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PubMed1984

Deficient superoxide-generating activity and its activation of blood monocytes in cancer patients.

Superoxide (O2-)-generating activity of blood monocytes, the precursors of macrophages, from patients with advanced cancer and/or infection was studied. Monocytes from normal subjects generated 0.288 +/- 0.022 nmol O2-/min/10(5) cells (mean +/- S.E.M., n = 36) after sequential stimulation with cytochalasin E and wheat germ agglutinin. Monocytes from 69 non-infected adult patients with advanced malignancy of the stomach, esophagus and liver, and 7 pediatric patients with neoplastic disease released significantly less O2- than those from normal subjects (0.176 +/- 0.015, P less than 0.005). Infection increased the activity about 4-fold in patients with malignancy compared to non-infected cancer patients. These results suggest that monocytes of cancer patients are defective in secreting O2-, though the activity may be stimulated by infection.

Adolescent↗
PubMed2004

Annexin 7 mobilizes calcium from endoplasmic reticulum stores in brain.

Mobilization of intracellular calcium from inositol-1,4,5-triphosphate (IP3)-sensitive endoplasmic reticulum (ER) stores plays a prominent role in brain function. Mice heterozygous for the annexin A7 (Anx7) gene have a profound reduction in IP3 receptor function in pancreatic islets along with defective insulin secretion. We examined IP3-sensitive calcium pools in the brains of Anx7 (+/-) mice by utilizing ATP/Mg(2+)-dependent (45)Ca(2+) uptake into brain membrane preparations and tissue sections. Although the Anx7 (+/-) mouse brain displayed similar levels of IP3 binding sites and thapsigargin-sensitive (45)Ca(2+) uptake as that seen in wild-type mouse brain, the Anx7 (+/-) mouse brain Ca(2+) pools showed markedly reduced sensitivity to IP3. A potent and saturable Ca(2+)-releasing effect of recombinant ANX7 protein was demonstrated in mouse and rat brain membrane preparations, which was additive with that of IP3. We propose that ANX7 mobilizes Ca(2+) from an endoplasmic reticulum-like pool, which can be recruited to enhance IP3-mediated Ca(2+) release.

Animals↗
PubMed2005

Diabetic changes in the redox status of the microsomal protein folding machinery.

Changes in assisted protein folding are largely unexplored in diabetes. In the present studies, we have identified a reductive shift in the redox status of rat liver microsomes after 4 weeks of streptozotocin-induced diabetes. This change was reflected by a significant increase in the total- and protein-sulfhydryl content, as well as in the free sulfhydryl groups of the major protein disulfide isomerases (PDIs), the 58 kDa PDI and the 57 kDa ERp57 but not other chaperones. A parallel decrease of the protein-disulfide oxidoreductase activity was detected in the microsomal fraction of diabetic livers. The oxidant of PDI, Ero1-Lalpha showed a more oxidized status in diabetic rats. Our results reveal major changes in the redox status of the endoplasmic reticulum and its redox chaperones in diabetic rats, which may contribute to the defective protein secretion of the diabetic liver.

Animals↗
PubMed2006

Diabetes, glucose toxicity, and oxidative stress: A case of double jeopardy for the pancreatic islet beta cell.

Diabetes is commonly referred to in terms of type 1 and type 2. Both forms involve pancreatic islet beta-cell abnormalities, characterized by death in type 1 and accelerated apoptosis in type 2. The resultant chronic hyperglycemia leads to chronic oxidative stress for all tissues because glucose in abnormally high concentrations forms reactive oxygen species. It has been repeatedly emphasized that this can lead to oxidative damage in the classical secondary targets of diabetes, such as eyes, kidneys, nerves, and blood vessels. However, it has been much less appreciated that the beta cell itself is also a prime target, a case of double jeopardy. This situation is all the more pernicious because islets contain among the lowest levels of antioxidant enzyme activities compared to other tissues. This adverse effect of high glucose concentrations is referred to as glucose toxicity. A major manifestation of glucose toxicity in the beta cell is defective insulin gene expression, diminished insulin content, and defective insulin secretion. The molecular mechanisms involve the development of decreased levels of two very important insulin promoter transcription factors, PDX-1 and MafA. Studies with animal models of type 2 diabetes have established that pharmacologic protection against oxidative stress ameliorates the severity of diabetes progression. Translational research with humans is now under way to ascertain whether this protection can be provided to patients experiencing inadequate glycemic control.

