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1.
Cells ; 13(3)2024 Feb 05.
Article in English | MEDLINE | ID: mdl-38334679

ABSTRACT

A well-known natural ingredient found in several medicinal plants, berberine (Ber), has been shown to have anticancer properties against a range of malignancies. The limited solubility and bioavailability of berberine can be addressed using Ber-loaded nanoparticles. In this study, we compared the in vitro cytotoxic effects of both Ber-loaded silver nanoparticles (Ber-AgNPs) and Ber-loaded selenium nanoparticles (Ber-SeNPs) in the human liver cancer cell line (HepG2) and mouse normal liver cells (BNL). The IC50 values in HepG2 for berberine, Ber-AgNPs, Ber-SeNPs, and cisplatin were 26.69, 1.16, 0.04, and 0.33 µg/mL, respectively. Our results show that Ber and its Ag and Se nanoparticles exerted a good antitumor effect against HepG2 cells by inducing apoptosis via upregulating p53, Bax, cytosolic cytochrome C levels, and caspase-3 activity, and the down-regulation of Bcl-2 levels. Similarly, incubation with Ber and both Ber-NPs (Ag and Se) led to a significant dose-dependent elevation in inflammatory markers' (TNF-α, NF-κB, and COX-2) levels compared to the control group. In addition, it led to the arrest of the G1 cell cycle by depleting the expression of cyclin D1 and CDK-2 mRNA. Furthermore, Ber and both Ber-NPs (Ag and Se) caused a significant dose-dependent increase in LDH activity in HepG2 cells. Furthermore, our findings offer evidence that Ber and its nanoparticles intensified oxidative stress in HepG2 cells. Furthermore, the migration rate of cells subjected to berberine and its nanoforms was notably decreased compared to that of control cells. It can be inferred that Ber nanoparticles exhibited superior anticancer efficacy against HepG2 compared to unprocessed Ber, perhaps due to their improved solubility and bioavailability. Furthermore, Ber-SeNPs exhibited greater efficacy than Ber-AgNPs, possibly as a result of the inherent anticancer characteristics of selenium.


Subject(s)
Berberine , Carcinoma, Hepatocellular , Liver Neoplasms , Metal Nanoparticles , Selenium , Mice , Animals , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Selenium/pharmacology , Berberine/pharmacology , Silver/pharmacology , Liver Neoplasms/pathology , Cell Line
2.
Environ Sci Pollut Res Int ; 29(55): 83723-83732, 2022 Nov.
Article in English | MEDLINE | ID: mdl-35773616

ABSTRACT

Prodigiosins have been shown to have anticancer activities. 5-Fluorouracil (5-FU) is broadly used chemotherapeutic drug that treats different solid tumors including breast cancer but has low response rates and a variety of side effects. In this study, we evaluated the anticancer properties of prodigiosins in a murine model "Ehrlich tumor" and tested whether it can be added to 5-FU to potentiate its effects. Markers of oxidative stress; MDA, NO, and GSH levels were evaluated as well as antioxidant enzyme activities of CAT SOD, GR, and GPx. The levels of Bax, Bcl-2, PCNA, and NF-κB proteins were measured using ELISA kits. The mRNAs of p53 and Cdc2 and Casp3 were quantitatively measured by real-time PCR and ELISA respectively. Cell cycle analysis was performed using flow cytometery. Prodigiosins did not influence tumor volume. Prodigiosins have not induced oxidative stress while 5-FU did increase MDA, NO but decreased GSH levels. The combination prodigiosins and 5-FU did reduce oxidative stress markers; MDA, NO and increased GSH levels. Prodigiosins significantly increased CAT only while 5-FU did decreased SOD, CAT, GPx, and GR. The combination prodigiosins and 5-FU increased the levels of these enzymes again. Prodigiosins increased the Bax/Bcl-2 ratio while the combination deceased it. In conclusion, prodigiosins have pronounced anticancer properties but their combination with 5-FU decreased oxidative stress exerted by 5-FU but weakened the apoptotic effects of 5-FU. Prodigiosins could affect a key mechanism through which 5-FU exerts its tumor inhibitory effects.


