Tag: haemoglobin

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Researchers Stumble on Haemoglobin in the Epidermis

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Researchers have shown for the first time that haemoglobin, a protein found in red blood cells where it binds oxygen, is also present in the epidermis. The study, which appears in the Journal of Investigative Dermatology, published by Elsevier, provides important insights into the properties of the skin’s protective external layer.

This research was driven by a curiosity about the protective role of the epidermis and what unexpected molecules are expressed in it. Researchers discovered the haemoglobin α protein in keratinocytes of the epidermis and in hair follicles. This unexpected evidence adds a new facet to the understanding of the workings of the skin’s defence mechanisms.

Lead investigator of the study Masayuki Amagai, MD, PhD, Department of Dermatology, Keio University School of Medicine, Tokyo, and Laboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, explains: “The epidermis consists of keratinised stratified squamous epithelium, which is primarily composed of keratinocytes. Previous studies have identified the expression of various genes with protective functions in keratinocytes during their differentiation and formation of the outer skin barrier. However, other barrier-related genes escaped prior detection because of difficulties obtaining adequate amounts of isolated terminally differentiated keratinocytes for transcriptome analysis.”

Haemoglobin binds gases such as oxygen, carbon dioxide, and nitric oxide, and it is an iron carrier via the heme complex. These properties make epidermal haemoglobin a prime candidate for antioxidant activity and potentially other roles in barrier function.

Professor Amagai continues: “We conducted a comparative transcriptome analysis of the whole and upper epidermis, both of which were enzymatically separated as cell sheets from human and mouse skin. We discovered that the genes responsible for producing haemoglobin were highly active in the upper part of the epidermis. To confirm our findings, we used immunostaining to visualise the presence of haemoglobin α protein in keratinocytes of the upper epidermis.”

Professor Amagai concludes: “Our study showed that epidermal haemoglobin was upregulated by oxidative stress and inhibited the production of reactive oxygen species in human keratinocyte cell cultures. Our findings suggest that haemoglobin α protects keratinocytes from oxidative stress derived from external or internal sources such as UV irradiation and impaired mitochondrial function, respectively. Therefore, the expression of haemoglobin by keratinocytes represents an endogenous defence mechanism against skin aging and skin cancer.”

Source: EurekAlert!

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Are Lower Haemoglobin Levels Protective?

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A new study challenges the view that high haemoglobin levels are always desirable for health. 

A study based on two large human cohorts as well as experimental work supported the idea that lower haemoglobin levels may protect against both obesity and metabolic syndrome. The phenomenon may be related to the body’s adaptive response to low-oxygen conditions, which is exploited by endurance athletes in high-altitude training.

Haemoglobin levels vary from one individual to another, with normal levels in Finnish population ranging from 117 to 155 grams per litre in females and 134 to 167 grams per litre in males.

A recent study showed that individual differences in haemoglobin levels are strongly associated with metabolic health in adulthood. The haemoglobin levels were associated with body mass index, glucose metabolism, blood lipids and blood pressure. Subjects with lower haemoglobin levels were healthier in terms of metabolic measures. The study examined haemoglobin values within the normal range.  

“We found a clear association between hemoglobin levels and key cardiovascular traits, and the associations became more pronounced as the subjects aged,” said principal investigators Professor Juha Auvinen, doctoral student Joona Tapio and postdoctoral researcher Ville Karhunen.  

The effect of lower haemoglobin observed in the study is related to a mild oxygen deficiency in the body and the corresponding hypoxia inducible factors (HIF) response which is activated as a result. The research team of Professor Peppi Karppinen is internationally known for its studies on this phenomenon. The finding reinforces the understanding of the central role that the HIF response has in regulating the body’s energy metabolism.

“Haemoglobin levels are a good measure of the body’s ability to carry oxygen. A mild lack of oxygen activates the HIF response, which makes the body’s energy metabolism less economical and thus may protect against obesity and unfavourable metabolism,” explained study leader Prof Karppinen.

Prof Karppinen’s team has already shown in previous research that activation of the hypoxia response protects mice from obesity, metabolic syndrome, fatty liver and atherosclerosis. This is the first study to show the link between oxygen deficiency and a wide range of metabolic health markers in humans as well.

“Although this study uses multiple methods to establish links between lower body oxygen levels and metabolic health, it is very challenging to establish causality for the observed associations in human data. However, combining evidence from different components of the study, the results support that hypoxia response may also play an important role in peoples’ metabolic health,”explained co-leader of the study Professor Marjo-Riitta Järvelin.