Animals↗
PubMed2005

Rho1 regulates signaling events required for proper Drosophila embryonic development.

The Rho small GTPase has been implicated in many cellular processes, including actin cytoskeletal regulation and transcriptional activation. The molecular mechanisms underlying Rho function in many of these processes are not yet clear. Here we report that in Drosophila, reduction of maternal Rho1 compromises signaling pathways consistent with defects in membrane trafficking events. These mutants fail to maintain expression of the segment polarity genes engrailed (en), wingless (wg), and hedgehog (hh), contributing to a segmentation phenotype. Formation of the Wg protein gradient involves the internalization of Wg into vesicles. The number of these Wg-containing vesicles is reduced in maternal Rho1 mutants, suggesting a defect in endocytosis. Consistent with this, stripes of cytoplasmic beta-catenin that accumulate in response to Wg signaling are narrower in these mutants relative to wild type. Additionally, the amount of extracellular Wg protein is reduced in maternal Rho1 mutants, indicating a defect in secretion. Signaling pathways downregulated by endocytosis, such as the epidermal growth factor receptor (EGFR) and Torso pathways, are hyperactivated in maternal Rho1 mutants, consistent with a general role for Rho1 in regulating signaling events governing proper patterning during Drosophila development.

Animals↗
PubMed2026

AAV-mediated CBLN1 replacement rescues hereditary ataxia caused by bi-allelic CBLN1 variants.

Cbln1 is a secreted synaptic organizer required for parallel fiber-Purkinje cell (PF-PC) synapse integrity, climbing fiber (CF) refinement, and cerebellar motor learning but has not previously been implicated in human disease. We identified bi-allelic CBLN1 missense variants (A63P and Y112C) in two unrelated families with early-onset cerebellar ataxia accompanied by oculomotor abnormalities, cerebellar atrophy, and variable cognitive delay. In heterologous cells, both variants showed reduced steady-state protein abundance, impaired maturation through the early secretory pathway, and little or no detectable secretion, resulting in markedly reduced extracellular CBLN1 availability. Consistently, cerebellar granule cells expressing CBLN1-Y112C failed to induce excitatory synapses onto glutamate receptor δ2 (GluD2)-expressing cells in vitro. A knockin mouse harboring Y112C lacked synaptic Cbln1 and recapitulated key features of Cbln1 deficiency, including disrupted PF-PC synapse organization, persistent CF multi-innervation, impaired PF-PC transmission, and long-term depression, and deficits in motor coordination and oculomotor learning. Notably, systemic delivery of an astrocyte-targeted adeno-associated virus expressing wild-type CBLN1 in adult mutant mice restored synaptic CBLN1 localization, cerebellar synaptic function, plasticity, and behavior. These findings establish CBLN1 deficiency as a cause of hereditary ataxia and identify extracellular CBLN1 replacement as a therapeutic strategy for a reversible cerebellar synaptopathy.

CBLN1↗
PubMed2000

Cystic fibrosis transmembrane conductance regulator does not affect neutrophil migration across cystic fibrosis airway epithelial monolayers.

Recent studies have shown that airway inflammation dominated by neutrophils, ie, polymorphonuclear cells (PMN) was observed in infants and children with cystic fibrosis (CF) even in the absence of detectable infection. To assess whether there is a CF-related anomaly of PMN migration across airway epithelial cells, we developed an in vitro model of chemotactic migration across tight and polarized CF(15) cells, a CF human nasal epithelial cell line, seeded on porous filters. To compare PMN migration across a pair of CF and control monolayers in the physiological direction, inverted CF(15) cells were infected with increasing concentrations of recombinant adenoviruses containing either the normal cystic fibrosis transmembrane conductance regulator (CFTR) cDNA, the DeltaF508 CFTR cDNA, or the beta-galactosidase gene. The number of PMN migrating in response to N-formyl-Met-Leu-Phe across inverted CF(15) monolayers expressing beta-galactosidase was similar to that seen across CF(15) monolayers rescued with CFTR, whatever the proportion of cells expressing the transgene. Moreover, PMN migration across monolayers expressing various amounts of mutated CFTR was not different from that observed across matched counterparts expressing normal CFTR. Finally, PMN migration in response to adherent or Pseudomonas aeruginosa was equivalent across CF and corrected monolayers. The possibility that mutated CFTR may exert indirect effects on PMN recruitment, via an abnormal production of the chemotactic cytokine interleukin-8, was also explored. Apical and basolateral production of interleukin-8 by polarized CF cells expressing mutated CFTR was not different from that observed with rescued cells, either in baseline or stimulated conditions. CF(15) cells displayed a CF phenotype that could be corrected by CFTR-containing adenoviruses, because two known CF defects, Cl(-) secretion and increased P. aeruginosa adherence, were normalized after infection with those viruses. Thus, we conclude that the presence of a mutated CFTR does not per se lead to an exaggerated inflammatory response of CF surface epithelial cells in the absence or presence of a bacterial infection.