Subject(s)
Antineoplastic Agents , Neoplasms , Mice , Animals , Fluorouracil/pharmacology , Prodigiosin , bcl-2-Associated X Protein/metabolism , Apoptosis , Antineoplastic Agents/pharmacology , Proto-Oncogene Proteins c-bcl-2/metabolism , Antioxidants/pharmacology , Superoxide Dismutase , Cell Line, Tumor
3.
J Diabetes Res ; 2020: 6762709, 2020.
Article in English | MEDLINE | ID: mdl-32626781

ABSTRACT

Diabetes mellitus (DM) is a chronic endocrine disease characterized by persistent hyperglycemia. Oxidative damage, inflammatory cytokines, and apoptotic cell death play a major role in the induction and progression of male testicular damage. Plant-derived phytochemicals such as green coffee (Coffea arabica) can possess antidiabetic effects with little toxicity. The current study is aimed at investigating the therapeutic roles of green coffee in diabetic testicular injury stimulated by high-fat diet/streptozotocin administration. Diabetes mellitus was induced by a high-fat diet and a single dose of streptozotocin (STZ) (35 mg kg-1) in male albino rats. Diabetic animals were orally given two different concentrations of green coffee (50 mg kg-1 and 100 mg kg-1) for 28 days. The levels of testosterone, luteinizing hormone, and follicle-stimulating hormone and parameters of oxidative stress, inflammation, and apoptosis were measured. mRNAs and protein levels were detected quantitatively by real-time PCR and ELISA, respectively. In the diabetic group, the levels of testosterone, luteinizing hormone, and follicle-stimulating hormone showed a significant reduction while they increased significantly after green coffee treatment. A significant increase of antioxidant markers glutathione, superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase along with decreased levels of lipid peroxides and nitric oxide was observed after green coffee treatment in the diabetic group. Finally, the levels of IL-1ß, TNF-α, Bax, and caspase-3 were also decreased in both treated groups (metformin and green coffee) when compared to the diabetic group. We conclude that testicular oxidative impairment induced by a high-fat diet (HFD) and STZ can be reversed by green coffee. Administration of green coffee could represent a promising therapeutic agent which can help the treatment of type 2 DM-induced testicular dysfunction.


Subject(s)
Apoptosis/drug effects , Coffea , Diabetes Complications/metabolism , Diabetes Mellitus, Experimental/metabolism , Oxidative Stress/drug effects , Plant Extracts/pharmacology , Testicular Diseases/metabolism , Testis/drug effects , Animals , Caspase 3/drug effects , Caspase 3/metabolism , Catalase/drug effects , Catalase/metabolism , Diet, High-Fat , Enzyme-Linked Immunosorbent Assay , Follicle Stimulating Hormone/metabolism , Glutathione/drug effects , Glutathione/metabolism , Glutathione Peroxidase/drug effects , Glutathione Peroxidase/metabolism , Glutathione Reductase/drug effects , Glutathione Reductase/metabolism , Hypoglycemic Agents/pharmacology , Inflammation/metabolism , Interleukin-1beta/drug effects , Interleukin-1beta/metabolism , Lipid Peroxidation/drug effects , Luteinizing Hormone/drug effects , Luteinizing Hormone/metabolism , Male , Metformin/pharmacology , Nitric Oxide/metabolism , RNA, Messenger , Rats , Real-Time Polymerase Chain Reaction , Streptozocin/toxicity , Superoxide Dismutase/drug effects , Superoxide Dismutase/metabolism , Testis/metabolism , Testosterone/metabolism , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/metabolism , bcl-2-Associated X Protein/drug effects , bcl-2-Associated X Protein/metabolism
4.
Mol Carcinog ; 49(1): 25-31, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19722178

ABSTRACT

Occupational exposure to polycyclic aromatic hydrocarbons (PAH) is associated with an increased risk of urothelial carcinoma (UC). FGFR3 is found mutated in about 70% of Ta tumors, which represent the major group at diagnosis. The influence of PAH on FGFR3 mutations and whether it is related to the emergence or shaping of these mutations is not yet known. We investigated the influence of occupational PAH on the frequency and spectrum of FGFR3 mutations. We included on 170 primary urothelial tumors from five hospitals from France. Patients (median age, 64 yr) were interviewed to gather data on occupational exposure to PAH, revealing 104 non- and possibly PAH exposed patients, 66 probably and definitely exposed patients. Tumors were classified as follows: 75 pTa, 52 pT1, and 43 > or =pT2. Tumor grades were as follows: 6 low malignant potential neoplasms (LMPN) and 41 low-grade and 123 high-grade carcinomas. The SnaPshot method was used to screen for the following FGFR3 mutations: R248C, S249C, G372C, Y375C, A393E, K652E, K652Q, K652M, and K652T. Occupational PAH exposure was not associated with a particular stage or grade of tumors. Thirty-nine percent of the tumors harbored FGFR3 mutations. After adjustment for smoking, occupational exposure to PAH did not influence the frequency [OR, 1.10; 95% CI, 0.78-1.52], or spectrum of FGFR3 mutations. Occupational exposure to PAH influenced neither the frequency nor the spectrum of FGFR3 mutations and there was no direct relationship between these mutations and this occupational hazard.


