scholarly journals β-Carotene-Induced Alterations in Haemoglobin Affinity to O2

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 451
Author(s):  
Joanna Fiedor ◽  
Mateusz Przetocki ◽  
Aleksander Siniarski ◽  
Grzegorz Gajos ◽  
Nika Spiridis ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Pilot Trial ◽  
Oxygen Affinity ◽  
Membrane Skeleton ◽  
Fine Tuning ◽  
Wilcoxon Test ◽  
Carotenoid Concentration ◽  
The Impact ◽  
Β Carotene

β-Carotene (β-Crt) can be dispersed in hydrophobic regions of the membrane of red blood cells (RBC). Its location, orientation and distribution strongly depend on carotenoid concentration. In the present pilot trial (six human subjects involved), it is demonstrated that incubation of RBCs with β-Crt (1.8 × 107 β-Crt molecules per RBC, 50 μmol/L) results in expansion of the membrane of RBCs and slight elongation of the cell. The changes are of statistical significance, as verified by the Wilcoxon test at p < 0.05. They indicate (i) a highly random orientation and location of β-Crt inside the membrane and (ii) a tendency for its interaction with membrane skeleton proteins. The accompanying effect of decreased RBC resistance to lysis is possibly a result of the incorrect functioning of ion channels due to their modification/disruption. At higher β-Crt concentrations, its clustering inside membranes may occur, leading to further alterations in the shape and size of RBCs, with the most pronounced changes observed at 1.8 × 108 β-Crt molecules per RBC (500 μmol/L). Due to the reduced permeability of ions, such membranes exhibit increased resistance to haemolysis. Finally, we show that interactions of β-Crt with the membrane of RBCs lead to an alteration in haemoglobin-oxygen affinity, shifting the oxyhaemoglobin dissociation curve toward higher oxygen partial pressures. If the impact of β-Crt on a curve course is confirmed in vivo, one may consider its role in the fine tuning of O2 transportation to tissues. Hence, at low concentrations, providing unchanged elastic and functional properties of RBCs, it could serve as a beneficial agent in optimising heart performance and cardiovascular load.

scholarly journals Reproducibility and Rigor in Animal-Based Research

ILAR Journal ◽  
2019 ◽  
Vol 60 (1) ◽  
pp. 17-23 ◽  
Author(s):  
Malcolm Macleod ◽  
Swapna Mohan
Keyword(s):  
Statistical Significance ◽  
Research Performance ◽  
Animal Experiments ◽  
Experimental Studies ◽  
Open Data ◽  
Study Protocols ◽  
Key Issues ◽  
New Treatments ◽  
The Impact

Abstract Increasing focus on issues of research reproducibility affords us the opportunity to review some of the key issues related in vivo research. First, we set out some key definitions, to guide the reader through the rest of the paper. Next we consider issues of epistemology, of how animal experiments lead to changes in our understanding of biomedicine and, potentially, to the development of new therapeutics. Here we consider the meaning of statistical significance; the importance of understanding whether findings have general truth; and the advances in knowledge which can result from ‘failed’ replication. Then, we consider weaknesses in the design, conduct and reporting of experiments, and review evidence for this from systematic reviews and from experimental studies addressing these issues. We consider the impact that these weaknesses have on the development of new treatments for human disease, and reflect on the response to these issues from the biomedical research community. Finally, we consider strategies for improvement including increased use of brief, pre-registered study protocols; pre-registration, open publication and open data; and the central importance of education in improving research performance.

scholarly journals Relative vitamin A values of 9-cis- and 13-cis-β-carotene do not differ when fed at physiological levels during vitamin A depletion in Mongolian gerbils (Meriones unguiculatus)

2014 ◽  
Vol 112 (2) ◽  
pp. 162-169 ◽  
Author(s):  
Kara A. Bresnahan ◽  
Christopher R. Davis ◽  
Sherry A. Tanumihardjo
Keyword(s):  
Vitamin A ◽  
Experimental Studies ◽  
Meriones Unguiculatus ◽  
Mongolian Gerbils ◽  
Plant Foods ◽  
Depletion Period ◽  
Oral Doses ◽  
The Impact ◽  
Β Carotene