Adenoviridae↗
PubMed2002

Chemo-enzymatic synthesis of the glycosylated alpha-mating factor of Saccharomyces cerevisiae and analysis of its biological activity.

The effect of glycosylation on a bioactive peptide was studied using yeast Saccharomyces cerevisiae alpha-mating factor, which is composed of 13 amino acids. In this study, we prepared glycosylated alpha-mating factor by chemo-enzymatic synthesis. At first, N-acetylglucosaminyl alpha-mating factor (Trp-His-Trp-Leu-Gln(GlcNAc)-Leu-Lys-Pro-Gly-Gln-Pro-Met-Tyr) was chemically synthesized by the solid-phase method. Then, using the transglycosylation activity of Mucor hiemalis endo-beta-N-acetylglucosaminidase, we synthesized glycosylated alpha-mating factor with a glutamine-linked sialo complex type oligosaccharide. The biological activity of alpha-mating factor derivatives was examined by means of a growth arrest assay using secreted-protease-defective a cells of S. cerevisiae. The results showed that the bioactivity of glycosylated alpha-mating factor was lower than that of native alpha-mating factor. However, when sialic acid was removed from the complex type sugar chain of glycosylated alpha-mating factor, its bioactivity was recovered. Glycosylated alpha-mating factor exhibited higher resistance against proteolysis than native alpha-mating factor. It was found that the bioactivity of N-acetylglucosaminyl alpha-mating factor was higher than that of alpha-mating factor. Circular dichroism studies indicated that a slight change in the structure of alpha-mating factor may influence its activity.

Acetylglucosamine↗
PubMed2003

Downregulation of islet hormone-sensitive lipase during long-term high-fat feeding.

Lipid accumulation in pancreatic beta-cells during high-fat (HF) feeding may be involved in inducing a defective insulin secretion due to lipotoxicity. Hormone-sensitive lipase (HSL) is expressed and active in beta-cells, but its importance for islet dysfunction during the development of type 2 diabetes is not known. In this study, prolonged HF feeding of C57BL/6J mice, resulted in decreased HSL expression in islets, representing only 25+/-4% of the levels observed in controls. This was paralleled by triglyceride accumulation and blunted insulin secretion both in vivo and in vitro. After switching the HF diet to a LF diet, HSL expression increased 10-fold compared to the HF fed mice. This was accompanied by reduced triglyceride levels and a restored insulin secretion. These results support the notion that HSL plays a critical role in the regulation of intracellular triglyceride levels in beta-cells, and that downregulation of the enzyme may serve to protect against fatty acid-induced islet dysfunction.

Administration, Oral↗
PubMed1996

New insights into the regulation of somatotrope function using genetic and transgenic models.

Growth hormone (GH) secretion is under the control of the hypothalamic hormones GH-releasing hormone (GHRH) and somatostatin (SRIF), and is regulated by feedback effects of GH and insulin-like growth factor (IGF-1). GHRH and SRIF act on somatotropes by binding to G-protein-coupled receptors. GHRH activates the stimulatory G protein (Gs), leading primarily to activation of adenylyl cyclase and protein kinase A. SRIF activates the inhibitory G protein (Gi). Several animal models enable the study of various disorders of GH secretion in vivo. Genetic models of impaired GH secretion include the little (lit) mouse, the dwarf (dw) rat, the fatty (fa) rat, and the high-growth (hg) mouse. Transgenic models of impaired and excessive GH secretion, respectively, include the tyrosine hydroxylase-human GH (TH-hGH) transgenic mouse and the metallothionein-human GHRH transgenic mouse. These models encompass a wide spectrum of disorders of GH secretion, involving defects of hypothalamic regulation, feedback control at the pituitary level, or the mechanism of GHRH action in the somatotrope. They may provide insights into our understanding of human GH secretory disorders.

