Biomedical subjects

S Rahbar

Publications and source records attributed to S Rahbar.

At least 19 recordsLinked to original sources

PubMed2003

LR-90 a new advanced glycation endproduct inhibitor prevents progression of diabetic nephropathy in streptozotocin-diabetic rats.

AIMS/HYPOTHESIS: Advanced glycation and lipoxidation endproducts have been implicated in the pathogenesis of diabetic complications, including diabetic nephropathy. LR-90, a new advanced glycation endproduct inhibitor, was investigated for its effects on the development of renal disease in diabetic rats. METHODS: Diabetic animals were randomly allocated into groups receiving LR-90 or vehicle (untreated). Age- and weight-matched non-diabetic rats were studied concurrently. Body weight, plasma glucose, glycated haemoglobin, urinary albumin and creatine excretions were measured serially. Kidney histopathology, AGE accumulation in cells and tissues, protein oxidation, were also examined. In vitro assays were used to assess the possible mechanism of action of LR-90. RESULTS: LR-90 inhibited the increase in albumin and creatinine concentrations, and concentrations of circulating AGE in diabetic rats without any effect on glycaemic control. LR-90 treated-rats also showed higher body weights than untreated diabetic rats. LR-90 prevented glomerulosclerosis, tubular degeneration and collagen deposition in the kidney. AGE-induced cross-linking and fluorescence of tail collagen were reduced by LR-90 treatment. LR-90 also decreased AGE accumulation in kidney glomeruli and nitrotyrosine deposition in the renal cortex. In vitro, LR-90 was capable of reacting with reactive carbonyl compounds and was a more potent metal chelator than pyridoxamine and aminoguanidine. CONCLUSION/INTERPRETATION: LR-90 reduces in vivo AGE accumulation, AGE-protein cross-linking and protein oxidation, and could be beneficial in preventing the progression of diabetic nephropathy. The AGE inhibitory and therapeutic effects of LR-90 could be attributed, at least in part, to its ability to react with reactive carbonyl species and/or potent metal chelating activity that inhibits glycoxidative-AGE formation.

Animals↗

PubMed2003

Routine laser assisted hatching results in significantly increased clincal pregnancies.

PURPOSE: To elucidate the appropriateness of current indications for assisted hatching (AH) in cleavage stage human embryos and to confirm our preliminary findings that only young patients (about 67%) benefit from AH. METHODS: Prior to transfer, 2 of 3 embryos selected for ET were subjected to laser assisted hatching (LAH). Control group consisted of patients matched by similar characteristics and protocol except LAH was not performed. RESULTS: The clinical pregnancy rate in women < or = 36 years was 64.9% (24/37) for embryos subjected to LAH but was significantly lower (p = 0.029) in the control (33.3%; 10/30). The implantation rate in women < or = 36 years in the test group was 38.1% (40/105) that was significantly higher than that of the control group (17.5%, 14/80; p = 0.0039). CONCLUSIONS: LAH is beneficial for women < or = 36 years but not for women > or = 37 years, for embryos with thin zonae (< or = 16 micron) but not with thick zonae (> or = 17 micron), and for those with repeated failures (37-50%).

Adult↗

PubMed2001

PACAP mediates the neural proliferative pathway of Mastomys enterochromaffin-like cell transformation.

