Activation of Nlrp3 Inflammasomes Enhances Macrophage Lipid-Deposition and Migration: Implication of a Novel Role of Inflammasome in Atherogenesis

Although Nlrp3 inflammasome activation in macrophages has been shown to be critical for the development of atherosclerosis upon atherogenic stimuli, it remains unknown whether activated Nlrp3 inflammasomes by other non-atherogenic stimuli induce alterations in macrophages that may contribute in the concert with other factors to atherogenesis. Thus, the present study tested the hypothesis that activation of Nlrp3 inflammasomes by ATP, which is a classical non-lipid danger stimulus, enhances the migration of macrophage and increases lipids deposition in macrophages accelerating foam cell formation. We first demonstrated that extracellular ATP (2.5 mM) markedly increased the formation and activation of Nlrp3 inflammasomes in bone marrow macrophages (BMMs) from wild type (Asc+/+) mice resulting in activation of caspase-1 and IL-1β production. In these Asc+/+ macrophages, such stimulation of inflammasomes by non-lipid ATP was similar to those induced by atherogenic stimuli such as cholesterol crystals or 7-ketocholesterol. Both non-lipid and lipid forms of stimuli induced formation and activation of Nlrp3 inflammasomes, which were prevented by Asc gene deletion. Interestingly, Asc+/+ BMMs had dramatic lipids accumulation after stimulation with ATP. Further, we demonstrated that large amount of cholesterol was accumulated in lysosomes of Asc+/+ BMMs when inflammasomes were activated by ATP. Such intracellular and lysosomal lipids deposition was not observed in Asc−/− BMMs and also prevented by caspase-1 inhibitor WEHD. In addition, in vitro and in vivo experiments revealed that migration of Asc+/+ BMMs increased due to stimulation of Nlrp3 inflammasomes, which was markedly attenuated in Asc−/− BMMs. Together, these results suggest that activation of Nlrp3 inflammasomes remarkably increases the susceptibility of macrophages to lipid deposition and their migration ability. Such novel action of inflammasomes may facilitate entry or retention of macrophages into the arterial wall, where they form foam cells and ultimately induce atherosclerosis

Redox Regulation of NLRP3 Inflammasomes: ROS as Trigger or Effector?

Significance: Inflammasomes are multiprotein complexes localized within the cytoplasm of the cell that are responsible for the maturation of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, and the activation of a highly inflammatory form of cell death, pyroptosis. In response to infection or cellular stress, inflammasomes are assembled, activated, and involved in host defense and pathophysiology of diseases. Clarification of the molecular mechanisms leading to the activation of this intracellular inflammatory machinery may provide new insights into the concept of inflammation as the root of and route to human diseases. Recent Advances: The activation of inflammasomes, specifically the most fully characterized inflammasome—the nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome, is now emerging as a critical molecular mechanism for many degenerative diseases. Several models have been developed to describe how NLRP3 inflammasomes are activated, including K+ efflux, lysosome function, endoplasmic reticulum (ER) stress, intracellular calcium, ubiquitination, microRNAs, and, in particular, reactive oxygen species (ROS). Critical Issues: ROS may serve as a “kindling” or triggering factor to activate NLRP3 inflammasomes as well as “bonfire” or “effector” molecules, resulting in pathological processes. Increasing evidence seeks to understand how this spatiotemporal action of ROS occurs during NLRP3 inflammasome activation, which will be a major focus of this review. Future Directions: It is imperative to know how this dual action of ROS works during NLRP3 inflammation activation on different stimuli and what relevance such spatiotemporal redox regulation of NLRP3 inflammasomes has in cell or organ functions and possible human diseases

