A quinoxaline-based derivative exhibited potent and selective anticancer activity with apoptosis induction in PC-3 cells through Topo II inhibition.

Quinoxaline constitutes a variety of derivatives that exhibit a range of biological characteristics, including anti-inflammatory and antitumor effects, and their importance in therapeutic chemistry is rising. The cytotoxicity effects of four quinoxaline compounds (I, II, III, and IV) against liver cancer cells (HepG2), prostate cancer cells (PC-3), and normal cells (Vero) were evaluated using the MTT assay. Compounds III and IV had the most anti-proliferative effects and highly selective indices against PC-3 cells with IC50 values of 4.11 and 2.11 µM, respectively. The apoptotic cell death for compounds III and IV in PC-3 cells was investigated using cell cycle, Annexin V-FITC/PI double staining-based flow cytometry, and DNA fragmentation assay. Compounds III or IV arrested the cell cycle at the S phase and caused apoptosis in PC-3 cells. Compounds III and IV showed inhibitory effects against topoisomerase II enzyme with IC50 values 21.98 and 7.529 µM, respectively, when compared to doxorubicin as a reference drug. Western Blot analysis displayed that compound IV treatment has significantly upregulated the pro-apoptotic proteins (p53, caspase-3, caspase-8) and downregulated the anti-apoptotic protein Bcl-2 in PC-3 cells in a dose-dependent manner, leading to cell apoptosis. The molecular docking study exhibited that compound IV had a good binding affinity for inhibiting topoisomerase II, consistent with the apoptotic mechanism. In vivo study using Ehrlich solid tumor model demonstrated that compound IV significantly reduced tumor volume and weight in vivo with minimal toxicity. This study reveals significant evidence for the antitumor efficacy of compound IV against prostate cancer cells as a topoisomerase II inhibitor.Communicated by Ramaswamy H. Sarma.

Effect of Copper and Zinc Ions on Biochemical and Molecular Characteristics of Calcium Oxalate Renal Stones: a Controlled Clinical Study.

Contradictory results are existed in the literature regarding the impact of trace elements on the pathogenesis of calcium oxalate (CaOx) stone patients. Therefore, the aim of our study was to investigate the effect of Cu and Zn on biochemical and molecular characteristics of CaOx stones. Plasma and urine concentrations of Cu and Zn in 30 CaOx stones patients and 20 controls were determined by flame atomic absorption spectrometry (FAAS). Urinary levels of citric acid and oxalate were measured by commercial spectrophotometric kits. Blood levels of glutathione reduced (GSH) and catalase (CAT) were determined as markers of antioxidant activity, while blood malondialdehyde (MDA) and urine level of nitric oxide (NO) were used to assess oxidative stress. Gene expression of MAPk pathway (ERK, P38, and JNK) were estimated. The plasma and urine levels of Cu were significantly increased in the patient group compared to those of controls, while the levels of Zn were decreased. Excessive urinary excretion of citric acid and oxalate were found among CaOx stone patients. The GSH and CAT concentration were significantly reduced in CaOx stones patients compared to healthy group. The plasma MDA and urine NO concentration were significantly increased in CaOx stones patients compared to control group. The expressions of the studied genes were significantly increased in CaOx stones patients. These findings suggest that alteration in Cu and Zn might contribute to pathogenesis of CaOx patients through oxidative stress and MAPK pathway genes (ERK, P38 and JNK).

Genetic polymorphisms of ACE I/D, IL-1ß G > A and IL-4 VNTR among Egyptian subjects with rheumatoid arthritis.

BACKGROUND: Various reports examined the contribution of ACE I/D, IL-1ß G > A and IL-4 VNTR with the susceptibility to RA but with conflicting findings. The goal of this study is to assess the impact of these three variants with the susceptibility, clinical and biochemical markers in addition to different composite indices of RA. SUBJECTS AND METHODS: This case-control survey enclosed 120 RA Egyptian patients who were emulated with 150 healthy controls from the same territory. Their genomic DNA was genotyped utilising the PCR approach. RESULTS: RA patients with ACE allele (D) and IL-4 VNTR allele (2 R) were expressively higher emulated with healthy controls (p < .05). Nevertheless, RA patients with IL-1ß (A allele) failed to achieve an apparent significant emulated with healthy controls (p > .05). CONCLUSIONS: This work specifies a noteworthy association for ACE I/D and IL-4 VNTR but not IL-1ß G > A polymorphisms with RA susceptibility among Egyptian subjects.

