Multi-targeted therapeutic potential of stigmasterol from the Euphorbia ammak plant in treating lung and breast cancer.

Cancer is the most prevalent disease globally, which presents a significant challenge to the healthcare industry, with breast and lung cancer being predominant malignancies. This study used RNA-seq data from the TCGA database to identify potential biomarkers for lung and breast cancer. Tumor Necrosis Factor (TNFAIP8) and Sulfite Oxidase (SUOX) showed significant expression variation and were selected for further study using structure-based drug discovery (SBDD). Compounds derived from the Euphorbia ammak plant were selected for in-silico study with both TNFAIP8 and SUOX. Stigmasterol had the greatest binding scores (normalized scores of -8.53 kcal/mol and -9.69 kcal/mol) with both proteins, indicating strong stability in their binding pockets throughout the molecular dynamics' simulation. Although Stigmasterol first changed its initial conformation (RMSD = 0.5 nm with the starting conformation) in SUOX, it eventually reached a stable conformation (RMSD of 1.5 nm). The compound on TNFAIP8 showed a persistent shape (RMSD of 0.35 nm), indicating strong protein stability. The binding free energy of the complex was calculated using the MM/GBSA technique; TNFAIP8 had a ΔGTOTAL of -24.98 kcal/mol, with TYR160 being the most significant residue, contributing -2.52 kcal/mol. On the other hand, the SUOX complex had a binding free energy of -16.87 kcal/mol, with LEU151 being the primary contributor (-1.17 kcal/mol). Analysis of the complexes' free energy landscape unveiled several states with minimum free energy, indicating robust interactions between the protein and ligand. In its conclusion, this work emphasises the favourable ability of Stigmasterol to bind with prospective targets for lung and breast cancer, indicating the need for more experimental study.

Prediction of anticancer peptides derived from the true lectins of Phoenix dactylifera and their synergetic effect with mitotane.

Background and aims: Cancer continues to be a significant source of both illness and death on a global scale, traditional medicinal plants continue to serve as a fundamental resource of natural bioactive compounds as an alternative source of remedies. Although there have been numerous studies on the therapeutic role of Phoenix dactylifera, the study of the role of peptides has not been thoroughly investigated. This study aimed to investigate the anticancer activity of lectin peptides from P. dactylifera using in silico and in vivo analysis. Methods: Different computational tools were used to extract and predict anticancer peptides from the true lectins of P. dactylifera. Nine peptides that are bioactive substances have been investigated for their anticancer activity against MCF-7 and T47D (two forms of breast cancer). To counteract the unfavorable effects of mitotane, the most potent peptides (U3 and U7) were combined with it and assessed for anticancer activity against MCF-7 and HepG2. Results: In silico analysis revealed that nine peptides were predicted with anticancer activity. In cell lines, the lowest IC50 values were measured in U3 and U7 against MCF-7 and T47D cells. U3 or U7 in combination with mitotane demonstrated the lowest IC50 against MCF-7 and HepG2. The maximum level of cell proliferation inhibition was 22% when U3 (500 µg/mL) and 25 µg/mL mitotane were combined, compared to 41% when 25 µg/mL mitotane was used alone. When mitotane and U3 or U7 were combined, it was shown that these bioactive substances worked synergistically with mitotane to lessen its negative effects. The combination of peptides and mitotane could be regarded as an efficient chemotherapeutic medication having these bioactive properties for treating a variety of tumors while enhancing the reduction of side effects.

Correction: Jamal et al. Preparation of 6-Mercaptopurine Loaded Liposomal Formulation for Enhanced Cytotoxic Response in Cancer Cells. Nanomaterials 2022, 12, 4029.

In the original publication [...].

Palladium and platinum complexes based on pyridine bases induced anticancer effectiveness via apoptosis protein signaling in cancer cells.