BACKGROUND AND AIM: Pituitary adenylate-cyclase activating peptide (PACAP) is a more potent proliferative agent than gastrin for rat enterochromaffin-like (ECL) cell proliferation in vitro. The role of this neurotransmitter during gastrin-mediated ECL cell tumor formation and gastrin-autonomous ECL cell neoplasia is unknown. METHODS AND RESULTS: ECL cell transformation was induced in the Mastomys using 16 wk H2 receptor blockade of acid inhibition. Examination of the epithelial fundic mucosa demonstrated that PACAP-immunoreactivity significantly increased in the tumor mucosa compared to the naïve stomach, and was associated with ECL cells. Naïve and tumor ECL cells were then purified (approximately 95%) from Mastomys and the presence of all three PACAP/VPAC receptor subtypes was demonstrated by polymerase chain-reaction amplification. Thereafter, cells were maintained in short-term (48 h) primary cultures. PACAP significantly (p<0.05) increased 24 h bromo-deoxyuridine uptake (approximately 4-fold) in both cell types with estimated EC(50) values of approximately 4x10(-16) M and approximately 2x10(-16) M, respectively. Specific receptor antagonists (PAC1/VPAC1) of PACAP competitively inhibited these proliferative effects in naïve cells. Oligonucleotide antisense directed against PAC1 significantly inhibited PACAP-stimulated DNA synthesis by approximately 85% (p<0.05) in tumor cells. CONCLUSION: PACAP is a potent and effective modulator of ECL cell proliferation. The expression of this neuropeptide and its receptors, particularly PAC1, suggest the existence of a neural regulatory pathway of ECL cell proliferation and transformation.

Animals↗

PubMed2000

Novel inhibitors of advanced glycation endproducts (part II).

Enhanced formation and accumulation of advanced glycation endproducts (AGEs), have been implicated as a major pathogenesis process leading to diabetic complications, normal aging, atherosclerosis, and Alzheimer's Disease. Several potential drug candidates as AGE inhibitors have been reported recently. The aim of this study was to develop classes of novel inhibitors of glycation, AGE formation, and AGE-crosslinking and to investigate their effects through in vitro chemical and immunochemical assays. A total of 92 compounds were designed and synthesized. The first 63 compounds were reported before. Nearly half of the 29 novel inhibitors reported here are benzoic acid derivatives and related molecules, and found to be potent inhibitors of multistage glycation, AGE formation, and AGE-protein crosslinking. All 29 compounds show some degrees of inhibitory activities as detected by the four assay methods, 9 compounds demonstrated high percent inhibition (PI) in all tests, 30 to 40 times stronger than aminoguanidine.

Animals↗

PubMed2000

Evidence that pioglitazone, metformin and pentoxifylline are inhibitors of glycation.

Enhanced formation and accumulation of advanced glycation end products (AGEs) have been proposed to play a major role in the pathogenesis of diabetic complications, and atherosclerosis, leading to the development of a range of diabetic complications including nephropathy, retinopathy and neuropathy. Several potential drug candidates as AGE inhibitors have been reported recently. Aminoguanidine is the first drug extensively studied. However, there are no currently available medications known to block AGE formation. We have previously reported a number of novel and structurally diverse compounds as potent inhibitors of glycation and AGE formation. We have now studied several of the existing drugs, which are in therapeutic practice for lowering blood sugar or the treatment of peripheral vascular disease in diabetic patients, for possible inhibitory effects on glycation. We show that that three compounds; pioglitazone, metformin and pentoxifylline are also inhibitors of glycation.

Enzyme-Linked Immunosorbent Assay↗

PubMed1999

Novel inhibitors of advanced glycation endproducts.

Enhanced formation and accumulation of advanced glycation endproducts (AGE's) have been proposed to play a major role in the pathogenesis of diabetic complications, aging, atherosclerosis, and Alzheimer disease leading to progressive and irreversible intermolecular protein crosslinkings. This process is accelerated in diabetes and has been postulated to contribute to the development of a range of diabetic complications including nephropathy, retinopathy and neuropathy. Several potential drug candidates as AGE inhibitors have been reported recently. Aminoguanidine is the first drug extensively studied both in vitro and in vivo. We have developed a new class of compounds as potent inhibitors of glycation and AGE formation. The novel inhibitors reported here are aryl (and heterocyclic) ureido, and aryl (and heterocyclic) carboxamido phenoxy isobutyric acids and related molecules, which were found by in vitro assay methods to be potent inhibitors of multiple stage of glycation and AGE formation.

Animals↗

PubMed1999

A new rapid method to detect inhibition of Amadori product generated by delta-gluconolactone.