Subject(s)
Mutation , Occupational Exposure/analysis , Polycyclic Aromatic Hydrocarbons/poisoning , Receptor, Fibroblast Growth Factor, Type 3/genetics , Urinary Bladder Neoplasms/genetics , Adult , Aged , Aged, 80 and over , DNA Mutational Analysis , Gene Frequency , Humans , Logistic Models , Male , Middle Aged , Neoplasm Staging , Urinary Bladder Neoplasms/chemically induced , Urinary Bladder Neoplasms/pathology
6.
Carcinogenesis ; 26(1): 177-84, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15347601

ABSTRACT

Smoking is a major risk factor for urothelial cell carcinoma of the bladder (UCC). Mutations in the FGFR3 and TP53 genes have been shown to define two distinct pathways in superficial papillary and invasive UCC disease, respectively. We investigated the relationship between smoking and these mutations by means of denaturing high performance liquid chromatography and sequencing for 110 primary UCC of the bladder. This study included 48 current smokers, 31 ex-smokers and 31 non-smokers. Thirty-five of the tumors were stage pTa, 40 pT1 and 35 > or =pT2. Fourteen of the tumors were grade 1, 37 were grade 2 and 59 grade 3. Smoking was associated with high stage (P = 0.03) and high grade tumors (P = 0.006). Twenty-two of the 110 tumors studied harbored TP53 mutations (20%) and 43 harbored FGFR3 mutations (39%). Odds ratios (OR) were higher for TP53 mutations in current smokers [OR, 2.25; 95% confidence interval (95% CI), 0.65-7.75] and ex-smokers (OR, 1.62; 95% CI, 0.41-6.42) than in non-smokers. Double TP53 mutations and the A:T-->G:C TP53 mutation pattern was found only in current smokers. Patients with the FGFR3(wild-type)/TP53(mutated) genotype had significantly higher levels of tobacco consumption, as measured in pack-years (P = 0.01). Smoking influenced neither the frequency nor the pattern of FGFR3 mutations. Our results suggest that smoking is associated with invasive and high grade UCCs, at initial presentation, and influenced TP53 or the molecular pathway defined by these mutations. In contrast, FGFR3 mutations are not affected by smoking and probably result from endogenous alterations. These data have potential implications for clinical management and prevention strategies.


Subject(s)
Carcinoma, Transitional Cell/etiology , Genes, p53/genetics , Protein-Tyrosine Kinases/genetics , Receptors, Fibroblast Growth Factor/genetics , Smoking/adverse effects , Urinary Bladder Neoplasms/etiology , Adult , Aged , Aged, 80 and over , Carcinogens , Carcinoma, Transitional Cell/genetics , Chromatography, High Pressure Liquid , DNA Mutational Analysis , Genes, p53/drug effects , Humans , Middle Aged , Mutation , Neoplasm Staging , Polymerase Chain Reaction , Protein-Tyrosine Kinases/drug effects , Receptor, Fibroblast Growth Factor, Type 3 , Receptors, Fibroblast Growth Factor/drug effects , Urinary Bladder Neoplasms/genetics
7.
Cancer Res ; 63(23): 8108-12, 2003 Dec 01.
Article in English | MEDLINE | ID: mdl-14678961

ABSTRACT

FGFR3 and TP53 mutations are frequent in superficial papillary and invasive disease, respectively. We used denaturing high-performance liquid chromatography and sequencing to screen for FGFR3 and TP53 mutations in 81 newly diagnosed urothelial cell carcinomas. Tumors were classified as follows: 31 pTa, 1 carcinoma in situ, 30 pT1, and 19 pT2-T4. Tumor grades were as follows: 10 G1, 29 G2, and 42 G3. FGFR3 mutations were associated with low-stage (P < 0.0001), low-grade (P < 0.008) tumors, whereas TP53 mutations were associated with high-stage (P < 0.003), high-grade (P < 0.02) tumors. Mutations in these two genes were almost mutually exclusive. Our results suggest that FGFR3 and TP53 mutations define separate pathways at initial diagnosis of urothelial cell carcinoma.


Subject(s)
Carcinoma, Transitional Cell/genetics , Genes, p53/genetics , Mutation , Protein-Tyrosine Kinases , Receptors, Fibroblast Growth Factor/genetics , Urinary Bladder Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Carcinoma, Transitional Cell/pathology , Humans , Middle Aged , Neoplasm Staging , Receptor, Fibroblast Growth Factor, Type 3 , Urinary Bladder Neoplasms/pathology
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