Palladium and platinum complexes, especially those that include cisplatin, can be useful chemotherapeutic drugs. Alternatives that have less adverse effects and require lower dosages of treatment could be provided by complexes containing pyridine bases. The complexes [Pd(SCN)2(4-Acpy)2] (1), [Pd(N3)2(4-Acpy)2] (2) [Pd(paOH)2].2Cl (3) and [Pt(SCN)2(paO)2] (4) were prepared by self-assembly method at ambient temperature; (4-Acpy = 4-acetylpyridine and paOH = pyridine-2-carbaldehyde-oxime). The structure of complexes 1-4 was confirmed using spectroscopic and X-ray crystallography methods. Complexes 1-4 have similar features in isomerism that include the trans coordination geometry of pyridine ligands with Pd or Pt ion. The 3D network structure of complexes 1-4 was constructed by an infinite number of discrete mononuclear molecules extending via H-bonds. The Pd and Pt complexes 1-4 with pyridine ligands were assessed on MCF-7, T47D breast cancer cells and HCT116 colon cancer cells. The study evaluated cell death through apoptosis and cell cycle phases in MCF-7 cells treated with palladium or platinum conjugated with pyridine base. Upon treatment of MCF-7 with these complexes, the expression of apoptotic signals (Bcl2, p53, Bax and c-Myc) and cell cycle signals (p16, CDK1A, CDK1B) were evaluated. Compared to other complexes and cisplatin, IC50 of complex 1 was lowest in MCF-7 cells and complex 2 in T47D cells. Complex 4 has the highest effectiveness on HCT116. The selective index (SI) of complexes 1-4 has a value of more than two for all cancer cell lines, indicating that the complexes were less toxic to normal cells when given the same dose. MCF-7 cells treated with complex 2 and platinum complex 4 exhibited the highest level of early apoptosis. p16 may be signal arrest cells in Sub G, which was observed in cells treated with palladium complexes that suppress excessive cell proliferation. High c-Myc expression of treated cells with four complexes 1-4 and cisplatin could induce p53. All complexes 1-4 elevated the expression of Bax and triggered by the tumor suppressor gene p53. p53 was downregulating the expression of Bcl2.

Synergistic effects of bee venom, hesperidin, and piperine with tamoxifen on apoptotic and angiogenesis biomarker molecules against xerographic MCF-7 injected rats.

Breast cancer ranks as the second leading most significant of mortality for women. Studies have demonstrated the potential benefits of natural compounds in cancer treatment and prevention, either in isolation or in conjunction with chemotherapy. In order to improve Tamoxifen's therapeutic efficacy in in-vivo studies, our research sought to determine the effects of hesperidin, piperine, and bee venom as natural compounds, as well as their combination effect with or without Tamoxifen. First, 132 female albino rats were equally divided into six groups and five subgroups, and breast cancer was induced in the selected groups by xenografting of MCF7 cells. Second, the effect of single and best ratio combinations treatment from previous in vitro studies were selected. Next, tumorous mammary glands were collected for apoptotic and antiapoptotic biomarkers and cell cycle analysis. Single or combined natural products with or without Tamoxifen revealed a significant up-regulation in apoptotic genes Bax and Casp3 and a downregulation of antiapoptotic and angiogenesis genes Bcl-2 and VEGF genes. We found that cell cycle arrest in the G0/G1 phase was exclusively caused by Tamoxifen and/ or hesperidin. However, the cell cycle arrest in the G2/M phase is a result of the combination of piperine and bee venom, with or without Tamoxifen by using the flow cytometric technique. Our research concludes that bee venom, hesperidin, and piperine can synergistically enhance to increase Tamoxifen's efficiency in the management of breast cancer.

Enhancing Ezetimibe Anticancer Activity Through Development of Drug Nano-Micelles Formulations: A Promising Strategy Supported by Molecular Docking.

