Physicochemical properties and stability of oil-in-water emulsions stabilized by soy protein isolate and xanthan gum.

The aim of this work was to determine rheological and disperse characteristics and stability of oil-in-water emulsions stabilized by soy protein isolate (SPI) and xanthan gum (XG), as natural components. The effects of their combination on emulsion stabilization have not been investigated yet. The existence of interactions between the two macromolecules were indicated by the influence of XG on SPI surface hydrophobicity and surface tension values. Increase in SPI concentration from 1 to 3 % shift of distribution curves towards smaller particle size, while the opposite effects of further increase of SPI was obtained. The emulsions stabilized by SPI showed shear-thinning flow behavior, which changed to thixotropic at 5 % of SPI concentration. The presence of XG in emulsions at low concentrations did not affect the size distribution of the droplets, while at 0.1 % of XG Sauter mean diameter value raised and distribution curves were shifted towards a higher particle size. The presence of XG at higher concentration resulted in thixotropic flow behavior of emulsions. Also, increase in XG concentration led to the increase in consistency index and extent of non-Newtonian behavior of emulsions and enhanced the influence of the elastic modulus and creaming stability of the systems.

The Influence of Starch Sweeteners on Functional Properties of Cellulose Fat Mimetics: Rheological and Textural Aspects.

Starch sweeteners are commonly used in many confectionery food products. Usually, considering the trend of producing low-energy and low-fat products, these products include fat mimetics. The aim of this study was to investigate the influence of fructose sweeteners on the development of functional properties of MCG fat mimetic, such as rheological and textural behavior. Fat mimetics made from Microcrystalline cellulose gel (MCG) consist of colloidal microcrystalline cellulose (MCC) and sodium carboxymethyl cellulose (NaCMC) and were observed in five different concentrations (1, 3, 5, 7, and 10%). The amount of starch sweetener in the mixture with the fat mimetics was 20%. The effect of pure crystalline fructose and a mixture of crystalline-fructose and high-fructose corn syrup in a ratio of 1:1 was analyzed. Rheological parameters significantly decreased with the application of starch sweeteners. By adding a mixture of starch sweeteners, this decrease was further increased by 10%. At higher gel concentrations of 5, 7, and 10%, the dominance of the elastic modulus G' was preserved. Texture parameters such as firmness, consistency, cohesiveness, and viscosity index were reduced accordingly. The presence of starch sweeteners significantly disrupted the networking of the three-dimensional structure of the MCG gel and the proper hydration process during the formation of fat mimetics.

Synthesis of octenyl succinic anhydride-modified levan and investigation of its microstructural, physicochemical, and emulsifying properties.

In this study, levan from Bacillus licheniformis NS032 was modified in an aqueous medium by octenyl succinic anhydride (OSA), and the properties of the obtained derivatives were studied. The maximum efficiency in the synthesis reaction was achieved at 40 °C and a polysaccharide slurry concentration of 30 %. Increasing the reagent concentration (2-10 %) led to an increase in the degree of substitution (0.016-0.048). Structures of derivatives were confirmed by FTIR and NMR. Scanning electronic microscopy, thermogravimetry, and dynamic light scattering analyses showed that the derivatives with degrees of substitution of 0.025 and 0.036 retained levan's porous structure and thermostability and showed better colloidal stability than the native polysaccharide. The intrinsic viscosity of derivatives increased upon modification, while the surface tension of the 1 % solution was lowered to 61 mN/m. Oil-in-water emulsions prepared with sunflower oil (10 % and 20 %) by mechanical homogenization and 2 and 10 % derivatives in the continuous phase showed mean oil droplet sizes of 106-195 µm, while the distribution curves exhibited bimodal character. The studied derivatives have a good capacity to stabilize emulsions, as they have a creaming index ranging from 73 % to 94 %. The OSA-modified levans could have potential applications in new formulations of emulsion-based systems.

Assessment of Soy Protein Acid Hydrolysate-Xanthan Gum Mixtures on the Stability, Disperse and Rheological Properties of Oil-in-Water Emulsions.