JOB SEARCH SYSTEM USING INTELLIGENT AGENT

Finding jobs that best suits the interests and skill set is quite a challenging task for the job seekers. The difficulties arise from not having proper knowledge on the organization’s objective, their work culture and current job openings. Summer jobs are becoming year-round side work. Even I’m rolling up my sleeves on the path of researching the best apps that will put to work on tasks, jobs and chores in one’s extra time. We set the hours and the amount of time you want to carve out for this side work. An app for finding small paid work in your local area. It is for users who are in need of some quick cash and willing to do small works like repairing a computer, babysitting, mowing a lawn and other similar tasks

An Efficient Single Instance Scheme With User Authentication To Cloud Data

Cloud Storage is a computer data storage method where digital data is stored on servers in off-site locations, managed by a third-party provider. This enables organizations to store, access, and maintain data without owning and operating their own data centers. Cloud storage is scalable, allowing organizations to expand or reduce their data footprint depending on their needs. Users upload data to servers via internet, which is saved on a virtual machine on a physical server. Cloud providers often spread data to multiple virtual machines in global data centers to maintain availability and redundancy. Google Cloud offers various scalable options for organizations to store their data in the cloud. The widespread use of cloud computing has made data sharing and storage more accessible, but concerns about data integrity, efficiency, and privacy remain. Duplication, a popular method of data compression, is used to reduce duplicate copies of data in cloud storage. However, data duplication also raises security and privacy concerns, as users' confidential data is vulnerable to attacks from insiders and outsiders. Traditional solutions for duplication, based on convergent encryption, provide confidentiality but do not maintain duplicate checks based on differential permissions. This paper proposes an approved data duplication plan that counts the number of users with differential privileges in the duplicate check.Users with differential privileges are added to the duplicate check, and files are encrypted with differential privilege keys to maintain stronger security. Users can only access files marked with matching privileges for copy checks. A third-party auditor can confirm file occurrence after duplication in the cloud, ensuring timely uploads. This paper offers advantages for both storage providers and users through duplication systems and auditing method

Effect of chronic administration of Boerhaavia diffusa Linn. leaf extract on experimental diabetes in rats

Purpose: The root and aerial parts of Boerhaavia diffusa Linn. (Nyctaginaceae) were used in Ayurveda for the treatment of diabetes. The present study is aimed at evaluating the antidiabetic activity of chloroform extract of Boerhaavia diffusa leaves on chronic administration in streptozotocin-induced non-insulin-dependent diabetes mellitus (NIDDM) model diabetic rats. Methods: The blood glucose lowering activity of the leaf extract was studied in streptozotocin-induced (65 mg/kg, i.v.) NIDDM model diabetic rats after oral administration of the extract at daily doses of 50, 100 and 200 mg/kg body weight for four weeks and compared with glibenclamide. Blood samples were collected from the tail vein before and also at weekly intervals for four weeks from the first dose of drug administration and blood glucose was analyzed by glucose-oxidase method using a visible spectrophotometer. Results: The leaf extract of B. diffusa produced dose-dependent reduction in blood glucose in streptozotocin-induced NIDDM rats comparable to that of glibenclamide. The results indicate that the reduction in blood glucose produced by the extract is probably through rejuvenation of pancreatic b-cells or through extrapancreatic action. Conclusion: The chloroform extract of Boerhaavia diffusa has significant antidiabetic activity and this supports the traditional usage of the plant by Ayurvedic physicians for the control of diabetes. Keywords: Blood glucose, Boerhaavia diffusa, Diabetes mellitus Streptozotocin, Rats> Tropical Journal of Pharmaceutical Research Vol. 3 (1) 2004: pp. 305-30

Gala Umong: Tradisi Gadai di Kecamatan Indarajaya Kabupaten Pidie (Kajian Tradisi Kebudayaan dan Usaha Solutif Terhadap Praktek Gadai yang Menyalahi Hukum Islam)