Background: Ezetimibe, initially recognized as a cholesterol-lowering agent, has recently attracted attention due to its potential anticancer properties. We aimed to explore an innovative approach of enhancing the drug anticancer activity through the development of drug nano-formulations. Materials and Methods: Fifteen different nano-micelles formulations were prepared utilizing D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and pluronic F127. The prepared formulations were characterized for size, polydispersity index (PDI), zeta potential, and entrapment efficiency (EE). The formulations were morphologically characterized using light and transmission electron microscopies and the drug-binding mode with the active site was investigated using the molecular docking. Cell viability against MCF-7 and T47D was studied. Apoptosis and cell cycle were assessed. Results: The prepared formulations were in the nano-size range (34.01 ± 2.00-278.34 ± 9.11 nm), zeta potential values were very close to zero, and the TPGS-based micelles formulations showed the highest ezetimibe EE (94.03 ± 1.71%). Morphological study illustrated a well-defined, spherical nanoparticles with a uniform size distribution. Molecular docking demonstrated good interaction of ezetimibe with Interleukin-1 Beta Convertase through multiple hydrogen bonding, covalent bond, and hydrophobic interaction. TPGS-based nano-micelle formulation (F5) demonstrated the lowest IC50 against MCF-7 (4.51 µg/mL) and T47D (8.22 µg/mL) cancer cells. When T47D cells were treated with IC50 concentrations of F5, it exhibited significant inhibition with late apoptosis (43.9%), a response comparable to T47D cells treated with an IC50 dose of ezetimibe. Cell cycle analysis revealed that both ezetimibe and F5-treated T47D cells exhibited an increase in the subG1 phase, indicating reduced DNA content and cell death. Conclusion: These findings suggest that F5 could serve as a proficient drug delivery system in augmenting the cytotoxic activity of ezetimibe against breast cancer.

Regulation of Protein-Induced Apoptosis and Autophagy in Human Hepatocytes Treated with Metformin and Paclitaxel In Silico and In Vitro.

Metformin and paclitaxel therapy offer promising outcomes in the treatment of liver cancer. Combining paclitaxel with metformin enhances treatment effectiveness and mitigates the adverse effects associated with paclitaxel alone. This study explored the anticancer properties of metformin and paclitaxel in HepG2 liver cancer cells, MCF-7 breast cancer cells, and HCT116 colon cancer cells. The results demonstrated that the combination of these agents exhibited a lower IC50 in the tested cell lines compared to paclitaxel monotherapy. Notably, treating the HepG2 cell line with this combination led to a reduction in the G0/G1 phase and an increase in the S and G2/M phases, ultimately triggering early apoptosis. To further investigate the interaction between the cellular proteins with paclitaxel and metformin, an in silico study was conducted using proteins chosen from a protein data bank (PDB). Among the proteins studied, AMPK-α, EGFRK, and FKBP12-mTOR exhibited the highest binding free energy, with values of -11.01, -10.59, and -15.63 kcal/mol, respectively, indicating strong inhibitory or enhancing effects on these proteins. When HepG2 cells were exposed to both paclitaxel and metformin, there was an upregulation in the gene expression of AMPK-α, a key regulator of the energy balance in cancer growth, as well as apoptotic markers such as p53 and caspase-3, along with autophagic markers including beclin1 and ATG4A. This combination therapy of metformin and paclitaxel exhibited significant potential as a treatment option for HepG2 liver cancer. In summary, the combination of metformin and paclitaxel not only enhances treatment efficacy but also reduces side effects. It induces cell cycle alterations and apoptosis and modulates key cellular proteins involved in cancer growth, making it a promising therapy for HepG2 liver cancer.

Exploring the Enhanced Antiproliferative Activity of Turmeric Oil and 6-Mercaptopurine in a Combined Nano-Particulate System Formulation.

6-Mercaptopurine (6-MP) is a chemotherapeutic agent with inadequate efficacy due to its poor aqueous solubility and limited bioavailability. Turmeric oil is a naturally occurring bioactive substance obtained from the rhizomes of Curcuma longa Linn that has well-known antiproliferative activities. The aim of this study was to develop a 6-MP-loaded turmeric oil-based self-nanoemulsifying drug delivery system (SNEDDS) to improve the anticancer activity of 6-MP. Turmeric oil was extracted and used in a range of 15-25% to develop SNEDDS formulations utilizing tween 80 and dimethyl sulfoxide as the surfactant and cosurfactant, respectively. The size, charge, and effect of the formulations on the viability against HepG2 and MCF-7 cell models, as well as the apoptosis and cell cycle, were analyzed. The prepared SNEDDS formulations were in the size range of 425.7 ± 7.4-303.6 ± 19.3 nm, using a polydispersity index of 0.429-0.692 and electronegative surface charges. Moreover, 6-MP-loaded SNEDDS with 15% turmeric oil content (F1) showed smaller particle sizes and a noticeable antiproliferative activity against both cell line models. Also, F1 showed a higher rate of late apoptosis than the pure drug and the corresponding non-medicated formulation. A morphological study revealed significant changes in the HepG2 cells compared to untreated cells. More cells halted in the S phase, and a marked decrease in the proportions of cells in the G1/G0 phase was observed when using SNEDDS formulation compared to pure drug. Thus, SNEDDS formulation is a promising drug delivery system for improving the antiproliferative activity of 6-MP, especially when turmeric oil is incorporated.