There is a growing need for natural ingredients that could be utilized for the production of food, pharmaceutical, and cosmetic emulsions. Soy protein acid hydrolysate (SPAH) is a plant-based additive used in the food industry mainly as a flavor enhancer. For the purpose of this work, however, it was mixed with a well-known natural polysaccharide, xanthan gum (XG), to produce stable 30% (w/w) sunflower oil-in-water emulsions using a rotor-stator homogenizer. In order to assess the emulsifying properties of the SPAH and its mixtures with XG, the surface tension properties of their water solutions, particle size, creaming stability, and rheological properties of the emulsions were investigated. Since the emulsions prepared using only SPAH, in various concentrations, were not stable, systems containing 5% of SPAH and 0.1, 0.2, 0.3, 0.4, or 0.5% of XG were then studied. The increase in concentration of the macromolecule led to an increase in creaming stability. The emulsions with 5% SPAH and 0.5% XG were stable for at least 14 days. The increase in XG concentration led to a decrease in d4,3, while consistency index and non-Newtonian behavior increased. The systems containing SPAH, in the absence of XG, showed shear-thinning flow behavior, which was changed to thixotropic with the addition of XG. Viscoelastic properties of emulsions containing over 0.2% of XG were confirmed by oscillatory rheological tests, demonstrating the dominance of elastic (G') over viscous (G") modulus.

CRISPR/Cas9-Targeted Disruption of Two Highly Homologous Arabidopsis thaliana DSS1 Genes with Roles in Development and the Oxidative Stress Response.

Global climate change has a detrimental effect on plant growth and health, causing serious losses in agriculture. Investigation of the molecular mechanisms of plant responses to various environmental pressures and the generation of plants tolerant to abiotic stress are imperative to modern plant science. In this paper, we focus on the application of the well-established technology CRISPR/Cas9 genome editing to better understand the functioning of the intrinsically disordered protein DSS1 in plant response to oxidative stress. The Arabidopsis genome contains two highly homologous DSS1 genes, AtDSS1(I) and AtDSS1(V). This study was designed to identify the functional differences between AtDSS1s, focusing on their potential roles in oxidative stress. We generated single dss1(I) and dss1(V) mutant lines of both Arabidopsis DSS1 genes using CRISPR/Cas9 technology. The homozygous mutant lines with large indels (dss1(I)del25 and dss1(V)ins18) were phenotypically characterized during plant development and their sensitivity to oxidative stress was analyzed. The characterization of mutant lines revealed differences in root and stem lengths, and rosette area size. Plants with a disrupted AtDSS1(V) gene exhibited lower survival rates and increased levels of oxidized proteins in comparison to WT plants exposed to oxidative stress induced by hydrogen peroxide. In this work, the dss1 double mutant was not obtained due to embryonic lethality. These results suggest that the DSS1(V) protein could be an important molecular component in plant abiotic stress response.

Myeloid p38 activation maintains macrophage-liver crosstalk and BAT thermogenesis through IL-12-FGF21 axis.

Obesity features excessive fat accumulation in several body tissues and induces a state of chronic low-grade inflammation that contributes to the development of diabetes, steatosis, and insulin resistance. Recent research has shown that this chronic inflammation is crucially dependent on p38 pathway activity in macrophages, suggesting p38 inhibition as a possible treatment for obesity comorbidities. Nevertheless, we report here that lack of p38 activation in myeloid cells worsens high-fat diet-induced obesity, diabetes, and steatosis. Deficient p38 activation increases macrophage IL-12 production, leading to inhibition of hepatic FGF21 and reduction of thermogenesis in the brown fat. The implication of FGF21 in the phenotype was confirmed by its specific deletion in hepatocytes. We also found that IL-12 correlates with liver damage in human biopsies, indicating the translational potential of our results. Our findings suggest that myeloid p38 has a dual role in inflammation and that drugs targeting IL-12 might improve the homeostatic regulation of energy balance in response to metabolic stress.

The Attitude of the General Dentist in the Republic of Croatia toward Treating Children.