Nama : Usman Boini NIM : 121309891 Fakultas/Prodi : Syari’ah dan Hukum/ Hukum Ekonomi Syariah Judul Skripsi : Gala Umong: tradisi gadai di kecamatan indarajaya kabupaten pidie ( Kajian Tradisi Kebudayaan dan Usaha Solutif Terhadap Praktek Gadai yang Menyalahi Hukum Islam) Tanggal Sidang : 19 Juli 2017 Tebal Skripsi : 62 Halaman Pembimbing I : Dr. Ridwan Nurdin, MCL Pembimbing II : Gamal Achyar, Lc. MA Praktik gadai (rahn) yang dilakukan oleh masyarakat Kecamatan Indra Jaya Kabupaten Pidie pada umumnya dipraktikkan dalam hal gadai sawah atau yang lebih dikenal oleh masyarakat setempat dengan istilah gala umong. Praktik gala umong (gadai sawah) yang dilakukan oleh masyarakat setempat secara umum hampir sama dengan praktik gala umong (gadai sawah) yang dipraktikkan oleh masyarakat Aceh pada umumnya yang mana sistem tersebut diadopsi secara turun temurun dari masyarakat terdahulu yang sudah menjadi hukum adat setempat, akan tetapi sistem praktik gala umong (gadai sawah) tersebut tidak sesuai dengan hukum Islam, dan hal ini tentu saja perlu dicari usaha solutif untuk mengubah pola praktik semacam ini supaya sesuai dengan hukum Islam. Penelitian ini bertujuan untuk mengetahui praktik gala umong (gadai sawah) di Kecamatan Indra Jaya Kabupaten Pidie dan usaha solutif yang dilakukan oleh masyarakat Kecamatan Indra jaya Kabupaten Pidie terhadap praktik gala umong (gadai sawah) yang menyalahi hukum Islam. Penelitian ini menggunakan metode deskriptif dan analisis dengan pendekatan kualitatif. Data yang diambil melalui library research dan field research, dengan teknik pengumpulan data observasi dan wawancara. Dari hasil penelitian diketahui bahwa praktik gala umong (gadai sawah) yang dilakukan oleh masyarakat Kecamatan Indra Jaya Kabupaten Pidie dipraktikkan menurut hukum adat yang sudah ada sejak lama secara turun temurun meskipun hukum adat tersebut tidak dituangkan ke dalam qanun dan praktik gala umong (gadai sawah) tersebut tidak sesuai dengan konsep gadai (rahn) dalam hukum Islam karena mengandung unsur riba. Sedangkan untuk usaha solutif yang dilakukan oleh masyarakat Kecamatan Indra jaya Kabupaten Pidie terhadap praktik gala umong (gadai sawah) yang menyalahi hukum Islam adalah belum ada langkah yang nyata yang dilakukan oleh masyarakat setempat karena menurut masyarakat setempat sistem praktik gala umong (gadai sawah) tersebut sudah dipraktikkan sejak lama dan sudah menjadi hukum adat setempat sehingga sangat sulit untuk diubah

The effects of chestnut orchard microclimate on burr development

Chestnut crop is regaining its fame worldwide with powerful investment perspectives. Unluckily the climate change effects are posing high threat to its cultivation with less available resources and increased production cost both in traditional and specialized orchards. Additionally, the chestnut physiological knowledge is still limited, especially as concern the burr development (i.e., the economical production target) and its relationship with the environmental parameters. The aim of the present study was to evaluate the seasonal, daily, and hourly burr growth pattern associated to environmental parameters for improving physiological knowledge on this species. The study was carried out in a traditional rainfed sweet chestnut orchard located in the Tuscan-Emilian Apennines (Monterenzio, Italy). The chestnut burr growth was measured, along the entire season, both with a digital calliper and through the use of plant-based sensors (fruit-gauges) that permitted to measure, in real-time, the burr growth pattern. Environmental data were recorded by a weather station placed in the middle of the orchard. Results evidenced a higher burr growth rate, in the last part of the season (from middle-end of August to full fall) while the daily growing pattern was characterized by increased oscillation, along the season, of night-swelling and daily-shrinkage. The night-swelling was found to be influenced by high nocturnal air relative humidity while the daily-shrinkage was influenced by the higher wind speed, solar radiation and vapour pressure deficit. Thus, the burr daily net growth can be associated, depending on the phenological stages, to environmental parameters. Precipitation but especially the atmosphere humidity, in September and October, were the main external drivers of burr daily net growth. These results could be promising for the adoption of sustainable (e.g., late season grass mowing, sprinkler irrigation) and smart practices for improving chestnut management in both traditional and specialized orchards

