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.

Combination chemotherapy against colorectal cancer cells: Co-delivery of capecitabine and pioglitazone hydrochloride by polycaprolactone-polyethylene glycol carriers.

BACKGROUND: Colorectal cancer causes numerous deaths despite many treatment options. Capecitabine (CAP) is the standard chemotherapy regimen for colorectal cancer, and pioglitazone hydrochloride (PGZ) for diabetic disease treatment. However, free drugs do not induce effective apoptosis. This work aims to co-encapsulate CAP and PGZ and evaluate cytotoxic and apoptotic effects on HCT-119, HT-29 colorectal cancer cells, and human umbilical vein endothelial cells (HUVECs). METHOD: CAP, PGZ, and combination treatment nano-formulations were prepared by triblock (TB) (PCL-PEG-PCL) biodegradable copolymers to enhance drugs' bioavailability as anti-cancer agents. The Ultrasonic homogenization method was used for preparing nanoparticles. The physicochemical characteristics of nanoparticles were studied using 1H NMR, FTIR, DLS, and FESEM techniques. The zeta potential, entrapment efficiency, drug release, and storage stability were studied. Also, cell viability and apoptosis were examined by using MTT, acridine orange (AO), and propidium iodide (PI), respectively. RESULT: The smaller hydrodynamic size (236.1 nm), polydispersity index (0.159), and zeta potential (-20.8 mV) were observed in nanoparticles. Nanoparticles revealed a proper formulation and storage stability at 25 °C than 4 °C in 90 days. The synergistic effect was observed in (CAP-PGZ)-loaded TB nanoparticles in HUVEC, HCT-116, and HT-29 cells. In (AO/PI) staining, the high percentage of apoptotic cells in the (CAP-PGZ)-loaded TB nanoparticles in HUVEC, HCT-116, and HT-29 were calculated as 78 %, 71.66 %, and 69.31 %, respectively. CONCLUSION: The (CAP-PGZ)-loaded TB nanoparticles in this research offer an effective strategy for targeted combinational colorectal cancer therapy.

Alantolactone triggers oxeiptosis in human ovarian cancer cells via Nrf2 signaling pathway.

Introduction: A growing body of evidence indicated that Alantolactone (ALT) promotes Reactive Oxygen Species (ROS) generation exclusively in cancer cells. Therefore, the aim of this study was to investigate the effect of ALT on the molecular mechanism of oxeiptosis, as a novel cell death pathway due to the high levels of intracellular ROS in ovarian cancer. Methods: MTT assay was used to evaluate the effect of ALT on SKOV3 cell viability. mRNA and protein expression levels of Nrf2 (nuclear factor erythroid 2-related factor 2), KEAP1 (Kelch-like ECH-associated protein 1), PGAM5 (phosphoglycerate mutase family member 5), AIFM1 (Mitochondrial Apoptosis-Inducing Factor), Glutathione synthetase (GSS) and glutathione peroxidase (GPX) were analyzed by real time PCR and western blotting methods respectively. Results: Our findings showed that ALT inhibits the proliferation of skov3 cells in a time and dose dependent manner and IC50 was 32 µM at 24h.A significant down-regulation of Nrf2, GSH and GPX mRNA levels was seen in skov3 cells incubated with 32 and 64 µM of ALT in comparison with control group, while, mRNA expression levels of PGAM5 and KEAP1 were increased.Western blot analysis showed that ALT significantly decreases protein levels of Nrf2 and increases PGAM5 and KEAP1.ALT dephosphorylated PS116-AIFM1 and total AIFM1 protein level was elevated. Conclusion: Our results provided evidence that ALT could be a potential option for ovarian cancer treatment by ROS-mediated oxeiptosis.

Cooperative Treatment of Gastric Cancer Using B7-H7 siRNA and Docetaxel; How Could They Modify Their Effectiveness?

