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Competing Interests: Conflict of interest: None declared.

The activity of 6-phosphofructo-1-kinase is strictly controlled by fructose-2,6-bisphosphate, the level of which is regulated by another enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2/FBP2). PFK2/FBP2 is a bifunctional enzyme, having kinase and phosphatase activities, and regulates both glycolysis and gluconeogenesis. Here, we examined the hormonal regulation of the PFK2/FBP2 gene in vitro using the reporter assay, the electromobility shift assay (EMSA), and the chromatin immunoprecipitation (ChIP) assay in HuH7 cells and also using the mouse liver in vivo. We found that the transcriptional activity of the PFK2/FBP2 gene was stimulated by insulin and inhibited by cAMP and glucocorticoid. Liver X receptor (LXR) α showed a potent and specific stimulatory effect on PFK2/FBP2 gene transcription. Deletion and mutagenesis analyses identified the LXR response element (LXRE) in the 5'-promoter region of the PFK2/FBP2 gene. Binding of LXRα was confirmed by the EMSA and ChIP assay. Endogenous PFK2/FBP2 mRNA in the mouse liver was increased in the fasting/refeeding state compared with the fasting state. Altogether, PFK2/FBP2 gene transcription is found to be regulated in a way that is more similar to other glycolytic enzyme genes than to gluconeogenic genes. Furthermore, our data strongly suggest that LXRα is one of the key regulators of PFK2/FBP2 gene transcription. [ABSTRACT FROM AUTHOR]

Low-grade inflammation (LGI) represents a key driver of type 2 diabetes (T2D) and its associated cardiovascular diseases (CVDs). Indeed, inflammatory markers such as hs-CRP and IL-6 predict the development of T2D and its complications, suggesting that LGI already increases before T2D diagnosis and remains elevated even after treatment. Overnutrition, unhealthy diets, physical inactivity, obesity, and aging are all recognized triggers of LGI, promoting insulin resistance and sustaining the pathogenesis of T2D. Once developed, and even before frank appearance, people with T2D undergo a pathological metabolic remodeling, with an alteration of multiple CVD risk factors, i.e., glycemia, lipids, blood pressure, and renal function. In turn, such variables foster a range of inflammatory pathways and mechanisms, e.g., immune cell stimulation, the accrual of senescent cells, long-lasting epigenetic changes, and trained immunity, which are held to chronically fuel LGI at the systemic and tissue levels. Targeting of CVD risk factors partially ameliorates LGI. However, some long-lasting inflammatory pathways are unaffected by common therapies, and LGI burden is still increased in many T2D patients, a phenomenon possibly underlying the residual inflammatory risk (i.e., having hs-CRP > 2 mg/dL despite optimal LDL cholesterol control). On the other hand, selected disease-modifying drugs, e.g., GLP-1RA, seem to also act on the pathogenesis of T2D, curbing the inflammatory trajectory of the disease and possibly preventing it if introduced early. In addition, selected trials demonstrated the potential of canonical anti-inflammatory therapies in reducing the rate of CVDs in patients with this condition or at high risk for it, many of whom had T2D. Since colchicine, an inhibitor of immune cell activation, is now approved for the prevention of CVDs, it might be worth exploring a possible therapeutic paradigm to identify subjects with T2D and an increased LGI burden to treat them with this drug. Upcoming studies will reveal whether disease-modifying drugs reverse early T2D by suppressing sources of LGI and whether colchicine has a broad benefit in people with this condition. [ABSTRACT FROM AUTHOR]

Glucocorticoid has diverse biological effects through induction or repression of its target genes via glucocorticoid receptor (GR). In addition to the wild-type GR (GR-alpha), a variety of GR variants has been reported, and these are thought to modify glucocorticoid action. Among others, GR-beta is reported be responsible for the glucocorticoid resistance frequently observed in steroid-resistant nephrotic syndrome, rheumatoid arthritis, and hematologic tumors, although the precise molecular mechanism remains unclear. In this study, we examined the function of GR-beta and some GR variants (GR-gamma and GR-Delta313-338) using GR-deficient BE(2)C and T84 cells in vitro. We found that GR-beta, when expressed alone, completely lost the capacity of both trans-activation and trans-repression on GR target genes. Interestingly, however, GR-beta showed a dominant-negative effect on GR-alpha only for its trans-repressive effects on cAMP-mediated and cAMP response element-dependent genes. Furthermore, both GR-beta and GR-gamma had dominant-negative effects on GR-alpha selectively for its trans-repressive effects on nuclear factor-kappaB-mediated and inflammation-related genes. These results suggest that 1) the GR-beta variant by itself has no receptor function, but 2) GR-beta and GR-gamma have properties to exert dominant-negative effects on the GR-alpha-mediated trans-repression, which may be responsible for the steroid resistance frequently observed in chronic inflammatory diseases under glucocorticoid therapy.

