Synthesis of metformin-derived fluorescent quantum dots: uptake, cytotoxicity, and inhibition in human breast cancer cells through autophagy pathway.

BACKGROUND: Breast cancer remains a challenge for physicians. Metformin, an antidiabetic drug, show promising anticancer properties against cancers. An emerging quantum dot (QD) material improves therapeutic agents' anticancer and imaging properties. QD are nano-sized particles with extreme application in nanotechnology captured by cells and accumulated inside cells, suggesting bioimaging and effective anticancer outcomes. In this study, a simple one-pot hydrothermal method was used to synthesize fluorescent metformin-derived carbon dots (M-CDs) and then investigated the cytotoxic effects and imaging features on two human breast cancer cell lines including, MCF-7 and MDA-MB-231 cells. RESULTS: Results showed that M-CDs profoundly decreased the viability of both cancer cells. IC50 values showed that M-CDs were more cytotoxic than metformin either 24-48 h post-treatment. Cancer cells uptake M-CDs successfully, which causes morphological changes in cells and increased levels of intracellular ROS. The number of Oil Red O-positive cells and the expression of caspase-3 protein were increased in M-CDs treated cells. Authophagic factors including, AMPK, mTOR, and P62 were down-regulated, while p-AMPK, Becline-1, LC3 I, and LC3 II were up-regulated in M-CDs treated cells. Finally, M-CDs caused a decrease in the wound healing rate of cells. CONCLUSIONS: For the first, M-CDs were synthesized by simple one-pot hydrothermal treatment without further purification. M-CDs inhibited both breast cancer cells through modulating autophagy signalling.

Evaluation the -174G>C Genetic Polymorphism of Interleukin-6 in Iranian Patients with Chronic Lymphocytic Leukemia.

Background & Objective: Interleukin-6 (IL-6) is involved in inflammation and has a significant role in chronic lymphocytic leukemia (CLL) progression. Accordingly, IL-6 level may increase in CLL-affected patients compared to healthy individuals. The -174G>C single nucleotide polymorphism (SNP) in IL-6 promoter region has been related to differences in IL-6 transcription. Therefore, we investigated the possible association of IL-6 polymorphism with CLL. Methods: We examined the -174G>C SNP in IL-6 gene and studied its possible relationship with CLL in affected patients and in healthy controls using Amplification Refractory Mutation System- polymerase chain reaction genotyping method. IL-6 plasma level was measured in both studied groups. Results: According to the results, IL-6 mean plasma concentration was increased significantly in the CLL patients compared to the controls. However, 174G>C genotype of the IL-6 gene was not associated with CLL. Furthermore, there were no significant differences in the distribution of allele and genotype frequencies between the CLL-affected patients and the controls (P>0.05). Conclusion: Our study showed that -174G>C SNP in promotor of IL-6 gene could not be considered a risk factor for CLL. Larger prospective studies should be performed to confirm our results.

Nitrogen and copper-doped saffron-based carbon dots: Synthesis, characterization, and cytotoxic effects on human colorectal cancer cells.

