Green synthesized silver nanoparticles using the plant-based reducing agent Matricaria chamomilla induce cell death in colorectal cancer cells.

OBJECTIVE: There is a need to treat cancer cells with safe and natural nanoparticles to avoid the side effects of chemotherapeutic agents. Chamomile is considered a safe, natural plant with anticancer activity. We synthesize simple, inexpensive, and eco-friendly silver nanoparticles (SNs) using Chamomile (CHM) to tune their anticancer properties. MATERIALS AND METHODS: SN-CHM was synthesized by reducing 1 mM silver nitrate aqueous solution in 100 mL with the aqueous ethanolic flower extract of CHM (18 mg/mL, w/v). The reaction proceeded overnight at 600 rpm and 28°C. SN-CHM was characterized for their % yield, average diameter, charge, morphology, and silver release. Moreover, SN-CHM was investigated for its antioxidant and anticancer activities at 200 µg/mL and 5 mg/ mL, respectively. RESULTS: A 59.12% yield and a uniform SN-CHM size of 115 ± 3.1 nm with a ζ-potential of -27.67 ± (-3.92) mv were observed. The UV-visible absorption showed shifts from 379.5 to 383.5 nm for CHM and SN-CHM, respectively. Moreover, Ag+ was ultimately released from SN-CHM after 5 h. Fourier Transform Infrared Spectroscopy (FT-IR) showed characteristic absorption peaks of CHM and produced SN-CHM. Furthermore, SN-CHM showed moderate antioxidant activity. SN-CHM inhibited the % viability of SW620 and HT-29 cell lines at 20 µM. SN-CHM may also greatly upregulate the apoptotic gene BAX while considerably downregulating the anti-apoptotic genes BCL2 and BCL-Xl. CONCLUSIONS: CHM can be a safe soft drink, especially when conjugated with Ag ions as anticancer NPs. SN-CHM is considered potent anticancer activity against SW620, and HT-29 cell lines.

Thermosensitive polymers-based injectable hydrogels: a quantitative validations design utilized for controlled delivery of gefitinib anticancer drug.

OBJECTIVE: Gefitinib (GFB) was loaded into different designs of thermos- and pH-responsive polymer-based hydrogels, namely chitosan (CH) and Pluronic F127 (Pl F127) with the aid of a crosslinking ß-glycerophosphate (ß-GP). MATERIALS AND METHODS: GFB was loaded in CH and P1 F127 hydrogel. The preparation was characterized and tested for their stability and efficacy as antitumor injectable therapy devices. The antiproliferative effect of the selected CH/ß-GP hydrogel formula was investigated against the hepatic cancerous cell, HepG2 using the MTT tetrazolium salt colorimetric assay. Furthermore, the pharmacokinetic was performed for GEF using a developed, reported and validated LC method. RESULTS: All hydrogel samples showed no changes in color, separation(s), and crystallization in both liquid and gel forms. The CH/ß-GP system showed a lower viscosity (110.3 ± 5.2 Cp) compared to CH/ß-GP/Pl F127 system (148.4 ± 4.4 Cp) in the sol phase. Also, the results confirmed a continued increase in rats' plasma during the first four days (Tmax) with a plasma peak level (Cmax) of 3.663 µg/mL followed by a decrease below the detection limit after 15 days. Moreover, the results indicated no significant difference (p < 0.05) between the predicted and observed GEF-concentration data and that the proposed CH-based hydrogel facilitated its sustained release as distinguished from the longer value of MRT of 9 days and an AUC0-t of 41.917 µg/L/day. CONCLUSIONS: The medicated CH/ß-GP hydrogel formula had a higher targeting-controlled efficiency against a solid tumor than the free poor water soluble GFB.

Topical silver nanoparticles reduced with ethylcellulose enhance skin wound healing.