Synthesis, Crystal Structure, DFT, and Anticancer Activity of Some Imine-Type Compounds via Routine Schiff Base Reaction: An Example of Unexpected Cyclization to Oxazine Derivative.

The synthesis, characterization, and anticancer properties of three imine-type compounds 1-3 and an unexpected oxazine derivative 4 are presented. The reaction of p-dimethylaminobenzaldehyde or m-nitrobenzaldehyde with hydroxylamine hydrochloride afforded the corresponding oximes 1-2 in good yields. Additionally, the treatment of benzil with 4-aminoantipyrine or o-aminophenol was investigated. Routinely, the Schiff base (4E)-4-(2-oxo-1,2-diphenylethylideneamino)-1,2-dihydro-1,5-dimethyl-2-phenylpyrazol-3-one 3 was obtained in the case of 4-aminoantipyrine. Unexpectedly, the reaction of benzil with o-aminophenol proceeded with cyclization to produce the 2,3-diphenyl-2H-benzo[b][1,4]oxazin-2-ol 4. The structures of compounds 3 and 4 were unambiguously determined by single crystal X-ray diffraction. Hirshfeld analysis of molecular packing revealed the importance of the O…H (11.1%), N…H (3.4%), C…H (29.4%), and C…C (1.6) interactions in the crystal stability of 3. In the case of 4, the O…H (8.8%), N…H (5.7%), and C…H (30.3%) interactions are the most important. DFT calculations predicted that both compounds have a polar nature, and 3 (3.4489 Debye) has higher polarity than 4 (2.1554 Debye). Different reactivity descriptors were calculated for both systems based on the HOMO and LUMO energies. The NMR chemical shifts were calculated and were found well correlated with the experimental data. HepG2 growth was suppressed by the four compounds more than MCF-7. The IC50 values of 1 against HepG2 and MCF-7 cell lines were the lowest, and it is considered the most promising candidate as an anticancer agent.

Potential Anticancer Activity of Juniperus procera and Molecular Docking Models of Active Proteins in Cancer Cells.

Medicinal plants provide a wide range of active compounds that can be exploited to create novel medicines with minimal side effects. The current study aimed to identify the anticancer properties of Juniperus procera (J. procera) leaves. Here, we demonstrate that J. procera leaves' methanolic extract suppresses cancer cells in colon (HCT116), liver (HepG2), breast (MCF-7), and erythroid (JK-1) cell lines. By applying GC/MS, we were able to determine the components of the J. procera extract that might contribute to cytotoxicity. Molecular docking modules were created that used active components against cyclin-dependent kinase 5 (Cdk5) in colon cancer, aromatase cytochrome P450 in the breast cancer receptor protein, the -N terminal domain in the erythroid cancer receptor of the erythroid spectrin, and topoisomerase in liver cancer. The results demonstrate that, out of the 12 bioactive compounds generated by GC/MS analysis, the active ingredient 2-imino-6-nitro-2H-1-benzopyran-3-carbothiamide proved to be the best-docked chemical with the chosen proteins impacted by DNA conformational changes, cell membrane integrity, and proliferation in molecular docking studies. Notably, we uncovered the capacity of J. procera to induce apoptosis and inhibit cell growth in the HCT116 cell line. Collectively, our data propose that J. procera leaves' methanolic extract has an anticancer role with the potential to guide future mechanistic studies.

Tuning anticancer properties and DNA-binding of Pt(ii) complexes via alteration of nitrogen softness/basicity of tridentate ligands.

