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PubMed1989

Temperature-sensitive sec mutants of Escherichia coli: inhibition of protein export at the permissive temperature.

Phenotypes of secY and secA temperature-sensitive mutants at permissive (low) temperature have been examined. The secY24 mutant was found to be extremely susceptible to export inhibition by a basal-level synthesis of the MalE-LacZ 72-47 hybrid protein or to overproduction of a normal secretory protein such as maltose-binding protein or beta-lactamase. Comparison of this phenotype of secY24 with those of the secY100 and secA51 mutants under similar conditions suggested that MalE-LacZ protein and overproduced secretory protein do not nonspecifically enhance the partial secretion defect but act synergistically with secY24 to inhibit protein export.

Bacterial Outer Membrane Proteins↗
PubMed1991

A novel Saccharomyces cerevisiae secretory mutant possesses a thermolabile phosphomannose isomerase.

A temperature-sensitive mutant of Saccharomyces cerevisiae was identified which at the restrictive temperature of 37 degrees C is unable to secrete a number of cell wall-associated proteins and thus resembles previously reported sec mutants. In contrast to other sec mutants, however, both the temperature-sensitive growth and the secretion defects can be repaired by the addition of D-mannose to growth media. We show that the mutant possesses a single, apparently recessive mutation which leads to the production of a thermolabile phosphomannose isomerase.

Hot Temperature↗
PubMed1993

Multiple effects of lcrD mutations in Yersinia pestis.

Plasmid pCD1 of Yersinia pestis contains a low-calcium response stimulon responsible for the temperature- and calcium-regulated expression and secretion of proteins involved in virulence, which include the V antigen and Yops. We have previously shown that insertional inactivation of the bicistronic lcrDR operon abolished the calcium requirement for growth at 37 degrees C and reduced expression of the V antigen and Yops. In this study, we constructed and characterized three mutants having nonpolar lcrD deletions. All three mutants lost the two main low-calcium response properties: a calcium requirement for growth at 37 degrees C and strong expression of the V antigen and Yops. The effects on virulence gene expression occurred at both the levels of transcription and secretion. The growth, transcription, and secretion defects could be at least partially complemented for two of the lcrD mutants by providing lcrD in trans. A third mutant could not be complemented, and a plasmid carrying this mutation had a dominant negative effect over normal LcrD function. In the three mutants, the amount of mutant LcrD protein detectable in immunoblots was inversely related to the amount of complementation. Taken together, these data indicate that LcrD function involves the interaction of LcrD with another molecule.

Amino Acid Sequence↗
PubMed1994

Genetic and molecular characterization of the Escherichia coli secD operon and its products.

The secD operon of Escherichia coli is required for the efficient export of proteins. We have characterized this operon, and found that, in addition to secD and secF, it contains the upstream gene yajC, but not the genes queA or tgt, in contrast to previous reports. An analysis of yajC mutations constructed in vitro and recombined onto the chromosome indicates that yajC is neither essential nor a sec gene. The secD operon is not induced in response to either secretion defects or temperature changes. TnphoA fusions have been used to analyze the topology of SecD in the inner membrane; the protein contains six transmembrane stretches and a large periplasmic domain. TnphoA fusions to SecD and SecF have also been recombined onto the chromosome and used to determine the level of these proteins within the cell. Our results indicate that there are fewer than 30 SecD and SecF molecules per cell.

Amino Acid Sequence↗
PubMed1996

Site-specific proteolysis of the Escherichia coli SecA protein in vivo.

A seven-amino-acid cleavage site specific for tobacco etch virus (TEV) protease was introduced into SecA at two separate positions after amino acids 195 and 252. Chromosomal wild-type secA was replaced by these secA constructs. Simultaneous expression of TEV protease led to cleavage of both SecA derivatives. In the functional SecA dimer, proteolysis directly indicated surface exposure of the TEV protease cleavage sites. Cleavage of SecA near residue 195 generated an unstable proteolysis product and a secretion defect, suggesting that this approach could be used to inactivate essential proteins in vivo.

Adenosine Triphosphatases↗
PubMed2000

Two regions of EpsL involved in species-specific protein-protein interactions with EpsE and EpsM of the general secretion pathway in Vibrio cholerae.

