Co-administration of Ceratonia siliqua extract nanoparticles promotes the oral bioavailability and neurotherapeutic efficacy of donepezil in a dementia model.

BACKGROUND: This study aimed to assess the herb-drug interactions between crude/silver nanoparticle (SNP)-loaded carob extract (Car, NCar, respectively) and donepezil-HCl (DPZ) and their impact on neurotherapeutic outcomes in a dementia model. METHODS: Carob pods were subjected to ethanol extraction, and their phytoconstituents were chromatographically analysed. SNP-loaded extract was synthesized and characterized, and dementia-like symptoms were induced in Wistar rats by repeated dosing with 175 mg/kg AlCl3 for 60 days, after which the animals were treated with Car, NCar, DPZ, and combinations of Car/NCar-DPZ for 30 days. The effect of carob formulations on DPZ bioavailability was in-silico profiled and the herb-drug interactions were mathematically assessed as combination indices. RESULTS: Different formulations significantly improved cognitive/spatial memory functions, restored dysregulated brain redox and cholinergic functions, and markedly inhibited cholinesterase, as reflected by the reduction/absence of amyloid plaques and neurofibrillary tangles. In silico profiling of the major phytoconstituents revealed their non-P-glycoprotein substrate nature and CYP3A4, 2C19, and 2C9 inhibition, which might have improved the oral bioavailability of DPZ. The combination index calculations revealed strong synergy between DPZ and both carob formulations, with the strongest effect exhibited by the DPZ/NCar combination. CONCLUSION: The co-administration of carob extract/SNPs represents a promising approach for enhancing the neurotherapeutic efficacy of DPZ.

Decreased apoptosis in advanced-stage/high-grade hepatocellular carcinoma complicating chronic hepatitis C is mediated through the downregulation of p21 ras.

OBJECTIVE AND BACKGROUND: Although p21 ras has been reported to be upregulated in hepatocellular carcinoma complicating chronic hepatitis C type I, p21 ras has a different role in advanced stages, as it has been found to be downregulated. The goal of this study was to investigate the status of p21 ras in early-stage/low-grade and late-stage/high-grade hepatocellular carcinoma and its possible link to apoptosis. MATERIAL AND METHODS: Thirty-five cases each of chronic HCV hepatitis type 4 (group I) and cirrhosis with hepatocellular carcinoma (HCC) complicating chronic HCV hepatitis (groups II and III) were immunohistochemically evaluated using a p21 ras polyclonal antibody. The apoptotic index was determined in histologic sections using the terminal deoxynucleotidyl transferase-mediated d-UTP biotin nick end labeling (TUNEL) assay. RESULTS: Significant differences (P=0.001) were detected in p21 ras protein expression between the three groups. A near 2-fold increase in p21 ras staining was observed in the cirrhotic cases compared to the hepatitis cases, and p21 ras expression was decreased in the HCC group. p21 ras expression correlated with stage (r=0.64, P=0.001) and grade (r=(-)0.65, P=0.001) in the HCC group and grade in the HCV group (r=0.44, P=0.008). Both p21 ras expression and TUNEL-LI were significantly lower in large HCCs compared to small HCCs (P=0.01 each). The TUNEL values were negatively correlated with stage in the HCC group (r=(-)0.85, P=0.001). The TUNEL values were also negatively correlated with grade in both the HCV and HCC groups (r=0.89, P=0.001 and r=(-)0.53, P=0.001, respectively). The p21 ras scores were significantly correlated with the TUNEL-LI values in the HCC group (r=0.63, P=0.001) and HCV group (r=0.88, P=0.001). CONCLUSIONS: p21 ras acts as an initiator in HCC complicating type 4 chronic HCV and is downregulated with HCC progression, which most likely promotes tumor cell survival because it facilitates the downregulation of apoptosis with tumor progression.

Toxicological profiling of a de novo synthesized benzimidazole derivative with potent and selective proapoptotic potentials against breast cancer.

This study aimed to investigate the toxicological profile of 1-(6-(1H-benzo[d]imidazole-2-yl)-2-methylpyridin-3-yl) ethanone (BMPE), both in vitro and in vivo. The proapoptotic/necrotic and cell cycle arrest potentials of BMPE were assessed in MCF-7 cell line. The in vivo toxicology was assessed in female Balb/c mice by repeated dosing of 5, 25, and 50 mg/kg for 21 consecutive days, then different biochemical, inflammatory, and oxidative markers were assessed in sera/tissue homogenates of treated animals. The new derivative showed a potent selective cytotoxicity against malignant cell lines with IC50 value 0.2 µM/mL, while the cytotoxic effect on normal Wi-38 cells was observed at IC50 value 0.4 µM/mL; i.e. twofold the effective anticancer dose. BMPE exhibited an early DNA fragmentation-derived cell apoptosis observed at the G0/G1 checkpoint. In vivo, BMPE was biochemically/immunologically tolerable at a pharmacological dose range of 5-25 mg/kg, with no significant rates of mortality/morbidity and minimal-to-moderate histopathological alterations recorded. The new derivative represents an attractive therapeutic candidate for breast cancer, considering its noticeable modulatory effect on the oxidative-inflammatory axis that would relate to its potent antitumor effect.

Protective and therapeutic impact of taurine on some biochemical, immunological and histological parameters in diabetic rats.

Background: Taurine is a non protein amino acid found in most animal tissues. It is a powerful antioxidant which shares in combating the harmful effect of the reactive oxygen species (ROS), associated to many chronic diseases as diabetes mellitus (DM). The disease is characterized by hyperglycemia and metabolic disorders in the body that leads to the release of ROS in the cells. Methods: The present work evaluates the biochemical and immunological role of taurine (500 mg/kg bwt) in ameliorating diabetes harm in rats when compared to the effect of the antidiabetic drug (amaryl). Six groups were established for the experiment. Group1: control rats without any supplementations. Group 2 : diabetic non treated rats. Group 3: rats received taurine for three weeks. Group 4: rats were supplemented with taurine for three weeks then injected streptozotocin (STZ) (prophylactic gp). Group 5: rats were injected with STZ then supplemented with taurine for four weeks (therapeutic gp). Group 6: rats were injected STZ then treated with amaryl drug for four weeks. Serum glucose and insulin levels in addition to liver function enzymes and lactate dehydrogenase enzyme were determined. ROS effect was monitored in liver tissue by detecting malondialdhyde resulting from lipid peroxidation and detecting glutathione reductase enzyme activity. With respect to the immunological responses, the thymocytes and splenocytes numbers were counted besides measuring serum IgG level. Histological and immunohistochemical studies were performed in pancreatic sections. Results: showed the ability of taurine in decreasing glucose level and increasing insulin with the same efficacy as amaryl drug besides affecting liver enzymes and improving the antioxidant system in cells. Taurine also restored the decrease in mean number of thymocytes and splenocytes caused by DM. Sera IgG levels from pre- and post-treatment with taurine showed non significant increase compared to the diabetic non treated group. Conclusion: post-treatment supplemention of taurine is recommended for T2DM.

Synthesis and molluscicidal activity of 5-oxo-5,6,7,8-tetrahydro-4H-chromene derivatives.

Furfurylidenemalononitriles and thienylidenemalononitriles were treated with 1,3-cyclohexanediones to afford 2-amino-4-hetaryl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile derivatives. The molluscicidal activity of these compounds was investigated.