scholarly journals FT-4202, an oral PKR activator, has potent antisickling effects and improves RBC survival and Hb levels in SCA mice

2021 ◽  
Vol 5 (9) ◽  
pp. 2385-2390
Author(s):  
Archana Shrestha ◽  
Mengna Chi ◽  
Kimberly Wagner ◽  
Astha Malik ◽  
Jennifer Korpik ◽  
...  
Keyword(s):  
Shear Stress ◽  
Blood Cell ◽  
Partial Pressure ◽  
Sickle Cell Anemia ◽  
Biological Effects ◽  
Membrane Damage ◽  
Partial Pressure Of Oxygen ◽  
Sickle Hemoglobin ◽  
Investigational Agent

Abstract Sickle cell anemia (SCA) results from an abnormal sickle hemoglobin (HbS). HbS polymerizes upon deoxygenation, resulting in red blood cell (RBC) sickling and membrane damage that cause vaso-occlusions and hemolysis. Sickle RBCs contain less adenosine triphosphate and more 2,3-diphosphoglycerate than normal RBCs, which allosterically reduces hemoglobin (Hb) oxygen (O2) affinity (ie, increases the partial pressure of oxygen at which hemoglobin is 50% saturated with oxygen [P50]), potentiating HbS polymerization. Herein, we tested the effect of investigational agent FT-4202, an RBC pyruvate kinase (PKR) activator, on RBC sickling and membrane damage by administering it to Berkeley SCA mice. Two-week oral FT-4202 administration was well tolerated, decreasing HbS P50 to levels similar to HbA and demonstrating beneficial biological effects. In FT-4202–treated animals, there was reduced sickling in vivo, demonstrated by fewer irreversibly sickled cells, and improved RBC deformability, assessed at varying shear stress. Controlled deoxygenation followed by reoxygenation of RBCs obtained from the blood of FT-4202–treated mice showed a shift in the point of sickling to a lower partial pressure of oxygen (pO2). This led to a nearly 30% increase in RBC survival and a 1.7g/dL increase in Hb level in the FT-4202–treated SCA mice. Overall, our results in SCA mice suggest that FT-4202 might be a potentially useful oral antisickling agent that warrants investigation in patients with SCA.

Positronium as a biomarker of hypoxia

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Paweł Moskal ◽  
Ewa Ł. Stępień
Keyword(s):  
Partial Pressure ◽  
High Sensitivity ◽  
Partial Pressure Of Oxygen ◽  
Physiological Processes ◽  
Positron Emission ◽  
Positronium Lifetime ◽  
Total Body ◽  
Living Organisms ◽  
Cancer Tissues

Abstract In this review article, we present arguments demonstrating that the advent of high sensitivity total-body PET systems and the invention of the method of positronium imaging, open realistic perspectives for the application of positronium as a biomarker for in-vivo assessment of the degree of hypoxia. Hypoxia is a state or condition, in which the availability of oxygen is not sufficient to support physiological processes in tissue and organs. Positronium is a metastable atom formed from electron and positron which is copiously produced in the intramolecular spaces in the living organisms undergoing positron emission tomography (PET). Properties of positronium, such as e.g., lifetime, depend on the size of intramolecular spaces and the concentration in them of oxygen molecules. Therefore, information on the partial pressure of oxygen (pO2) in the tissue may be derived from the positronium lifetime measurement. The partial pressure of oxygen differs between healthy and cancer tissues in the range from 10 to 50 mmHg. Such differences of pO2 result in the change of ortho-positronium lifetime e.g., in water by about 2–7 ps. Thus, the application of positronium as a biomarker of hypoxia requires the determination of the mean positronium lifetime with the resolution in the order of 2 ps. We argue that such resolution is in principle achievable for organ-wise positronium imaging with the total-body PET systems.

scholarly journals In vivo oxygen measurement in cerebrospinal fluid of pigs to determine physiologic and pathophysiologic oxygen values during CNS infections