NAD-dependent deacetylase SIRT1 is known to be activated by caloric restriction and is related to longevity. A natural polyphenolic compound resveratrol is also shown to increases SIRT1 activity and extends lifespan. However, the transcriptional regulation of SIRT1 gene has not completely examined in the context of metabolism. Thus, in this study, we characterized the 5' -flanking region of human SIRT1 gene. We first found that representative metabolic hormones and related factors (glucocorticoid, glucagon/cAMP, and insulin) did not show significant effect on SIRT1 gene transcription. PPARalpha and PPARgamma1 without/with their specific ligands did not have significant effect as well. In contrast, expression of PPARbeta/delta (PPARdelta markedly increased the 5' -promoter activity of SIRT1 gene, which was further amplified by the addition of GW501516, a selective PPARdelta agonist. Deletion/mutation mapping analyses failed to identify PPAR binding element but revealed the presence of canonical Sp1 binding site, which was conserved among species. The Sp1 site is functional, because Sp1 overexpresson significantly enhanced SIRT1 promoter activity, and the binding of Sp1 to the element was confirmed by EMSA and ChIP assays. Interestingly, specific Sp1 antagonist mithramycin completely abolished the PPARdelta-mediated induction of SIRT1 gene transcription. Altogether, our data suggest the predominant role of PPARdelta in the transcriptional regulation of SIRT1 gene. Furthermore, the effects of PPARdelta seem to be mediated by Sp1. We assume that, in vivo, starvation increases lipolysis-derived free fatty acid and activates PPARdelta and the resultant increase in SIRT1 expression, in addition to the activation by NAD and AMPK, facilitates the deacetylation of a variety of proteins involved in mitochondrial beta-oxidation pathway and cell survival.

Both glucocorticoid and insulin are known to have an anabolic effect on lipogenesis. Acetyl-CoA, an intermediate product of glycolysis, is supplied for fatty acid synthesis when carbohydrate intake is sufficient. Acetyl-CoA carboxylase (ACC), consisting of two isoenzymes ACC1 and ACC2, mediates the conversion from acetyl-CoA to malonyl-CoA, and thus plays a key role for the regulation of lipogenesis. In this study, we surveyed the effects of glucocorticoid and insulin on the transcriptional activity of the alternative promoters of ACCs (PI-PIII for ACC1, and PI and PII for ACC2) using the HepG2 human hepatocyte cell line in vitro. We also examined the roles of the insulin and/or glucose-regulated transcriptional factor(s) such as SREBP1c, LXRalpha/beta, and ChREBP on each promoter of the ACC genes. We found that both insulin and glucocorticoid had potent positive effects on all the promoters examined, and additive effects of both hormones were recognized in ACC1 PI and ACC2 PI. Furthermore, a representative insulin-responsive transcription factor SREBP1c showed significant stimulatory effects on all the promoters of ACC genes, among which those on ACC1 PIII and ACC2 PI were most prominent. On the other hand, the effect of LXRalpha was rather selective; it showed a marked stimulatory effect only on ACC1 PII. LXRbeta and ChREBP had minimal, if any, effects on some of the promoters. Altogether, our data suggest that insulin and glucocorticoid have positive effects on both ACC1 and ACC2 gene transcription. SREBP1c might be a master regulator of the expression of both genes regardless of the promoter utilized, whereas LXRalpha seems to play a promoter-specific role. Since ACC1 facilitates lipogenesis by stimulating fatty acid synthesis and ACC2 inhibits lipolysis, both insulin and glucocorticoid seem to play an important role in the pathogenesis of obesity and/or hepatic steatosis.

Both glucocorticoid and insulin are known to have an anabolic effect on lipogenesis. The glycolytic pathway is a part of the lipogenic pathway in the liver, and glycolytic enzymes mediate the conversion from glucose to pyruvate, and pyruvate dehydrogenase complex (PDC) mediates the conversion from pyruvate to acetyl-CoA, the activity of which is regulated by pyruvate dehydrogenase kinases (PDKs) and phosphatases (PDPs). In this study, we surveyed the effects of glucocorticoid, insulin, and forskolin (used as a surrogate of glucagon) on the transcriptional activity of glucokinase (GK), phosphofructokinase-1 (PFK1), liver-type pyruvate kinase (LPK), and all the PDKs/PDPs isoform genes. We found that both glucocorticoid and insulin had positive effects on PFK1 and LPK, whereas on GK the two hormones showed the opposite effect. Regarding the PDKs/PDPs, glucocorticoid significantly stimulated the transcriptional activity of all PDKs, among which the effect on PDK4 was the most prominent. Insulin alone had minimal effects on PDKs, but dampened the positive effects of glucocorticoid. On PDPs, glucocorticoid and forskolin showed negative effects, whereas insulin had positive effects; insulin and glucocorticoid/forskolin antagonized each other. Altogether, our data suggest that both glucocorticoid and insulin have lipogenic effects through positive effects on PFK1 and LPK expression. However, glucocorticoid antagonizes the effect of insulin at the level of GK to maintain glucose homeostasis and that of PDKs/PDPs to facilitate gluconeogenesis. Glucagon may also enhance gluconeogenesis by inhibiting PDPs.

Adiponectin (AdN), an adipokine derived from the adipose tissue, has an insulin-sensitizing effect, and plasma AdN is shown to be decreased in obesity and/or insulin resistant state. To clarify whether changes in AdN are also responsible for the development of glucocorticoid-induced insulin resistance, we examined AdN concentration in plasma and AdN expression in the adipose tissue, using corticotropin-releasing hormone (CRH) transgenic mouse (CRH-Tg), an animal model of Cushing syndrome. We found, unexpectedly, that plasma AdN levels in CRHTg were significantly higher than those in wild-type littermates (wild-type: 19.7+/-2.5, CRH-Tg: 32.4+/-3.1 microg/mL, p<0.01). On the other hand, AdN mRNA and protein levels were significantly decreased in the adipose tissue of CRH-Tg. Bilateral adrenalectomy in CRH-Tg eliminated both their Cushing's phenotype and their increase in plasma AdN levels (wild-type/sham: 9.4+/-0.5, CRH-Tg/sham: 15.7+/-2.0, CRH-Tg/ADX: 8.5+/-0.4 microg/mL). These results strongly suggest that AdN is not a major factor responsible for the development of insulin resistance in Cushing syndrome. Our data also suggest that glucocorticoid increases plasma AdN levels but decreases AdN expression in adipocytes, the latter being explained possibly by the decrease in AdN metabolism in the Cushing state.

