In vivo effects of propyl gallate,a novel Ca sensitizer,in a mouse model of dilated cardiomyopathy caused by cardiac troponin T mutation

Aims

We have previously demonstrated that propyl gallate has a Ca^2 + sensitizing effect on the force generation in membrane-permeabilized (skinned) cardiac muscle fibers. However, in vivo beneficial effects of propyl gallate as a novel Ca^2 + sensitizer remain uncertain. In the present study, we aim to explore in vivo effects of propyl gallate.

Main methods

We compared effects of propyl gallate on ex vivo intact cardiac muscle fibers and in vivo hearts in healthy mice with those of pimobendan, a clinically used Ca^2 + sensitizer. The therapeutic effect of propyl gallate was investigated using a mouse model of dilated cardiomyopathy (DCM) with reduced myofilament Ca^2 + sensitivity due to a deletion mutation ΔK210 in cardiac troponin T.

Key findings

Propyl gallate, as well as pimobendan, showed a positive inotropic effect. Propyl gallate slightly increased the blood pressure without changing the heart rate in healthy mice, whereas pimobendan decreased the blood pressure probably through vasodilation via inhibition of phosphodiesterase and increased the heart rate. Propyl gallate prevented cardiac remodeling and systolic dysfunction and significantly improved the life-expectancy of knock-in mouse model of DCM with reduced myofilament Ca^2 + sensitivity due to a mutation in cardiac troponin T. On the other hand, gallate, a similarly strong antioxidant polyphenol lacking Ca^2 + sensitizing action, had no beneficial effects on the DCM mice.

Significance

These results suggest that propyl gallate might be useful for the treatment of inherited DCM caused by a reduction in the myofilament Ca^2 + sensitivity.     

Neonatal mouse testis-derived multipotent germline stem cells improve the cardiac function of acute ischemic heart mouse model

Multipotent germline stem (mGS) cells have been established from neonatal mouse testes. We previously reported that undifferentiated mGS cells are phenotypically similar to embryonic stem cells and that fetal liver kinase 1 (Flk1)⁺ mGS cells have a similar potential to differentiate into cardiomyocytes and endothelial cells compared with Flk1⁺ embryonic stem cells. Here, we transplanted these Flk1⁺ mGS cells into an ischemic heart failure mouse model to evaluate the improvement in cardiac function. Significant increase in left ventricular wall thickness of the infarct area, left ventricular ejection fraction and left ventricular maximum systolic velocity was observed 4 weeks after when sorted Flk1⁺ mGS cells were transplanted directly into the hearts of the acute ischemic model mice. Although the number of cardiomyocytes derived from Flk1⁺ mGS cells were too small to account for the improvement in cardiac function but angiogenesis around ischemic area was enhanced in the Flk1⁺ mGS cells transplanted group than the control group and senescence was also remarkably diminished in the early phase of ischemia according to β-galactosidase staining assay. In conclusion, Flk1⁺ mGS cell transplantation can improve the cardiac function of ischemic hearts by promoting angiogenesis and by delaying host cell death via senescence.     

Relationship between fructosamine with serum protein, albumin and glucose concentrations in dairy ewes

The aim of the study was to investigate the changes in blood fructosamine concentrations of ewes during late pregnancy and lactation. The relationship of serum fructosamine to changes in the serum glucose and blood protein and albumin concentrations were measured in 10 crossbred dairy ewes. Blood was sampled 10 days prior to lambing (D − 10), on day 10 (D + 10), day 20 (D + 20), day 90 (D + 90) and on day 130 post partum (D + 130). The concentration of serum fructosamine significantly decreased on D + 10, then significantly increased on D + 20 (p < 0.05), remaining on the same level until D + 130. The concentration of serum glucose was highest on D − 10, and gradually decreased, being significantly lower on D + 130 post partum, compared to D − 10. Similarly the serum albumin and total protein concentrations were highest on D − 10, and significantly decreased on D + 10. The concentration of both parameters increased by D + 20, but then decreased on D + 90 and D + 130. The significant decrease in fructosamine concentration observed on D + 10 probably resulted from the substantial and rapid decrease in total serum protein and albumin concentrations, also established during the same period. The results confirm that in ewes, similar to other species, the shorter serum protein life span during the transition period has an influence on the decrease in blood fructosamine concentrations. These should be considered during the interpretation of serum fructosamine concentration as part of blood biochemical findings during the pre and post partum period.     

