the role of the microvasculature in regulating brain iron uptake and the importance of cues regarding iron status in the extracellular fluid.

The apelinergic system is widely expressed and acts through autocrine and paracrine signaling to exert protective effects, including vasodilatory, metabolic, and inotropic effects on the cardiovascular (CV) system. The apelin pathway’s dominant physiological role has delineated therapeutic implications for coronary artery disease, heart failure (HF), aortic aneurysm, pulmonary arterial hypertension (PAH), and transplant vasculopathy. Apelin peptides interact with the renin–angiotensin system (RAS) by promoting angiotensin converting enzyme 2 (ACE2) transcription leading to increased ACE2 protein and activity while also antagonizing the effects of angiotensin II (Ang II). Apelin modulation of the RAS by increasing ACE2 action is limited due to its rapid degradation by proteases, including ACE2, neprilysin (NEP), and kallikrein. Apelin peptides are hence tightly regulated in a negative feedback manner by ACE2. Plasma apelin levels are suppressed in pathological conditions, but its diagnostic and prognostic utility requires further clinical exploration. Enhancing the beneficial actions of apelin peptides and ACE2 axes while complementing existing pharmacological blockade of detrimental pathways is an exciting pathway for developing new therapies. In this review, we highlight the interaction between the apelin and ACE2 systems, discuss their pathophysiological roles and potential for treating a wide array of CV diseases (CVDs).

No abstract