Hyperinsulinemia is a known risk factor for cardiovascular events, but its molecular basis is not completely understood. In this study, we examined the effects of insulin alone, or insulin and proinflammatory cytokines, on the expression of inflammation/coagulation-related genes in hepatocytes. We found that, in the HepG2 human hepatocyte cell line, insulin stimulated the transcriptional activity of plasminogen activator inhibitor 1 (PAI-1), fibrinogen-gamma and C-reactive protein (CRP) genes in time- and dose-dependent manners. These effects were completely inhibited by MAP kinase inhibitor PD98059, but not by PI3 kinase inhibitor wortmannin. As previously reported, proinflammatory cytokines like interleukin 1beta and interleukin 6 showed stimulatory effects on the expression of these genes, and we now found that the combination of insulin and the cytokines showed more than additive effects in most cases. Interleukin 1beta and insulin also cooperatively increased the endogenous mRNA level of PAI-1. These results suggest that the coexistence of high insulin and cytokines may induce inflammation and hypercoagulation in a synergistic manner. This may partly explain why the accumulation of multiple risk factors, especially hyperinsulinemia caused by insulin resistance and enhanced production of proinflammatory cytokines, results in inflammation, thrombosis, and cardiovascular events in metabolic syndrome.

While lipopolysaccharides (LPS) are known to activate the hypothalamo-pituitary-adrenal axis, their direct effects on proopiomelanocortin (POMC) and adrenocorticotropin (ACTH) expression at the pituitary level through Toll-like receptors (TLRs) remain unclear. In this study, we examined the effects of LPS on ACTH secretion and the transcription of the POMC gene in the AtT20 mouse pituitary corticotroph cell line. RT-PCR analysis showed that TLR1-4 and 6 subtype mRNAs were expressed in AtT20 cells. When the cells were treated with LPS, a significant increase in the 5'-promoter activity of POMC gene was observed at 24 h, without any stimulatory effect on ACTH secretion. LPS also stimulated the expression of c-Fos gene and protein, and AP1-, but not NF-kappaB-, mediated transcription. Overall, our data show the expression of TLRs in the pituitary corticotroph cells, and suggest the direct stimulatory effect of LPS on POMC gene expression via TLR (probably TLR4), although the intracellular signaling pathways in the corticotroph may be different from those in immune cells.

Starvation is known to activate the hypothalamo-pituitary-adrenal (HPA) axis, a representative antistress system in the living organism. In this study, we investigated in vitro whether activation of the AMP-activated protein kinase (AMPK), which is known to occur in intracellular energy depletion, influences the expression of POMC gene that encodes adrenocorticotropin. We first confirmed that each subunit of AMPK was expressed in the AtT20 corticotroph cell line. We then found that AICAR, a cell-permeable AMP analog and an activator of AMPK, potently stimulated the 5'-promoter activity of POMC gene in a dose-dependent manner. The effects were promoter specific because AICAR enhanced the AP1-mediated POMC promoter activities but did not influence other transcription factor-induced transcription. The effect of AICAR on POMC gene transcription was completely eliminated by specific AMPK inhibitor compound C or by dominant negative AMPK, whereas overexpression of constitutively active AMPK mimicked the effect of AICAR. Finally, experiments using specific kinase inhibitors suggested that the PI 3-kinase-mediated signaling pathway is at least partly involved in the effect. Our results suggest that intracellular energy depletion with the resultant activation of AMPK directly stimulates the HPA axis at the pituitary level by increasing the expression of POMC gene.

Systemic inflammation has been recognized as the cause and consequence of metabolic dysregulation in diabetes mellitus (DM). Presepsin has recently emerged as a promising biomarker for the detection of bacterial infections and sepsis. There is evidence that gut dysbiosis results in the increased circulating concentrations of Gram-negative bacteria lipopolysaccharide, the linkage of presepsin, which in turn promotes insulin resistance and correlates with the risk of diabetic complications. Thus, we hypothesized that presepsin could reflect the magnitude of systemic inflammation and metabolic decompensation in patients with DM even in the absence of infection. In this cross-sectional pilot study, we included 75 infection-free individuals with well-controlled (n = 19) and uncontrolled (n = 23) type 2 diabetes (T2D), well-controlled (n = 10) and uncontrolled (n = 10) type 1 diabetes (T1D), and normoglycemic controls (n = 13). Presepsin levels were compared between the groups and potential associations with demographic, clinical, and laboratory parameters were explored. We observed that the duration of DM was associated with presepsin values (p = 0.008). When the participants were classified into the type of DM groups, the presepsin levels were found to be lower in the patients with T2D compared to those with T1D (p = 0.008). However, significance in that case was driven by the difference between the well-controlled groups. After adjusting for the effects of DM duration, presepsin was significantly lower in the well-controlled T2D group compared to the well-controlled T1D group [1.34 (2.02) vs. 2.22 (4.20) ng/mL, p = 0.01]. Furthermore, we adjusted our findings for various confounders, including age, body mass index, and waist circumference, and found that the difference in the presepsin values between the adequately controlled groups remained significant (p = 0.048). In conclusion, our findings suggest that presepsin could potentially serve as a surrogate marker of inflammation and metabolic control in people with DM. [ABSTRACT FROM AUTHOR]