Hemoglobin plus myoglobin concentrations and near infrared light pathlength in phantom and pig hearts determined by diffuse reflectance spectroscopy

To noninvasively determine absolute concentrations of hemoglobin (Hb) plus myoglobin (Mb) in cardiac tissue by means of regular near infrared (NIR) light diffuse reflectance measurements, a first derivative approach was applied. The method was developed to separately calculate oxygenated and deoxygenated [Hb + Mb] as well as an effective pathlength, which NIR light passes through in the tissue between optodes. Applying a cotton wool-based phantom, which mimics muscle tissue, it was shown that the intensity of the pseudo-optical density first derivative depends linearly on both oxygenated and deoxygenated Hb concentration, thereby validating the Lambert-Beer law in the range of 0 to 0.25 mM tetrameric Hb. A high correlation (R = 0.995) was found between concentrations of Hb loaded onto the phantom and those determined spectrophotometrically, thereby verifying the first derivative method validity. The efficiency of the method was tested using in vivo pig hearts prior to and after ischemia initiated experimentally by left anterior descending artery branches occlusion. The results showed that the total [Hb + Mb] was 0.9-1.2 mM heme, the average tissue oxygen saturation was approximately 70% (which reduced to nearly 0% after occlusion), and the NIR (700-965 nm) light pathlength was 2.3 mm (differential pathlength factor [DPF] = 2.7-2.8) in a living heart tissue.     

microRNA-342, microRNA-191 and microRNA-510 are differentially expressed in T regulatory cells of type 1 diabetic patients

Regulatory T cells (Tregs) are critical regulators of autoimmune diseases, including type 1 diabetes mellitus. It is hypothesised that Tregs’ function can be influenced by changes in the expression of specific microRNAs (miRNAs). Thus, we performed miRNAs profiling in a population of Tregs separated from peripheral blood of five type 1 diabetic patients and six healthy donors. For more detailed molecular characterisation of Tregs, we additionally compared miRNAs expression profiles of Tregs and conventional T cells. Tregs were isolated according to CD3+, CD4+, CD25^hi+ and CD127− by flow cytometry, and miRNA expression profiling was performed using TaqMan Array Human MicroRNA Panel-1 (384-well low density array). In Tregs of diabetic patients we found significantly increased expression of miRNA-510 (p = 0.05) and decreased expression of both miRNA-342 (p < 0.0001) and miRNA-191 (p = 0.0079). When comparing Tregs and T cells, we revealed that Tregs had significant higher expression of miRNA-146a and lower expression of eight specific miRNAs (20b, 31, 99a, 100, 125b, 151, 335, and 365). To our knowledge, this is the first study demonstrating changes in miRNA expression profiles occurring in Tregs of T1D patients and a miRNAs signature of adult Tregs.     

Cartilage Acidic Protein 2 a hyperthermostable,high affinity calcium-binding protein

Cartilage Acidic Protein 2 (CRTAC2) is a novel protein present from prokaryotes to vertebrates with abundant expression in the teleost fish pituitary gland and an isoform of CRTAC1, a chondrocyte marker in humans. The two proteins are non-integrins containing N-terminal integrin-like Ca^2 +-binding motifs and their structure and function remain to be assigned. Structural studies of recombinant sea bream (sb)CRTAC2 revealed it is composed of 8.8% α-helix, 33.4% β-sheet and 57.8% unordered protein. sbCRTAC2 bound Ca^2 + with high affinity (K_d = 1.46 nM) and favourable Gibbs free energy (?G = − 12.4 kcal/mol). The stoichiometry for Ca^2 + bound to sbCRTAC2 at saturation indicated six Ca^2 + ligand-binding sites exist per protein molecule. No conformational change in sbCRTAC2 occurred in the presence of Ca^2 +. Fluorescence emission revealed that the tertiary structure of the protein is hyperthermostable between 25 °C and 95 °C and the fully unfolded state is only induced by chemical denaturing (4 M GndCl). sbCRTAC has a widespread tissue distribution and is present as high molecular weight aggregates, although strong reducing conditions promote formation of the monomer. sbCRTAC2 promotes epithelial cell outgrowth in vitro suggesting it may share functional homology with mammalian CRTAC1, recently implicated in cell–cell and cell–matrix interactions.     