“We also already know that in people living high above sea level, low oxygen levels in the habitat cause long-term activation of the HIF response. These people are slimmer, and they have better sugar tolerance and a lower risk of cardiovascular death,” said Prof Karppinen.

The study was based on a large cohort of people born in Northern Finland in 1966, which followed the health of 12 000 people since birth. The results were also replicated in The Cardiovascular Risk in Young Finns Study cohort material, which covers more than 1800 individuals. 

“Although this study uses multiple methods to establish links between lower body oxygen levels and metabolic health, it is very challenging to establish causality for the observed associations in human data. However, combining evidence from different components of the study, the results support that hypoxia response may also play an important role in peoples’ metabolic health”, explained study co-leader Professor Marjo-Riitta Järvelin.

Professor Peppi Karppinen said, “We also already know that in people living high above sea level, low oxygen levels in the habitat cause long-term activation of the HIF response. These people are slimmer, and they have better sugar tolerance and a lower risk of cardiovascular death.”

A question for future research is how to reduce the body’s oxidation levels if needed. This would be to achieve a permanent low-level activation of the HIF response and thus obesity protection. According to Prof Karppinen, the HIF enzymes that prompt a hypoxic response could potentially be used as targets of obesity and metabolism drugs in humans. Currently they are being used in Asia to treat renal anaemia.

Source: University of Oulu

Journal information: Auvinen, J., et al. (2021) Systematic evaluation of the association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia. Science Advances. doi.org/10.1126/sciadv.abi4822.

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Discovery Offers New Treatment for Sickle Cell Anaemia

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In a promising step towards a new treatment for sickle cell anaemia, researchers have discovered a small molecule that boosts levels of foetal hemoglobin, a healthy form that adults normally do not make.

Current treatment options are few, including bone marrow transplants and gene therapy, and only address a subset of symptoms. Opioids are used for pain management, with their hazard for addiction and abuse.
The researchers presented their results at the spring meeting of the American Chemical Society (ACS).

“Using our proprietary small molecule probe and CRISPR guide RNA libraries, we screened a disease-relevant cell model that allowed us to pinpoint a treatment target,” said Ivan V Efremov, PhD, senior director, head of medicinal chemistry of Fulcrum Therapeutics.

Sickle cell disease occurs when genes for two of haemoglobin’s four proteins contains an error, resulting in a rigid, sickle-like shape. This has consequences in reduced oxygen transport, and painful blockages of the irregularly shaped cells called vaso-occlusive crises. The red blood cells die fast, leading to anaemia. These patients are also at high risk of developing stroke, heart disease, kidney failure and other potentially deadly conditions.

While in the womb, humans make “foetal” haemoglobin that carries oxygen normally but three or four months after birth, cells switch to an adult haemoglobin version. Although the adult haemoglobin expressed by sickle cell patients is defective, stem cells in their bone marrow still have the capacity to produce foetal haemoglobin.

Some individuals have a hereditary persistence of foetal hemoglobin, and so tap this resource automatically. “They have the sickle cell mutation, but additional mutations result in continued expression of fetal hemoglobin into adulthood,” said Christopher Moxham, PhD, chief scientific officer of Fulcrum Therapeutics. With foetal hemoglobin levels of around 25-30%, he said, enough red blood cells function well enough that patients may become asymptomatic.

The team developed a drug, called FTX-6058, that mimics the effect seen in patients with the hereditary persistence of foetal hemoglobin. It attaches to a protein inside bone marrow stem cells that will mature into red blood cells and reinstates their foetal haemoglobin expression. “What is really key is FTX-6058 upregulates fetal hemoglobin across all red blood cells, a pancellular distribution,” Dr Efremov said. “If some red blood cells did not express this, they could still sickle and cause disease symptoms.” Fulcrum began a phase 1 safety trial in healthy adult volunteers last year after preclinical experiments showed an increase in fetal hemoglobin levels to around 25-30%.

“What distinguishes FTX-6058 is that we are targeting the root cause of sickle cell disease,” Dr Moxham said. “Other drugs approved in this space, particularly since 2019, are treating the disease’s symptoms, either the anemia or the vaso-occlusive crises.”

Preclinical experiments showed that FTX-6058 outperformed another foetal heamoglobin booster, hydroxyurea, approved in the 1990s.

A phase 2 clinical trial is planned for people living with sickle cell disease which should begin by the end of 2021. The researchers are also further characterising the therapeutic molecule. Fulcrum is also considering exploring the use of FTX-6058 in people living with β-thalassemia, a blood disorder in which haemoglobin production is reduced.

Source: Medical Xpress