AIM: Doped carbon dots (CDs) have attracted tremendous attention in cancer therapy. We aimed to synthesize copper, nitrogen-doped carbon dots (Cu, N-CDs) from saffron and investigated their effects on HCT-116 and HT-29 colorectal cancer (CRC) cells. MAIN METHODS: CDs were synthesized by hydrothermal method and characterized by transmission electron microscopy (TEM), energy-dispersive X-ray (EDX), Fourier transform infrared (FT-IR) spectroscopy, ultraviolet-visible (UV-Vis) absorption spectroscopy, and fluorescence spectroscopy. HCT-116 and HT-29 cells were incubated with saffron, N-CDs, and Cu, N-CDs for 24 and 48 h for cell viability. Cellular uptake and intracellular reactive oxygen species (ROS) were evaluated by immunofluorescence microscopy. Oil Red O staining was used to monitor lipid accumulation. Apoptosis was evaluated using acridine orange/propidium iodide (AO/PI) staining and quantitative real-time polymerase chain reaction (Q-PCR) assay. The expression of miRNA-182 and miRNA-21 was measured by Q-PCR, while the generation of nitric oxide (NO) and lysyl oxidase (LOX) activity was calculated by colorimetric methods. KEY FINDINGS: CDs were successfully prepared and characterized. Cell viability decreased in the treated cells dose- and time-dependently. HCT-116 and HT-29 cells uptook Cu, N-CDs with a high level of ROS generation. The Oil Red O staining showed lipid accumulation. Concomitant with an up-regulation of apoptotic genes (p < 0.05), AO/PI staining showed increased apoptosis in the treated cells. In comparison to control cells, NO generation, and miRNA-182 and miRNA-21 expression significantly changed in the Cu, N-CDs treated cells (p < 0.05). SIGNIFICANCE: The results indicated that Cu, N-CDs could inhibit CRC cells through the induction of ROS generation and apoptosis.

Tumor Cells-derived exosomal CircRNAs: Novel cancer drivers, molecular mechanisms, and clinical opportunities.

Recently, circular RNAs (circRNAs) have appealed to a growing interest due to their abundant expression and potential functions in cancer development. The most biological function of circRNAs may include acting as a sponge for miRNAs and proteins in different physio/pathological conditions. CircRNAs promote cancer progression by regulating several procedures such as growth, invasion, metastasis, angiogenesis, and drug resistance. Emerging evidence has shown that circRNAs frequently have tumor-specific expression, proposing these molecules serve as diagnostic and prognostic cancer biomarkers. Furthermore, circRNAs may be used as a potential target for the treatment of cancers as they can sponge oncogenic miRNAs and proteins. Exosomes, a subtype of extracellular vesicles mediate intercellular communication, contain circRNAs and deliver them to target cells inducing cancer development through different signaling pathways. Exosomal circRNAs may serve as a diagnostic and prognostic biomarker for cancers. Targeting exosomes may represent novel approaches for the treatment of cancers through using them as cell-free therapy and drug-delivery system and inhibiting their biogenesis and distribution. However, research on circRNAs biology is advancing and some concerns such as technical issues in the characterization and analysis of circRNAs along with biological understanding gaps necessary to be considered to transfer this undeveloped field to the vanguard of clinical studies. In this review, we discuss the existing information on the formation of circRNA and its roles in the tumor as a biomarker and treatment target. Furthermore, we describe tumor-derived exosomes enclosed circRNAs and their possible roles in cancer development and their potential as biomarkers and therapeutic approaches.

Signaling Pathways Involved in 5-FU Drug Resistance in Cancer.

Anti-metabolite drugs prevent the synthesis of essential cell growth compounds. 5-fluorouracil is used as an anti-metabolic drug in various cancers in the first stage of treatment. Unfortunately, in some cancers, 5-fluorouracil has low effectiveness because of its drug resistance. Studies have shown that drug resistance to 5-fluorouracil is due to the activation of specific signaling pathways and increased expressions of enzymes involved in drug metabolites. However, when 5-fluorouracil is used in combination with other drugs, the sensitivity of cancer cells to 5-fluorouracil increases, and the effect of drug resistance is reversed. This study discusses how the function of 5-fluorouracil in JAK/STAT, Wnt, Notch, NF-κB, and hedgehogs in some cancers.

MicroRNAs and drug resistance in colorectal cancer with special focus on 5-fluorouracil.