Provitamin A biofortification of staple crops may decrease the prevalence of vitamin A (VA) deficiency if widely adopted in target countries. To assess the impact of processing methods on the VA value of plant foods, the unique bioefficacies ofcis-βC isomers (formed during cooking) compared with all-trans(at) β-carotene (βC) must be determined. The bioefficacies of 9-cis(9c)- and 13-cis(13c)-βC isomers were compared with those of the at-βC isomer and VA positive (VA+) and negative (VA − ) controls in VA-depleted Mongolian gerbils (Meriones unguiculatus) in two experimental studies (study 1,n56; study 2,n57). A 3- or 4-week depletion period was followed by a 3- or 4-week treatment period in which the groups received oral doses of the 9c-, 13c- or at-βC isomers in cottonseed oil (study 1, 15 nmol/d; study 2, 30 nmol/d). In study 1, the βC isomers did not maintain baseline liver VA stores in all groups (0·69 (sd0·20) μmol/liver) except in the VA+group (0·56 (sd0·10) μmol/liver) (P= 0·0026). The βC groups were similar to the VA+group, but the 9c- and 13c-βC groups did not differ from the VA − group (0·39 (sd0·09) μmol/liver). In study 2, the βC isomers maintained baseline liver VA stores in all the βC groups (0·35 (sd0·13) μmol/liver), and in the VA+group, the VA supplement (0·54 (sd0·19) μmol/liver) exceeded the baseline VA status (0·38 (sd0·15) μmol/liver) (P< 0·0001); however, the 9c-βC group did not differ from the VA − group (0·20 (sd0·07) μmol/liver).In vivoisomerisation of βC was confirmed in both experimental studies. Lower VA bioconversion factor values were obtained for thecis-βC isomers in study 2 when compared with study 1, but higher values were obtained for the at-βC isomer. Dose and VA status clearly affect bioconversion factors. In conclusion, thecis-βC isomers yielded similar liver VA stores to the at-βC isomer in Mongolian gerbils, and liver VA stores of the 9c- and 13c-βC groups did not differ when the doses were provided at physiological levels over time in two studies.

scholarly journals Modelling co-translational dimerisation for programmable nonlinearity in synthetic biology

2020 ◽  
Author(s):  
Ruud Stoof ◽  
Ángel Goñi-Moreno
Keyword(s):  
Nonlinear Dynamics ◽  
Biological Networks ◽  
Rational Design ◽  
Fine Tuning ◽  
Genetic Circuits ◽  
On Demand ◽  
Regulatory Circuits ◽  
Protein Dimers ◽  
The Impact

AbstractNonlinearity plays a fundamental role in the performance of both natural and synthetic biological networks. Key functional motifs in living microbial systems, such as the emergence of bistability or oscillations, rely on nonlinear molecular dynamics. Despite its core importance, the rational design of nonlinearity remains an unmet challenge. This is largely due to a lack of mathematical modelling that accounts for the mechanistic basics of nonlinearity. We introduce a model for gene regulatory circuits that explicitly simulates protein dimerization—a well-known source of nonlinear dynamics. Specifically, our approach focusses on modelling co-translational dimerization: the formation of protein dimers during—and not after—translation. This is in contrast to the prevailing assumption that dimer generation is only viable between freely diffusing monomers (i.e., post-translational dimerization). We provide a method for fine-tuning nonlinearity on demand by balancing the impact of co- versus post-translational dimerization. Furthermore, we suggest design rules, such as protein length or physical separation between genes, that may be used to adjust dimerization dynamics in-vivo. The design, build and test of genetic circuits with on-demand nonlinear dynamics will greatly improve the programmability of synthetic biological systems.

Microvascular oxygen transport: impact of a left-shifted dissociation curve

1992 ◽  
Vol 262 (2) ◽  
pp. H517-H522 ◽  
Author(s):  
J. C. Stein ◽  
M. L. Ellsworth
Keyword(s):  
Oxygen Transport ◽  
Striated Muscle ◽  
Oxygen Affinity ◽  
Capillary Network ◽  
Retractor Muscle ◽  
Hemodynamic Parameters ◽  
Arterial Blood ◽  
Hemoglobin Oxygen Affinity ◽  
The Impact

