Hemolysis contributes to anemia during long-duration space flight

Anemia in astronauts has been noted since the first space missions, but the mechanisms contributing to anemia in space flight have remained unclear. Here, we show that space flight is associated with persistently increased levels of products of hemoglobin degradation, carbon monoxide in alveolar air and iron in serum, in 14 astronauts throughout their 6-month missions onboard the International Space Station. One year after landing, erythrocytic effects persisted, including increased levels of hemolysis, reticulocytosis and hemoglobin. These findings suggest that the destruction of red blood cells, termed hemolysis, is a primary effect of microgravity in space flight and support the hypothesis that the anemia associated with space flight is a hemolytic condition that should be considered in the screening and monitoring of both astronauts and space tourists.

Macrophages and Iron: A Special Relationship

Macrophages perform a variety of different biological functions and are known for their essential role in the immune response. In this context, a principal function is phagocytic clearance of pathogens, apoptotic and senescent cells. However, the major targets of homeostatic phagocytosis by macrophages are old/damaged red blood cells. As such, macrophages play a crucial role in iron trafficking, as they recycle the large quantity of iron obtained by hemoglobin degradation. They also seem particularly adapted to handle and store amounts of iron that would be toxic to other cell types. Here, we examine the specific and peculiar iron metabolism of macrophages.

Chloroquine and Hydroxychloroquine: The History Revisited

The medicinal properties of the bark of the Cinchona tree have been known for centuries. It was known to cure fever and malaria. The active alkaloid was first isolated by the French chemists Pelletier and Coventou in 1820. The organized use of a large amount of quinine to prevent and treat malaria was largely done by the colonial military units in the tropics, especially in Africa and Southeast Asia. Scientists soon learned to synthesize quinine-like compounds which included chloroquine and hydroxychloroquine. Quinine (C18H26CIN3) was first synthesized successfully in 1934. In 1946, hydroxychloroquine (C18H26CIN3O) was developed as its less toxic alternative. Quinine derivatives, CQ and HCQ, are weak bases chemically. They are accumulated in acidic food vacuoles of intraerythrocytic trophozoites. Its antimalarial action is due to the induction of selective toxicity to lysosomes in parasites, thereby preventing hemoglobin degradation. For a long time the role of CQ as an anti-inflammatory agent has been investigated. It is used as a disease-modifying agent against rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). It has antitumor activities also and has been studied in glioblastoma, colon, and pancreatic cancers. In the recent outbreak of the corona pandemic, there is a resurgence of interest in its use as an antiviral agent. Its mechanism of action is not fully understood; it may involve multiple pathways to act as an antiviral agent. The research activities to explore its efficacy and new applications in various diseases have never ceased. Despite its long history the drug and its derivatives have attracted scientists world-wide.

The potential role of T2*-weighted multi-echo data image combination as an imaging marker for intraplaque hemorrhage in carotid plaque imaging

Background Carotid atherosclerotic plaques with intraplaque hemorrhage (IPH) are associated with elevated stroke risk. IPH is predominantly imaged based on paramagnetic properties of the upstream hemoglobin degradation product methemoglobin. This is an explorative observational study to test the feasibility of a spoiled gradient echo based T2* weighted MRI sequence (3D MEDIC) for carotid plaque imaging, and to compare signs suggestive of the downstream degradation product hemosiderin on 3D MEDIC with signs of methemoglobin on a T1wBB sequence. Methods Patients with recent TIA or stroke were selected based on the presence on non-calcified plaque components on CTA to promote an enriched prevalence of IPH in the material. Patients (n = 42) underwent 3T MRI with 3D MEDIC and 2D turbo spin echo T1w black blood (T1wBB). Images were independently evaluated by two neuroradiologists and Cohens Kappa was used for inter-reader agreement for each sequence. Results The technical feasibility for 3D MEDIC, was 34/42 patients (81%). Non-calcified plaque components with susceptibility effect without simultaneous T1-shortening—a combination suggestive of hemosiderin, was seen in 13/34 of the plaques. An equally large group display elevated T1w signal in combination with signal loss on 3D MEDIC, a combination suggestive of both hemosiderin and methemoglobin. Cohen’s kappa for inter-reader agreement was 0.64 (CI 0.345–0.925) for 3D MEDIC and 0.94 (CI 0.81–1.00) for T1wBB. Conclusions 3D MEDIC shows signal loss, without elevated T1w signal on T1wBB, in non-calcified tissue in many plaques in this group of patients. If further studies, including histological verification, confirm that the 3D MEDIC susceptibility effect is indeed caused by hemosiderin, 3D MEDIC could aid in the detection of IPH, beyond elevation of T1w signal.

Evaluation of Two Fecal Occult Blood Tests for Detecting Non-Perforating Abomasal Lesions in Cattle

Non-perforating abomasal lesions occur with a high prevalence in slaughtered dairy cattle. Ante mortem diagnosis is a challenge, but the presence of occult blood in feces is suggested as a diagnostic criterion. The lower detection limit of Hemo-Fec® (Med-Kjemi, Asker, Norway) and Hemoccult II® SENSA® (Beckman Coulter, Brea, California, USA) for fecal occult blood were estimated. The Hemo-Fec® and Hemoccult II® SENSA® could detect 1–2 mL and 2–4.5 mL of blood in 1000 g of feces, respectively. Therefore, the Hemo-Fec® test was selected to access hemoglobin degradation in the rumen to establish if blood from outside the gastrointestinal tract could result in false-positive tests and an observational study to estimate the diagnostic sensitivity and specificity. Rumen microbiota did not degrade hemoglobin in a 1% blood concentration in vitro during 48 h of fermentation. The Hemo-Fec® test was only able to detect cattle with ≥4 acute lesions (diagnostic sensitivity: 0.40 [95% confidence interval (95% CI): 0.32–0.48] and ≥4 chronic lesions (sensitivity: 0.44 [95% CI: 0.35–0.52]). The Hemo-Fec® test had no diagnostic potential to detect superficial erosions or scar tissue in abomasa. Furthermore, the specificity was 0.71 [95% CI: 0.68–0.75%], and a positive test is thus not equivalent with abomasal lesions in cattle.