Differential expression of BK channel isoforms and β-subunits in rat neuro-vascular tissues

We investigated the expression of splice variants and β-subunits of the BK channel (big conductance Ca²⁺-activated K⁺ channel, Slo1, MaxiK, K_Ca1.1) in rat cerebral blood vessels, meninges, trigeminal ganglion among other tissues. An α-subunit splice variant X1_+ 24 was found expressed (RT-PCR) in nervous tissue only where also the SS4_+ 81 variant was dominating with little expression of the short form SS4₀. SS4_+ 81 was present in some cerebral vessels too. The SS2_+ 174 variant (STREX) was found in both blood vessels and in nervous tissue. In situ hybridization data supported the finding of SS4_+ 81 and SS2_+ 174 in vascular smooth muscle and trigeminal ganglion. β-subunits β2 and β4 showed high expression in brain and trigeminal ganglion and some in cerebral vessels while β1 showed highest expression in blood vessels. β3 was found only in testis and possibly brain. A novel splice variant X2_+ 92 was found, which generates a stop codon in the intracellular C-terminal part of the protein. This variant appears non-functional as a homomer but may modulate the function of other splice-variants when expressed in Xenopus oocytes. In conclusion a great number of splice variant and β-subunit combinations likely exist, being differentially expressed among nervous and vascular tissues.     

The protective effect of peony extract on acute myocardial infarction in rats

To investigate the protective effects, and the mechanisms involved, of an extract of the medicinal herb radix paeoniae rubra (PE) on cardiovascular disease, acute myocardial infarction (AMI) was induced by ligation of the left coronary artery in Sprague Dawley rats. Animals were randomly divided into six groups: control, sham-operated, AMI, AMI + PE low dose, AMI + PE high dose, and AMI + positive control. Myocardial enzymes, cytokines, oxidative stress, blood coagulation times, a marker for early stage apoptosis, caspase-3 activity, and expression levels of bax, bcl-2 and fas in isolated primary cardiomyocytes were examined. In contrast with control and sham groups, significant increases in the following parameters were measured in the blood of AMI group animals: activities of cardiac enzymes including glutamic oxaloacetic transaminase, creatine kinase, creatine kinase-MB, lactate dehydrogenase, α-hydroxybutyric dehydrogenase, and levels of IL-10, TNFα, and lipid peroxidation. Under the same conditions, superoxide dismutase activity, thrombin time and activated partial thromboplastin time decreased significantly. PE showed a dose-dependent protection against AMI-induced alterations in cardiac enzymes, cytokines, oxidative stress, and coagulation. In AMI cardiomyocytes, compared with control and sham groups, the left ventricular end-diastolic pressure, early stage apoptosis, caspase-3 activity and expression levels of bax, bcl-2 and fas significantly increased, while the ratio bcl-2/bax decreased. PE showed dose-dependent protection. These results suggest that PE is an effective agent for protecting against AMI; possible mechanisms may include the regulation of cardiac enzymes, cytokines, oxidative stress, coagulation and apoptosis.     

Cryopreservation of human ovarian tissue: Comparison of novel direct cover vitrification and conventional vitrification

Objective

To compare the effect of novel direct cover vitrification (DCV) and conventional vitrification (CV) for human ovarian tissue.

