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Sci Rep ; 14(1): 3823, 2024 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-38360784


Zebrafish have been utilized for many years as a model animal for pharmacological studies on diabetes and obesity. High-fat diet (HFD), streptozotocin and alloxan injection, and glucose immersion have all been used to induce diabetes and obesity in zebrafish. Currently, studies commonly used both male and female zebrafish, which may influence the outcomes since male and female zebrafish are biologically different. This study was designed to investigate the difference between the metabolites of male and female diabetic zebrafish, using limonene - a natural product which has shown several promising results in vitro and in vivo in treating diabetes and obesity-and provide new insights into how endogenous metabolites change following limonene treatment. Using HFD-fed male and female zebrafish, we were able to develop an animal model of T2D and identify several endogenous metabolites that might be used as diagnostic biomarkers for diabetes. The endogenous metabolites in males and females were different, even though both genders had high blood glucose levels and a high BMI. Treatment with limonene prevented high blood glucose levels and improved in diabesity zebrafish by limonene, through reversal of the metabolic changes caused by HFD in both genders. In addition, limonene was able to reverse the elevated expression of AKT during HFD.

Diabetes Mellitus , Hiperglicemia , Animais , Feminino , Masculino , Hipoglicemiantes/farmacologia , Limoneno , Peixe-Zebra/metabolismo , Glicemia/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Obesidade/metabolismo , Dieta Hiperlipídica , Hiperglicemia/complicações
3 Biotech ; 14(1): 22, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38156037


The present study aims to investigate the physicochemical characteristics of phenylalanine ammonia-lyase (PAL) extracted from agricultural waste and its potential use as an anticancer agent in comparison to microbial PAL. We extracted and partially purified PAL from agricultural waste sources. We assessed the temperature and pH range of PAL and determined enzyme kinetics parameters including Michaelis constants (Km), maximum velocity (Vmax), and specificity constant values (Vmax/Km). Additionally, we examined the effects of different storage temperatures on PAL activity. In our analysis, we compared the efficacy of agricultural waste-derived PAL with PAL from Rhodotorula glutinis. The results demonstrated that PAL extracted from agricultural waste exhibited significantly higher specific activity (Vmax/Km) compared to its microbial counterpart. The agricultural waste-derived PAL displayed a stronger affinity for phenylalanine, as indicated by a lower Km value than the microbial PAL did. Furthermore, PAL from agricultural waste maintained activity across a broader temperature and pH range (15-75 °C, pH 5-11), in contrast to microbial PAL (20-60 °C, pH 5.5-10). Importantly, the PAL derived from agricultural waste exhibited superior stability, retaining over 90% of its activity after 6 months of storage at room temperature (25 °C), whereas microbial PAL lost more than 70% of its activity under similar storage conditions. In anticancer experiments against various cancer cell lines, agricultural waste-derived PAL demonstrated greater anticancer activity compared to microbial PAL. These findings suggest that PAL sourced from agricultural waste has the potential to be a safe and effective natural anticancer agent.

Front Chem ; 11: 1231030, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37601910


Being the sixth most diagnosed cancer and the fourth leading cause of cancer-related deaths worldwide, liver cancer is considered as a serious disease with a high prevalence and poor prognosis. Current anticancer drugs for liver cancer have drawbacks, such as limited efficacy in later stages of the disease, toxicity to healthy cells, and the potential for drug resistance. There is ample evidence that coumarin-based compounds are potent anticancer agents, with numerous analogues currently being investigated in preclinical and clinical studies. The current study aimed to explore the antitumor potency of a new class of 8-methoxycoumarin-3-carboxamides against liver cancer. Toward this aim, we have designed, synthesized, and characterized a new set of N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamide analogues. The assessment of antitumor activity revealed that the synthesized class of compounds possesses substantial cytotoxicity toward Hep-G2 cells when compared to staurosporine, without significant impact on normal cells. Out of the synthesized compounds, compound 7 demonstrated the most potent cytotoxic effect against Hep-G2 cells with an IC50 of 0.75 µM, which was more potent than the drug staurosporine (IC50 = 8.37 µM). The investigation into the mechanism behind the antiproliferative activity of compound 7 revealed that it interferes with DNA replication and induces DNA damage, leading to cell cycle arrest as demonstrated by a significant decrease in the percentage of cells in the G1 and G2/M phases, along with an increase in the percentage of cells in the S phase. Flow cytometric analysis further revealed that compound 7 has the ability to trigger programmed cell death by inducing necrosis and apoptosis in HepG-2 cells. Further explorations into the mechanism of action demonstrated that compound 7 displays a potent dual-inhibitory activity toward cytochrome P450 and vascular endothelial growth factor receptor-2 (VEGFR-2) proteins, as compared to sorafenib drug. Further, detailed computational studies revealed that compound 7 displays a considerable binding affinity toward the binding cavity of VEGFR2 and CYP450 proteins. Taken together, our findings indicate that the newly synthesized class of compounds, particularly compound 7, could serve as a promising scaffold for the development of highly effective anticancer agents against liver cancer.