Impact of cancer occurrence on health-related quality of life: A longitudinal pre-post assessment

BACKGROUND: Investigations focusing and implementing on the impact of cancer on health-related quality of life (HRQoL) by the way of a mean comparison between cancer patients and subjects from the general population, are scarce and usually cross-sectional. Longitudinal application of HRQoL instruments to a general, initially healthy population allows for change to be assessed as an event occurs, rather than afterwards. The objective of the present study was to investigate the impact of new cancer on HRQoL. METHODS: The 36-item Short Form (SF-36) and 12-item General Health Questionnaire (GHQ-12) were applied to the French SU.VI.MAX cohort in 1996 and 1998. A controlled longitudinal study was used to determine the impact on HRQoL of newly diagnosed cancer: 84 patients with cancer that occurred between the 2 HRQoL measures were compared with 420 age- and sex-matched cancer-free controls. RESULTS: Initial HRQoL level was similar in the two groups. A new cancer had a particularly marked effect on the SF-36 Physical functioning, Role-physical and General health dimensions (more than 6.6-point difference in change in HRQoL evolution on a 0–100 scale). The Bodily pain and Vitality dimensions were less severely affected (difference in change varying from 4.4 to 6.3 points), and there was no effect on either the GHQ-12 score or the SF-36 Mental health, Role-emotional and Social functioning dimensions. CONCLUSIONS: The negative impact of cancer on the lives of patients was assessed in terms of HRQoL. The aspects most likely to be affected were those with a physical component, and general health perceptions. These results can thus help quantify the impact of a new cancer on HRQoL evolution and potentially facilitate early intervention by identifying the most affected HRQoL domains

Rolle von SGK1 in der Salzempfindlichkeit von Blutdruck und der Glukoseaufnahme : Studien in Knockoutmäusen