Study design

Ovarian biopsy specimens obtained from 12 patients were randomly allocated into five groups: Fresh, DCV1, DCV2, DCV3 and CV. Three concentrations of cryoprotectants were used in DCV group. The equilibration solution of DCV1, DCV2, DCV3 was 5% EG + 5% DMSO + DPBS, 7.5% EG + 7.5%DMSO + DPBS, 10% EG + 10% DMSO + DPBS, respectively. And the vitrification solution of DCV1, DCV2, DCV3 was 10% EG + 10% DMSO + DPBS, 15%EG+15% DMSO + DPBS, 20% EG + 20% DMSO + DPBS, respectively. The equilibration solution and the vitrification solution of CV group was same as DCV3 group. The effects of cryopreserved procedure on human ovarian tissue were studied by histology, TUNEL assay, transmission electron microscopy (TEM) and heterotopic allograft.

Results

The percentages of morphologically normal and viable follicles of DCV2 were significantly higher than DCV1, DCV3 and CV groups (P < 0.05). TUNEL assay demonstrated that the incidence of apoptotic cell in vitrification ovarian tissue was significantly higher than fresh tissue (P < 0.05), but there were no difference in various groups with cryopreservation. TEM showed that less damage was detected in DCV2 group. After grafting, the follicle density of DCV2 was greater than DCV1, DCV3 and CV groups (P < 0.05).

Conclusions

The novel cover vitrification with optimal concentration of cryoprotectants is superior to conventional vitrification. It is suitable for human ovarian tissue fragments with high efficiency and facility.     

Tanshinone IIA increases recruitment of bone marrow mesenchymal stem cells to infarct region via up-regulating stromal cell-derived factor-1/CXC chemokine receptor 4 axis in a myocardial ischemia model

Systemic administration with bone marrow mesenchymal stem cells (BMSCs) is a promising approach to cure myocardial ischemia (MI), while the efficacy of cell transplantation is limited by the low engraftment of BMSCs. Tanshinone IIA (Tan IIA) has been reported many times for the treatment of MI. Therefore, the present study was performed to investigate whether Tan IIA could increase the migration of BMSCs to ischemic region and its potential mechanisms. In our study, we found that combination treatment with Tan IIA and BMSCs significantly alleviated the infarct size when compared with control group (31.46 ± 3.00% vs. 46.95 ± 6.51%, p < 0.05). Results of real-time PCR showed that Tanshinone IIA (Tan IIA) did increase the migration of BMSCs to ischemic region in vivo, which was correlated with cardiac function recovery after MI. Furthermore, 2 μM Tan IIA could enhance the migration capability of BMSCs in vitro (3.69-fold of control), and this enhancement could be blocked by AMD3100 (a CXC chemokine receptor 4 blocker). CXCR4, together with its specific receptor, stromal cell-derived factor-1 (SDF-1) plays a critical role in the stem cell recruitment. Our experiment indicated that Tan IIA could promote SDF-1α expression in the infarct area and enhance the CXCR4 expression of BMSCs in vitro. Therefore, we postulated that Tan IIA could increase the BMSCs migration via up-regulating SDF1/CXCR4 axis.     

Cardiac proteasome dysfunction during cold ischemic storage and reperfusion in a murine heart transplantation model

Recent observations suggest that the ubiquitin-proteasome system (UPS) contributes to the pathophysiology of myocardial ischemia-reperfusion injury. Since its regulation during cold ischemia-reperfusion is unknown, we evaluated the cardiac UPS in a model of heart transplantation in mice. Cardiac ubiquitylation rates and ubiquitin-protein conjugates increased after 3 h of cold ischemia (CI) and normalized post-transplant. 20S proteasome content and proteasome peptidase activities were unchanged after CI. 4 h/24 h post-transplant 20S proteasome concentrations decreased and chymotryptic-like but not tryptic-like proteasome peptidase activity was inactivated. Epoxomicin sensitivity of the proteasome increased 5.7-fold during CI and normalized 4 h/24 h post-transplant. This was accompanied by the disappearance of a 13.5 kDa-ubiquitin-conjugate during CI that could be attenuated by addition of epoxomicin to the preservation fluid. We conclude that substrate specificity of the proteasome changes during cold ischemia and that proteasome inhibition preserves the physiological ubiquitin-protein conjugate pool during organ preservation. Reduced proteasome activity during reperfusion is caused by a decrease in proteasome content and enzyme inhibition.     