The aim of this study was to determine the attitude of general dentists in the Republic of Croatia toward working with children. The questionnaire survey involved 361 general dentists. The questionnaire was divided into three parts and contained 34 questions. The first part of the questionnaire survey contained demographic data questions. In the second part, dentists answered questions about the characteristics of the dental offices where they work, the materials that they mostly use, and how they work with children. The third part of the questionnaire referred to attitudes about working and treating young children and consisted of 12 statements, to which the answers were offered on a Likert scale from one to five. This study showed that only 12.46% of dentists have a positive attitude toward treating children and 30.19% of dentists have a negative attitude toward treating children. In addition, the attitude toward working with children correlates with both the knowledge they acquired during dental studies (R = 0.355; p ≤ 0.001) and gender (R = -0.103; p = 0.035). This study confirmed that women have a more often positive attitude toward treating young children. There was a major correlation between the level of education and positive attitudes toward treating children. The child's non-cooperative behavior was the main reason why general dentists refuse to work with children.

Cocoa Spread with Grape Seed Oil and Encapsulated Grape Seed Extract: Impact on Physical Properties, Sensory Characteristics and Polyphenol Content.

The aim of this study was to utilize grape pomace, as a polyphenol-rich by-product of wine production, in the manufacture of enriched cocoa spread. The formulation of the cocoa spread has been modified by substitution of refined sunflower oil with cold-pressed grape seed oil. The spread with grape seed oil (Cg) was further enriched with grape seed extract encapsulated on maltodextrins (E), where 10% and 15% of E was added to Cg obtaining the samples Cg10 and Cg15. The results showed an increase in volume-weighted mean in spread samples, from 19.17 µm in Cg to 19.71 µm in Cg10 and 21.04 µm in Cg15. Casson yield stress and Casson viscosity significantly (p ˂ 0.05) increased from 16.41 Pa and 1.58 Pa·s in Cg to 29.45 Pa and 5.70 Pa·s in Cg15 due to the reduction of the fat-phase content in enriched spreads. The addition of E had no significant effect on the melting temperature (Tpeak) of the enriched spreads, while increasing the amount of E significantly (p ˂ 0.05) increased their hardness. The incorporation of grape seed oil in the cocoa spread formulation contributed to an increase in total polyphenols and flavonoids. Moreover, the addition of 10% and 15% of E to Cg resulted in approximately 1.5× and 2× higher content of phenolic compounds in Cg10 and Cg15 compared to control spread with sunflower oil (Cs). Flavonoids increased from 0.43 mg CE/g in Cs to 0.74 mg CE/g in Cg 10 and 1.24 mg CE/g in Cg15. Encapsulates positively affected sensory characteristics of enriched spread samples by reducing their grape seed oil aroma and sweetness.

Advances in cardiac resuscitation in the emergency department.

Cardiogenic shock, cardiac arrest, and circulatory failure are life-threatening, and recognizing the underlying etiology and initiating treatment to promote perfusion are key to managing these patients and improving outcomes. This issue reviews the current evidence on diagnosis and management of cardiogenic shock, including oxygen supplementation, red blood cell transfusion, vasopressors, and inotropes. A summary of the various mechanical circulatory support options, including inclusion/exclusion criteria and admission and inter-facility transfer guidance, is included. Special considerations regarding the resuscitation and management of patients with intracorporeal left ventricular assist devices who are experiencing circulatory failure are outlined, including testing, imaging, and treatment.

MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation.

Stress-activated p38 kinases control a plethora of functions, and their dysregulation has been linked to the development of steatosis, obesity, immune disorders, and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members (p38α, p38ß, p38γ, and p38δ) that are activated by MKK3 and MKK6. Here, we demonstrate that lack of MKK6 reduces the lifespan in mice. Longitudinal study of cardiac function in MKK6 KO mice showed that young mice develop cardiac hypertrophy which progresses to cardiac dilatation and fibrosis with age. Mechanistically, lack of MKK6 blunts p38α activation while causing MKK3-p38γ/δ hyperphosphorylation and increased mammalian target of rapamycin (mTOR) signaling, resulting in cardiac hypertrophy. Cardiac hypertrophy in MKK6 KO mice is reverted by knocking out either p38γ or p38δ or by inhibiting the mTOR pathway with rapamycin. In conclusion, we have identified a key role for the MKK3/6-p38γ/δ pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38α inhibitors in the long-term treatment since they might result in cardiotoxicity.