Excess salt intake increases blood pressure particularly during states of hyperinsulinism and insulin resistance. Insulin is presumably effective through activation of ENaC. Excess salt intake further decreases peripheral glucose uptake thus impairing glucose tolerance. Stimulation of both, the epithelial Na+ channel ENaC and of cellular glucose uptake involves phosphatidylinositide 3-kinase (PI-3K) which signals through protein kinase B (Akt/PKB) and all three members of the serum and glucocorticoid inducible kinase (SGK) family of kinases SGK1, SGK2 and SGK3. All three kinases have been previously shown to modify a variety of transporters including ENaC and the glucose transporter SGLT1. To explore the role of SGK1 in salt sensitive hypertension and peripheral glucose uptake, experiments were performed in male or female SGK1 knockout mice (sgk1-/-) and their wild type littermates (sgk1+/+) which were subjected to standard diet, high-fat diet, high fructose diet or dexamethasone treatment and allowed free access to either tap water (control-salt) or 1% saline (high-salt). Under control diet fluid intake, blood pressure, urinary flow rate and urinary Na+, K+, Cl- excretion were similar in sgk1-/- and sgk1+/+mice, plasma aldosterone concentration was however significantly higher in sgk1-/- (1.22 ± 0.18 ng/ml) than in sgk1+/+mice (0.57 ± 0.11 ng/ml). Under standard diet, high-salt-intake (1% NaCl in drinking water for 25 days) increased fluid intake, urinary flow rate and urinary Na+, K+, Cl- excretion similarly in sgk1-/- and sgk1+/+mice without significantly altering blood pressure. High-fat-diet alone (17 weeks) did not significantly alter fluid intake, urinary flow rate, urinary Na+, K+, Cl- excretion or plasma aldosterone levels, but increased plasma insulin, total cholesterol and triglyceride concentrations as well as systolic blood pressure to the same extent in both genotypes. Additional high-salt-intake (1% NaCl in drinking water for 25 days) on top of high-fat-diet did not affect hyperinsulinemia nor hyperlipidemia but increased fluid intake, urinary flow rate and urinary NaCl excretion significantly more in sgk1-/- than in sgk1+/+mice. Furthermore, in animals receiving high fat diet, additional salt intake increased blood pressure only in sgk1+/+mice (132 ± 3 mmHg) but not in sgk1-/-mice (120 ± 4 mmHg). Renal SGK1 protein abundance of sgk1+/+ mice was significantly elevated following high fat diet. During control diet, fluid intake, urinary flow rate, urinary Na+, K+ and Cl- excretion and blood pressure were similar in sgk1-/- and sgk1+/+ mice. Addition of 10 % fructose to drinking water increased fluid intake and urinary flow rate in both genotypes and did not significantly alter urinary Na+, K+ and Cl- output in neither genotype. Additional high NaCl diet (4 % NaCl) did not significantly alter fluid intake and urine volume but markedly increased urinary output of Na+ and Cl-, approaching values significantly (p < 0.05) larger in sgk1-/- than in sgk1+/+ mice. Blood pressure was similar in sgk1+/+ and sgk1-/- mice at control diet or fructose alone but increased only in sgk1+/+ mice (115 ± 1 vs. 103 ± 0.7 mmHg, p < 0.05) following combined fructose and high salt intake. Renal SGK1 transcript levels of sgk1+/+ mice were significantly elevated following fructose diet. Acute intravenous insulin infusion (during glucose clamp) caused antinatriuresis in sgk1+/+ mice, an effect significantly blunted in sgk1-/- mice. The observations reveal a pivotal role of SGK1 in insulin mediated sodium retention and the salt sensitizing hypertensive effect of high