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Nicole de Buhr ◽  
Alexander Martens ◽  
Marita Meurer ◽  
Marta C. Bonilla ◽  
Franz Söbbeler ◽  
...  
Keyword(s):  
Partial Pressure ◽  
Ph Value ◽  
Cell Number ◽  
Bacterial Number ◽  
Oxygen Level ◽  
Partial Pressure Of Oxygen ◽  
Oxygen Levels ◽  
In Vivo Measurement ◽  
Cns Infections

AbstractDuring infection and inflammation, a reduced oxygen level clearly affects cellular functions. Oxygen levels during CNS infections are unknown. Here we established and evaluated an in vivo measurement system to characterize the oxygen level in parallel with bacterial numbers (CFU/mL), the cell number and pH level inside the CSF of healthy compared to Streptococcus suis-infected pigs. The animals were anesthetized over a seven-hour period with isoflurane in air/oxygen at physiologic arterial partial pressure of oxygen. Oxygen levels in CSF of anesthetized pigs were compared to euthanized pigs. The detected partial pressure of oxygen in the CSF remained constant in a range of 47–63 mmHg, independent of the infection status (bacterial or cell number). In contrast, the pH value showed a slight drop during infection, which correlated with cell and bacterial number in CSF. We present physiologic oxygen and pH values in CSF during the onset of bacterial meningitis.

scholarly journals Circulating prostate cancer cells have differential resistance to fluid shear stress-induced cell death

2021 ◽  
Vol 134 (4) ◽  
pp. jcs251470
Author(s):  
Jacob M. Hope ◽  
Matthew R. Bersi ◽  
Jenna A. Dombroski ◽  
Andrea B. Clinch ◽  
Rebecca S. Pereles ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Death ◽  
Shear Stress ◽  
Cell Lines ◽  
Fluid Shear Stress ◽  
Membrane Damage ◽  
Fluid Shear ◽  
Membrane Repair ◽  
Cell Membrane Damage

ABSTRACTCirculating tumor cells (CTCs) are exposed to fluid shear stress (FSS) of greater than 1000 dyn/cm2 (100 Pa) in circulation. Normally, CTCs that are exposed to FSS of this magnitude die. However, some CTCs develop resistance to this FSS, allowing them to colonize distant organs. We explored how prostate CTCs can resist cell death in response to forces of this magnitude. The DU145, PC3 and LNCaP human prostate cancer cell lines were used to represent cells of different metastatic origins. The cell lines were briefly treated with an average FSS of 3950 dyn/cm2 (395 Pa) using a 30 G needle and a syringe pump. DU145 cells had no change in cell viability, PC3 cells had some cell death and LNCaP cells exhibited significant cell death. These cell death responses correlated with increased cell membrane damage, less efficient membrane repair and increased stiffness. Additionally, FSS treatment prevented the LNCaP FSS-sensitive cell line from forming a growing tumor in vivo. This suggests that these properties play a role in FSS resistance and could represent potential targets for disrupting blood-borne metastasis.

scholarly journals Low-dose Exposure to Black Carbon and Cadmium Significantly Induce Lung Injury by Promoting Cellular Apoptosis

2021 ◽  
Author(s):  
Lingjuan Wang ◽  
Shanyu Bao ◽  
Xiaolong Liu ◽  
Fan Wang ◽  
Jinwei Zhang ◽  
...  
Keyword(s):  
Synergistic Effects ◽  
Biological Effects ◽  
Membrane Damage ◽  
The Body ◽  
Cell Membrane Damage ◽  
Induce Lung Injury ◽  
Cellular Apoptosis ◽  
Cd Exposure

Abstract PMs has adverse biological effects on major living organs in the body, including lungs. The complex composition of PM2.5, including carbon black and heavy metals, cause toxic effects to the lung. The synergistic effects of CB and Cd were less investigated in previous study. In our research, we deciphered the combination of CBs and Cd enhanced the cytotoxicity in BEAS-2B cells in vitro and in vivo. In the molecular level, the intracellular level of Cd increased, as a result of the cell membrane damage, causing high expression of MT-1 in BEAS-2B cells. Moreover, the expression of BAX increased, and the expression of BCL-2 decreased. Collectively, our data suggests the apoptosis effect of synergistic effects of CB and Cd exposure.

