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1.
Oncogene ; 34(26): 3429-40, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25174398

ABSTRACT

Helicobacter pylori infection causes gastric cancer, the third leading cause of cancer death worldwide. More than half of the world's population is infected, making universal eradication impractical. Clinical trials suggest that antibiotic treatment only reduces gastric cancer risk in patients with non-atrophic gastritis (NAG), and is ineffective once preneoplastic lesions of multifocal atrophic gastritis (MAG) and intestinal metaplasia (IM) have occurred. Therefore, additional strategies for risk stratification and chemoprevention of gastric cancer are needed. We have implicated polyamines, generated by the rate-limiting enzyme ornithine decarboxylase (ODC), in gastric carcinogenesis. During H. pylori infection, the enzyme spermine oxidase (SMOX) is induced, which generates hydrogen peroxide from the catabolism of the polyamine spermine. Herein, we assessed the role of SMOX in the increased gastric cancer risk in Colombia associated with the Andean mountain region when compared with the low-risk region on the Pacific coast. When cocultured with gastric epithelial cells, clinical strains of H. pylori from the high-risk region induced more SMOX expression and oxidative DNA damage, and less apoptosis than low-risk strains. These findings were not attributable to differences in the cytotoxin-associated gene A oncoprotein. Gastric tissues from subjects from the high-risk region exhibited greater levels of SMOX and oxidative DNA damage by immunohistochemistry and flow cytometry, and this occurred in NAG, MAG and IM. In Mongolian gerbils, a prototype colonizing strain from the high-risk region induced more SMOX, DNA damage, dysplasia and adenocarcinoma than a colonizing strain from the low-risk region. Treatment of gerbils with either α-difluoromethylornithine, an inhibitor of ODC, or MDL 72527 (N(1),N(4)-Di(buta-2,3-dien-1-yl)butane-1,4-diamine dihydrochloride), an inhibitor of SMOX, reduced gastric dysplasia and carcinoma, as well as apoptosis-resistant cells with DNA damage. These data indicate that aberrant activation of polyamine-driven oxidative stress is a marker of gastric cancer risk and a target for chemoprevention.


Subject(s)
Adenocarcinoma , Helicobacter Infections/complications , Helicobacter pylori/physiology , Oxidoreductases Acting on CH-NH Group Donors/physiology , Stomach Neoplasms , Adenocarcinoma/epidemiology , Adenocarcinoma/genetics , Adenocarcinoma/microbiology , Adult , Animals , Cells, Cultured , Colombia/epidemiology , DNA Damage/genetics , Enzyme Induction , Gerbillinae , Helicobacter Infections/genetics , Humans , Hydrogen Peroxide/metabolism , Male , Middle Aged , Oxidative Stress/genetics , Risk Factors , Stomach Neoplasms/epidemiology , Stomach Neoplasms/genetics , Stomach Neoplasms/microbiology , Polyamine Oxidase
2.
Arch Pathol Lab Med ; 123(6): 529-32, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10383807

ABSTRACT

OBJECTIVE: To determine if the DNA strand breaks caused by tissue sectioning result in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) reactivity. METHODS: The incidence and location of TUNEL-positive nuclei were determined in 5- and 15-micron sections of human stomach. Five- and 15-micron sections of tonsil were stained as a positive control. RESULTS: In 5-micron gastric sections, 69% of nuclei were labeled; in 15-micron sections, only 30% were labeled. In the latter sections, almost all labeled nuclei were located at the cut surface of sections. Labeled nuclei did not have apoptotic morphology. Apototic bodies and tingible body macrophages were labeled throughout 15-micron sections of tonsil. CONCLUSIONS: Tissue sectioning creates TUNEL reactivity. The morphologic findings on routine stains should be considered the gold standard for the detection of apoptosis on tissue sections.


Subject(s)
Artifacts , Cell Nucleus/genetics , DNA/analysis , In Situ Nick-End Labeling , Microtomy , Palatine Tonsil/cytology , Stomach/cytology , Cell Count , DNA Fragmentation , False Positive Reactions , Humans
3.
J Bone Miner Res ; 13(11): 1679-86, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9797475

ABSTRACT

To understand the mechanisms responsible for the persistent hypercalciuria and reduced glomerular filtration rate (GFR) previously found in 6 of 10 patients surgically cured of primary hyperparathyroidism (PHPx), the tubular handling of lithium, sodium, calcium, and phosphate as well as the renal hemodynamics were evaluated in these 10 PHPx patients, in 10 control subjects, and in 5 patients with renal hypercalciuria (RH), during fasting and after an oral calcium load. A positive correlation between the fractional excretions of calcium and sodium was found in all groups, but the PHPx patients excreted more calcium for the same amount of sodium than control subjects. The fractional proximal sodium reabsorption (FPRNa), distal delivery, and fractional phosphate reabsorption were similar in all groups; a significant positive correlation was found between the fractional calcium reabsorption and the FPRNa, indicating that proximal tubular function was preserved and that the urinary calcium losses in RH and in the hypercalciuric PHPx patients (h-PHPx) occurred in the distal nephron. However, only h-PHPx patients had reduced renal plasma flow, renal blood flow, and GFR, as well as a high renal vascular resistance, which was even more evident after the calcium challenge. These findings lead us to conclude that RH and h-PHPx patients are very different, as far as kidney dysfunction is concerned, and that a hypercalcemic nephropathy is the most probable cause of the alterations in distal calcium reabsorption and renal hemodynamics found in the h-PHPx patients.