Extracellular secretion of proteins via the type II or general secretion pathway in gram-negative bacteria requires the assistance of at least 12 gene products that are thought to form a complex apparatus through which secreted proteins are translocated. Although this apparatus is specifically required only for the outer membrane translocation step during transport across the bacterial cell envelope, it is believed to span both membranes. The EpsE, EpsL, and EpsM proteins of the type II apparatus in Vibrio cholerae are thought to form a trimolecular complex that is required to either control the opening and closing of the secretion pore or to transduce energy to the site of outer membrane translocation. EpsL is likely to play an important role in this relay by interacting with both the cytoplasmic EpsE protein and the cytoplasmic membrane protein EpsM, which is predominantly exposed on the periplasmic side of the membrane. We have now extended this model and mapped the separate regions within EpsL that contain the EpsE and EpsM binding domains. By taking advantage of the species specificity of the type II pathway, we have used chimeric proteins composed of EpsL and its homologue, ExeL, from Aeromonas hydrophila together with either EpsE or its Aeromonas homologue, ExeE, to complement the secretion defect in both epsL and exeL mutant strains. These studies have mapped the species-specific EpsE binding site to the N-terminal cytoplasmic region between residues 57 and 216 of EpsL. In addition, the species-specific EpsM binding site was mapped to the C-terminal half of EpsL by coimmunoprecipitation of EpsM with different EpsL-ExeL chimeras. This site is present in the region between amino acids 216 and 296, which contains the predicted membrane-spanning segment of EpsL.

Bacterial Proteins↗
PubMed2006

A targeted apoB38.9 mutation in mice is associated with reduced hepatic cholesterol synthesis and enhanced lipid peroxidation.

Familial hypobetalipoproteinemia (FHBL) due to truncation-specifying mutations of apolipoprotein B (apoB), which impair hepatic lipid export in very low-density lipoprotein (VLDL) particles, is associated with fatty liver. In an FHBL-like mouse with the apoB38.9 mutation, fatty liver develops despite reduced hepatic fatty acid synthesis. However, hepatic cholesterol contents in apoB38.9 mice are normal. We found that cholesterogenic enzymes (3-hydroxy-3-methylglutaryl-coenzyme A reductase, sterol-C5-desaturase, and 7-dehydrocholesterol reductase) were consistently downregulated in two separate expression-profiling experiments using a total of 19 mice (n = 7 each for apob(+/+) and apob(+/38.9), and n = 5 for apob(38.9/38.9)) and Affymetrix Mu74Av2 GeneChip microarrays. Results were confirmed by real-time PCR. Cholesterol synthesis rates in cultured hepatocytes were reduced by 35% and 25% in apob(38.9/38.9) and apob(+/38.9), respectively, vs. apob(+/+). Hepatic triglycerides and lipid peroxides, the latter measured by thiobarbituric acid-reactive substances (TBARS) assay, were significantly elevated in apob(+/38.9) (117%) and apob(38.9/38.9) (132%) vs. apob(+/+) (100%), as were mRNA expression of the microsomal lipid peroxidizing enzymes Cyp4A10 and Cyp4A14. Hepatic lipid peroxide levels were positively correlated with triglyceride contents (r = 0.601, P = 0.0065). Thus the fatty liver due to a VLDL secretion defect is associated with insufficient adaptation to triglyceride accumulation and with increased lipid peroxidation. In contrast, apoB38.9 mice effectively maintain cholesterol homeostasis in the liver, at least in part, by reducing hepatic cholesterol synthesis.

Animals↗
PubMed1994

Adult growth hormone deficiency.

Several reports have focused on the clinical features of the untreated GH-deficient adult and the effect of GH therapy. The results reported are strikingly unanimous. Untreated GH-deficient adults have been shown to have increased cardiovascular mortality, reduced exercise capacity, reduced muscle strength, subnormal glomerular filtration rate and renal plasma flow, defective sweat secretion and defective thermoregulation, reduced energy expenditure and basal metabolic rate, abnormal thyroid hormone metabolism, reduced myocardial function and clinical signs of premature atherosclerosis. Body composition has been found abnormal with increased fat mass, decreased lean body mass, decreased muscle fat ratio, visceral obesity, reduced extracellular fluid volume and reduced bone mineral content. Furthermore, two independent groups have reported impaired psychological wellbeing as compared to normal subjects. Apart from the observation on total mortality, all the above-reported abnormalities improve during GH substitution. The only recognisable side effects so far has been fluid retention, which is usually transient and dose-dependent. It is concluded that GH deficiency has distinct clinical consequences all of which can be totally or partially alleviated by GH replacement therapy.

Adult↗
PubMed2002

Pathophysiology of type 2 diabetes mellitus in children and adolescents: treatment implications.