The human heart can increase its size to supply more blood to the body's organs. This process, called hypertrophy, can happen during exercise or be caused by medical conditions, such as high blood pressure or inherited genetic diseases. If hypertrophy is continually driven by illness, this can cause the heart to fail and no longer be able to properly pump blood around the body. For hypertrophy to happen, several molecular changes occur in the cells responsible for contracting the heart, including activation of the p38 pathway. Within this pathway is a p38 enzyme as well as a series of other proteins which are sequentially turned on in response to stress, such as inflammatory molecules or mechanical forces that alter the cell's shape. There are different types of p38 enzyme which have been linked to other diseases, making them a promising target for drug development. However, clinical trials blocking individual members of the p38 family have had disappointing results. An alternative approach is to target other proteins involved in the p38 pathway, such as MKK6, but it is not known what effect this might have. To investigate, Romero-Becerra et al. genetically modified mice to not have any MKK6 protein. As a result, these mice had a shorter lifespan, with hypertrophy developing at a young age that led to heart problems. Romero-Becerra et al. used different mice models to understand why this happened, showing that a lack of MKK6 reduces the activity of a specific member of the p38 family called p38α. However, this blockage boosted a different branch of the pathway which involved two other p38 proteins, p38γ and p38δ. This, in turn, triggered another key pathway called mTOR which also promotes hypertrophy of the heart. These results suggest that drugs blocking MKK6 and p38α could lead to side effects that cause further harm to the heart. A more promising approach for treating hypertrophic heart conditions could be to inhibit p38γ and/or p38δ. However, before this can be fully explored, further work is needed to generate compounds that specifically target these proteins.

Conventional type 1 dendritic cells protect against age-related adipose tissue dysfunction and obesity.

Conventional dendritic cells (cDCs) scan and integrate environmental cues in almost every tissue, including exogenous metabolic signals. While cDCs are critical in maintaining immune balance, their role in preserving energy homeostasis is unclear. Here, we showed that Batf3-deficient mice lacking conventional type 1 DCs (cDC1s) had increased body weight and adiposity during aging. This led to impaired energy expenditure and glucose tolerance, insulin resistance, dyslipidemia, and liver steatosis. cDC1 deficiency caused adipose tissue inflammation that was preceded by a paucity of NK1.1+ invariant NKT (iNKT) cells. Accordingly, among antigen-presenting cells, cDC1s exhibited notable induction of IFN-γ production by iNKT cells, which plays a metabolically protective role in lean adipose tissue. Flt3L treatment, which expands the dendritic cell (DC) compartment, mitigated diet-induced obesity and hyperlipidemia in a Batf3-dependent manner. This effect was partially mediated by NK1.1+ cells. These results reveal a new critical role for the cDC1-iNKT cell axis in the regulation of adipose tissue homeostasis.

Newly synthesized palladium(II) complexes with aminothiazole derivatives: in vitro study of antimicrobial activity and antitumor activity on the human prostate cancer cell line.

Five new complexes of the palladium(II) ion (C1-C5) having the general formula [(PdL2)]Cl2 with some 2-aminothiazoles (L1-L5), where L1 = 2-amino-4-(3,4-difluorophenyl)thiazole, L2 = 2-amino-5-methyl-4-phenylthiazole, L3 = 2-amino-4-phenylthiazole, L4 = 2-amino-4-(4-chlorophenyl)thiazole, and L5 = 2-amino-4-(2,4-difluorophenyl)thiazole, have been synthesized and characterized by elemental microanalysis and infrared, 1H NMR and 13C NMR spectroscopy. The in vitro antimicrobial activity of the five ligands and the corresponding Pd(II) complexes is investigated. Testing is performed by the microdilution method and the minimum inhibitory concentration (MIC) and minimum microbicidal concentration (MMC) have been determined. Testing is conducted against 11 microorganisms (nine strains of pathogenic bacteria and two yeast species). The tested ligands and palladium(II) complexes show selective, high and moderate activity. There is a difference in antimicrobial activity between the ligands and the corresponding palladium(II) complexes. The complexes have significant anti-staphylococcal activity and activity on Pseudomonas aeruginosa which is better than the positive control. The interactions of newly synthesized palladium(II) complexes with calf thymus DNA (CT-DNA) were investigated using UV-Vis absorption and fluorescence spectroscopy. Analysis of UV-absorption and fluorescence spectra indicates the formation of a complex between the palladium(II) complexes and DNA. The high values of intrinsic binding constants, Kb, of the order 104 M-1 and Stern-Volmer quenching constants, KSV, of the order 105 M-1 indicated very good binding of all complexes to CT-DNA. Also, the new Pd(II) complexes show high cytotoxic activity towards the human prostate cancer cell line and insignificant activity towards non-cancerous human fibroblasts. Future research could additionally explore the biological activity of Pd(II) complexes presented in this paper and investigate the possibility of their implementation in clinical practice.