OBJECTIVE: Silver nanoparticles (G-AgNPs) improve wound healing by promoting skin cell proliferation and differentiation. Therefore, G-AgNPs could act as drug carriers and wound healers in biomedicine. The current study aimed to improve skin wound healing using natural, safe G-AgNPs. MATERIALS AND METHODS: The G-AgNPs were reduced with ethylcellulose (EC) and incorporated into an oil-in-water cream base. The size, charges, and wavelength were used to characterize the prepared G-AgNPs. Further, the transmission electron microscope (TEM) and the scanning electron microscope (SEM) were used to provide the shape of G-AgNPs. Moreover, the skin wound healing was evaluated with the appropriate histopathological techniques in a mouse model with skin injury to prove the curative effects of G-AgNPs which was conducted for 15 days on 45 adult male albino rats. The effectiveness of G-AgNPs-EC cream for treating surgical skin wounds was assessed by histopathological (HP) examination of hematoxylin and eosin (H&E) stained sections. RESULTS: The produced G-AgNPs-EC showed a size of 183.9 ± 0.854 nm and a charge of -14.0 ± 0.351 mV. UV-VIS spectra showed a strong absorption of electromagnetic waves in the visible region at 381 nm. Furthermore, the TEM and SEM showed rounded NPs in nano size of the prepared G-AgNPs-EC. The G-AgNPs cream was pivotal in enhancing wounds' healing properties, improving the formation of wound granulation tissue, and enhancing the proliferation of epithelial tissue in rats. CONCLUSIONS: The current study showed that G-AgNPs-EC is a new skin wound healer that speeds up healing.

Green synthesis of silver nanoparticles reduced with Trigonella foenum-graecum and their effect on tumor necrosis factor-α in MCF7 cells.

OBJECTIVE: Silver nanoparticles (AgNPs) are known to exhibit anti-inflammatory and anticancer activities. They have been reported to reduce the levels of tumor necrosis factor (TNF) - a proinflammatory cytokine involved in cell proliferation, differentiation, and apoptosis - in cell lines. As patients with breast cancer have been reported to have higher serum TNF levels, we aimed at developing a novel treatment for breast cancer by evaluating the effect of Trigonella foenum-graecum extract (TFG)-reduced AgNPs on the MCF-7 cell line, which serves as a model of human breast cancer. MATERIALS AND METHODS: TFG-capped AgNPs were synthesized using a green reduction method, in which TFG reduced silver nitrate to generate AgNPs-TFG. The particle size, surface charge, ultraviolet (UV)-visible (VIS) spectra, surface morphology, % yield, and in vitro Ag+ release of the formulated AgNPs-TFG were evaluated. Additionally, the prepared NPs were examined for cytotoxicity using real-time polymerase chain reaction (real-time PCR), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and enzyme-linked immunosorbent assay (ELISA). RESULTS: The prepared AgNPs-TFG were uniform, small, discrete, and non-aggregated with a particle size of 22.5±0.75 nm and ζ-potential of -47.45±0.666 mV. The yield of AgNPs-TFG was 224.545±3.9 µM. Furthermore, the AgNP-TFG thin film exhibited a prolonged release of Ag+ in phosphate buffer for up to 11 h. AgNPs-TFG suppressed TNF-α expression at mRNA and protein levels in MCF-7 cells. Additionally, the formulated AgNPs-TFG did not exhibit any toxicity toward MCF-7 cells. CONCLUSIONS: This study showed that AgNP-TFG could effectively inhibit TNF-α. These results provide significant insights for developing new therapeutic strategies for cancer and other inflammatory illnesses.

Effects of CMF and MET on glutamate and dopamine levels in the brain, and their impact on cognitive function.

OBJECTIVE: Chemotherapy can cause cognitive impairment in cancer survivors. CMF, the combination of cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU), is employed for the treatment of several types of cancers, such as metastatic breast cancer. Metformin (MET) is an antidiabetic medication used to treat type 2 diabetes that can reportedly alleviate some toxic effects. In the current study, we investigated the ability of MET to alleviate the effects of CMF in neuronal toxicity. MATERIALS AND METHODS: Rats were treated with two doses of CMF (intraperitoneal injection) and MET (in the daily drinking water). Rats were subjected to fear conditioning memory tests to evaluate memory function following treatment, and brain samples were collected and homogenized using neuronal lysis buffer for assessment of glutamate and dopamine levels by high-performance liquid chromatography (HPLC). RESULTS: Fear conditioning memory tests revealed a significant reduction in memory function in CMF and CMF+MET groups vs. controls, but no significant change in MET groups vs. controls was detected. Similarly, CMF and CMF+MET groups revealed a significant increase in glutamate and dopamine levels in the brain of MET, CMF, and MET+CMF groups vs. controls based on HPLC results. In addition, although glutamate and dopamine levels were increased, levels varied between groups, with highest levels in the CMF+MET group. CONCLUSIONS: Our results demonstrate that cognitive impairment in CMF and CMF+MET groups could result from increased glutamate and dopamine levels in the brain, leading to brain toxicity and failure of MET to alleviate the toxic effects of CMF.