Type 2 diabetes mellitus was considered an exclusive disease of adulthood until the late 1970s, when reports of an increased prevalence in the pediatric age group emerged in the literature. The concerning upswing in the rate of diagnosis of type 2 diabetes mellitus in children and adolescents has continued, parallel to the increasing rates of obesity. The disease is not specific to the U.S.; it has proven to be a global problem. The current information on type 2 diabetes mellitus in children and adolescents is mostly extrapolated from studies in adults with type 2 diabetes mellitus, due to the paucity of studies conducted in youth. Obesity, family history of type 2 diabetes mellitus, minority ethnicity and race, polycystic ovary syndrome, maternal diabetes mellitus or impaired glucose tolerance during gestation, and acanthosis nigricans are the major risk factors and markers of youth-onset type 2 diabetes mellitus. The pathophysiology, which involves both an insulin secretion defect and resistance to insulin, needs further clarification in pediatric studies. Current management approaches involve lifestyle modification (nutritional and exercise) along with pharmacologic agents, such as insulin and oral antihyperglycemic medications, as indicated. A recent study on the use of metformin in childhood-onset type 2 diabetes mellitus demonstrated the drug to be effective and to have a good safety profile in this population. However, the outcomes of ongoing studies and future studies focusing on type 2 diabetes mellitus in the pediatric age group will be crucial in terms of fine-tuning management plans and setting up appropriate prevention strategies.

Adolescent↗
PubMed2003

Identification of subjects with insulin resistance and beta-cell dysfunction using alternative definitions of the metabolic syndrome.

Recently, the metabolic syndrome (MetS) has attracted much attention as a risk cluster for cardiovascular disease. Although it is believed that individuals with the MetS have insulin resistance (IR), there are few data using direct measures of IR such as glucose clamps or frequently sampled intravenous glucose tolerance tests (FSIGTTs). We examined associations of MetS with FSIGTT-derived measures of insulin sensitivity and secretion among nondiabetic subjects in the Insulin Resistance Atherosclerosis Study. Two sets of MetS criteria were evaluated: those from the 1999 World Health Organization (WHO) and the 2001 National Cholesterol Education Program (NCEP). Both WHO and NCEP MetS definitions were significantly associated with risk of being in the lowest quartile of directly measured insulin sensitivity (P < 0.0001 for all subjects as well as within ethnic subgroups). However, the associations with WHO-MetS were stronger for all subjects combined (WHO: odds ratio [OR] = 10.2; 95% CI 7.5-13.9; NCEP: OR = 4.6; 3.4-6.2) and in separate analyses of non-Hispanic whites, blacks, and Hispanics. WHO and NCEP MetS definitions were also significantly associated with risk of being in the lowest quartile of insulin sensitivity-adjusted acute insulin response (AIR) and disposition index (DI; all P < 0.01), although the associations were generally weaker than those for insulin sensitivity and there was no difference between the two definitions in all subjects combined (low AIR, WHO: OR = 1.7, 1.2-2.4; NCEP: OR = 1.7, 1.2-2.5). There were, however, a number of ethnic differences, including a stronger association of NCEP-MetS with low AIR among blacks. WHO-MetS was significantly more sensitive than NCEP-MetS in detecting low insulin sensitivity (65.4 vs. 45.6%, respectively; P < 0.0001), with no significant differences in specificity between the definitions (84.4 vs. 84.6%; P = 0.91), although WHO-MetS had a larger area under the receiver operating characteristic curve (75% vs. 65%; P < 0.0001). In conclusion, although both the WHO and NCEP MetS criteria identify nondiabetic individuals with low insulin sensitivity, the associations were notably stronger using the WHO definition. The definitions are generally less useful for identifying those with low AIR or DI, although NCEP-MetS seems to differentiate black subjects with insulin secretion defects.

Black People↗
PubMed2005

Insulin signaling in the central nervous system: a critical role in metabolic homeostasis and disease from C. elegans to humans.

Insulin and its signaling systems are implicated in both central and peripheral mechanisms governing the ingestion, distribution, metabolism, and storage of nutrients in organisms ranging from worms to humans. Input from the environment regarding the availability and type of nutrients is sensed and integrated with humoral information (provided in part by insulin) regarding the sufficiency of body fat stores. In response to these afferent inputs, neuronal pathways are activated that influence energy flux and nutrient metabolism in the body and ensure reproductive competency. Growing evidence supports the hypothesis that reduced central nervous system insulin signaling from either defective secretion or action contributes to the pathogenesis of common metabolic disorders, including diabetes and obesity, and may therefore help to explain the close association between these two disorders. These considerations implicate insulin action in the brain, an organ previously considered to be insulin independent, as a key determinant of both glucose and energy homeostasis.

Animals↗
PubMed2000

Hepatocyte nuclear factor 1, a transcription factor at the crossroads of glucose homeostasis.