fructose intake. Prior to dexamethasone treatment, the fluid intake, urinary flow rate, urinary Na+, K+ and Cl- excretion, plasma electrolyte and glucose concentrations as well as blood pressure were similar in sgk1-/- and sgk1+/+ mice. Dexamethasone treatment (3mg/kg, b.w. i.p. for 14 days) did not significantly alter renal Na+, K+ and Cl- excretion, but it tended to decrease renal Ca2+ excretion in sgk1+/+ mice but significantly increased renal Ca2+ excretion in sgk1-/- mice and significantly decreased renal phosphate excretion in sgk1+/+ mice. Dexamethasone treatment significantly increased fasting blood glucose concentrations in both genotypes. Dexamethasone treatment significantly increased blood pressure in sgk1+/+ mice, an effect significantly blunted in sgk1-/- mice. The subsequent replacement of the tap drinking water with saline increased the fluid intake, urinary flow rate and urinary NaCl excretion in both genotypes but increased plasma K+ concentration only in sgk1-/- mice. Saline loading increased blood pressure in both, sgk1-/- and sgk1+/+ mice and dissipated the difference between genotypes. Intraperitoneal injection of glucose (3g/kg/body-weight) into sgk1+/+ mice transiently increased plasma glucose concentration approaching significantly higher values ([glucose]p,max) in high-salt (281 ± 39 mg/dl) than in control animals (164 ± 23 mg/dl). DOCA did not significantly modify [glucose]p,max in control sgk1+/+ mice but significantly decreased [glucose]p,max in high-salt sgk1+/+ mice, an effect reversed by spironolactone (50 mg/kg/body-weight). [glucose]p,max was in sgk1-/-mice insensitive to high-salt and significantly higher than in control sgk1+/+mice. Uptake of 3H-deoxy-glucose into skeletal muscle and fat tissue was significantly smaller in sgk1-/- mice than in sgk1+/+ mice and decreased by high-salt in sgk1+/+ mice. According to Western blotting, high-salt decreased and DOCA (35 mg/kg/body-weight) increased SGK1 protein abundance in skeletal muscle and fat tissue of sgk1+/+ mice. Transfection of HEK293 cells with active S422DSGK1 but not inactive K127NSGK stimulated phloretin-sensitive glucose uptake. In conclusion, lack of SGK1 protects against the hypertensive effects of combined high-fat-diet/high-salt-intake or high fructose/high salt diet and mediates the salt sensitive peripheral glucose uptake. The present observations provide insight into prerequisites for the SGK1 dependent increase of blood pressure and thus may provide a clue to the increased blood pressure in those 5% of the common population carrying the SGK1 gene variant. The observations suggest that SGK1 plays a critical role in the hypertensive effect of hyperinsulinism. As a gain of function gene variant of SGK1 could simultaneously increase blood pressure and body mass index, SGK1 may indeed be one of the signalling molecules contributing to metabolic syndrome or syndrome X, a condition characterized by the coincidence of several disorders including hypertension, obesity, insulin resistance and hyperinsulinemia. Metabolic syndrome shares several attributes of Cushing´s syndrome, but does not require increased plasma cortisol levels. Instead, the disorder may be caused by inappropriate activity of downstream signaling elements which could well include the serum and glucocorticoid inducible kinase SGK1.Exzessive Salzaufnahme erhöht den Blutdruck, besonders unter Hyperinsulinämie und Insulinresistenz. Insulin wirkt vermutlich über Aktivierung des epithelialen Natriumskanals ENaC. Weiterhin vermindert exzessive Salzaufnahme die periphere Glucoseaufnahme und beeinträchtigt