Elucidating the mechanism underlying cognitive dysfunction by investigating the effects of CMF and MET treatment on hippocampal neurons.

OBJECTIVE: Chemotherapy causes long-term cognitive impairment in cancer survivors. A combination of cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU) (i.e., CMF) is widely used for cancer treatment. Metformin (MET), an oral antidiabetic drug, confers protection against the adverse effects of chemotherapeutic agents, such as CYP. To elucidate the potential mechanism underlying cognitive dysfunction, we investigated the impact of CMF and MET treatment on the activities of mitochondrial respiratory chain complexes I and IV, as well as lipid peroxidation, in hippocampal neurons. MATERIALS AND METHODS: Hippocampal neurons (H19-7) cells were treated for 24 h with MET (0.5 mM) alone; CYP (1 µM), MTX (0.5 µM), and 5-FU (1 µM); and MET (0.5 mM) + CYP (1 µM), MTX (0.5 mM), and 5-FU (1 µM). A 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay was performed to evaluate cell survival. Neurons were collected and homogenized in a neuronal lysis buffer to assess mitochondrial complexes (I and IV) activity and lipid peroxidation. RESULTS: Compared to the control, MET-treated cells showed no significant difference in survival rate; however, CMF- and CMF + MET-treated cells showed a significant reduction in survival rate. In addition, relative to the control, CMF- and CMF + MET-treated cells showed a reduction in mitochondrial complex I activity, whereas no significant changes were observed in mitochondrial complex IV activity. MET-treated cells showed no significant differences in lipid peroxidation, but CMF- and CMF + MET-treated cells showed a slight increase in lipid peroxidation. CONCLUSIONS: The reduction in the activity of mitochondrial complex I and a slight increase in lipid peroxidation levels may explain the cognitive impairment following CMF and MET treatments.

CMF and MET treatment induce cognitive impairment through upregulation of IL-1α in rat brain.

OBJECTIVE: Cyclophosphamide (CYP), methotrexate (MTX) and 5-fluorouracil (5-FU) (CMF) are chemotherapeutic agents known to cause acute and long-term cognitive impairment in cancer patients. Cognitive function is regulated mainly by neuronal circuitry in the brain, especially the cortex and hippocampus as well as other components of the limbic area. Neuroinflammation mediated by proinflammatory cytokines is a well-known cause of cognitive impairment. Our previous study showed that metformin induced cognitive impairment and neuroinflammation in CMF-treated rats. Understanding the effects and mechanisms of CMF and MET treatment on chemotherapy-related cognitive impairment and the relationship with neuroinflammation may help prevent some of the adverse effects of this type of chemotherapy in cancer patients. MATERIALS AND METHODS: Rats were divided into four groups: control (normal saline), CMF (50 mg/kg CYP, 2 mg/kg MTX, 50 mg/kg 5-FU; two doses administered by intraperitoneal injection over two weeks), MET (2.5 mg/ml - oral administration daily), and CMF+MET group. IL-1α, IRS-1, Akt-a and TNF-α levels in brain tissues were measured by ELISA and data were analyzed by one-way ANOVA test followed by Tukey's test. RESULTS: Compared with the control group, IL-1α levels were significantly increased in the CMF+MET group, whereas there were no significant differences in the MET and CMF groups. On the other hand, IRS-1, TNF-α and Akt-a expression and mitochondrial complex 1 activity indicated that systemic CMF and MET treatment did not change the expression of these proteins in the brain compared to the control group. CONCLUSIONS: Our results indicate that cognitive function is impaired by the administration of two doses of CMF and MET over a period of two weeks as a result of IL-1α overexpression in the brain.