Panicle-type structure is an important factor affecting rice yield, and an excellent panicle type has become a key indicator in rice breeding. In this study, the indica rice variety R766, which has an open panicle type, was obtained through natural mutation and hybrid selection. Through analyzing differences in panicle structure, panicle yield, and chemical composition between open panicle rice R766 and conventional panicle rice R2928, we found that the angles of the middle and lower branches in R766 were 186.99% and 135.93% greater than those in R2928, respectively. By comparing the grain-filling characteristics of different panicle positions in the two rice varieties, we found that the grain filling at the middle and lower panicle positions of R2928 was significantly lower, accompanied by an increase in the percentage of empty spikelets. However, in R766, the grain-filling rates in the middle and lower panicle positions were consistent with those in the upper panicle position, with significantly higher rates of grain filling and grain plumpness in the middle and lower panicle positions than in R2928. The empty grain rate at the lower panicle position of R766 was 15.25% lower than that of R2928, and the grain filling was 24.75% higher than that of R2928. Additionally, the variation in the 1000-grain weight of grains at different panicle positions in R766 was relatively small, with decreases of 1.55% and 0.38% in the middle and lower panicle positions, respectively, compared with the upper position, whereas R2928 showed decreases of 5.99% and 7.12% in the 1000-grain weight of grains at the middle and lower panicle positions, respectively, compared with the upper position. The cellulose content in the stems of R766 was 7.51% higher than that of R2928, with no significant difference in the cellulose content in the panicle axis and primary branches compared to R2928. The lignin content of the panicle axis in R766 was 8.03% higher than that in R2928, whereas there was no significant difference between the lignin content of the stems and primary branches. This preliminary study revealed the open panicle characteristics of R766 and the reasons for its high basal grain setting rate. This study provides a reference for promoting this open panicle-type indica rice variety to improve yield and disease resistance in environments with high humidity and low sunlight levels. [ABSTRACT FROM AUTHOR]

Cushing's disease is characterized by persistent ACTH secretion under hypercortisolemia. In an attempt to clarify the molecular mechanism, we examined the effect of 11beta-hydroxysteroid dehydrogenase (HSD) inhibition on glucocorticoid suppression of ACTH release using murine corticotroph tumor cells. We found that 11beta-HSD2, as well as -HSD1, was expressed in the cells and that its inhibition by carbenoxolone significantly improved the negative feedback effect of glucocorticoid. Carbenoxolone also enhanced apoptosis induced by cortisol. These effects are most likely attributable to inhibition of 11beta-HSD2 because only cortisol, a substrate of 11beta-HSD2, was present in these experimental conditions. We conclude that ectopic expression of 11beta-HSD2 is, at least in part, responsible for the impaired glucocorticoid suppression in corticotroph adenoma. Inhibition of 11beta-HSD2 may be applicable to the medical therapy for Cushing's disease.

Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS), the representative sex steroid precursors, are postulated to have antiinflammatory effects, although the molecular background remains unknown. In this study, we examined the effects of these sex steroid precursors on cytokine-induced, nuclear factor-kappaB (NF-kappaB)-mediated transcription. The HuH7 human hepatocyte cell line was stably transfected with an NF-kappaB-luciferase reporter gene or transiently transfected with other representative response elements-luciferase fusion genes, and the effects of DHEA/DHEAS on proinflammatory cytokine-induced transcription were estimated by luciferase assay. The results showed that DHEA/DHEAS potently inhibited TNF-alpha-induced NF-kappaB-dependent transcription in a time- and dose-dependent manner. The effect was more obvious for DHEAS than for DHEA, and both steroids preferentially inhibited the cytokine-stimulated rather than basal NF-kappaB-mediated transcription. Similar effects were observed in activator protein-1-dependent but not constitutive Rous sarcoma virus promoter-dependent transcription. Two major downstream products of the sex steroid precursors, estradiol and testosterone, had no effect, indicating that the observed suppressive effect is not mediated by these metabolites. In contrast, glucocorticoids showed inhibitory effects on both basal and stimulated transcription and had an additive effect with DHEAS, suggesting the independent mechanisms of action of these steroid hormones. Finally, DHEAS eliminated hydroxyradical-induced activation of NF-kappaB-dependent transcription as well. Altogether, these results suggest that DHEA/DHEAS have an antiinflammatory effect in such a way that they inhibit proinflammatory cytokine-stimulated, NF-kappaB-mediated transcription, at least partly through their antioxidant properties.

Objectives: Coronary collateral flow often mitigates the effects of coronary artery obstruction and has a significant impact on the prognosis of patients with coronary artery disease. In the presence of variable degrees of coronary collateral flow, digital radiographic assessment of myocardial blood flow has not been quantitatively validated., Methods: A distal coronary arterial collateral path was created into the left anterior descending coronary artery (LAD) bed in 8 anesthetized pigs. Both LAD and collateral paths were pump-perfused and corresponding flows measured. A number of commonly used digital indices and parametric images of myocardial perfusion were then extracted from the sequence of images filmed before and during the injection of contrast. Data were acquired at 5 levels of total flow (LAD flow + collateral flow): 100, 85, 70, 55 and 40% of maximally vasodilated, baseline flow. At each level of total flow, data were acquired at 4 levels of collateral flow ratios (collateral flow/total flow): 0, 10, 25 and 50%., Results: Regional percent segment shortening, reflecting myocardial blood flow, decreased as total flow fell, and remained unaltered when coronary collateral ratio alone was altered without change in total flow. On the other hand, linear regression between total flow and digital indices at 10, 25 and 50% coronary collateral flow ratios, compared with 0%, showed a successive and significant downward displacement, documenting an underestimation of flow by all digital indices in the presence of collateral flow., Conclusions: In the absence of a collateral pathway and during maximal coronary vasodilation with adenosine, digital radiographic indices of myocardial perfusion, based upon indicator dilution theory, show a relatively good correlation with regional transmural myocardial blood flow. However, due to underestimation of total transmural blood flow, these indices have limited utility when myocardial perfusion is provided in part by a collateral pathway. The effect is probably related to an alteration in the regional vascular volume into which iodinated contrast is injected.