C-type natriuretic peptide ameliorates ischemia/reperfusion-induced acute kidney injury by inhibiting apoptosis and oxidative stress in rats

Aims

Although atrial natriuretic peptide has been shown to attenuate ischemia–reperfusion (IR)-induced kidney injury, the effect of natriuretic peptide receptor (NPR)-B activation on IR-induced acute kidney injury is not well documented. The purpose of the present study was to identify the effect of C-type natriuretic peptide (CNP), a selective activator of NPR-B, on the IR-induced acute kidney injury and its mechanisms involved.

Main methods

Unilaterally nephrectomized rats were insulted by IR in their remnant kidney, and they were randomly divided into three groups: sham, vehicle + IR, and CNP + IR groups. CNP (0.2 μg/kg/min) was administered intravenously at the start of a 45-min renal ischemia for 2 h. Rats were then killed 24 h after I/R, and the blood and tissue samples were collected to assess renal function, histology, TUNEL assay, and Western blot analysis of kidney Bax and Bcl-2 expressions.

Key findings

The levels of blood urea nitrogen and serum creatinine were significantly increased in rats after IR compared with vehicle-treated rats. IR elevated apoptosis, Bcl-2/Bax ratio, TUNEL positivity, oxidative stress parameters, malondialdehyde concentration, and superoxide dismutase activity. IR also induced epithelial desquamation of the proximal tubules and glomerular shrinkage. CNP significantly attenuated the IR-induced increase in BUN and serum creatinine. Furthermore, CNP restored the suppressed renal cyclic guanosine 3′ 5′-monophosphate levels caused by IR insult.

Significance

Study findings suggest that CNP could ameliorate IR-induced acute kidney injury through inhibition of apoptotic and oxidative stress pathways, possibly through NPR-B-cGMP signaling.     

Safflower seeds in corn silage and alfalfa hay based early lactation diets: A practice within an optimum forage choice

Safflower seed (SS), Carthamus tinctorius L., has the highest concentration of linoleic acid among 80 oilseeds. It was hypothesized that an Iranian variety of SS can be effectively fed with cottonseeds (CS) to maintain feed intake, energy metabolism and productivity of early lactation cows under negative energy balance. Our objective was to determine effects of feeding diets containing 100 g whole CS with (1) no SS (SS0), (2) 75 g CS + 25 g SS (SS25), or (3) 50 g CS + 50 g SS (SS50), per kg of dietary DM, on feed intake, rumen fermentation, blood metabolites and milk production of early lactation cows fed diets based on a uniform mixtures of alfalfa hay and corn silage. Nine multiparous early lactation Holstein cows (46 ± 7 d in milk) were used in a replicated 3 × 3 Latin square design study with three 21-d periods. Each period had 14 d of adaptation and 7 d of data collection. Dietary inclusion of SS did not affect (P>0.10) DM intake, rumen pH and concentrations of ammonia and VFA, blood concentrations of insulin, non-esterified fatty acids, urea and triglycerides, and milk production. Adding SS linearly reduced blood glucose (P=0.05) and beta-hydroxybutyric acid (P<0.05), and increased blood total cholesterol (P<0.01) and low-density lipoproteins (P<0.05) concentrations. Results demonstrated that SS as an economical and rich source of essential fatty acids can be included up to 50 g/kg of dietary DM alongside CS for early lactation cows without affecting feed intake while maintaining rumen fermentation, peripheral energy supply and milk production.     

Ammonium-related metabolic changes affect somatic embryogenesis in pumpkin (Cucurbita pepo L.)