The impact of an increased hemoglobin oxygen affinity (decreased P50) on oxygen transport was evaluated in capillaries of the retractor muscle under nonhypoxic (FIo2 = 0.30 and 0.21) and hypoxic (FIo2 = 0.10) conditions in hamsters with normal oxygen affinity [control; P50 = 26.1 +/- 1.0 (SD) mmHg, n = 12] and in hamsters with an increased oxygen affinity [treated; P50 = 16.2 +/- 1.6 (SD) mmHg, n = 7] induced by chronic short-term administration of sodium cyanate. Using in vivo video microscopy and computer-aided image analysis, we determined oxygen saturation (SO2) and associated hemodynamic parameters in both arteriolar (n = 30 control, 18 treated) and venular (n = 25 control, 17 treated) capillaries. In response to hypoxia, systemic arterial PO2 decreased to 29.6 +/- 6.0 (SD) mmHg in control animals and 24.7 +/- 3.8 (SD) mmHg in treated animals associated with abrupt decreases in systemic arterial blood pressure and increases in respiratory rate. The decrease in SO2 across the capillary network during nonhypoxic ventilation was 13.3% SO2 for control animals and 11.0% SO2 for treated animals. During hypoxic ventilation, the decrease in SO2 was 9.1% SO2 in control animals and 8.7% SO2 in treated animals. Hemodynamic parameters were not significantly different in the two groups during hypoxia. Estimated end-capillary PO2 was significantly lower in the treated animals. These data indicate that an increased oxygen affinity does not provide an obvious advantage for oxygen transport during hypoxia at the level of the capillary network in resting striated muscle; however, such an advantage might become apparent in the presence of an increased metabolic rate or a more severe hypoxic challenge.

scholarly journals Gag Mutations Can Impact Virological Response to Dual-Boosted Protease Inhibitor Combinations in Antiretroviral-Naïve HIV-Infected Patients

2010 ◽  
Vol 54 (7) ◽  
pp. 2910-2919 ◽  
Author(s):  
Lucile Larrouy ◽  
C. Chazallon ◽  
R. Landman ◽  
C. Capitant ◽  
G. Peytavin ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Virological Response ◽  
Cleavage Site ◽  
Pilot Trial ◽  
Baseline Viral Load ◽  
Coding Region ◽  
Site Mutation ◽  
Hiv Rna ◽  
The Impact

ABSTRACT ANRS 127 was a randomized pilot trial involving naïve patients receiving two dual-boosted protease inhibitor (PI) combinations. Virological response, defined as a plasma HIV RNA level of <50 copies/ml at week 16, occurred in only 41% patients. Low baseline plasma HIV RNA level was the only significant predictor of virological response. The purpose of this study was to investigate the impact on virological response of pretherapy mutations in cleavage sites of gag, gag-pol, and the gag-pol frameshift region. The whole gag gene and protease-coding region were amplified and sequenced at baseline and at week 16 for 48 patients still on the allocated regimen at week 16. No major PI resistance-associated mutations were detected either at baseline or in the 26 patients who did not achieve virological response at week 16. Baseline cleavage site substitutions in the product of the gag open reading frame at positions 128 (p17/p24) (P = 0.04) and 449 (p1/p6 gag ) (P = 0.01) were significantly more frequent in those patients not achieving virological response. Conversely, baseline cleavage site mutation at position 437 (TFP/p6 pol ) was associated with virological response (P = 0.04). In multivariate analysis adjusted for baseline viral load, these 3 substitutions remained independently associated with virological response. We demonstrated here, in vivo, an impact of baseline polymorphic gag mutations on virological response in naïve patients receiving a combination of two protease inhibitors. However, it was not possible to link the substitutions selected under PI selective pressure with virological failure.

scholarly journals Phytochemical and Pharmacological Study on the Leaves of Bauhinia Purpurea L. for Antilithiatic Activity

2020 ◽  
Vol 5 (1) ◽  
Keyword(s):  
Uric Acid ◽  
Serum Level ◽  
Renal Stone ◽  
Histopathological Examination ◽  
Statistical Significance ◽  
Pharmacological Study ◽  
Reference Standard ◽  
Bauhinia Purpurea ◽  
The Impact

The main purpose of this study was to investigate the impact of ethanolic concentrate of Bauhinia purpurea L. leaves on lithiatic action in rat. Twenty four rats were divided into 6 groups comprising four animals per groups. The blood was collected from the retro-orbital sinus; serum was separated by centrifugation and analyzed for creatinine and uric acid. Both kidneys from each animal were removed and sectioned for histopathological examination. The results were expressed as mean ± standard error mean (SEM) and the statistical significance was assessed using one-way analysis of variance (ANOVA) followed by Dunnett’s comparison test and p<0.05 was considered significant. In the present in-vivo study, renal stone inciting treatment to rodents came about in hyper-oxaluria. Ethanolic concentrate of B. purpurea L. was exposed to antilithiatic action in rodents where ethylene glycol 0.75% (v/v) utilized as the causing lithiasis specialist. Ethanolic concentrate of B. purpurea (at 100 and 200 mg/kg) showed a portion subordinate noteworthy enemy of lithiatic action on treatment. The concentrate portion of 100 mg/kg likewise caused decrease of Ca, oxalates, P and creatinine in blood serum level the outcomes were found factually noteworthy. The impact of ethanol concentrate of this movement was discovered critical than the reference standard. By and large investigation uncovers that the ethanolic concentrate of B. purpurea L. demonstrates the mellow to direct antilithiatic movement with correlation with cystone.