Colorectal cancer is globally one of the most common cancers in all age groups. The current chemotherapy combinations for colorectal cancer treatment include 5-fluorouracil-based regimens; however, drug resistance remains one of the main reasons for chemotherapy failure and disease recurrence. Many studies have determined colorectal cancer chemoresistance mechanisms such as drug efflux, cell cycle arrest, DNA damage repair, apoptosis, autophagy, vital enzymes, epigenetic, epithelial-mesenchymal transition, stem cells, and immune system suppression. Several microRNAs affect drug resistance by regulating the drug resistance-related target genes in colorectal cancer. These drug resistance-related miRNAs may be used as promising biomarkers for predicting drug response or as potential therapeutic targets for treating patients with colorectal cancer. This work reviews and discuss the role of selected microRNAs in 5-fluorouracil resistance and their molecular mechanisms in colorectal cancer.

MicroRNAs as therapeutic targets in breast cancer metastasis.

Breast cancer is a complex disease with multiple risk factors involved in its pathogenesis. Among these factors, microRNAs are considered for playing a fundamental role in the development and progression of malignant breast tumors. In recent years, various studies have demonstrated that several microRNAs exhibit increased or decreased expression in metastatic breast cancer, acting as indicators of metastatic potential in body fluids and tissue samples. The identification of these microRNA expression patterns could prove instrumental for the development of novel therapeutic molecules that either mimic or inhibit microRNA action. Additionally, an efficient delivery system mediated by viral vectors, nonviral carriers, or scaffold biomaterials is a prerequisite for implementing microRNA-based therapies; therefore, this review attempts to highlight essential microRNA molecules involved in the metastatic process of breast cancer and discuss recent advances in microRNA-based therapeutic approaches with potential future applications to the treatment sequence of breast cancer.

Performance of capecitabine in novel combination therapies in colorectal cancer.

Colorectal cancer is one of the most common cancers throughout the world, and no definitive cure has ever been found. Perhaps a new insight into the effectiveness of chemotherapy drugs could help better treat patients. Targeted therapies have significantly improved the median overall survival of colorectal cancer patients. One of the standard chemotherapy regimens used for colorectal cancer is capecitabine, which is important in monotherapy and combination therapies. Capecitabine, with other chemotherapeutic agents (irinotecan, oxaliplatin, perifosine, 17-allylamino-17-demethoxygeldanamycin, aspirin, celecoxib, statins, quinacrine, inositol hexaphosphate and inositol, cystine/theanine, curcumin, and isorhamnetin), and biological ones (antibodies) plays an important role in the inhibition of some signaling pathways, increasing survival, reducing tumor growth and side effects of capecitabine. However, some drugs, such as proton pump inhibitors, are negatively related to capecitabine; therefore, the purpose of this work is to review and discuss the performance of capecitabine combination therapies in colorectal cancer.

Neurological effects of long-term exposure to low doses of pesticides mixtures in male rats: Biochemical, histological, and neurobehavioral evaluations.

Humans are usually exposed to multiple pesticides in real life, but little is known as yet about the safety of low-dose pesticides mixtures. This study was conducted to evaluate the effects of long-term exposure to very low doses of pesticide mixtures on biochemical, histological, and neurobehavioral alterations in the rat model. For 90 days, four groups of male Wistar rats were given a mixture of five pesticides (in drinking water) in doses of 0, 0.25, 1 and 5 times the legally permitted levels (mg/kg body weight/day). After three-month exposure, the neurobehavioral effects of pesticide mixtures were evaluated by the Morris water maze, elevated plus maze and the open field tests. Then the biochemical and histopathological alterations in the hippocampus of studied animals were evaluated. Results showed that long-term exposure to a combination of five pesticides affected the nervous system in dose-dependent manner. As expected, nearly all of the parameters determined in this study were adversely changed in the high dose group. Exposure to medium dose (permitted level of pesticides mixture) was also able to induce oxidative stress and impaired memory and learning ability, although not all parameters were significantly changed in this group. It means that pesticides may behave differently when mixed. Interestingly, the administration of low doses of these chemicals induced an adaptive response by stimulating the redox system. In conclusion, it seems that the prolonged exposure to pesticide mixtures may cause adverse neurobehavioral effects, even at permitted levels.