Background: A brief, sustained constriction of the descending and the ascending aortas produces systolic loads at different times during ejection, and descending intervention prolongs left ventricular (LV) relaxation more than ascending intervention. Although alterations in the sequence of loading the ventricle have been suggested as a cause of such load-induced relaxation abnormalities, the relation of the loading system to relaxation has been unclear., Methods and Results: LV peak systolic pressure was elevated by approximately 40 mm Hg by constricting the descending and ascending aortas in seven anesthetized dogs. The descending intervention increased aortic end-systolic pressure (AoESP, 110.4 +/- 9.3 to 150.8 +/- 11.5 mm Hg; P < .05), reduced aortic flow (P < .05), and prolonged LV relaxation (time constant [T], 31.9 +/- 4.4 to 69.8 +/- 12.8 ms; P < .05). LV ejection time was reduced, but the systolic time interval was unchanged. In contrast, ascending intervention decreased AoESP (111.9 +/- 11.4 to 101.5 +/- 10.3 mm Hg; P < .05), reduced aortic flow (P < .05), and prolonged T (31.2 +/- 5.4 to 42.2 +/- 8.3 ms; P < .05), whereas ejection time and systolic time interval increased (both P < .01). Prolongation of T was significantly greater during descending intervention (P < .05) and was associated with an increase in AoESP during descending intervention but a decrease in AoESP during ascending intervention., Conclusions: Descending intervention induced greater prolongation of T than ascending intervention. Prolongation of T was closely related to an increase in AoESP in the descending intervention but a decrease in AoESP in the ascending intervention. These data suggest that not only the loading sequence but also the pressure level at the onset of isovolumic relaxation determines LV relaxation.

This article briefly reviews recent experimental studies which show that beta-adrenergic receptor stimulation produces an important enhancement of the force-frequency relation on myocardial contractility. The basic property of the force-frequency effect to progressively enhance myocardial contractility as heart rate increases is augmented at each level of increasing adrenergic stimulation. This newly described intrinsic mechanism for the control of cardiac inotropic state, graded beta-adrenergic amplification of the force-frequency relation, is strongly manifested during normal exercise and infusion of a beta-adrenergic agonist at rest, and it influences both systolic and diastolic ventricular function. Significant impairment of adrenergic amplification of the force-frequency relation is observed in experimental heart failure and could contribute to impaired cardiac function during stress or exercise in this setting.

Objectives: The purpose of the present study was to investigate how loading conditions and regional nonuniformity affect left ventricular relaxation in dilated cardiomyopathy., Background: Left ventricular relaxation is impaired in dilated cardiomyopathy. It has been suggested that relaxation abnormality is related to loading conditions and regional nonuniformity in the diseased heart., Methods: Left ventriculography with simultaneous pressure manometry was performed in 10 patients with dilated cardiomyopathy before and during nitroprusside infusion. Ten normal subjects served as a control group. Left ventricular hemodynamics, regional wall motion (assessed by the area method) and regional wall stress (Janz method) were analyzed., Results: When compared with control subjects, the patients with dilated cardiomyopathy had a reduced left ventricular ejection fraction (p < 0.01) and prolonged relaxation time constants (p < 0.01). Left ventricular wall motion was both hypokinetic and asynchronous in the patient group. In addition, systolic regional wall stress was significantly greater, the time to peak wall stress was longer and the regional myocardial relaxation time constant was greater for each ventricular area assessed in the patient group (each p < 0.01). Administration of nitroprusside reduced left ventricular pressure and increased ejection fraction in the 10 patients with dilated cardiomyopathy. For each region, systolic regional wall stress and the time to peak wall stress decreased, and both regional hypokinesia and asynchrony lessened. These changes in loading conditions and regional nonuniformity were accompanied by an improvement in both regional and global ventricular relaxation that was significant, particularly during the early to midrelaxation phase when regional asynchrony was greatest., Conclusions: These results suggest that myocardial relaxation is sensitive to loading conditions and regional nonuniformity in dilated cardiomyopathy and that load reduction can improve both relaxation and systolic performance of the left ventricle.

The vasoconstrictive peptide endothelin-1 (ET-1) has been reported to exert a very important positive inotropic effect in vitro. To assess the effect of ET-1 on myocardial contractility in vivo, we compared the effect of intracoronary infusion of 10(-8) M ET-1 (constant coronary blood flow) to that of 10(-8) M dobutamine in 8 swine. ET infusion did not produce changes in segmental shortening (control vs. drug, mean +/- SD): 33.8 +/- 14.3 vs. 30.8 +/- 12.1%, shortening velocity: 10.3 +/- 4.3 vs. 10.7 +/- 4.5 mm/s, or maximum +dP/dt: 1,691 +/- 701 vs. 1,772 +/- 773 mm Hg/s, whereas dobutamine infusion induced an important increase in these measurements; segmental shortening: 36.9 +/- 14 vs. 48.4 +/- 18.8%, shortening velocity: 10.1 +/- 2.6 vs. 14.7 +/- 4.5 mm/s, and maximum +dP/dt: 2,041 +/- 567 vs. 2,389 +/- 765 mm Hg/s (all p less than 0.05). Mean myocardial blood flow assessed by microspheres was unchanged by ET-1 despite a marked increase in coronary artery pressure (88.6 +/- 12.9 vs. 157 +/- 8.8 mm Hg, p less than 0.001). Regional infusion of ET-1 at a dose provoking extensive coronary vasoconstriction does not induce any change in regional or global myocardial function in swine.