Nine tridentate Schiff base ligands of the type (N^N^O) were synthesized from reactions of primary amines {2-picolylamine (Py), N-phenyl-1,2-diaminobenzene (PhN), and N-phenyl-1,2-diaminoethane(EtN)} and salicylaldehyde derivatives {3-ethoxy (OEt), 4-diethylamine (NEt2) and 4-hydroxy (OH)}. Complexes with the general formula Pt(N^N^O)Cl were synthesized by reacting K2PtCl4 with the ligands in DMSO/ethanol mixtures. The ligands and their complexes were characterized by NMR spectroscopy, mass spectrometry and elemental analysis. The DNA-binding behaviours of the platinum(ii) complexes were investigated by two techniques, indicating good binding affinities and a two-stage binding process for seven complexes: intercalation followed by switching to a covalent binding mode over time. The other two complexes covalently bond to ct-DNA without intercalation. Theoretical calculations were used to shed light on the electronic and steric factors that lead to the difference in DNA-binding behavior. The reactions of some platinum complexes with guanine were investigated experimentally and theoretically. The binding of the complexes with bovine serum albumin (BSA) indicated a static interaction with higher binding affinities for the ethoxy-containing complexes. The half maximal inhibitory concentration (IC50) values against MCF-7 and HepG2 cell lines suggest that platinum complexes with tridentate ligands of N-phenyl-o-phenylenediamine or pyridyl with 3-ethoxysalicylimine are good chemotherapeutic candidates. Pt-Py-OEt and Pt-PhN-OEt have IC50 values against MCF-7 of 13.27 and 10.97 µM, respectively, compared to 18.36 µM for cisplatin, while they have IC50 values against HepG2 of 6.99 and 10.15 µM, respectively, compared to 19.73 µM for cisplatin. The cell cycle interference behaviour with HepG2 of selected complexes is similar to that of cisplatin, suggesting apoptotic cell death. The current work highlights the impact of the tridentate ligand on the biological properties of platinum complexes.

Preparation of 6-Mercaptopurine Loaded Liposomal Formulation for Enhanced Cytotoxic Response in Cancer Cells.

6-Mercaptopurine (6-MP) is a well-known immunosuppressive medication with proven anti-proliferative activities. 6-MP possesses incomplete and highly variable oral absorption due to its poor water solubility, which might reduce its anti-cancer properties. To overcome these negative effects, we developed neutral and positively charged drug-loaded liposomal formulations utilizing the thin-film hydration technique. The prepared liposomal formulations were characterized for their size, polydispersity index (PDI), zeta potential, and entrapment efficiency. The average size of the prepared liposomes was between 574.67 ± 37.29 and 660.47 ± 44.32 nm. Positively charged liposomes (F1 and F3) exhibited a lower PDI than the corresponding neutrally charged ones (F2 and F4). Entrapment efficiency was higher in the neutral liposomes when compared to the charged formulation. F1 showed the lowest IC50 against HepG2, HCT116, and MCF-7 cancer cells. HepG2 cells treated with F1 showed the highest level of inhibition of cell proliferation with no evidence of apoptosis. Cell cycle analysis showed an increase in the G1/G0 and S phases, along with a decrease in the G2/M phases in the cell lines treated with drug loaded positively charged liposomes when compared to free positive liposomes, indicating arrest of cells in the S phase due to the stoppage of priming and DNA synthesis outside the mitotic phase. As a result, liposomes could be considered as an effective drug delivery system for treatment of a variety of cancers; they provide a chance that a nanoformulation of 6-MP will boost the cytotoxicity of the drug in a small pharmacological dose which provides a dosage advantage.

Tuning the anticancer properties of Pt(ii) complexes via structurally flexible N-(2-picolyl)salicylimine ligands.