Hepatocyte nuclear factor 1 (HNF1) is a transcription factor involved in the regulation of a large set of hepatic genes, including albumin, beta-fibrinogen, and alpha1-antitrypsin. HNF1 is expressed in the liver, digestive tract, pancreas, and kidney. Mice lacking HNF1 exhibit hepatic, pancreatic, and renal dysfunctions. HNF1-deficient mice fail to express the hepatic phenylalanine hydroxylase gene, giving rise to hyperphenylalaninemia. Renal proximal tubular reabsorption of glucose, phosphate, arginine, and other metabolites is affected, producing severe renal glucosuria, phosphaturia, and amino aciduria. Homozygous mutant mice also exhibit a dramatic insulin secretion defect. This dysfunction resembles that exhibited by patients with maturity-onset diabetes mellitus of the young type 3, who carry mutations in the human HNF1 gene in the heterozygous state. These data show that HNF1 is a major regulator of glucose homeostasis, regulating the expression of genes that are expressed in the liver, kidney, and pancreas.

Animals↗
PubMed2001

["MODY" diabetes. Beyond a monogenic disease].

Maturity Onset Diabetes of the Young is a particular form of type 2 diabetes, classically defined by an autosomal dominant inheritance, a young age at diagnosis (before 25 years) and an insulin secretion defect. At this time, six MODY genes have been described. Beyond the apparent simplicity, the study of such monogenic model of disease may help us to approach a complex disease such as type 2 diabetes, where is involved to conserve a genetic and environmental factors network. This different approach may help us to better understand type 2 diabetes physiopathology.

Adolescent↗
PubMed2001

The Spacelab 3 simulation: basis for a model of growth plate response in microgravity in the rat.

Data from Spacelab 3 (SL3) suggested that spaceflight significantly reduces the activity of the rat tibial growth plate. Animal processing after SL3 began twelve hours post-landing, so data reflect post-flight re-adaptation in addition to spaceflight effects. To determine if a twelve-hour period of weight bearing after seven days of unloading could affect the physes of spaceflown rats, the present study assessed the growth plate response to unloading with or without a reloading period. Rats were subjected to hind-limb suspension for seven days and then euthanized, with or without twelve hours of reloading. Activity of the growth plate was assessed by morphometric analysis. Rats suspended without reloading had reserve zone (RZ) height greater than controls, and shorter hypertrophy/calcification zone (HCZ) with fewer cells. The greater RZ was associated with a larger cell area, indicating a possible mitotic delay or secretion defect. Twelve hours of reloading decreased RZ height and cell number, and restored the number of cells in HCZ to control values, but the number of cells in the proliferative zone and height in HCZ were reduced. These results suggest the rebound response to preserve/restore skeletal function after a period of unloading involves an acceleration of growth associated with a decreased cell cycle time in PZ. Changes during the reloading period in this simulation support our hypothesis that the effects of spaceflight on SL3 growth plates were altered by changes that occurred post-landing. The similarities in response to unloading by suspension or during spaceflight are used to propose a model of growth plate response during spaceflight.

Animals↗
PubMed2003

[Pituitary tumors: hormonal status and immunohistochemical evaluation].

UNLABELLED: New imaging modalities and hormonal diagnostic improvement have markedly increased the number of newly recognized pituitary tumours. Introduction of immunohistochemical assays in histopathological diagnostics of pitutary adenomas resulted in better understanding of pathology and clinics of these neoplasms. The aim of the study was to correlate the hormonal status and hematoxylin-eosin staining results with immunohistochemical staining of pituitary tumours. The study included 40 patients aged 43.8 +/- 18.3 years, diagnosed with a pituitary tumour in the Department of Endocrinology Collegium Medicum UJ, who subsequently underwent trans-sphenoidal surgery in the Department of Neurosurgery Collegium Medicum UJ. The serum pituitary hormone levels were assessed by means of radioimmuno-assays. The surgically obtained tumour tissue was evaluated both by hematoxylin-eosin and immunohistochemical staining. Using traditional staining 33 patients were diagnosed with chromophobic adenoma, 1 with basophilic adenoma, and remaining 6 with eosinophilic tumour. Immunohistochemical assays were ACTH-positive in 16, TSH-positive in 7, GH-positive in 14 and PRL-positive in 17 cases. In 15 subjects immunohistochemical staining was positive for at least two pituitary hormones. In 34 of 54 patients with positive immunohistochemical staining results, no increase in corresponding pituitary hormone serum levels was observed. In 5 of 9 patients with negative immunohistochemical staining, no increase in serum hormone level was noted, remaining 4 were characterized by hyperprolactinaemia. Tumour cells were ACTH-positive in 5 of 6 patients with elevated serum ACTH levels and GH- or TSH-positive in all cases of increased levels of these hormones. Only 6 of 15 subjects with hyperprolactinaemia revealed positive PRL immunohistochemical staining. CONCLUSIONS: Positive immunohistochemical staining often do not correlate with elevated basal serum pituitary hormone levels, which may be related to either impaired synthesis or excretion of the hormones by tumour cells. Increased serum levels of ACTH, TSH or GH are usually connected with positive immunohistochemical staining results. Hyperprolacinaemia in cases of PRL-negative assays arises from PRL secretion defects caused by the tumour presence itself.