Advanced glycation endproducts (AGEs) have been implicated as a major pathogenic process in leading to diabetic complications. An increasing number of drug candidates have recently been developed as potential inhibitors of AGEs. Aminoguanidine, a hydrazine-like molecule is the first drug that was extensively studied both in vitro and in vivo as an inhibitor of AGE formation. Several assay methods have been proposed to determine the inhibitory effect of glycation inhibitors, including assays based on inhibition of specific fluorescence generated in the course of glycation and AGE-formation; assays based on the inhibition of AGE-protein crosslinks, and dimer and trimer formation; and specific ELISA assays using anti-AGE antibodies for quantitative measurement of AGEs in the presence and absence of the inhibitor. However, none of these assays can accurately evaluate chemical intermediates and products generated during the early stages of glycation. We have devised a new rapid assay method for evaluation of the early stage of glycation (Amadori product). This assay is based on the interaction of delta-gluconolactone (delta-Glu), an oxidized (ketoaldehyde) analogue of glucose, with hemoglobin present in blood samples. The assay involves determination of the percentage of glycated hemoglobin (HbA1C) after incubation at 37 degrees for 16 h with delta-Glu (50 mmol/L) using a dedicated ion-exchange high-performance liquid chromatography (HPLC) system. The results using normal human red blood cells show HbA1C levels to be 180% higher than baseline controls. The effects of various inhibitors are determined by measuring the levels of HbA1C by the compound in question compared to delta-Glu-treated vehicle only blood samples. This new assay provides a relevant and physiological model to study glycation and potential inhibitors. Furthermore, it offers a means to differentiate between inhibitors of the early and late stages of glycation and provides a rapid method of screening large numbers of potential inhibitors of glycation. Contrary to the assay methods, which are based on the measurement of fluorescence of fluorophores generated during glycation, the proposed assay does not suffer from the possible problem of overlapping and interference of AGE-specific fluorescence with the intrinsic fluorescence of the inhibitor compound.

Chromatography, High Pressure Liquid↗

PubMed1997

Hb Watts [alpha 74(EF3) or alpha 75(EF4)Asp-->0]: a shortened alpha chain variant due to the deletion of three nucleotides in exon 2 of the alpha 2-globin gene.

We have identified a new, slightly unstable alpha chain hemoglobin variant, present in a Mexican-American family. Amino acid sequencing and mass spectral analysis of the aberrant peptide (alpha T-9) of the variant revealed that the aspartic acid is deleted either at position 74 or 75 of one of the alpha-globin chains. Sequencing of the amplified alpha 2- or alpha 1-globin genes revealed a trinucleotide deletion (GAC) at codon 74 or 74 of the alpha 2 gene. Although the aspartic acid residues of 74 and 75 of the alpha chain are neither a heme nor an inter chain contact, the slight instability of Hb Watts may be due to disturbance of the central cavity of hemoglobin by the deletion of an aspartic acid residue in the EF helix. Hb Watts is the first example of a trinucleotide deletion in the alpha 2-globin gene.

Adult↗

PubMed1995

A novel intrachromosomal rearrangement in the beta-globin gene found in an African-American family.

We describe here a deletion of 34 nucleotides from the 3' end of the first intervening sequence of the beta-globin gene covering the AGGC splice junction, and the insertion of 32 nucleotides of the delta-globin gene at the same location. This gene rearrangement was detected in three members of an African-American family. The proband, a 28-year-old female, and her mother had a history of chronic anemia. One of her two brothers, who inherited the same gene defect, was apparently healthy with no symptoms of hemolytic anemia. The proband, her father, and her two brothers, including the one who carried the beta-globin gene rearrangement, were found to be heterozygous for alpha-thalassemia-2 (-alpha 3.7). Although the AGGC splice junction is disrupted (AGGC-->AGAT), the invariant AG has remained intact after this gene rearrangement. Our investigations could not detect any defect in RNA processing in the affected beta-globin genes. The discrepancies between the phenotypes and the globin chain synthesis ratios of the mother, her daughter, and her son who inherited the same gene defect at their beta-globin genes, remain unexplained.

Adult↗

PubMed1995