Three tridentate Schiff base ligands were synthesized from the reactions between 2-picolylamine and salicylaldehyde derivatives (3-ethoxy (OEt), 4-diethylamino (NEt2) and 4-hydroxy (OH)). Complexes with the general formula Pt(N^N^O)Cl were obtained from reactions between the ligands and K2PtCl4. The ligands and their complexes were characterized by NMR spectroscopy, mass spectrometry and elemental analysis. Further confirmation of the structure of Pt-OEt was achieved by single-crystal X-ray diffraction. The DMSO/chlorido exchange process at Pt-OEt was investigated by monitoring the change in conductivity, revealing very slow dissociation in DMSO. Moreover, solvent/chlorido exchange for Pt-OEt and Pt-NEt2 were investigated by NMR spectroscopy in DMSO and DMSO/D2O; Pt-NEt2 forms an adduct with DMSO while Pt-OEt forms adducts with DMSO and water. The DNA-binding behaviour of the platinum(ii) complexes was investigated by two techniques. Pt-NEt2 has the best apparent binding constant. The intercalation mode of interaction with ct-DNA was suggested by molecular docking studies and the increase in the relative viscosity of ct-DNA with increasing concentrations of the platinum(ii) complexes. However, the gradual decrease in the relative viscosity over time at constant concentration of platinum(ii) complexes indicated a shift from intercalation to a covalent binding mode. Anticancer activities of the ligands and their platinum(ii) complexes were examined against two cell lines. The platinum(ii) complexes exhibit superior cytotoxicity to that of their ligands. Among the platinum(ii) complexes, Pt-OEt possesses the best IC50 against both cell lines, its cytotoxicity being comparable to that observed for cisplatin. Cell cycle arrest in the HepG2 cell line upon treatment with Pt-OEt and Pt-NEt2 was investigated and compared to that of cisplatin; the change in the cell accumulation patterns supports the presumption of an apoptotic cell death pathway. The optimized structures of the B-DNA trimer adducts with the platinum complexes showed hydrogen-bonding interactions between the ligands and nucleobases, affecting the inter-strand hydrogen bonding within the DNA, and highlighting the strong ability of the complexes to induce conformational changes in the DNA, leading to the activation of apoptotic cell death. In summary, the current study demonstrates promising new anticancer platinum(ii) complexes with highly flexible tridentate ligands; the functional groups on the ligands are important in tuning their DNA binding/anticancer properties.

Potential Anticancer Activities and Catalytic Oxidation Efficiency of Platinum(IV) Complex.

The treatment of an aqueous acetonitrile solution of chloroplatinic acid hydrate H2PtCl6.xH2O and pyridine-2-carbaldehyde-oxime (paOH) in the presence of potassium thiocyanate at room temperature (25°) led to the formation of a new Pt(IV) complex with the formula [Pt(SCN)2(paO)2], (1). Complex 1 was fully characterized by FT-IR, UV-vis and NMR spectroscopic techniques as well as elemental analysis. The crystallographic structure of complex 1 was obtained by single-crystal X-ray diffraction. The structure of complex 1 consists of a distorted octahedral geometrical environment around the platinum center in which the coordination sites are occupied by two terminal thiocyanate ligands in trans arrangement and two bidentate paO ligands through four nitrogen atoms. In addition, the in vitro evaluation of the cytotoxicity of platinum complex 1 against four different cancer cell lines was performed. The IC50 values for colon (HCT116), liver (HepG2), breast (MCF-7) and erythroid (JK-1) treated with complex 1 are 19 ± 6, 21 ± 5, 22 ± 6, and 13 ± 3 µM, respectively. In HCT116 cells treated with the IC50 dose of our title compound, apoptosis and necrosis were increased by 34% and 27.8%, respectively. Cells halted in the proliferative phase (S phase) to 21.7 % and 29.8% in HCT116 and HepG2 cells treated with complex 1 have anti-proliferative actions. Furthermore, the catalytic activity of synthesized complex 1 was examined in the oxidation reaction of benzyl alcohols in the presence of an oxidant. Finally, the luminescence behavior of complex 1 was investigated.

Impact of anthocyanin on genetic stability in mammary adenocarcinoma-induced mice treated with methotrexate.

BACKGROUND: Genetic instability leads to genome mutations, changes in nucleotide sequences, rearrangements, and gains or losses of part of the chromosomes. This instability can initiate and develop cancer. This study evaluated genomic stability in methotrexate and anthocyanin-treated mammary adenocarcinoma model. Seventy albino mice were divided into seven groups: negative control, anthocyanin, methotrexate, Ehrlich's solid tumor; Ehrlich's solid tumor and methotrexate; Ehrlich's solid tumor and anthocyanin; and Ehrlich's solid tumor, methotrexate, and anthocyanin groups. RESULTS: Tumor weight and size were evaluated. Serum arylesterase activity was low in all the induced tumors and those treated with anthocyanin, methotrexate, or both. Poly[adenosine diphosphate (ADP)-ribose] polymerase activity was high, and glutathione S-transferase activity was low in the tumors treated with anthocyanin, methotrexate, or both, compared with that of the untreated tumor. There was an increase in DNA damage in the mice with solid tumors and those injected with methotrexate or methotrexate and anthocyanin, compared with that in the untreated mice. CONCLUSIONS: There was a decrease in genetic instability and DNA damage in the tumor-bearing mice treated with anthocyanin, with a concomitant increase in nuclear poly[adenosine diphosphate (ADP)-ribose] polymerase activity, compared with those of the untreated group. Anthocyanin exerted positive effects in the treatment of mammary adenocarcinoma.

