Curcumin and cinnamon mitigates lead acetate-induced oxidative damage in the spleen of rats

Lead toxicity is a common occupational and environmental health hazard that exerts many toxic effects on animals and humans, including immunotoxicity. Curcumin (CUR) and cinnamon (CIN) are common medicinal herbs with immunostimulatory and antioxidant properties. Therefore, this study investigated the protective effect of curcumin and cinnamon against lead acetate (LA)-induced splenotoxicity in rats via hemato-biochemical, immunological, oxidative stress marker, CYP-2E1 expression, histological, and immunohistological evaluations. Four groups of seven rats each were used: the control group received corn oil as a vehicle; the lead acetate group received (100 mg/kg), the CUR + LA group received curcumin (400 mg/kg) plus lead acetate, and the CIN + LA group received cinnamon (200 mg/kg) plus lead acetate orally for 1 month. LA exposure induced macrocytic hypochromic anemia, leukocytosis, neutrophilia, monocytosis, and lymphopenia. Additionally, significant elevations in serum iron, ferritin levels, and transferrin saturation percentage with significant decline of total and unsaturated iron binding capacities (TIBC and UIBC), transferrin, and immunoglobulin G and M levels were recorded. In addition, lead acetate significantly upregulated splenic CYP-2E1 expression, that was evident by significant depletion of reduced glutathione (GSH) activity and elevation of malondihyde (MDA), nitric oxide (NO), and protein carbonyl (PC) concentrations in the spleen. Histologically, hyperplasia of lymphoid follicles, hemosiderin deposition, and disturbance of CD3 and CD68 immuno-expressions were evident in the spleen from the lead acetate group. However, curcumin and cinnamon administration restored the hemato-biochemical, immunological, and oxidative stress parameters as well as histological and immunohistological pictures toward normalcy. In conclusion, curcumin and cinnamon can partially ameliorate LA-induced oxidative damage in the spleen, possibly through their antioxidant, immunomodulatory, and gene-regulating activities

Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives

Co-expression of the epidermal growth factor receptor (EGFR, also known as ErbB1) and human epidermal growth factor receptor 2 (HER2) has been identified as a diagnostic or prognostic sign in various tumors. Despite the fact that lapatinib (EGFR/HER2 dual inhibitor) has shown to be successful, many patients do not respond to it or develop resistance for a variety of reasons that are still unclear. As a result, new approaches and inhibitory small molecules are still needed for EGFR/HER2 inhibition. Herein, novel lapatinib derivatives possessing 4-anilinoquinazoline and imidazole scaffolds (6a–l) were developed and screened as EGFR/HER2 dual inhibitors. In vitro and in silico investigations revealed that compound 6j has a high affinity for the ATP-binding regions of EGFR and HER2. All of the designed candidates were predicted to not penetrate the BBB, raising the expectation for the absence of CNS side effects. At 10 µM, derivatives possessing 3-chloro-4-(pyridin-2-ylmethoxy)aniline moiety (6i–l) demonstrated outstanding ranges of percentage inhibition against EGFR (97.65–99.03%) and HER2 (87.16–96.73%). Compound 6j showed nanomolar IC50 values over both kinases (1.8 nM over EGFR and 87.8 nM over HER2). Over EGFR, compound 6j was found to be 50-fold more potent than staurosporine and 6-fold more potent than lapatinib. A kinase selectivity panel of compound 6j showed poor to weak inhibitory activity over CDK2/cyclin A, c-MET, FGFR1, KDR/VEGFR2, and P38a/MAPK14, respectively. Structure–activity relationship (SAR) that were obtained with different substitutions were justified. Additionally, molecular docking and molecular dynamics studies revealed insights into the binding mode of the target compounds. Thus, compound 6j was identified as a highly effective and dual EGFR/HER2 inhibitor worthy of further investigation