Transcriptional activity of tumor necrosis factor-alpha gene in peripheral blood mononuclear cells in patients with coronary slow flow.

BACKGROUND: Coronary slow flow (CSF), an angiographic phenomenon that is characterized by a delayed coronary blood flow in the absence of obstructive coronary artery stenosis, is known as a disorder of the coronary microcirculation. Inflammation has an important role in the vascular hemostasis and endothelial dysfunction especially regarding monocyte adhesion and infiltration. Pro-inflammatory cytokines released by inflammatory cells result in endothelial cell dysfunction and cardiovascular diseases. It has been demonstrated that tumor necrosis factor-alpha (TNF-α) mainly influences the vascular homeostasis and endothelial dysfunction. In the present enquiry the transcriptional activity of TNF-α gene in peripheral blood mononuclear cells (PBMCs) of patients with CSF was compared with healthy controls in order to further survey the role of TNF-α in pathophysiology of CSF. METHODS: The study was carried out on 30 patients with CSF and 30 matched healthy controls. To analysis gene expression of TNF-α, total mRNA was isolated from PBMCs. The quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) was used to compare the transcriptional activity of TNF-α gene between patients with CSF and controls. RESULTS: The mean ± standard error of mean of fold in CSF patients and controls were 0.20 ± 0.04 and 1.38 ± 0.27, respectively. The mRNA mean expressions of TNF-α (fold) were different in tested groups, which indicated a significant decrease in TNF-α in patients with CSF group (P = 0.0001). CONCLUSION: Expression of TNF-α was decreased in patients with CSF. Changes in TNF-α expression suggest a potential role for altered immune function in the pathophysiology of CSF.

Factors affecting complications according to the modified Clavien classification in complete supine percutaneous nephrolithotomy.

INTRODUCTION: An increase in percutaneous nephrolithotomy (PCNL) has been accompanied by an increase in complications. We identified the parameters affecting the severity of complications using the modified Clavien classification (MCC). METHODS: From 2008 to 2013, 330 patients underwent complete supine PCNL using subcostal access, one-shot dilation, rigid nephroscopy, and pneumatic lithotripsy. We assessed the impact of the following factors on complication severity based on the MCC: age, gender, body mass index, hypertension, diabetes, previous stone surgery and extracorporeal shock wave lithotripsy, preoperative hemoglobin, renal dysfunction (creatinine >1.4 mg/dL), preoperative urinary tract infection, anatomic upper urinary tract abnormality (AUUTA), significant (moderate-severe) hydronephrosis, stone-related parameters (opacity, number, burden, location, staghorn, complex stones), anesthesia type, kidney side, imaging and calyx for access, tract number, tubeless approach, operative time, postoperative hemoglobin, and hemoglobin drop and stone-free results. RESULTS: The complication rate was 19.7% (MCC: 0=80.3%, I=6.4%, II=11.2%, ≥III=2.1%). On univariate analyses, only the following factors affected MCC: gender, preoperative hemoglobin, AUUTA, significant hydronephrosis, imaging for access, calyx for access, tract number, postoperative hemoglobin, hemoglobin drop and stone-free result. Renal dysfunction was accompanied by higher complications, yet the results were not statistically significant. Multivariate logistic regression analysis demonstrated renal dysfunction, absence of significant hydronephrosis, AUUTA, multiple tracts, lower postoperative hemoglobin, and higher postoperative hemoglobin drop as the significant parameters which affected MCC and predicted higher grades. The paper's limitations include a low number of cases in the higher Clavien grades and some subgroups of variables, and not applying some techniques due to surgeon preference. INTERPRETATION: Many of the complete supine PCNL complications were in the lower Clavien grades and major complications were uncommon. Renal dysfunction, AUUTA, significant hydronephrosis, tract number, postoperative hemoglobin, and hemoglobin drop were the only factors affecting MCC.