Adenoma↗
PubMedDate not supplied

New developments in the pathogenesis of ANCA-associated vasculitis.

In recent years there have been substantial developments in the understanding of the pathogenesis of ANCA-associated vasculitidies. Animal models have now been developed that finally prove a direct pathogenic role for ANCA, a subject fiercely debated since their original identification. We are also closer to understanding how ANCA exert their effects to cause disease. Progress has been made in elucidating how ANCA activate neutrophils, from how they bind antigen and where that antigen is located, to how antigen binding is translated into intracellular activity. The effects of ANCA activation on the effector functions of neutrophils and monocytes are being further dissected and the flow-based assay is allowing interactions with endothelium to be studied in more detail. Knowledge of the role of T cells has been enhanced by examining contributions to disease by differing subsets and their cytokine secretions. Defects in apoptosis playing a role in the initiation of other autoimmune diseases has prompted investigations into whether a similar pathogenesis is relevant in vasculitis, and various genetic polymorphisms have been discovered to be important in determining in whom vasculitis develops. This article reviews how recent research has helped in the understanding of the pathogenesis of small vessel vasculitis.

Animals↗
PubMed2003

[Immunologic and genetic aspects of latent autoimmune diabetes in the adult].

The presence of islet cell autoantibodies (ICA), and especially of glutamic acid decarboxylase autoantibodies (GAD65Ab), in patients with non-insulin-dependent diabetes mellitus identifies the so-called latent autoimmune diabetes in the adult (LADA). LADA patients have an increased risk for developing insulin deficiency, and in 60-80% of cases the exogenous insulin therapy must be started within 5-6 years. GAD65Ab identify a subgroup of type 2 diabetic (T2DM) patients with low body mass index (BMI) at the time of diagnosis. The presence of GAD65Ab at high titres and directed against COOH-terminal epitopes of the autoantigen, or the presence of both GAD65Ab and ICA, discriminates patients with clinical characteristics very similar to those of a slowly progressive form of type 1 diabetes (T1DM). On the other hand, the presence of low levels GAD65Ab, in the absence of ICA or other immune markers, such as IA-2 antibodies, characterizes a subgroup of patients with clinical characteristics almost indistinguishable from those of typical T2DM patients. The autoimmune origin of LADA is also demonstrated by the increased frequency of thyroid and adrenal autoantibodies, as compared to GAD65Ab-negative T2DM patients, and by the strong genetic association with HLA-DR3-DQ2, -DR4-DQ8 and the polymorphisms of the MHC class I chain-related A (MICA) and CTLA-4 genes. Metabolic studies have shown the coexistence of insulin resistance and insulin secretion defect supporting the hypothesis that LADA may be the result of the interaction of a genetic background predisposing for islet autoimmunity and a genetic background predisposing for T2DM.

Adult↗
PubMed2004

Diabetes mellitus--a modifier of periodontal disease expression.

The understanding of causes and progression of periodontal disease has increased considerably in recent years making it all the more important to gain knowledge about diabetes and its interrelationship with periodontal disease so as to be able to assess their impact on one another more accurately. Strong evidence exists to support the fact that diabetic patients are at an increased risk for periodontitis. A number of underlying factors are known to contribute to enhanced periodontal destruction in diabetics. There has been intensive research to characterise the mechanisms responsible for the pathogenesis of both microvascular and macrovascular complications. It is also known that there is variability in the rate of development and severity of these complications with some diabetics experiencing none of them. Many of the host response traits that confer susceptibility to periodontitis in otherwise healthy individuals are exaggerated in diabetics. These diabetes associated susceptibility traits include neutrophil dysfunction, abnormal cross-linking and glycosylation of collagen, defective secretion of growth factors and subsequent impaired healing. However it is uncertain which of the hypothesised mechanisms or combinations of mechanisms is directly responsible for the pathogenesis of the complications or whether different mechanisms are operative in different tissues.

Collagen↗