somit die Glucosetoleranz. Bei der Stimulation des epithelialen Natriumkanals ENaC als auch der zellulären Glucoseaufnahme ist die Phosphatidylinositol-3-kinase (PI-3K) beteiligt, deren Signalkaskade die Proteinkinase B (Akt/PKB) und alle drei Mitglieder der Serum- und Glukokortikoid-induzierbaren Kinase (SGK)-Familie SGK1, SGK2 und SGK3 einschließt. Für alle drei Kinasen wurde kürzlich gezeigt, dass sie eine Vielzahl von Transportern regulieren, darunter ENaC und den Glucosetransporter SGLT1. Um die Rolle von SGK1 bei salzabhängiger Hypertonie und peripherer Glucoseaufnahme zu untersuchen, wurden Experimente in SGK1-Knockout-Mäusen (sgk1-/-) und den Wildtyp-Geschwistern (sgk1+/+) durchgeführt, die einer Standard-Diät, einer fettreichen Diät, einer hohen Fructose-Diät und Dexamethasonbehandlung unterzogen wurden und die freien Zugang entweder zu Leitungswasser (Kontrolle) oder zu 1%iger NaCl-Lösung (hohe Salzzufuhr) hatten. Unter Kontrollbedingungen waren Flüssigkeitsaufnahme, Blutdruck, Harnflussrate und Ausscheidung von Na+, K+ und Cl- mit dem Urin bei sgk1-/-- und sgk1+/+-Mäusen ähnlich, die Plasma-Aldosteron-Konzentration war jedoch bei sgk1-/--Mäusen (1.22 ± 0.18 ng/ml) signifikant höher als bei sgk1+/+-Mäusen (0.57 ± 0.11 ng/ml). Unter Standarddiät erhöhte eine hohe Salzzufuhr (1% NaCl im Trinkwasser für 25 Tage) Flüssigkeitsaufnahme, Harnflussrate und Urin-Ausscheidung von Na+, K+ und Cl- bei sgk1-/-- und sgk1+/+-Mäusen in ähnlicher Weise ohne den Blutdruck signifikant zu ändern. Eine alleinige fettreiche Diät über 17 Wochen änderte Flüssigkeitsaufnahme, Harnflussrate, Urin-Ausscheidung von Na+, K+ und Cl- oder die Plasma-Aldosteron-Spiegel nicht signifikant, aber erhöhte bei beiden Genotypen die Plasmainsulinspiegel im gleichen Ausmaß, die Plasmakonzentrationen von Gesamtcholesterin und Triglyceriden ebenso wie den systolischen Blutdruck. Eine zur fettreichen Diät zusätzlich verabreichte Salzzufuhr (1% NaCl im Trinkwasser für 25 Tage) beeinflusste weder Hyperinsulinämie noch Hyperlipidämie, aber Flüssigkeitsaufnahme, Harnflussrate und Urin-Ausscheidung von Na+ und Cl-. Letztere waren bei sgk1-/--Mäusen im Vergleich zu sgk1+/+-Mäusen signifikant erhöht. Diese Behandlung erhöhte nur bei sgk1+/+-Mäusen den Blutdruck (132 ± 3 mmHg) nicht jedoch bei sgk1-/--Mäusen (120 ± 4 mmHg). Die Proteinexpression der SGK1 in der Niere war bei sgk1+/+-Mäusen nach einer fettreichen Diät signifikant erhöht. Ein Zusatz von 10% Fructose zum Trinkwasser erhöhte Flüssigkeitsaufnahme und Harnflussrate bei beiden Genotypen und änderte die Urin-Ausscheidung von Na+, K+ and Cl- nicht. Eine zusätzliche Salzbelastung in Form einer NaCl-reichen Diät (4% NaCl) änderte Flüssigkeitsaufnahme und Harnvolumen nicht signifikant, aber erhöhte deutlich die Urin-Ausscheidung von Na+ und Cl- und erreichte bei sgk1-/--Mäusen signifikant höhere Werte als bei sgk1+/+-Mäusen. Der Blutdruck war bei sgk1+/+- und sgk1-/--Mäusen unter Kontrolldiät oder alleiniger Fructosezugabe ähnlich und war nur bei sgk1+/+-Mäusen (115 ± 1 vs. 103 ± 1 mmHg) unter einer kombinierten Fructose- und hohen Salzaufnahme erhöht. Eine akute intravenöse Insulininfusion unter gleichzeitiger Glucoseinfusion bewirkte in sgk1+/+-Mäusen eine Antinatriurese. Dieser Effekt war bei sgk1-/--Mäusen signifikant abgeschwächt. Die Beobachtungen zeigten, dass SGK1 bei Insulin-vermittelter Natriumretention und bei salzabhängigen hypertensiven Effekten durch hohe Fructoseaufnahme eine zentrale Rolle spielt. Vor Behandlung mit Dexamethason waren Flüssigkeitsaufnahme, Harnflussrate, Urin-Ausscheidung von Na+, K+ and Cl-, Plasmaelektrolyt- und