The orientation of sickle hemoglobin fibers within fascicles

1988 ◽  
Vol 46 ◽  
pp. 400-401
Author(s):  
Christopher A. Miller ◽  
Bridget Carragher ◽  
William A. McDade ◽  
Robert Josephs
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Relative Orientation ◽  
Unit Cell ◽  
Red Cell ◽  
High Ph ◽  
Sickle Hemoglobin ◽  
Polar Crystal ◽  
Helical Configuration

Highly ordered bundles of deoxyhemoglobin S (HbS) fibers, termed fascicles, are intermediates in the high pH crystallization pathway of HbS. These fibers consist of 7 Wishner-Love double strands in a helical configuration. Since each double strand has a polarity, the odd number of double strands in the fiber imparts a net polarity to the structure. HbS crystals have a unit cell containing two double strands, one of each polarity, resulting in a net polarity of zero. Therefore a rearrangement of the double strands must occur to form a non-polar crystal from the polar fibers. To determine the role of fascicles as an intermediate in the crystallization pathway it is important to understand the relative orientation of fibers within fascicles. Furthermore, an understanding of fascicle structure may have implications for the design of potential sickling inhibitors, since it is bundles of fibers which cause the red cell distortion responsible for the vaso-occlusive complications characteristic of sickle cell anemia.

Effects of Preloading of Stannous Compounds on the Distribution of 99mTc-Pertechnetate

1977 ◽  
Vol 16 (01) ◽  
pp. 26-29 ◽  
Author(s):  
D. D. Greenberg ◽  
P. Som ◽  
G. E. Meinken ◽  
D. F. Sacker ◽  
H. L. Atkins ◽  
...  
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Plasma Ratio ◽  
99Mtc Pertechnetate ◽  
Time Period ◽  
Stannous Ion ◽  
Distribution Studies

Summary 99mTc-pertechnetate distribution studies were performed in rabbits and mice following pretreatment between 5—336 hours with various routinely used stannous complexes (HSA, MAA, GHT, DTPA, PYPs) containing different amounts of Sn++ (0.17 —15.0 μ mg/kg). Beyond a concentration of 0.26 mg/kg of Sn++ an alteration in 99mTc-pertechnetate distribution was observed. The red blood cell was found to be the most prominent target. An in-vivo reduction of 99mTc-pertechnetate apparently occurred by the presence of stannous ion within the red blood cell. Preloading time period between 5—24 hours did not alter the uptake of RBC/plasma ratio. Beyond that period it decreased slowly and still persisted up to 2 weeks following pretreatment. RBC/ plasma ratio of 99mTcO4 - increased with increased Sn++ content of various commercially available pharmaceutical kits.

Factors Influencing Leukocyte Adherence in Microvessels

1977 ◽  
Vol 38 (04) ◽  
pp. 0823-0830 ◽  
Author(s):  
Mayrovttz N. Harvey ◽  
Wiedeman P. Mary ◽  
Ronald F. Tuma
Keyword(s):  
Blood Flow ◽  
Shear Stress ◽  
Tissue Injury ◽  
Threshold Value ◽  
In Vivo Studies ◽  
Leukocyte Adherence ◽  
Rolling Velocity ◽  
Subsequent Behavior ◽  
Flow Stasis

SummaryIn vivo studies of the microcirculation of an untraumatized and unanesthetized animal preparation has shown that leukocyte adherence to vascular endothelium is an extremely rare occurrence. Induction of leukocyte adherence can be produced in a variety of ways including direct trauma to the vessels, remote tissue injury via laser irradiation, and denuding the epithelium overlying the observed vessels. The role of blood flow and local hemodynamics on the leukocyte adherence process is quite complex and still not fully understood. From the results reported it may be concluded that blood flow stasis will not produce leukocyte adherence but will augment pre-existing adherence. Studies using 2 quantitative measures of adherence, leukocyte flux and leukocyte velocity have shown these parameters to be affected differently by local hemodynamics. Initial adherence appears to be critically dependent on the magnitude of the blood shear stress at the vessel wall as evidenced by the lack of observable leukocyte flux above some threshold value. Subsequent behavior of the leukocytes as characterized by their average rolling velocity shows no apparent relationship to shear stress but, for low velocities, may be related to the linear blood velocity.

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