White Chocolate with Resistant Starch: Impact on Physical Properties, Dietary Fiber Content and Sensory Characteristics.

Resistant starch (RS) is a part of insoluble dietary fiber, and it could be recognized as a functional food ingredient in some types of confectionery products that lack dietary fiber. Unlike dark and milk chocolate, white chocolate does not contain fat-free cocoa solids rich in dietary fiber. In the present study, 5%, 10%, and 15% of white chocolate were substituted with RS in order to improve the nutritional value of enriched white chocolate. The influence of RS on rheological, textural, and thermal properties of the chocolate fat phase was firstly investigated, and then further influence on physical properties, dietary fiber content, and sensory characteristics of enriched white chocolates were investigated. The obtained results showed that enriched chocolates had increased content of total dietary fiber and reduced total fats and protein content in accordance with the added amount of RS. At the same time, RS increased viscosity and reduced the hardness and volume mean diameter in enriched chocolates in accordance with the added amount. RS improved the nutritional composition of white chocolate by increasing the content of dietary fiber. At the same time, RS did not impair the color and sensory characteristics of enriched white chocolates.

Intrinsically disordered protein AtDSS1(V) participates in plant defense response to oxidative stress.

DSS1 is a small protein, highly conserved across different species. As a member of the intrinsically disordered protein family, DSS1 interacts with different protein partners, thus forming complexes involved in diverse biological mechanisms: DNA repair, regulation of protein homeostasis, mRNA export, etc. Additionally, DSS1 has a novel intriguing role in the post-translational protein modification named DSSylation. Oxidatively damaged proteins are targeted for removal with DSS1 and then degraded by proteasome. Yet, DSS1 involvement in the maintenance of genome integrity through homologous recombination is the only function well studied in Arabidopsis research. The fact that animal DSS1 shows wide multifunctionality imposes a need to investigate the additional roles of two Arabidopsis thaliana DSS1 homologs. Having in mind the universality of various biological processes, we considered the possibility of plant DSS1 involvement in cellular homeostasis maintenance during stress exposure. Using real-time PCR and immunoblot analysis, we investigated the profiles of DSS1 gene and protein expression under oxidative stress. We grew and selected the homozygous Arabidopsis mutant line, carrying the T-DNA intron insertion in the DSS1(V) gene. The mutant line was phenotypically described during plant development, and its sensitivity to oxidative stress was characterized. This is the first report which indicates that plant DSS1 gene expression has an altered profile under the influence of oxidative stress. dss1(V)-/- plants showed an increased sensitivity to oxidative stress, germinated faster than WT, but generally showed developmental delay in further stages. Our results indicate that the DSS1 protein could be a crucial player in the molecular mechanisms underlying plant abiotic stress responses.

Circulating BMP9 Protects the Pulmonary Endothelium during Inflammation-induced Lung Injury in Mice.

