Effect of lyophilized Azadirachta indica leaf powder on biochemical parameters of testis and epididymis in albino rats

The aim of the present study was to investigate the effect of lyophilized A. indica leaf extract (125, 250 and 375 mg in suspension of 1 mL Propylene Glycol, respectively / kg body weight) on androgen-dependent biochemical parameters such as cholesterol and glycogen in the testis, total protein, total free sugar, enzymes like acid phosphatase (ACP), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) in the testis and epididymis of both control and treated groups. Results indicated no significant difference in their body weight. However, testis and epididymis showed a significant decrease in their weights. The biochemical analysis showed a general decrease in the total protein content and the activity ofACP and, an increase in the total free sugar, glycogen, cholesterol contents and the activities of ALP and LDH in the dose-dependent treated rats. Since it is known that the accumulation of cholesterol and glycogen in the testis and epididymis are indicators of androgen deprivation. In this study such effects may have resulted from the deficiency in the level of circulating androgen, probably due to androgen deficiency resulting to the anti-androgenic property of the carbohydrate-rich nature of lyophilized A. indica leaf extract.© 2010 International Formulae Group. All rights reserved.Keywords: Lyophilized A. indica leaf extract, Testis, Epididymis, Biochemical parameters, Albino rats

Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors

Background Covalent (irreversible) Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations in BTK at residue C481, the binding site of covalent BTK inhibitors. Noncovalent (reversible) BTK inhibitors overcome this mechanism and other sources of resistance, but the mechanisms of resistance to these therapies are currently not well understood. Methods We performed genomic analyses of pretreatment specimens as well as specimens obtained at the time of disease progression from patients with CLL who had been treated with the noncovalent BTK inhibitor pirtobrutinib. Structural modeling, BTK-binding assays, and cell-based assays were conducted to study mutations that confer resistance to noncovalent BTK inhibitors. Results Among 55 treated patients, we identified 9 patients with relapsed or refractory CLL and acquired mechanisms of genetic resistance to pirtobrutinib. We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell-receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors.Conclusions Resistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors. (Funded by the American Society of Hematology and others.