Synthesis, characterisation and enhanced apoptotic effect of gemcitabine-loaded albumin nanoparticles coating with chitosan.

Gemcitabine was loaded in albumin nanoparticles then coated with chitosan. The diameter of GEM-ANPs/CS was 200 ± 4 nm. Gemcitabine was loaded in GEM-ANPs/CS with an efficacy of 75%. The IC50 of GEM-ANPs/CS was found to be 12.98 and 6.08 µg/ml after incubation for 48 and 72 h with MCF-7 cells, respectively. Treatment of MCF-7 cells with IC50 of GEM-ANPS, and GEM-ANPS/CS resulted in membrane damage which led to elevated LDH activity of 4 and 3.4, and increasing GSH level of 4.6 and 9.3, respectively, when compared with untreated cells. DNA fragmentation and up-regulated of caspase-3 and p53 had illustrated the apoptotic effect of MCF-7 treated with GEM-ANPS/CS. The tumour suppressor RRM1 gene expression was down-regulated in MCF-7 cells treated with GEM-ANPS/CS. The modified ANPs coated with chitosan may be used as a promising nanomatrix for gemcitabine delivery and targeting to improve its therapeutic index against MCF-7 cells.

Evaluation of MicroRNA92, MicroRNA638 in Acute Lymphoblastic Leukemia of Egyptian Children.

OBJECTIVE: miRNA considers a small non-coding RNA molecule that has tumor suppressor or oncogenic functions and regulates gene expression. miRNA may be involved in the pathogenesis of acute lymphoblastic leukemia (ALL).  miRNA was evaluated in patients with ALL to correlate their importance in the clinical prediction and the response to chemotherapy. SUBJECT AND METHODS: The study population included 30 healthy control and 71 children with ALL is divided into 4 groups: healthy, newly diagnosed, remitted, and relapsed groups. We quantify miRNA 92a, miRNA 638 expression using real-time PCR in childhood ALL. RESULTS: plasma miRNA 92a and miRNA 638 expressions were elevated in ALL cases at the time of diagnosis (2.51 and 2.19 folds), and relapsed (2.1 and 1.61 folds) than that of patients with remitted ALL. There was a positive correlation between miRNA 92a and miRNA 638 patients with ALL. Also, total leukocyte and blast correlated with miRNA 92a and miRNA 638 unlike hemoglobin, and platelets didn't correlate with miRNA 92a and miRNA 638. The sensitivity of miRNA 92a and miRNA 638 were 41.5% and 54.7% respectively while the specificity was 100 % of miRNA 92a and miRNA 638. CONCLUSION: miRNA 92a and miRNA 638 are recommended to be used as potential predictive and follow-up markers in children with ALL remitted and relapsed cases.

Tioconazole and Chloroquine Act Synergistically to Combat Doxorubicin-Induced Toxicity via Inactivation of PI3K/AKT/mTOR Signaling Mediated ROS-Dependent Apoptosis and Autophagic Flux Inhibition in MCF-7 Breast Cancer Cells.