Purpose: Despite the high prevalence of gastric cancer (GC), drug resistance is a major problem for effective chemotherapy. B7-H7 is a novel member of the B7 superfamily and is expressed in most common cancers. However, the role of B7-H7 on the aggressiveness of GC and chemosensitivity has remained unknown. Therefore, this study was designed to assess the effect of B7-H7 suppression using small interference RNA (siRNA) in combination with docetaxel on GC cells. Methods: MTT test was applied to determine the IC50 of docetaxel and the combined effect of B7-H7 siRNA and docetaxel on the viability of the MKN-45 cells. To determine B7-H7, BCL-2, BAX, and caspase-3-8-9 genes expression, qRT-PCR was performed. Furthermore, flow cytometry was applied to evaluate apoptosis and the cell cycle status. Finally, to evaluate the effect of this combination therapy on migratory capacity and colony-forming ability, wound healing assay and colony formation test were employed, respectively. Results: B7-H7 suppression increased the chemo-sensitivity of MKN-45 cells to docetaxel. The expression of B7-H7 mRNA was reduced after using B7-H7 siRNA and docetaxel in MKN-45 GC cells. Also, B7-H7 suppression alongside docetaxel reduced cell migration and colony formation rate, arrested the cell cycle at the G2-M phase, and induced apoptosis by modulating the expression of apoptotic target genes. Conclusion: B7-H7 plays a significant role in the chemo-sensitivity and pathogenesis of GC. Therefore, B7-H7 suppression, in combination with docetaxel, may be a promising therapeutic approach in treating GC.

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.

Serum Levels of Interleukin-1ß and Disease Progression in Multiple Myeloma Patients: A Case and Control Study.

OBJECTIVE: Multiple myeloma  (MM) is known as an incurable heterogeneous plasma cell malignancy that presents with a variety of clinical manifestations. Inflammation plays an important role in this disease. Cytokines and Chemokines cause the progression of the disease. One of them is interleukin-1ß (IL-1ß), which may be involved in the pathogenesis of MM. Other markers such as calcium, albumin, creatinine, globulins, and total protein are also used to diagnose and prognosis patients. The main purpose of this study was to evaluate the serum level of IL-1ß and various forms of calcium (total calcium, ionized calcium, and corrected calcium), albumin, creatinine, globulin, and total protein on stage-I of MM patients and healthy controls. METHODS: Serum samples from 30 stage-I MM patients and 30 healthy subjects as controls were examined in this study. The protein concentrations of serum IL-1ß was assessed by enzyme-linked immunosorbent assay (ELISA), total calcium, albumin, creatinine, total protein, and globulin Measured by auto analyzer BT3000, an electrolyte analyzer was used to measure ionized calcium (Ca++) and a special equation was used to calculate the corrected calcium. RESULT: The mean level of IL-1ß was significantly elevated in stage-I MM. The mean levels of IL-1ß were 7.04±1.15 ng/ml in stage-I MM and 3.12± 0.90 ng/ml in controls (p<0.001). The mean levels of total calcium (total Ca) were 9.45±0.56 mg/dl in stage-I MM and 9.09±0.43mg/dl in controls (p=0.008). The mean levels of ionized calcium (Ca++) was 4.65±0.28mg/dl in stage-I MM and 4.75±0.33mg/dl in controls (p=0.2). The mean ratio of serum ionized calcium to total calcium (Ca++/ total Ca) was 0.49±0.054 in stage-I MM and 0.52±0.047 in controls (p=0.02). The mean ratio of serum ionized calcium to corrected calcium (Ca++/corrected Ca) was 0.42±0.033 in stage-I MM and the Mean ratio of serum ionized calcium to calcium total (Ca++/ total Ca) was 0.52±0.047 in controls, Comparison of the mean of the two groups shows a significant difference (p<0.001). The mean level of albumin was 1.72±0.35 g/dl in stage-I MM and4.32±0.41g/dl in controls (p<0.001). The mean level of total protein was 12.65±0.81g/dl in stage-I MM and 7.07±0.4 g/dl in controls (p<0.001). The mean level of globulin was 11.00±0.96 mg/dl in stage-I MM and 2.85±0.77 mg/dl in controls (p<0.001). The mean level of creatinine was 1.15±0.25 mg/dl in stage-I MM and 0.96±0.15 mg/dl in controls (p=0.001). CONCLUSION: The results of the study indicate the possible involvement of IL-1ß at stage-I MM and it can indicate the role of chemokines in the disease process, especially in the early stages. Changes in the chemical profiles mentioned can help in the diagnosis and prognosis of the disease.

Influence of Maternal Ethanol Exposure on Systemic Hemodynamic Variables and Histopathological Changes in the Aorta Wall of Male Rat Offspring: A Three-month Follow-up.