Somatic embryogenesis in pumpkin can be induced on auxin-containing medium and also on hormone-free medium containing 1 mM ammonium (NH₄⁺) as the sole source of nitrogen. Growth of NH₄⁺-induced embryogenic tissue was slow and caused considerable acidification of the culture medium. Small spherical cells with dense cytoplasma formed proembryogenic cell clusters that could not develop into late stage embryos. Buffering of NH₄⁺ medium with 25 mM 2-(N-morpholino)-ethane-sulfonic acid enhanced tissue proliferation, but no further differentiation was observed. Later stage embryos developed only after re-supply of nitrogen in form of nitrate or l-glutamine. Effects of nitrogen status and pH of culture media on ammonium assimilation were analyzed by following the activity of glutamine synthetase (GS) in relation to phenylalanine ammonia-lyase (PAL). Increased activity of GS and PAL in NH₄⁺ induced tissue coincided with significantly higher activity of stress-related enzymes superoxide dismutase (SOD) and soluble peroxidase (POD), indicating oxidative stress response of embryogenic tissue to NH₄⁺ as the sole source of nitrogen. In addition, considerable increase was observed in callose accumulation and esterase activity, the early markers of somatic embryogenesis. Activity of stress-related enzymes decreased after the re-supply of nitrate (20 mM) or Gln (10 mM) in combination with NH₄⁺ (1 mM), which subsequently triggered globular embryo development. Together, these results suggest that stress responses, as affected by nitrogen supply, contribute to the regulation of embryogenic competence in pumpkin.     

Effects of sub-chronic aluminum chloride exposure on rat ovaries

Aims

This experiment investigated the effects of sub-chronic aluminum chloride (AlCl₃) exposure on rat ovaries.

Main methods

Eighty female Wistar (5 weeks old) rats, weighed 110–120 g, were randomly divided into four treatment groups: control group (CG), low-dose group (LG, 64 mg/kg BW AlCl₃), mid-dose group (MG, 128 mg/kg BW AlCl₃) and high-dose group (HG, 256 mg/kg BW AlCl₃). The AlCl₃ was administered in drinking water for 120 days. The ovarian ultrastructure was observed. The activities of acid phosphatase (ACP), alkaline phosphatase (ALP), succinate dehydrogenase (SDH), Na⁺–K⁺-ATPase, Mg^2 +-ATPase and Ca^2 +-ATPase, the contents of Fe, Cu and Zn, and the protein expression of follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) in the ovary were determined.

Key findings

The results showed that the structure of the ovary was disrupted, the activities of ALP, ACP, SDH, Na⁺–K⁺-ATPase, Mg^2 +-ATPase and Ca^2 +-ATPase, the contents of Zn, Fe and the protein expression of FSHR and LHR were lowered, and the content of Cu was increased in AlCl₃-treated rats than those in control.

Significance

The results indicate that sub-chronic AlCl₃ exposure caused the damage of the ovarian structure, the disturbed metabolism of Fe, Zn and Cu and the decreased activities of Na⁺–K⁺-ATPase, Mg^2 +-ATPase and Ca^2 +-ATPase in the ovary, which could result in suppressed energy supply in the ovary. A combination of suppression of energy supply and reduction of expression of FSHR and LHR could inhibit ovulation and corpus luteum development, leading to infertility in female rats.     

Oxygen consumption of human heart cells in monolayer culture

Tissue engineering in cardiovascular regenerative therapy requires the development of an efficient oxygen supply system for cell cultures. However, there are few studies which have examined human cardiomyocytes in terms of oxygen consumption and metabolism in culture. We developed an oxygen measurement system equipped with an oxygen microelectrode sensor and estimated the oxygen consumption rates (OCRs) by using the oxygen concentration profiles in culture medium. The heart is largely made up of cardiomyocytes, cardiac fibroblasts, and cardiac endothelial cells. Therefore, we measured the oxygen consumption of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), cardiac fibroblasts, human cardiac microvascular endothelial cell and aortic smooth muscle cells. Then we made correlations with their metabolisms. In hiPSC-CMs, the value of the OCR was 0.71 ± 0.38 pmol/h/cell, whereas the glucose consumption rate and lactate production rate were 0.77 ± 0.32 pmol/h/cell and 1.61 ± 0.70 pmol/h/cell, respectively. These values differed significantly from those of the other cells in human heart. The metabolism of the cells that constitute human heart showed the molar ratio of lactate production to glucose consumption (L/G ratio) that ranged between 1.97 and 2.2. Although the energy metabolism in adult heart in vivo is reported to be aerobic, our data demonstrated a dominance of anaerobic glycolysis in an in vitro environment. With our measuring system, we clearly showed the differences in the metabolism of cells between in vivo and in vitro monolayer culture. Our results regarding cell OCRs and metabolism may be useful for future tissue engineering of human heart.     