Animals↗
PubMed1997

Defect in interleukin-1beta secretion prevents sickness behavior in C3H/HeJ mice.

To examine the role of interleukin-1beta (IL-1beta) in mediating sickness, we studied the effects of lipopolysaccharide (LPS) and IL-1beta on social behavior in endotoxin-responsive C3H/HeOuJ (OuJ) mice and endotoxin-resistant C3H/HeJ (HeJ) mice. Whereas LPS (1, 10 and 100 microg) depressed social behavior and body weight compared to saline in OuJ mice, in HeJ mice it did not. To determine if the refractoriness of HeJ mice to the behavioral effects of LPS was related to secretion of IL-1beta, in a second study, HeJ and OuJ mice were injected IP with LPS (10 microg) and plasma concentration of IL-1beta was determined postinjection. At 4 h postinjection, the plasma concentration of IL-1beta was increased by LPS in OuJ mice, but not in HeJ mice. The increase in plasma IL-1beta in OuJ mice corresponded to the maximal depression in social behavior. To further verify that HeJ mice are refractory to the behavioral effects of LPS because they fail to respond and produce cytokines, the social behavior of HeJ and OuJ mice injected IP with recombinant murine IL-1beta (0, 50, 100, or 200 ng) was compared. As anticipated, exogenous IL-1beta depressed social behavior similarly in endotoxin-responsive OuJ mice and endotoxin-resistant HeJ mice. These data indicate that a genetic mutation in HeJ mice that prevents LPS-induced synthesis of cytokines also renders HeJ mice refractory to the behavioral effects of LPS.

Animals↗
PubMed1999

Pathogenesis of non-insulin-dependent (type II) diabetes mellitus (NIDDM) - genetic predisposition and metabolic abnormalities.

Non-insulin-dependent diabetes mellitus (NIDDM), also known as type II diabetes, is characterized by abnormal glucose homeostasis, resulting in hyperglycemia, and is associated with microvascular, macrovascular, and neuropathic complications. NIDDM is a complex disease with many causes. Both genetic and environmental factors play important roles in the pathogenesis of NIDDM. Cumulative evidence on the high prevalence of NIDDM in certain ethnic groups, the high concordance rate for the disease in monozygotic twins, familial aggregation, and familial transmission patterns suggests that the genetic component plays an important etiological role in the development of NIDDM. In genetically predisposed individuals, there is a slow progression from a normal state to hyperglycemia, largely due to a combination of insulin resistance and defects in insulin secretion. Although numerous candidate genes responsible for insulin resistance and for the defects in insulin secretion have been reported, no specific gene(s) accounting for the majority of cases of the common type of NIDDM has been identified. Considerable evidence indicates that environmental and other factors, including diet, stress, physical activity, obesity and aging, also play an important role in the development of the disease. In conclusion, the pathogenic process of NIDDM depends on a complex interaction between genetic and environmental factors.

Journal Article↗
PubMed1996

Primary distal renal tubular acidosis as a result of a gradient defect.

It has been generally accepted that primary distal renal tubular acidosis (DRTA) is the result of a defect in proton secretion in the distal nephron (secretory defect). We report an infant with DRTA, evidenced by spontaneous hyperchloremic metabolic acidosis with low urinary ammonium excretion rate and inability to decrease urine pH during acidosis, who nevertheless exhibited an intact ability to increase urinary carbon dioxide partial pressure (pCO2) during maximal urine alkalinization and normal ability to acidify the urine after furosemide, suggestive of a gradient-type defect DRTA. This patient had never been exposed to amphotericin B. To our knowledge, this is the first fully documented report of primary DRTA that can be attributed to gradient defect.

Acetazolamide↗
PubMed1997

The kidney: an unwilling accomplice in syndrome X.