Rationale: Pulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome. Circulating BMP9 (bone morphogenetic protein 9) is emerging as an important regulator of pulmonary vascular homeostasis. Objectives:To determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity and whether loss of endogenous BMP9 occurs during LPS challenge. Methods: A BMP9-neutralizing antibody was administrated to healthy adult mice, and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human lung endothelial cells. The impact of BMP9 administration was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and from endotoxemic mice. Measurements and Main Results: Subacute neutralization of endogenous BMP9 in mice (N = 12) resulted in increased lung vascular permeability (P = 0.022), interstitial edema (P = 0.0047), and neutrophil extravasation (P = 0.029) compared with IgG control treatment (N = 6). In pulmonary endothelial cells, BMP9 regulated transcriptome pathways implicated in vascular permeability and cell-membrane integrity. Augmentation of BMP9 signaling in mice (N = 8) prevented inhaled LPS-induced lung injury (P = 0.0027) and edema (P < 0.0001). In endotoxemic mice (N = 12), endogenous circulating BMP9 concentrations were markedly reduced, the causes of which include a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human patients with sepsis (N = 10), circulating concentratons of BMP9 were also markedly reduced (P < 0.0001). Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial-protective factor, downregulated during inflammation. Exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in lung injury.

Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism.

Liver metabolism follows diurnal fluctuations through the modulation of molecular clock genes. Disruption of this molecular clock can result in metabolic disease but its potential regulation by immune cells remains unexplored. Here, we demonstrated that in steady state, neutrophils infiltrated the mouse liver following a circadian pattern and regulated hepatocyte clock-genes by neutrophil elastase (NE) secretion. NE signals through c-Jun NH2-terminal kinase (JNK) inhibiting fibroblast growth factor 21 (FGF21) and activating Bmal1 expression in the hepatocyte. Interestingly, mice with neutropenia, defective neutrophil infiltration or lacking elastase were protected against steatosis correlating with lower JNK activation, reduced Bmal1 and increased FGF21 expression, together with decreased lipogenesis in the liver. Lastly, using a cohort of human samples we found a direct correlation between JNK activation, NE levels and Bmal1 expression in the liver. This study demonstrates that neutrophils contribute to the maintenance of daily hepatic homeostasis through the regulation of the NE/JNK/Bmal1 axis.

Every day, the body's biological processes work to an internal clock known as the circadian rhythm. This rhythm is controlled by 'clock genes' that are switched on or off by daily physical and environmental cues, such as changes in light levels. These daily rhythms are very finely tuned, and disturbances can lead to serious health problems, such as diabetes or high blood pressure. The ability of the body to cycle through the circadian rhythm each day is heavily influenced by the clock of one key organ: the liver. This organ plays a critical role in converting food and drink into energy. There is evidence that neutrophils ­ white blood cells that protect the body by being the first response to inflammation ­ can influence how the liver performs its role in obese people, by for example, releasing a protein called elastase. Additionally, the levels of neutrophils circulating in the blood change following a daily pattern. Crespo, González-Terán et al. wondered whether neutrophils enter the liver at specific times of the day to control liver's daily rhythm. Crespo, González-Terán et al. revealed that neutrophils visit the liver in a pattern that peaks when it gets light and dips when it gets dark by counting the number of neutrophils in the livers of mice at different times of the day. During these visits, neutrophils secreted elastase, which activated a protein called JNK in the cells of the mice's liver. This subsequently blocked the activity of another protein, FGF21, which led to the activation of the genes that allow cells to make fat molecules for storage. JNK activation also switched on the clock gene, Bmal1, ultimately causing fat to build up in the mice's liver. Crespo, González-Terán et al. also found that, in samples from human livers, the levels of elastase, the activity of JNK, and whether the Bmal1 gene was switched on were tightly linked. This suggests that neutrophils may be controlling the liver's rhythm in humans the same way they do in mice. Overall, this research shows that neutrophils can control and reset the liver's daily rhythm using a precisely co-ordinated series of molecular changes. These insights into the liver's molecular clock suggest that elastase, JNK and BmaI1 may represent new therapeutic targets for drugs or smart medicines to treat metabolic diseases such as diabetes or high blood pressure.

The role of stress kinases in metabolic disease.