Cancer is a complex devastating disease with enormous treatment challenges, including chemo- and radiotherapeutic resistance. Combination therapy demonstrated a promising strategy to target hard-to-treat cancers and sensitize cancer cells to conventional anti-cancer drugs such as doxorubicin. This study aimed to establish molecular profiling and therapeutic efficacy assessment of chloroquine and/or tioconazole (TIC) combination with doxorubicin (DOX) as anew combination model in MCF-7 breast cancer. The drugs are tested against apoptotic/autophagic pathways and related redox status. Molecular docking revealed that chloroquine (CQ) and TIC could be potential PI3K and ATG4B pathway inhibitors. Combination therapy significantly inhibited cancer cell viability, PI3K/AkT/mTOR pathway, and tumor-supporting autophagic flux, however, induced apoptotic pathways and altered nuclear genotoxic feature. Our data revealed that the combination cocktail therapy markedly inhibited tumor proliferation marker (KI-67) and cell growth, along with the accumulation of autophagosomes and elevation of LC3-II and p62 levels indicated autophagic flux blockage and increased apoptosis. Additionally, CQ and/or TIC combination therapy with DOX exerts its activity on the redox balance of cancer cells mediated ROS-dependent apoptosis induction achieved by GPX3 suppression. Besides, Autophagy inhibition causes moderately upregulation in ATGs 5,7 redundant proteins strengthened combinations induced apoptosis, whereas inhibition of PI3K/AKT/mTOR pathway with Beclin-1 upregulation leading to cytodestructive autophagy with overcome drug resistance effectively in curing cancer. Notably, the tumor growth inhibition and various antioxidant effects were observed in vivo. These results suggest CQ and/or TIC combination with DOX could act as effective cocktail therapy targeting autophagy and PI3K/AKT/mTOR pathways in MCF-7 breast cancer cells and hence, sensitizes cancer cells to doxorubicin treatment and combat its toxicity.

Hepatoprotective Effects of (-) Epicatechin in CCl4-Induced Toxicity Model Are Mediated via Modulation of Oxidative Stress Markers in Rats.

OBJECTIVE: (-) Epicatechin (EP) is a naturally occurring antioxidant flavonoid found in some green plants. The current study was designed to evaluate the potential role of antioxidant mechanisms in the hepatoprotective properties of EP using the carbon tetrachloride (CCl4)-induced acute liver injury model. MATERIALS AND METHODS: Rats (n = 7 per group) were divided into five groups including control group, (-) epicatechin group (20 mg·kg-1 body weight), CCl4 group (1 mL-1 body weight), CCl4-EP treatment group, and CCl4-silymarin (SILY) group. The levels of enzymes including hepatic malondialdehyde (MDA), glutathione (GSH), catalase (CAT), glutathione S-transferase (GST), nitric oxide synthase (NOS), glutathione peroxidase (GPx), and cytochrome P450 (CYP450) were analyzed via enzyme-linked immunosorbent assay (ELISA). Histological studies were performed on all groups to assess the regenerative effects of test sample and compare it with the control group. RESULTS: Test compound EP and standard drug silymarin (SILY) considerably reduced liver function enzyme levels in the blood, which were raised by CCl4 administration, and increased serum albumin and total protein (TP) concentrations. The hepatic malondialdehyde (MDA) level was considerably declined, whereas glutathione (GSH), catalase (CAT), glutathione S-transferase (GST), nitric oxide synthase (NOS), glutathione peroxidase (GPx), and cytochrome P450 (CYP450) levels were upregulated in the EC-treated groups. The hepatoprotective results of the study were further confirmed via the histological assessments, which indicated a regeneration of the damaged hepatic tissue in treated rats. CONCLUSIONS: The results of this study revealed a significant protective efficacy of EP against CCl4-induced liver injury, which was potentially mediated via upregulation of antioxidant enzymes and direct scavenging effects of the compound against free radicals.

Fat mass and obesity-associated (FTO) and leptin receptor (LEPR) gene polymorphisms in Egyptian obese subjects.

BACKGROUND: Several studies addressed the contribution of fat mass and obesity-associated (FTO) and leptin receptor (LEPR) polymorphisms for the susceptibility to obesity among different ethnic subjects. The main purpose of this work is to evaluate the association of these polymorph\isms with obesity among Egyptian subjects. SUBJECTS AND METHODS: This case-control study was carried out on 110 unrelated obese Egyptian subjects who were compared with 122 controls. Their genomic DNA was genotyped using the PCR technique. RESULTS: The allelic frequencies of FTO rs9939609 (A) and LEPR rs1137101 (223R) were significantly higher in obese subjects compared with non-obese controls (p < .001). Comparing different phenotype frequencies including clinical, anthropometric, and biochemical parameters in obese subjects revealed no significant difference in relation to their genotype frequencies (p> .05). CONCLUSIONS: This study designates a strong association for FTO and LEPR variants with the risk of obesity among Egyptian subjects.