Effects of leptin replacement on hypothalamic-pituitary growth hormone axis function and circulating ghrelin levels in ob/ob mice

2007 ◽  
Vol 292 (3) ◽  
pp. E891-E899 ◽  
Author(s):  
Raul M. Luque ◽  
Zhi H. Huang ◽  
Bhumik Shah ◽  
Theodore Mazzone ◽  
Rhonda D. Kineman
Keyword(s):  
Growth Hormone ◽  
Food Intake ◽  
Statistical Significance ◽  
Mrna Levels ◽  
Ghrelin Receptor ◽  
Positive Effects ◽  
In Vivo Effects ◽  
The Impact

Leptin-deficient obese mice ( ob/ob) have decreased circulating growth hormone (GH) and pituitary GH and ghrelin receptor (GHS-R) mRNA levels, whereas hypothalamic GH-releasing hormone (GHRH) and somatostatin (SST) expression do not differ from lean controls. Given the fact that GH is suppressed in diet-induced obesity (a state of hyperleptinemia), it remains to be determined whether the absence of leptin contributes to changes in the GH axis of ob/ob mice. Therefore, to study the impact of leptin replacement on the hypothalamic-pituitary GH axis of ob/ob mice, leptin was infused for 7 days (sc), resulting in circulating leptin levels that were similar to wild-type controls (∼1 ng/ml). Leptin treatment reduced food intake, body weight, and circulating insulin while elevating circulating n-octanoyl ghrelin concentrations. Leptin treatment did not alter hypothalamic GHRH, SST, or GHS-R mRNA levels compared with vehicle-treated controls. However, leptin significantly increased pituitary GH and GHRH-R expression and tended to enhance circulating GH levels, but this latter effect did not reach statistical significance. In vitro, leptin (1 ng/ml, 24 h) did not affect pituitary GH, GHRH-R, or GHS-R mRNA but did enhance GH release. The in vivo effects of leptin on circulating hormone and pituitary mRNA levels were not replicated by pair feeding ob/ob mice to match the food intake of leptin-treated mice. However, leptin did prevent the fall in hypothalamic GHRH mRNA and circulating IGF-I levels observed in pair-fed mice. These results demonstrate that leptin replacement has positive effects on multiple levels of GH axis function in ob/ob mice.

scholarly journals Comparative Carotenoid Accumulation and Retention in Near-isogenic rprp and RPRP Inbred Carrot Lines

2002 ◽  
Vol 127 (2) ◽  
pp. 284-289 ◽  
Author(s):  
W.Y.L. Poon ◽  
I.L. Goldman
Keyword(s):  
Vegetative Growth ◽  
Field Experiments ◽  
Root Tissue ◽  
Total Carotenoid ◽  
Postharvest Storage ◽  
Carotenoid Concentration ◽  
Carotenoid Accumulation ◽  
Rate Of Increase ◽  
The Impact ◽  
Β Carotene

The rp allele causes a significant reduction in total carotenoid pigmentation in carrot (Daucus carota L.) roots. The objective was to investigate the effect of rp on the composition, accumulation, and retention of carotenoids in two near-isolines of carrot, W266RPRP and W266rprp, during vegetative growth and postharvest storage. Field experiments were conducted during 1996 and 1997 in which roots were sampled weekly from 62 to 100 days after seed-sowing and biweekly during postharvest storage at 4 °C up to 386 days after sowing. Linear increases in total carotenoid concentration were observed for W266RPRP and W266rprp during vegetative growth. The average daily rate of increase in total carotenoid concentration in W266RPRP and in W266rprp was 12.7 and 1.3 mg·g-1 dry weight, respectively. A linear decrease in carotenoid concentration was measured for W266RPRP but not for W266rprp during postharvest storage. At 100 days after sowing, high-performance liquid chromatography analyses showed W266rprp had 20-fold lower concentrations of a-carotene and 50-fold lower concentrations of β-carotene in root tissue compared to W266RPRP. Levels of β-carotene and lutein in the first true leaves were reduced by ≈50% in W266rprp compared to W266RPRP. Results from this investigation suggest that the rp allele affects the concentration of root and foliage carotenoids, as well as the rate of carotenoid accumulation and degradation in carrot roots. The impact of the rp allele is far greater in root tissue than in foliage, suggesting it may act as a transcription factor or structural gene affecting primarily root carotenoid biosynthesis.