Allosteric modulation of zinc speciation by fatty acids

Background

Serum albumin is the major protein component of blood plasma and is responsible for the circulatory transport of a range of small molecules that include fatty acids, hormones, metal ions and drugs. Studies examining the ligand-binding properties of albumin make up a large proportion of the literature. However, many of these studies do not address the fact that albumin carries multiple ligands (including metal ions) simultaneously in vivo. Thus the binding of a particular ligand may influence both the affinity and dynamics of albumin interactions with another.

Scope of review

Here we review the Zn^2 + and fatty acid transport properties of albumin and highlight an important interplay that exists between them. Also the impact of this dynamic interaction upon the distribution of plasma Zn^2 +, its effect upon cellular Zn^2 + uptake and its importance in the diagnosis of myocardial ischemia are considered.

Major conclusions

We previously identified the major binding site for Zn^2 + on albumin. Furthermore, we revealed that Zn^2 +-binding at this site and fatty acid-binding at the FA2 site are interdependent. This suggests that the binding of fatty acids to albumin may serve as an allosteric switch to modulate Zn^2 +-binding to albumin in blood plasma.

General significance

Fatty acid levels in the blood are dynamic and chronic elevation of plasma fatty acid levels is associated with some metabolic disorders such as cardiovascular disease and diabetes. Since the binding of Zn^2 + to albumin is important for the control of circulatory/cellular Zn^2 + dynamics, this relationship is likely to have important physiological and pathological implications. This article is part of a Special Issue entitled Serum Albumin.     

Increased urinary glucocorticoid metabolites are associated with metabolic syndrome, hypoadiponectinemia, insulin resistance and β cell dysfunction

Metabolic syndrome (MetS) may have increased cortisol (F) production caused by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in liver and adipose tissue and/or by HPA axis dysregulation. F is then mainly metabolized by liver reductases into inactive tetrahydrometabolites (THMs). We measured THM levels in patients with or without MetS and evaluate the correlation between THMs and anthropometric and biochemical parameters. We recruited 221 subjects, of whom 130 had MetS by ATP III. We evaluated F, cortisone (E), adipokines, glucose, insulin and lipid profiles as well as urinary (24 h) F, E and THM levels. β Cell function was estimated by the HOMA Calculator. We observed that patients with MetS showed higher levels of THMs, HOMA-IR and leptin and lower levels of adiponectin and HOMA-β but no differences in F and E in plasma or urine. THM was associated with weight (r = +0.44, p < 0.001), waist circumference (r = +0.38, p < 0.01), glycemia (r = +0.37, p < 0.01), and triglycerides (r = +0.18, p = 0.06) and negatively correlated with adiponectin (r = −0.36, p < 0.001), HOMA-β (r = −0.21, p < 0.001) and HDL (r = −0.29, p < 0.01). In a logistic regression model, THM levels were associated with hypertension, hyperglycemia and dyslipidemia. We conclude that MetS is associated with increased urinary THMs but not with F and E levels in plasma or urine. Increased levels of THM, reflecting the daily cortisol production subsequently metabolized, are correlated with hypoadiponectinemia, hypertension, dyslipidemia, insulin resistance and β cell dysfunction. A subtle increased in glucocorticoid production may further account for the phenotypic and biochemical similarities observed in central obesity and Cushing’s syndrome.