Subject(s)
Calcium Metabolism Disorders/urine , Calcium/metabolism , Hyperparathyroidism/complications , Hyperparathyroidism/surgery , Kidney Tubules/metabolism , Adenoma/surgery , Adult , Aged , Analysis of Variance , Calcium Metabolism Disorders/etiology , Female , Glomerular Filtration Rate , Hemodynamics , Humans , Linear Models , Lithium/urine , Male , Middle Aged , Parathyroid Neoplasms/surgery , Phosphates/urine , Sodium/urine
4.
J Endocrinol Invest ; 19(1): 12-20, 1996 Jan.
Article in English | MEDLINE | ID: mdl-8851686

ABSTRACT

The hypercalciuria that eventually remains after the successful removal of a solitary parathyroid adenoma may originate from excessive intestinal calcium absorption, bone resorption or deficient renal reabsorption. In order to clarify this question, ten patients surgically cured from primary hyperparathyroidism (PHPx), ten age-matched normal subjects and five nephrolithiasic patients with renal hypercalciuria (RH) were studied after five days on a low calcium diet, either during fasting or after oral calcium load. Fasting serum calcium, amino-terminal and intact PTH levels and also urinary cAMP excretion were normal in every individual patient. Serum ionized calcium and inulin clearance (GFR) were used for calculations of the filtered load (FL Ca) and the fractional excretion of calcium (FE Ca). Six PHPx patients displayed fasting calciuria above the upper limit calculated for control subjects, despite having the lowest GFR and FL Ca (p < 0.05 vs control). These patients (h-PHPx) had a small calciuric response to oral calcium load. Serum 1,25-(OH)2D3 and 25OHD3 did not correlate with calciuria. Our findings exclude intestinal hyperabsorption and excessive bone resorption in h-PHPx patients, and strongly suggest a renal tubular defect in calcium reabsorption as the cause of their hypercalciuria. This defect could be primary, as in RH, but only three hPHPx patients had recurrent kidney stones before surgery. On the other hand, as a negative correlation between GFR and FE Ca was only found in PHPx patients, it seems probable that the disturbances in glomerular and tubular functions were secondary to the long standing hypercalcemic hyperparathyroidism.


Subject(s)
Calcium Metabolism Disorders/urine , Calcium/metabolism , Hyperparathyroidism/complications , Hyperparathyroidism/surgery , Kidney/metabolism , Adenoma/surgery , Adolescent , Adult , Aged , Calcium Metabolism Disorders/etiology , Female , Glomerular Filtration Rate , Humans , Kidney Tubules/metabolism , Male , Middle Aged , Parathyroid Hormone/blood , Parathyroid Neoplasms/surgery
5.
Hypertension ; 19(4): 378-84, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1555869

ABSTRACT

To assess the effects of genetic predisposition of essential hypertension on early renal function in recent insulin-dependent diabetics, we studied inulin, para-aminohippuric, sodium, and lithium clearances in 69 unselected diabetics with (n = 20) and without (n = 49) a family history of essential hypertension. Despite similar metabolic control, glomerular filtration rate and mean arterial pressure were significantly higher in diabetics with than in those without a family history of hypertension. However, no difference was found between the two groups regarding renal vascular resistance, sodium excretion, or fractional proximal and distal sodium reabsorption. Renal responses to acute captopril (75 mg) administration were evaluated in 27 patients (six with family history of hypertension). Captopril decreased filtration fraction and mean arterial pressure similarly in both groups, whereas glomerular filtration rate and renal vascular resistance decreased more dramatically in diabetics with family history of hypertension. These findings indirectly suggest an abnormal response to angiotensin of vascular tone in recent diabetics with familial predisposition to hypertension. Renal response to acute nicardipine (2.5 mg i.v.) administration was analyzed in 24 patients (five with family history of hypertension). In both groups, nicardipine similarly decreased mean arterial pressure and renal vascular resistance and induced a marked natriuretic effect due to a predominant reduction in proximal reabsorption of sodium. However, the increase in sodium excretion was twofold to threefold more pronounced in diabetics with a family history of hypertension. Whether these early renal abnormalities may contribute to the risk of diabetic nephropathy, as suggested by retrospective studies, remains to be determined.