To determine the characteristic change in the Doppler hepatic venous flow velocity pattern in patients with pulmonary hypertension (PH), 21 patients with PH in sinus rhythm were examined with pulsed Doppler echocardiography. The control group included 13 subjects with chest pain syndrome and normal pulmonary arterial pressure. The hepatic vein Doppler signal was biphasic with one peak during ventricular systole (S wave) and the other in diastole (D wave). A reversed signal was recorded after contraction (A wave). The peak velocity of the A wave (Va), S wave (Vs), and D wave (Vd), the time velocity integral of these waves (VIa, VIs, and VId), the acceleration time (t-AC), and the slope of acceleration (s-AC) in the S wave were measured. Compared with controls the PH group had a higher value of Va (26.88 +/- 10.30 vs 13.41 +/- 3.69 cm/sec; p less than 0.01), VIa (2.55 +/- 1.18 vs 1.20 +/- 0.34 cm; p less than 0.01), VIa/(VIs+VId) (0.34 +/- 0.22 vs 0.14 +/- 0.06; p less than 0.01), and s-AC (372 +/- 156 vs 203 +/- 103 cm/sec2; p less than 0.01). They also had a shorter t-AC (101 +/- 32 vs 136 +/- 27 msec; p less than 0.01). There was a weak correlation between the reversed atrial flow and the right heart pressures (r = 0.43 to 0.66). Thus, the hepatic venous flow velocity pattern by Doppler echocardiography is clinically useful in evaluating pulmonary hypertension.

To study the effect of left ventricular systolic function on the Doppler transmitral flow velocity pattern, Doppler echocardiographic variables were correlated with hemodynamic indexes in 11 control subjects and 58 patients with heart disease. All underwent cardiac catheterization performed with use of a Millar micromanometer. The time constant of left ventricular isovolumetric pressure decrease and left ventricular end-diastolic myocardial stiffness was calculated. The 58 patients were classified into two groups according to ejection fraction: group I (n = 30; ejection fraction greater than 55%) and group II (n = 28; ejection fraction less than 50%). Compared with the control subjects, patients in group I had impairment only of left ventricular relaxation (time constant 47 +/- 9 vs. 38 +/- 3 ms; p less than 0.01), whereas patients in group II had, in addition to impaired left ventricular relaxation (time constant 52 +/- 11 vs. 38 +/- 3 ms; p less than 0.01), increased preload, increased pulmonary capillary pressure (12 +/- 8 vs. 5 +/- 3 mm Hg; p less than 0.01) and increased myocardial stiffness (2,018 +/- 980 vs. 1,050 +/- 218 g/cm2; p less than 0.01). In group I, there was a significant partial correlation coefficient between the time constant and deceleration half-time (r = 0.54). In group II, a strong correlation existed between myocardial stiffness and peak atrial filling velocity (r = -0.71) and between myocardial stiffness and the ratio of peak atrial to peak rapid filling velocity (r = -0.71).(ABSTRACT TRUNCATED AT 250 WORDS)

The ThMn12-type SmFe12-based rare-earth permanent magnet has attracted widespread attention due to its excellent intrinsic magnetic properties and high-temperature stability. However, the challenge in realizing continuous non-magnetic or weakly magnetic grain boundary phases equilibrated with the SmFe12 main phase hinders the enhancement in extrinsic magnetic properties of the SmFe12-based permanent magnet, especially for the coercivity. In this work, by controlling the cooling rate, the uniform distribution of paramagnetic Fe2Ti phases at grain boundaries is achieved in the SmFe12-based alloy ribbon, resulting in a high coercivity of 7.95 kOe. This improvement is attributed to the elimination of the impurity phase within the SmFe12 main phase and the magnetic isolation effect of the grain boundary phase composed of paramagnetic Fe2Ti, which is directly observed by transmission electron microscopy and further confirmed by micromagnetic simulation. Moreover, first-principles calculations show that the V element can dope into Fe2Ti and facilitate the transition of its paramagnetic state at room temperature. This study provides new insights into constructing weakly magnetic grain boundary phases for SmFe12-based permanent magnets, offering a novel approach to enhance coercivity. [ABSTRACT FROM AUTHOR]

Digestive system diseases, such as gastritis, gastric ulcers, chronic liver disease, inflammatory bowel disease (IBD), and colorectal cancer, represent a major group of diseases that have high morbidity and death rates worldwide. Their incidence continues to rise owing to factors such as dietary structure changes, accelerated lifestyles, increased environmental pollution, and population aging. Despite the rapid development of the medical technology, the treatment of digestive diseases still faces many challenges, such as addressing drug-resistant Helicobacter pylori infections, treating IBD, and improving the efficacy of advanced gastrointestinal tumor therapies. Fortunately, the emergence of drug-releasing materials has provided new insights that can be used in the treatment of digestive disorders. Drug-releasing materials are a category of specially designed carriers or systems capable of carrying drugs and controlling their release at specific time intervals on demand to achieve the desired therapeutic effect. This article reviews recent research progress of drug-releasing materials used to diagnose and treat digestive disorders. First, the limitations of traditional oral drug delivery methods, such as low bioavailability and nonspecific distribution, are discussed. Second, different types of drug-releasing materials, such as liposomes, dendritic polymers, micelles, nanogels, inorganic nanoparticles, and extracellular vesicles, along with their advantages in terms of improved drug stability, biocompatibility, targeting, and controlled release, are outlined. In addition, the application strategies and preclinical findings of various drug release materials for different digestive disorders are discussed in detail. This Review could help researchers explore more advanced nanomaterials for personalized treatment of drug delivery for digestive disorders. [ABSTRACT FROM AUTHOR]