Subarachnoid Hemorrhage Increases Level of Heme Oxygenase-1 and Biliverdin Reductase in the Choroid Plexus

Subarachnoid hemorrhage is a specific, life-threatening form of hemorrhagic stroke linked to high morbidity and mortality. It has been found that the choroid plexus of the brain ventricles forming the blood-cerebrospinal fluid barrier plays an important role in subarachnoid hemorrhage pathophysiology. Heme oxygenase-1 and biliverdin reductase are two of the key enzymes of the hemoglobin degradation cascade. Therefore, the aim of present study was to investigate changes in protein levels of heme oxygenase-1 and biliverdin reductase in the rat choroid plexus after experimental subarachnoid hemorrhage induced by injection of non-heparinized autologous blood to the cisterna magna. Artificial cerebrospinal fluid of the same volume as autologous blood was injected to mimic increased intracranial pressure in control rats. Immunohistochemical and Western blot analyses were used to monitor changes in the of heme oxygenase-1 and biliverdin reductase levels in the rat choroid plexus after induction of subarachnoid hemorrhage or artificial cerebrospinal fluid application for 1, 3, and 7 days. We found increased levels of heme oxygenase-1 and biliverdin reductase protein in the choroid plexus over the entire period following subarachnoid hemorrhage induction. The level of heme oxygenase-1 was the highest early (1 and 3 days) after subarachnoid hemorrhage indicating its importance in hemoglobin degradation. Increased levels of heme oxygenase-1 were also observed in the choroid plexus epithelial cells at all time points after application of artificial cerebrospinal fluid. Biliverdin reductase protein was detected mainly in the choroid plexus epithelial cells, with levels gradually increasing during subarachnoid hemorrhage. Our results suggest that heme oxygenase-1 and biliverdin reductase are involved not only in hemoglobin degradation but probably also in protecting choroid plexus epithelial cells and the blood-cerebrospinal fluid barrier from the negative effects of subarachnoid hemorrhage.

Spirofused tetrahydroisoquinoline-oxindole hybrids as a novel class of fast acting antimalarial agents with multiple modes of action

Molecular hybridization of privileged scaffolds may generate novel antiplasmodial chemotypes that display superior biological activity and delay drug resistance. In the present study, we describe the in vitro activities and mode of action of 3′,4′-dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones, a novel class of spirofused tetrahydroisoquinoline–oxindole hybrids, as novel antimalarial agents. Whole cell phenotypic screening of these compounds identified (14b), subsequently named (±)-moxiquindole, as the most potent compound in the current series with equipotent antiplasmodial activity against both chloroquine sensitive and multidrug resistant parasite strains with good selectivity. The compound was active against all asexual stages of the parasite including inhibition of merozoite egress. Additionally, (±)-moxiquindole exhibited significant inhibitory effects on hemoglobin degradation, and disrupted vacuolar lipid dynamics. Taken together, our data confirm the antiplasmodial activity of (±)-moxiquindole, and identify 3′4′-dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones as a novel class of antimalarial agents with multiple modes of action.

Combined CADD and Virtual Screening to Identify Novel Nonpeptidic Falcipain-2 Inhibitors

Background: : Plasmodium falciparum is the most dangerous and widespread disease-causing species of malaria. Falcipain-2 (FP2) of Plasmodium falciparum, is a potential target for antimalarial chemotherapy since it is involved in an essential cellular function such as hemoglobin degradation during the parasite’s life cycle. However, despite their central role in the life cycle of the parasite, no commercial drug targeting Falcipain-2 has been developed to date. Prior efforts to develop peptide-based drugs against Plasmodium have been futile due to their susceptibility to being degraded by host enzymes. Objective:: Here we report computer-aided drug design of new nonpeptidic inhibitors against FP2, which are likely to be safe from degradation by host enzymes. Method: : We have virtually screened for the probable FP2 inhibitors from the PubChem database by submitting the wellequilibrated 3-D structure of FP2. Furthermore, virtual screenings and dockings were carried out using PyRx and Discovery Studio. Result: : We found 15 top-ranking molecules with carbaldehyde pharmacophore having a good fit with the target protein. Based on the C-Docker values, the top 4 hits (PubChem 44138738, PubChem 20983198, PubChem 20983081 and PubChem 28951461) for FP2 were identified. These four hits have been observed to bound to the active cleft of the protein. Moreover, their complexes were also found to be stable from the RMSD and Radius of Gyration analysis. Conclusion:: The selected compounds 2-(benzylamino)-8-methylquinoline-3-carbaldehyde (PubChem44138738), 6- bromo-2-(3,4-dihydro-1H-isoquinolin-2-yl)quinoline-3-carbaldehyde (PubChem 20983198), 2-(3,4-dihydro-1Hisoquinolin-2-yl)-6-ethylquinoline-3-carbaldehyde(PubChem20983081)and 2-[benzyl(methyl)amino]quinoline-3- carbaldehyde (PubChem 28951461) may be the starting point for further modification as a new type of nonpeptidic drug for malaria disease.