Glucosekonzentrationen ebenso wie Blutdruck bei sgk1-/-- und sgk1+/+-Mäusen ähnlich. Behandlung mit Dexamethason (3mg/kg Körpergewicht, i.p. für 14 Tage) veränderte die renale Na+-, K+- und Cl--Ausscheidung nicht signifikant, aber verringerte die renale Ca2+-Ausscheidung bei sgk1+/+-Mäusen tendenziell, bei sgk1-/--Mäusen kam es allerdings zu einer signifikanten Erhöhung der renalen Ca2+-Ausscheidung. Die Dexamethason-Behandlung erhöhte die Blutglucosekonzentration nach Fasten bei beiden Genotypen signifikant. Darüberhinaus, erhöhte die Dexamethason-Behandlung den Blutdruck bei sgk1+/+-Mäusen signifikant, dieser Effekt war bei sgk1-/--Mäusen signifikant abgeschwächt. Im folgenden wurde das Trinkwasser mit Salz versetzt, was Flüssigkeitsaufnahme, Harnflussrate und NaCl-Ausscheidung im Urin bei beiden Genotypen erhöhte, die Plasma-K+-Konzentration jedoch nur bei sgk1-/--Mäusen erhöhte. Die Salzlast erhöhte den Blutdruck sowohl bei sgk1-/-- als auch bei sgk1+/+-Mäusen und es gab keinen Unterschied zwischen beiden Genotypen. Während eines intraperitonealen Glucosetoleranztests (3g/kg/Körpergewicht) in sgk1+/+-Mäusen stieg die Plasmaglucosekonzentration vorübergehend an und erreichte dabei bei Mäusen unter NaCl-reichen Diät (281 ± 39 mg/dl) signifikant höhere Spitzenwerte als bei den Kontrolltieren (164 ± 23 mg/dl). DOCA (35 mg/kg/KG) alleine veränderte in der Kontrollgruppe der sgk1+/+-Mäuse die Spitzenwerte nicht signifikant, aber verminderte diese signifikant unter gleichzeitiger NaCl-reichen Diät. Dieser Effekt konnte durch Spironolacton (50 mg/kg/KG) umgekehrt werden. Die Spitzenwerte waren bei sgk1-/--Mäusen unabhängig von hoher Salzdiät signifikant höher als in der Kontrollgruppe der sgk1+/+-Mäuse. Die Aufnahme von 3H-desoxy-glucose in den Skelettmuskel und ins Fettgewebe war bei sgk1-/--Mäusen signifikant geringer als bei sgk1+/+-Mäusen und bei sgk1+/+-Mäusen durch eine hohe Salzdiät verringert. Im Western-Blot verminderte eine hohe Salzzufuhr die Proteinexpression der SGK1 im Skelettmuskel und im Fettgewebe von sgk1+/+-Mäusen, DOCA erhöhte diese. Die Transfektion von HEK293-Zellen mit aktivem S422DSGK1, aber nicht inaktivem K127NSGK stimulierte die Phloretin-abhängige Glucoseaufnahme. Schlussfolgernd kann man sagen, dass ein Mangel an SGK1 vor hypertensiven Effekten unter kombinierter hoher Fettdiät und hoher Salzzufuhr oder unter hoher Fructosezufuhr und hoher Salzdiät schützt und die salzabhängige periphere Glucoseaufnahme moduliert. Die aktuellen Beobachtungen ergeben Hinweise für die SGK1-abhängige Steigerung des Blutdrucks und stellen damit möglicherweise einen Erklärungsansatz für den erhöhten Blutdruck bei jenen 5% der Gesamtbevölkerung mit einem SGK1-Genpolymorphismus dar. Die Beobachtungen lassen vermuten, dass die SGK1 eine entscheidende Rolle im Hinblick auf hypertensive Effekte unter Hyperinsulinämie spielt. Da eine Überfunktion der SGK1-Genvariante gleichzeitig den Blutdruck und den Körpermassenindex BMI erhöhen könnte, ist SGK1 vermutlich in der Tat eines der Signalmoleküle, das zum metabolischen Syndrom oder Syndrom X führt, ein Zustand, der durch das Zusammenwirken mehrerer Funktionsstörungen charakterisiert ist, darunter Bluthochdruck, Übergewicht, Insulinresistenz und Hyperinsulinämie. Das metabolische Syndrom hat einige Merkmale mit dem Cushing-Syndrom gemeinsam, aber weist keinen erhöhten Plasma-Cortisolspiegel auf. Stattdessen wird die Störung vermutlich von unangemessen erhöhter Aktivität von "downstream"-Signalelementen verursacht, die durchaus die Serum- und Glukokortikoid-induzierbare Kinase SGK1 miteinschließen könnte