Diacerein ameliorates kidney injury induced by cisplatin in rats by activation of Nrf2/Ho-1 pathway and Bax down-regulation.

Cisplatin is an antineoplastic medicine used for solid tumor treatment. The main side effect that limits its dose is nephrotoxicity. Diacerein has been used for the treatment of joint diseases like osteoarthritis. It also has exhibited analgesic effects and antipyretic activities in animal models so this study targets to indicate the diacerein effect on nephrotoxicity induced by cisplatin in rats. Rats were distributed into four groups: normal healthy control; diacerein, which received diacerein daily by gastric gavage (50 mg/kg/day); cisplatin, which received only one intraperitoneal injection of cisplatin (6 mg/kg) and cisplatin and diacerein, which received diacerein daily after the cisplatin injection till 7th and 12th days, respectively. Diacerein treatment decreased kidney function markers so the cisplatin effect was reversed. Also, diacerein increased the renal antioxidants and decreased oxidative stress. Diacerein up-regulated Ho-1 (heme oxygenase 1), Nrf2 (Nuclear factor erythroid 2-related factor 2) and endothelial nitric oxide synthase (eNOS) genes expression, while down-regulated Bcl-2-associated X protein (Bax) gene expression. Furthermore, the renal transforming growth factor beta-1 (TGF-ß1) decreased by the diacerein effect. Consequently, diacerein has a curative effect against cisplatin due to its anti-inflammatory, antioxidant, and antiapoptotic properties.

Design, Synthesis and Anticancer Evaluation of Substituted Cinnamic Acid Bearing 2-Quinolone Hybrid Derivatives.

A new series of hybrid molecules containing cinnamic acid and 2-quinolinone derivatives were designed and synthesized. Their structures were confirmed by 1H-NMR, 13C-NMR and mass analyses. All the synthesized hybrid molecules were assessed for their in vitro antiproliferative activity against more than one cancer cell lines. Compound 3-(3,5-dibromo-7,8-dihydroxy-4-methyl-2-oxoquinolin-1(2H)-ylamino)-3-phenylacrylic acid (5a) with IC50 = 1.89 µM against HCT-116 was proved to the most potent compound in this study, as compared to standard drug staurosporin. DNA flow cytometry assay of compound 5a revealed G2/M phase arrest and pre-G1 apoptosis. Annexin V-FITC showed that the percentage of early and late apoptosis was increased. The results of topoisomerase enzyme inhibition activity showed that the hybrid molecule 5a displays potent inhibitory activity compared with control.

Protective role of zinc oxide nanoparticles in kidney injury induced by cisplatin in rats.

Cisplatin used as chemotherapy for various cancers may leads to accumulation of platinum within the kidney and disturb its function. Zinc oxide nanoparticles (ZnO-NPs) are of low toxicity nanomaterials and have many medical fields so this study aims to indicate ZnO-NPs effect in kidney injury induced by cisplatin. Adult male rats were pre-injected with one dose of ZnO-NPs (5 mg/kg IP) and after 2 h from injection, the rats were injected with also only one dose of cisplatin (6 mg/kg IP) and two additional groups were served as controls treated with either ZnO-NPs or cisplatin only, respectively, and normal control was involved and euthanization occurred after 7 and 12 days. Cisplatin-induced nephropathy increased kidney function parameters; serum creatinine, blood urea nitrogen and microalbuminuria. Conversely, these parameters were down regulated after ZnO-NPs treatment. ZnO-NPs reversed the decrease of renal superoxide dismutase, catalase and glutathione reductase and the increase of renal malondialdehyde induced by cisplatin. In addition, the annexin V demonstrated that the proportion of viable cells was significantly elevated and the proportion of apoptotic and necrotic cells significantly reduced. Also, the level of renal transforming growth factor beta 1 decreased in group pre-treated with ZnO-NPs. The Nuclear factor-E2-related factor, heme oxygenase-1 and endothelial nitric oxide synthase expression genes were up regulated while Bcl-2-associated X protein expression was down regulated in kidney tissue via ZnO-NPs. Histopathological and immunohistochemical observations were context with these findings. In conclusion, ZnO-NPs treatment revealed renoprotective effect against cisplatin drug, probably via its antioxidant, anti-inflammatory and antiapoptotic properties.

