Structure Modification Converts the Hepatotoxic Tacrine into Novel Hepatoprotective Analogs.

The liver is responsible for critical functions such as metabolism, secretion, storage, detoxification, and the excretion of various compounds. However, there is currently no approved drug treatment for liver fibrosis. Hence, this study aimed to explore the potential hepatoprotective effects of chlorinated and nonchlorinated 4-phenyl-tetrahydroquinoline derivatives. Originally developed as tacrine analogs with reduced hepatotoxicity, these compounds not only lacked hepatotoxicity but also displayed a remarkable hepatoprotective effect. Treatment with these derivatives notably prevented the chemically induced elevation of hepatic indicators associated with liver injury. Additionally, the compounds restored the activities of defense antioxidant enzymes as well as levels of inflammatory markers (TNF-α and IL-6), apoptotic proteins (Bax and Bcl2), and fibrogenic mediators (α-SMA and TGF-ß) to normal levels. Histopathologic analysis confirmed the hepatoprotective activity of tetrahydroquinolines. Furthermore, computer-assisted simulation docking results were highly consistent with those of the observed in vivo activities. In conclusion, the designed tacrine analogs exhibited a hepatoprotective role in acute liver damage, possibly through their antioxidative, anti-inflammatory, and antifibrotic effects.

The genotype distribution of the XRCC1, XRCC3, and XPD DNA repair genes and their role for the development of acute myeloblastic leukemia.

AIM: To investigate if there is an association between the different DNA repair gene polymorphisms and the risk of development of acute myeloid leukemia (AML) in a sample of the Egyptian population and to find out if there is any interaction between these polymorphisms and the NQO1 gene that acts to protect the cells from oxidative damage. RESULTS: Our study was conducted on 90 patients with de novo AML and 60 healthy subjects with matched age and sex. We studied polymorphisms in three DNA repair genes; XRCC1, XRCC3, and XPD. We also assessed the incidence of the NQO1 gene polymorphism. We genotyped the polymorphisms by polymerase chain reaction- restriction fragment length polymorphism. CONCLUSION: The distribution of XRCC1Arg 339Gln genotypes showed a significant difference between patients and controls (p=0.025). The presence of at least one XRCC1 399Gln allele indicated an increased risk of AML and the proportion of AML patients homozygous for the Gln/Gln allele was significantly higher than in the control group (p=0.025). However, distributions of the XRCC3 Thr241Met, XPD Lys751Gln, and NQO1Pro 187Ser genotypes were not significantly different between patients and controls. Combined analysis of the studied DNA repair gene polymorphisms did not show an interaction with the detoxification NQO1 Pro187Ser polymorphism.

Antibody screening in repeatedly transfused patients.

The purpose of pretransfusion compatibility testing is to prevent immune mediated hemolytic transfusion reactions. Our study aimed to evaluate the gel test for detection of clinically significant antibodies in repeatedly transfused patients. We investigated 200 thalassemic patients in whom, blood group, Rh-D, Rh phenotype determination, antibody screening and identification were done using an ID Microtyping System. Red cell alloantibodies were detected in 21 patients (10.5%). Among these patients, Anti-E was detected in 5 (23.8%), anti-D in 4 (19%), anti-K in 4 (19%), anti-e in 3 (14.3%) and each of anti-Fy(a), anti-Js(a), anti-Lu(a), anti-N and anti-s in one patient (4.8%). Anti-E showed the highest frequency in the 21 positive cases that developed clinically significant antibodies. The study revealed statistically significant correlation between development of transfusion reactions, frequency of blood transfusion and the duration of blood transfusion with the incidence of development of clinically significant alloantibodies. It is concluded that the gel test is an easy, quick and reliable method for detecting clinically significant antibodies. Antibody screening and identification is recommended prior to transfusion to detect if there is blood group incompatibility other than the ABO and Rh.

Dual color FISH on CBF primary acute myeloid leukemia.

In acute myeloid leukemia (AML), clonal chromosomal aberrations constitute markers of diagnostic value and the molecular characterization of numerous abnormalities has greatly improved the understanding of the biology of distinct subtypes of the disease. Two of the most common recurring chromosomal abnormalities in AML are t(8;21) and inversion of chromosome 16 or its variant which belong to core binding factor (CBF) AML group. We aimed to compare between cytogenetics and dual color Fluorescence In Situ Hybridization (FISH) regarding their sensitivity for detection of CBF AML associated translocations including t(8;21) and inv(16)/t(16;16). Fifty five consecutive patients diagnosed as de novo AML were studied by chromosome banding analysis. Among them 32 patients were studied by FISH for the detection of AML1/ETO fusion gene and 11 patients for the detection of CBFbeta/MYH11. Four cases of AML (M2) subtype were positive for t(8;21) and 1 (M4) subtype was positive for inv(16) by karyotyping analysis. When FISH was applied 6 cases all of AML (M2) subtype were positive for t(8;21), 2 of them were of normal karyotype, and 5 cases all of M4EO subtype were found to be positive for inv(16)/ t(16;16) and 4 of them showed normal karyotypes. In conclusion, FISH can be used as a complementary technique to identify t(8;21) and inv16/t(16;16) in de novo AML as these abnormalities are difficult to diagnose in most cases by conventional cytogenetics alone.

A fluorescence in situ hybridization map of 6q deletions in acute lymphocytic leukemia: identification and analysis of a candidate tumor suppressor gene.

With the objective of identifying candidate tumor suppressor genes, we used fluorescence in situ hybridization to map leukemia-related deletions of the long arm of chromosome 6 (6q). Twenty of 24 deletions overlapped to define a 4.8-Mb region of minimal deletion between markers D6S1510 and D6S1692 within chromosome 6 band q16. Using reverse transcription-PCR, we found evidence of expression in hematopoietic cells for 3 of 15 genes in the region (GRIK2, C6orf111, and CCNC). Comparison between our own and published deletion data singled out GRIK2 as the gene most frequently affected by deletions of 6q in acute lymphocytic leukemia (ALL). Sequence analysis of GRIK2 in 14 ALL cases carrying heterozygous 6q deletions revealed a constitutional and paternally inherited C to G substitution in exon 6 encoding for an amino acid change in one patient. The substitution was absent among 232 normal alleles tested, leaving open the possibility that heterozygous carriers of such mutations may be susceptible to ALL. Although low in all normal hematopoietic tissues, quantitative reverse transcription-PCR showed higher baseline GRIK2 expression in thymus and T cells than other lineages. Among T-cell ALL patients, 6q deletion was associated with a statistically significant reduction in GRIK2 expression (P = 0.0001). By contrast, elevated GRIK2 expression was measured in the myelomonocytic line THP-1 and in one patient with common ALL. Finally, we detected significant levels of GRIK2 expression in prostate, kidney, trachea, and lung, raising the possibility that this gene may be protective against multiple tumor types.