Pregnane neuroactive steroids, notably allopregnanolone and pregnenolone, exhibit efficacy in mitigating inflammatory signals triggered by toll-like receptor (TLR) activation, thus attenuating the production of inflammatory factors. Clinical studies highlight their therapeutic potential, particularly in conditions like postpartum depression (PPD), where the FDA-approved compound brexanolone, an intravenous formulation of allopregnanolone, effectively suppresses TLR-mediated inflammatory pathways, predicting symptom improvement. Additionally, pregnane neurosteroids exhibit trophic and anti-inflammatory properties, stimulating the production of vital trophic proteins and anti-inflammatory factors. Androstane neuroactive steroids, including estrogens and androgens, along with dehydroepiandrosterone (DHEA), display diverse effects on TLR expression and activation. Notably, androstenediol (ADIOL), an androstane neurosteroid, emerges as a potent anti-inflammatory agent, promising for therapeutic interventions. The dysregulation of immune responses via TLR signaling alongside reduced levels of endogenous neurosteroids significantly contributes to symptom severity across various neuropsychiatric disorders. Neuroactive steroids, such as allopregnanolone, demonstrate efficacy in alleviating symptoms of various neuropsychiatric disorders and modulating neuroimmune responses, offering potential intervention avenues. This review emphasizes the significant therapeutic potential of neuroactive steroids in modulating TLR signaling pathways, particularly in addressing inflammatory processes associated with neuropsychiatric disorders. It advances our understanding of the complex interplay between neuroactive steroids and immune responses, paving the way for personalized treatment strategies tailored to individual needs and providing insights for future research aimed at unraveling the intricacies of neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

In this review article, we focus on the relationship between permanent magnets and the electric motor, as this relationship has not been covered in a review paper before. With the increasing focus on battery research, other parts of the electric system have been neglected. To make electrification a smooth transition, as has been promised by governing bodies, we need to understand and improve the electric motor and its main component, the magnet. Today's review papers cover only the engineering perspective of the electric motor or the material-science perspective of the magnetic material, but not both together, which is a crucial part of understanding the needs of electric-motor design and the possibilities that a magnet can give them. We review the road that leads to today's state-of-the-art in electric motors and magnet design and give possible future roads to tackle the obstacles ahead and reach the goals of a fully electric transportation system. With new technologies now available, like additive manufacturing and artificial intelligence, electric motor designers have not yet exploited the possibilities the new freedom of design brings. New out-of-the-box designs will have to emerge to realize the full potential of the new technology. We also focus on the rare-earth crisis and how future price fluctuations can be avoided. Recycling plays a huge role in this, and developing a self-sustained circular economy will be critical, but the road to it is still very steep, as ongoing projects show. [ABSTRACT FROM AUTHOR]

Epitaxy is the process of crystallization of monocrystalline layers and nanostructures on a crystalline substrate. It allows for the crystallization of various semiconductor layers on a finite quantity of semiconductor substrates, like GaAs, InP, GaP, InGaP, GaP, and many others. The growth of epitaxial heterostructures is very complicated and requires special conditions and the precise control of the growth temperature, the pressure in the reactor, and the flow of the precursors. It is used to grow epitaxial structures in lasers, diodes, detectors, photovoltaic structures, and so on. Semiconductors themselves are not suitable materials for application in surface-enhanced Raman spectroscopy (SERS) due to poor plasmonic properties in the UV/VIS range caused by missing free electrons in the conduction band due to the existing band gap. A plasmonic material is added on top of the nanostructured pattern, allowing for the formation of mixed photon–plasmon modes called localized surface plasmon-polaritons which stand behind the SERS effect. Typically, gold and silver are used as functional plasmonic layers. Such materials could be deposited via chemical or physical process. Attention has also been devoted to other plasmonic materials, like ones based on the nitrides of metals. The SERS performance of a functional surface depends both on the response of the plasmonic material and the morphology of the underlying semiconductor epitaxial layer. In the context of SERS, epitaxial growth allows for the fabrication of substrates with well-defined 3D nanostructures and enhanced electromagnetic properties. In this work, we described the possible potential plasmonic modification, composed of various coatings such as noble metals, TiN, and others, of well-developed epitaxial nanostructures for the construction of a new type of highly active SERS platforms. This abstract also highlights the role of epitaxial growth in advancing SERS, focusing on its principles, methods, and impact. Furthermore, this work outlines the potential of epitaxial growth to push the boundaries of SERS. The ability to design substrates with tailored plasmonic properties opens avenues for ultralow concentration detection. [ABSTRACT FROM AUTHOR]

Real-time monitoring of the state of charge (SOC) of the batteries used in a wide variety of applications is becoming increasingly important, especially given the impetus by the current targets towards "net-zero". In this research, an advanced approach was used involving fiber Bragg grating (FBG)-based sensors that were developed and implemented for the measurement of the key parameters required to ensure optimum battery performance. In this work, one of the biggest challenges to assess (and then map) the data from the sensor system developed is tackled in order to better understand the key parameters of the battery in an efficient and improved way. It is well known that the relationship between the changes in the resonance wavelength of the FBGs used in the sensor system, arising due to change in the electrical parameters of the battery, is complex and dependent on several different factors. In this work, this effect was evaluated by coupling the sensor data to a data-driven regression model approach that was developed for the measurement of the SOC of the batteries used, and this was obtained directly and conveniently from the FBG data. In this comprehensive study, FBG-based sensors were fabricated and then installed onto the battery, which then was subjected to a range of charging–discharging cycles, following which the electrical parameters of the battery were estimated from recorded data using a black-box machine learning (ML) model. Data-driven regression algorithms were employed for the training of the black-box model. The efficiency of the estimation of the SOC of the battery from the FBG-based sensor data was found to be high, at 99.62% (R2 values of Estimated SOC and True SOC line), creating a very satisfactory result for this key measurement. Thus, the work shows the robustness of the FBG-based sensor system combined with the neural network algorithm as an effective way to evaluate the electrical parameters of the battery, which is particularly important, as no physical/electrochemical/electrical model of the system is thus required. [ABSTRACT FROM AUTHOR]