The ability of insulin to stimulate glucose disposal by muscle varies widely within the population at large. Individuals with muscle insulin resistance develop type 2 diabetes if they cannot compensate for this defect by secreting large amounts of insulin. Although this philanthropic effort on the part of the pancreatic B-cell may prevent gross decompensation of glucose homeostasis, it renders such individuals at increased risk to develop a cluster of abnormalities (syndrome X) associated with coronary heart disease. Although the kidney is not considered to be an insulin sensitive tissue, two features of syndrome X, hyperuricemia and hypertension, are likely to be dependent on the retention of normal insulin action on the kidney. More specifically, there is evidence to support the hypothesis that elevated plasma insulin concentrations may enhance renal sodium retention and decrease urinary uric acid clearance. As such, it is possible that a normal kidney response to the compensatory hyperinsulinemia associated with insulin resistance in nondiabetic subjects contributes to the development of hyperuricemia and hypertension in such individuals.

Diabetes Mellitus, Type 2↗
PubMed2000

Treatment of diabetes in patients with severe obesity.

Besides genetic predisposition, obesity is the most important risk factor for the development of diabetes mellitus, and weight reduction has been shown to markedly improve blood glucose control in obese subjects with type 2 diabetes. Therapeutic strategies for the obese diabetic patient include: 1) promoting weight loss through lifestyle modifications (hypocaloric diet and exercise) and anti-obesity drugs (orlistat, sibutramine, etc.); 2) improving blood glucose control, essentially through the reduction of insulin resistance (metformin, eventually thiazolidinediones) or insulin need (alpha-glucosidase inhibitors) and, at a later stage, the correction of defective insulin secretion (sulphonylureas, repaglinide) or low circulating insulin levels (exogenous insulin); and 3) treating common associated risk factors, such as arterial hypertension and dyslipidaemias, to improve cardiovascular prognosis. When morbid obesity is present, both restoring a good glycemic control and correcting associated risk factors can only be obtained through marked and sustained weight loss. This primary objective justifies more aggressive weight reduction programmes, including very low-calorie diets and bariatric surgery, but only within a multidisciplinary approach and in well-selected patients.

Anti-Obesity Agents↗
PubMedDate not supplied

The role of transcription factors in maturity-onset diabetes of the young.

The study of maturity-onset diabetes of the young (MODY), an autosomal dominant form of early-onset diabetes mellitus characterised by defective insulin secretion has been extremely successful in two ways. Firstly it has enabled definitive diagnosis for patients. This allows more accurate prediction of disease and treatment requirements. Secondly it has facilitated an increased understanding of the genes and pathways that are crucial for normal beta-cell function. Five of the six MODY genes, TCF1 (encoding HNF-1alpha), TCF2 (encoding HNF-1beta) HNF4A, insulin promoter factor (IPF)1, and NEUROD1, are transcription factors that operate in a complex network of gene regulation. Several genes have been shown to be regulated by the MODY transcription factors in a beta-cell specific manner. This includes the co-regulation of HNF-1alpha and HNF-4alpha by each other. The exact mechanism of how mutations in these transcription factors result in diabetes in humans remains unknown. However, current opinion favours pleiotropic adverse effects on many genes; extensive in vitro and in vivo studies of these genes has highlighted their importance in both glucose sensing-insulin secretion coupling and maintaining the fully differentiated beta-cell phenotype.

Alleles↗
PubMed2002

Cholestatic liver disease: pathophysiology and therapeutic options.

Cholestasis results from defective canalicular secretion of bile or obstruction to bile flow distal to the canaliculus. In early primary biliary cirrhosis, bile secretion continues, because of the secretory pressure of bile or because some ductules are not obstructed. With complete cholestasis, a bile acid deficiency occurs in the small intestinal lumen leading to lipid maldigestion and fat-soluble vitamin malabsorption. Bacterial proliferation, bacterial translocation to lymph nodes and endotoxemia may also occur leading to an acute phase reaction. Retention of bile acids in the hepatocyte leads to apoptosis. Accumulation of bile acids in the systemic circulation leads to pruritus, and may contribute to endothelial injury in the lungs and kidney. Early attempts to mimic hepatic excretory function by hemoperfusion over adsorbent columns were unsuccessful for a variety of reasons. Extracorporeal dialysis against albumin offers promise of a realistic albeit partial simulation of hepatic excretory function.

Cholestasis, Intrahepatic↗