Obesity is a health condition that has reached pandemic levels and is implicated in the development and progression of type 2 diabetes mellitus, cancer and heart failure. A key characteristic of obesity is the activation of stress-activated protein kinases (SAPKs), such as the p38 and JNK stress kinases, in several organs, including adipose tissue, liver, skeletal muscle, immune organs and the central nervous system. The correct timing, intensity and duration of SAPK activation contributes to cellular metabolic adaptation. By contrast, uncontrolled SAPK activation has been proposed to contribute to the complications of obesity. The stress kinase signalling pathways have therefore been identified as potential targets for the development of novel therapeutic approaches for metabolic syndrome. The past few decades have seen intense research efforts to determine how these kinases are regulated in a cell-specific manner and to define their contribution to the development of obesity and insulin resistance. Several studies have uncovered new and unexpected functions of the non-classical members of both pathways. Here, we provide an overview of the role of SAPKs in metabolic control and highlight important discoveries in the field.

UV irradiation induces apoptosis in the human endometrial stromal cell line (ThESC).

PURPOSE: The treatment options of endometrial hyperplasia consist of surgical, interventional and medical therapies including apoptosis-inducing agents. The purpose of the study was to evaluate the effects of ultraviolet (UV) radiation on the viability and the type of cell death on the human endometrial stromal cells (ThESC) line. METHODS: We investigated the effect of UV exposure on human endometrial stromal cell line (ThESC) on cell viability using MTT assay as well as changes in cell morphology using phase microscopy and acridine orange (AO)/ethidium bromide (EB) cell staining. RESULTS: UV treatment significantly decreased the percentage of the viable ThESC cells compared to the viability of untreated control cells using MTT assay (p<0.05). In addition, UV treatment of ThESC cells for 60 and 90 min induced high level of cell morphology disruption, followed with loss of both the cell shape and the presence of defragmented debris and stained with intense red color. CONCLUSIONS: The obtained results suggest the potential role of UV light application as additional treatment option of benign endometrium hyperplasia alone or in combination with other treatment modalities.

Circulating NEDD9 is increased in pulmonary arterial hypertension: A multicenter, retrospective analysis.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a highly morbid disease characterized by elevated pulmonary vascular resistance (PVR) and pathogenic right ventricular remodeling. Endothelial expression of the prometastatic protein NEDD9 is increased in fibrotic PAH arterioles, and NEDD9 inhibition decreases PVR in experimental PAH. We hypothesized that circulating NEDD9 is increased in PAH and informs the clinical profile of patients. METHODS: Clinical data and plasma samples were analyzed retrospectively for 242 patients from 5 referral centers (2010-2017): PAH (n = 139; female 82%, 58 [48-67] years), non-PAH pulmonary hypertension (PH) (n = 54; female 56%, 63.4 ± 12.2 years), and dyspnea non-PH controls (n = 36; female 75%, 54.2 ± 14.0 years). RESULTS: Compared with controls, NEDD9 was increased in PAH by 1.82-fold (p < 0.0001). Elevated NEDD9 correlated with PVR in idiopathic PAH (ρ = 0.42, p < 0.0001, n = 54), connective tissue disease (CTD)-PAH (ρ = 0.53, p < 0.0001, n = 53), and congenital heart disease-PAH (ρ = 0.68, p < 0.0001, n = 10). In CTD-PAH, NEDD9 correlated with 6-minute walk distance (ρ = -0.35, p = 0.028, n = 39). In contrast to the PAH biomarker N-terminal pro-brain natriuretic peptide (n = 38), NEDD9 correlated inversely with exercise pulmonary artery wedge pressure and more strongly with right ventricular ejection fraction (ρ = -0.41, p = 0.006, n = 45) in a mixed population. The adjusted hazard ratio for lung transplant-free survival was 1.12 (95% confidence interval [CI], 1.02-1.22, p = 0.01) and 1.75 (95% CI, 1.12-2.73, p = 0.01) per 1 ng/ml and 5 ng/ml increase in plasma NEDD9, respectively, by Cox proportional hazard model. CONCLUSIONS: In PAH, plasma NEDD9 is increased and associates with key prognostic variables. Prospective studies that include hard end points are warranted to validate NEDD9 as a novel PAH biomarker.

Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension.

Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor.Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH.Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260).Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations.Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.