Cancer is one of the leading causes of death worldwide. Because each person's cancer may be unique, diagnosing and treating cancer is challenging. Advances in nanomedicine have made it possible to detect tumors and quickly investigate tumor cells at a cellular level in contrast to prior diagnostic techniques. Quantum dots (QDs) are functional nanoparticles reported to be useful for diagnosis. QDs are semiconducting tiny nanocrystals, 2–10 nm in diameter, with exceptional and useful optoelectronic properties that can be tailored to sensitively report on their environment. This review highlights these exceptional semiconducting QDs and their properties and synthesis methods when used in cancer diagnostics. The conjugation of reporting or binding molecules to the QD surface is discussed. This review summarizes the most recent advances in using QDs for in vitro imaging, in vivo imaging, and targeted drug delivery platforms in cancer applications. [ABSTRACT FROM AUTHOR]

The glucocorticoid receptor α (GRα) is a member of the nuclear receptor superfamily and functions as a glucocorticoid (GC)-responsive transcription factor. GR can halt inflammation and kill off cancer cells, thus explaining the widespread use of glucocorticoids in the clinic. However, side effects and therapy resistance limit GR's therapeutic potential, emphasizing the importance of resolving all of GR's context-specific action mechanisms. Fortunately, the understanding of GR structure, conformation, and stoichiometry in the different GR-controlled biological pathways is now gradually increasing. This information will be crucial to close knowledge gaps on GR function. In this review, we focus on the various domains and mechanisms of action of GR, all from a structural perspective. [ABSTRACT FROM AUTHOR]

Background: Epicardial fat represents visceral adiposity. Many observational studies have reported that increased epicardial is associated with adverse metabolic profile, cardiovascular risk factors, and coronary atherosclerosis in patients with cardiovascular diseases and in general population. We and others have previously reported the association of increased epicardial fat with left ventricular (LV) hypertrophy and diastolic dysfunction as well as the development of heart failure (HF) and coronary artery disease in these populations. In some studies, however, the association did not reach statistical significance. The inconsistent results may be due to limited power, different imaging modalities for quantifying epicardial fat volume, and different outcome definitions. Accordingly, we aim to perform the systematic review and meta-analysis of studies on the association of epicardial fat with cardiac structure and function and cardiovascular outcomes. Methods: This systematic review and meta-analysis will include observational studies examining the association of epicardial fat with cardiac structure and function or the cardiovascular outcomes. Relevant studies will be identified by searching electronic databases including PubMed, Web of Science, and Scopus and by manual screening of reference lists of relevant reviews and retrieved studies. The primary outcome will be cardiac structure and function. The secondary outcome will be cardiovascular events including death from cardiovascular causes, hospitalization for HF, nonfatal myocardial infarction, and unstable angina. Discussion: The results of our systematic review and meta-analysis will provide evidence regarding the clinical usefulness of epicardial fat assessment. Systematic review registration: INPLASY 202280109. [ABSTRACT FROM AUTHOR]

Cav1.2 Ca2+ channels, a type of voltage-gated L-type Ca2+ channel, are ubiquitously expressed, and the predominant Ca2+ channel type, in working cardiac myocytes. Cav1.2 channels are regulated by the direct interactions with calmodulin (CaM), a Ca2+-binding protein that causes Ca2+-dependent facilitation (CDF) and inactivation (CDI). Ca2+-free CaM (apoCaM) also contributes to the regulation of Cav1.2 channels. Furthermore, CaM indirectly affects channel activity by activating CaM-dependent enzymes, such as CaM-dependent protein kinase II and calcineurin (a CaM-dependent protein phosphatase). In this article, we review the recent progress in identifying the role of apoCaM in the channel 'rundown' phenomena and related repriming of channels, and CDF, as well as the role of Ca2+/CaM in CDI. In addition, the role of CaM in channel clustering is reviewed. [ABSTRACT FROM AUTHOR]

Inflammation, an innate immune response mediated by macrophages, has been a hallmark leading to the pathophysiology of diseases. In this study, we examined the inhibitory effects of ginsenoside compound K (CK) on lipopolysaccharide (LPS)-induced inflammation and metabolic alteration in RAW 264.7 macrophages by regulating sirtuin 1 (SIRT1) and histone deacetylase 4 (HDAC4). LPS suppressed SIRT1 while promoting HDAC4 expression, accompanied by increases in cellular reactive oxygen species accumulation and pro-inflammatory gene expression; however, the addition of CK elicited the opposite effects. CK ameliorated the LPS-induced increase in glycolytic genes and abrogated the LPS-altered genes engaged in the NAD+ salvage pathway. LPS decreased basal, maximal, and non-mitochondrial respiration, reducing ATP production and proton leak in macrophages, which were abolished by CK. SIRT1 inhibition augmented Hdac4 expression along with increased LPS-induced inflammatory and glycolytic gene expression, while decreasing genes that regulate mitochondrial biogenesis; however, its activation resulted in the opposite effects. Inhibition of HDAC4 enhanced Sirt1 expression and attenuated the LPS-induced inflammatory gene expression. In conclusion, CK exerted anti-inflammatory and antioxidant properties with the potential to counteract the alterations of energy metabolism, including glycolysis and mitochondrial respiration, through activating SIRT1 and repressing HDAC4 in LPS-stimulated macrophages. [ABSTRACT FROM AUTHOR]