Inflammatory Biomarkers of Cardiometabolic Risk in Obese Egyptian Type 2 Diabetics.

Inflammatory biomarkers provide a minimally invasive means for early detection and specific treatment of metabolic syndrome and related disorders. The objective of this work was to search for inflammatory biomarkers of cardiometabolic risk in obese type 2 diabetics. The study was performed on 165 persons attending the medical outpatient clinic of Ismailia General Hospital. Their mean age was (50.69 ± 10.15) years. They were divided into three groups. The control group was composed of 55 non-obese, non-diabetic healthy volunteers, 32 males and 23 females. Two study groups were included in this study: group 2 was composed of 55 obese, non-diabetic subjects, 25 males and 30 females matched for age and gender. All patients including the control were subjected to clinical history taking, a clinical examination for the measurement of body mass index (BMI). Investigations were carried out for fasting blood glucose, fasting serum insulin, insulin resistance (IR), the lipid profile, lipoprotein band lipoprotein phospholipase A2, and non-high-density lipoprotein cholesterol (non-HDL-C). Urea, albumin and creatinine analysis and liver function tests were performed, and a complete blood count (CBC) was taken. Hemoglobin A1C (HbA1C), serum high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were tested. There were statistically significant differences among the studied groups in terms of total cholesterol, non-HDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), lipoprotein-associated phospholipase A2 and apolipoprotein B. The inflammatory biomarkers hs-CRP, IL-6 and TNF-α were significantly statistically increased in the study groups by (1.62 ± 0.99, 2.32 ± 1.11), (1.73 ± 1.14, 2.53 ± 1.34), and (1.87 ± 1.09, 2.17 ± 0.89) respectively, where p < 0.01. Significant positive correlation was found between Homeostatic Model Assessment (HOMA)-IR, hs-CRP and IL-6. There was a significant positive correlation between non-HDL and hs-CRP, IL-6 and TNF-α and triglycerides and hs-CRP. In conclusion, in this study, CRP, IL-6, and TNF-α were significantly elevated in obese Egyptian type 2 diabetics and were positively correlated with insulin resistance, non-HDL and triglycerides. These inflammatory biomarkers could help in the premature identification of obese type 2 diabetic patients at high cardiometabolic risk. Additionally, these biomarkers are critical for providing prognostics and the validity of future potential anti-inflammatory therapeutic modalities.

The antiatherogenic, renal protective and immunomodulatory effects of purslane, pumpkin and flax seeds on hypercholesterolemic rats.

BACKGROUND: Atherosclerosis remains one of the leading causes of death all over the world. Flax, pumpkin and purslane seeds are rich sources of unsaturated fatty acids, antioxidants and fibers, known to have antiatherogenic activities. AIMS: This study was to examine the efficiency of using either flax/pumpkin or purslane/pumpkin seed mixture (components of ω-3 and ω-6) on hyperlipidemia, kidney function and as immunomodulators in rats fed high cholesterol diets. MATERIALS AND METHODS: 40 male albino rats were divided into four groups: control group, hypercholesterolemic rats, fed the balanced diet supplemented with cholesterol at a dose level of 2 g/100 g diet; the other two groups of animals fed the same previous hypercholesterolemic diet supplemented with either flax/pumpkin seed mixture or pumpkin/purslane seed mixture at ratio of (5/1) (ω-3 and ω-6). RESULTS: The present study showed that 2% cholesterol administration caused a significant increase in total cholesterol, total lipids, and triacylglycerol in both serum and liver. Serum phospholipids, LDL-C, and atherogenic index AI also significantly increased compared to control group. Cholesterol-enriched diet significantly increased serum urea, creatinine, sodium and potassium levels as well as significantly increased serum IgG and IgM compared to healthy control. Consumption of flax/pumpkin or purslane/pumpkin seed mixtures by hypercholesterolemic rats resulted in a significantly decrement in lipid parameters and significant improvement in IgG and IgM levels as compared with hypercholesterolemic rats. CONCLUSION: Our results suggests that both flax/pumpkin and purslane/pumpkin seed mixtures had anti-atherogenic hypolipidemic and immunmodulator effects which were probably mediated by unsaturated fatty acids (including alpha linolenic acid) present in seed mixture.