scholarly journals Generation and Characterization of B7-H4/B7S1/B7x-Deficient Mice

2006 ◽  
Vol 26 (17) ◽  
pp. 6403-6411 ◽  
Author(s):  
Woong-Kyung Suh ◽  
Seng Wang ◽  
Gordon S. Duncan ◽  
Yoshiyuki Miyazaki ◽  
Elizabeth Cates ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Leishmania Major ◽  
Inflammatory Responses ◽  
Fine Tuning ◽  
Th2 Cells ◽  
The Impact ◽  
Deficient Mice

ABSTRACT Members of the B7 family of cosignaling molecules regulate T-cell proliferation and effector functions by engaging cognate receptors on T cells. In vitro and in vivo blockade experiments indicated that B7-H4 (also known as B7S1 or B7x) inhibits proliferation, cytokine production, and cytotoxicity of T cells. B7-H4 binds to an unknown receptor(s) that is expressed on activated T cells. However, whether B7-H4 plays nonredundant immune regulatory roles in vivo has not been tested. We generated B7-H4-deficient mice to investigate the roles of B7-H4 during various immune reactions. Consistent with its inhibitory function in vitro, B7-H4-deficient mice mounted mildly augmented T-helper 1 (Th1) responses and displayed slightly lowered parasite burdens upon Leishmania major infection compared to the wild-type mice. However, the lack of B7-H4 did not affect hypersensitive inflammatory responses in the airway or skin that are induced by either Th1 or Th2 cells. Likewise, B7-H4-deficient mice developed normal cytotoxic T-lymphocyte reactions against viral infection. Thus, B7-H4 plays a negative regulatory role in vivo but the impact of B7-H4 deficiency is minimal. These results suggest that B7-H4 is one of multiple negative cosignaling molecules that collectively provide a fine-tuning mechanism for T-cell-mediated immune responses.

scholarly journals The chemical structure and phosphorothioate content of hydrophobically modified siRNAs impact extrahepatic distribution and efficacy

2020 ◽  
Vol 48 (14) ◽  
pp. 7665-7680
Author(s):  
Annabelle Biscans ◽  
Jillian Caiazzi ◽  
Sarah Davis ◽  
Nicholas McHugh ◽  
Jacquelyn Sousa ◽  
...  
Keyword(s):  
Chemical Structure ◽  
Clinical Stage ◽  
Sirna Delivery ◽  
Fine Tuning ◽  
Endosomal Escape ◽  
Systematic Evaluation ◽  
Small Interfering Rnas ◽  
Tissue Accumulation ◽  
The Impact

Abstract Small interfering RNAs (siRNAs) have revolutionized the treatment of liver diseases. However, robust siRNA delivery to other tissues represents a major technological need. Conjugating lipids (e.g. docosanoic acid, DCA) to siRNA supports extrahepatic delivery, but tissue accumulation and gene silencing efficacy are lower than that achieved in liver by clinical-stage compounds. The chemical structure of conjugated siRNA may significantly impact invivo efficacy, particularly in tissues with lower compound accumulation. Here, we report the first systematic evaluation of the impact of siRNA scaffold—i.e. structure, phosphorothioate (PS) content, linker composition—on DCA-conjugated siRNA delivery and efficacy in vivo. We found that structural asymmetry (e.g. 5- or 2-nt overhang) has no impact on accumulation, but is a principal factor for enhancing activity in extrahepatic tissues. Similarly, linker chemistry (cleavable versus stable) altered activity, but not accumulation. In contrast, increasing PS content enhanced accumulation of asymmetric compounds, but negatively impacted efficacy. Our findings suggest that siRNA tissue accumulation does not fully define efficacy, and that the impact of siRNA chemical structure on activity is driven by intracellular re-distribution and endosomal escape. Fine-tuning siRNA chemical structure for optimal extrahepatic efficacy is a critical next step for the progression of therapeutic RNAi applications beyond liver.

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