Subject(s)
Blood Pressure/physiology , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/physiopathology , Diabetic Nephropathies/genetics , Diabetic Nephropathies/physiopathology , Family , Hypertension/genetics , Hypertension/physiopathology , Kidney/physiopathology , Sodium/metabolism , Adult , Female , Glomerular Filtration Rate/physiology , Humans , Kidney/blood supply , Male , Regional Blood Flow , Vascular Resistance
6.
Clin Sci (Lond) ; 81(4): 457-64, 1991 Oct.
Article in English | MEDLINE | ID: mdl-1657491

ABSTRACT

1. A sustained high glomerular filtration rate in diabetes mellitus is associated with increased proximal reabsorption, suggesting alterations in the tubuloglomerular feedback system. To test this hypothesis, renal function was studied in eight control subjects and 14 recent-onset euglycaemic insulin-dependent diabetic patients before and after infusion of the carbonic anhydrase inhibitor, acetazolamide (5 mg/kg body weight). 2. Acetazolamide induced a dramatic fall in glomerular filtration rate in both diabetic patients and control subjects (from 138 +/- 5 to 114 +/- 4 and from 127 +/- 3 to 113 +/- 2 ml min-1 1.73 m-2, respectively, P less than 0.0001). This fall in glomerular filtration rate was strongly correlated with the acetazolamide-induced decrease in absolute proximal reabsorption calculated by using lithium clearance. 3. To further assess the potential role of angiotensin II in the acetazolamide-induced tubulo-glomerular feedback response, 11 additional diabetic patients were investigated before and after the administration of acetazolamide plus the angiotensin-converting enzyme inhibitor, enalaprilat (1.25 mg intravenously). Despite the effective blockade of angiotensin II formation and a slight decrease in renal vascular resistance, the glomerular filtration rate fell significantly and by a similar magnitude as seen with acetazolamide alone. 4. These results indirectly suggest that there is an altered basal tubulo-glomerular feedback system in diabetic patients but a normal response to the increase in distal delivery. No convincing role for an angiotensin II-mediated effect on the afferent limb of the tubuloglomerular feedback response could be demonstrated.


Subject(s)
Acetazolamide , Diabetes Mellitus, Type 1/physiopathology , Kidney/physiopathology , Adolescent , Adult , Enalaprilat/pharmacology , Feedback , Glomerular Filtration Rate/drug effects , Humans , Kidney/metabolism , Kidney Glomerulus/physiopathology , Kidney Tubules/physiopathology , Lithium/metabolism , Vascular Resistance/drug effects
7.
Kidney Int ; 37(4): 1126-33, 1990 Apr.
Article in English | MEDLINE | ID: mdl-2188030

ABSTRACT

To investigate mechanisms underlying GFR control in diabetes mellitus, renal hemodynamics and segmental tubular handling of sodium, using lithium clearance, were assessed in 41 insulin-dependent diabetics (IDD) treated by insulin for 11 +/- 8 days, and in 19 normal controls. Average GFR and effective renal plasma flow (ERPF) were slightly but not significantly higher (136 +/- 22 vs. 123 +/- 16 ml/min.1.73 m2) in IDD than in normal subjects. GFR and ERPF were positively and strongly correlated in controls (r = 0.61, P less than 0.001) and in diabetics (r = 0.72, P less than 0.0001) indicating the marked flow dependency of GFR in both populations. After adjustment for ERPF, GFR was significantly higher in diabetics, suggesting a role of increased glomerular capillary pressure and ultrafiltration coefficient in the subset of "hyperfiltering" patients. Both fractional (FPRNa) and absolute (APRNa) proximal sodium reabsorption were significantly higher in IDD and significantly correlated with GFR. The ensuing decrease in sodium distal delivery could deactivate the tubuloglomerular feedback response and thus favor sustained vasodilation and high GFR in some diabetics. The renal effects of acute administration of drugs acting predominantly at either the pre- or the postglomerular resistance using nicardipine (N = 16) or captopril (N = 25) were further evaluated in IDD. The renal response to captopril or nicardipine was different in IDD. Whereas both drugs induced a marked decrease in renal vascular resistance, GFR was slightly decreased by captopril and was unchanged after nicardipine; these results are similar to those observed in normotensive non-diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Diabetes Mellitus, Type 1/physiopathology , Kidney Tubules/physiopathology , Renal Circulation/physiology , Adult , Captopril/pharmacology , Female , Glomerular Filtration Rate/drug effects , Glomerular Filtration Rate/physiology , Hemodynamics/drug effects , Hemodynamics/physiology , Humans , Kidney Tubules/drug effects , Lithium/pharmacokinetics , Male , Nicardipine/pharmacology , Renal Circulation/drug effects , Sodium/metabolism
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