Background: Alcohol consumption in pregnancy is associated with an increased risk of cardiovascular abnormalities, but the mechanisms are unknown. This study evaluated the impact of ethanol exposure on the offspring's aorta structural, functional, and molecular alterations on postnatal (PN) both on days 21 and 90. Methods: This experimental study was conducted at Urmia University of Medical Sciences (Urmia, Iran) in 2019. Twenty Pregnant Wistar rats on the seventh day of Gestation Day (GD) were randomly divided into two groups: control and ethanol-treated groups (n=10 per group). From the seventh day of GD throughout lactation, rats in the ethanol group were fed binge alcohol (4.5 g/Kg body weight) once daily. Systemic hemodynamic variables in the offspring were analyzed using waveform contour analysis 90 days after birth. On postnatal days (PN) 21 and 90, aorta wall histological alterations and the level of inflammatory factors were assessed in the aorta of male offspring. The statistical differences were examined via an independent samples t test. P<0.05 was considered to be statistically significant. Results: The results revealed that offspring in the ethanol group had higher systolic, diastolic, mean arterial pressure, and dicrotic pressure than the control group (P<0.001). The level of aorta tissue tumor necrosis factor (TNF)-α, intercellular adhesion molecule (ICAM)-1, nuclear factor (NF)-κ, and endothelin-1 were significantly higher in the ethanol offspring group than in the control group (P<0.001). Histopathological changes such as total aorta thickness, tunica media, tunica adventitia, elastin fiber thickness, fiber interval, and elastin/media ratio significantly increased in the aorta of the offspring of the ethanol group compared to the control group 21 and 90 days after birth. Conclusion: Our findings suggest that prenatal and early postnatal ethanol exposure-induced cardiovascular abnormalities are, in part, due to predisposing the aorta to atherosclerosis, which was mediated through the aorta wall remodeling and inflammation process.

Alpha7 nicotinic acetylcholine receptor expression in Sorafenib-resistant Hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC), the most prevalent kind of liver cancer, remains one of the world's main causes of death. The alpha7 nicotinic acetylcholine receptor (α7nAchR) has been recognized to be overexpressed in malignancies and chemoresistance. Since little is known about the role of α7nAchR expression in drug-resistant cells, this study was designed to investigate the effect of α7nAchR suppression in combination with Sorafenib (SOR) on SOR-resistant HCC cells. First, SOR-resistant HCC cells were generated. To suppress the expression of α7nAchR, cells were treated with SOR following siRNA transfection. qRT-PCR was used to examine the expression of α7nAchR and apoptotic genes by evaluating the IC50 of SOR and the combination of α7nAchR siRNA and SOR on the survival of resistant cells. Moreover, apoptosis, autophagy, and cell cycle analysis for resistant HCC cells were performed using flow cytometry. Cell migration and colony formation assays were also used for further confirmation. Our results suggest that inhibiting α7nAchR can lead resistant HCC cells to become sensitive. Furthermore, when siRNA and SOR were treated together, HCC-resistant cells showed a considerable reduction in α7nAchR mRNA gene expression. In addition, when α7nAchR was downregulated in combination with SOR, migration and colony formation were inhibited. Apoptosis was triggered by modulating the expression of apoptotic target genes, and cell cycle arrest was observed in the G2-M and subG1 phases. Overexpression of α7nAchR in SOR-resistant HCC cells suggests that it might be a therapeutic target for HCC cell resistance therapy.

miR-589-5p Inhibits Cell Proliferation by Targeting Histone Deacetylase 3 in Triple Negative Breast Cancer.

BACKGROUND: Histone deacetylase 3 (HDAC3) is a potential oncogene that is significantly up-regulated in patients with breast cancer. MicroRNAs (miRs) are a group of small non-coding and regulatory RNAs which have recently been proposed as promising molecules for breast cancer target therapy. In the current study, we investigated the impact of miR-589-5p/ HDAC3 axis on cancer cell development in triple negative breast cancer (TNBC) cells. METHODS: In-silico analysis determined that miR-589-5p potentially targets HDAC3. We evaluated the HDAC3 and mir-589-5p expression levels in clinical samples and breast cancer cell lines including MDA-MB-231, MDA-MB-468, MCF-7 and MCF-10A. HDAC3 was knocked out to investigate its role on cancer cell progression. Anti-cancerous role of the miR-589-5p was assessed using an expression vector. We evaluated possible alteration in the cell cycle progression, cell viability and cell proliferation, after transient transfection. RESULTS: HDAC3 was over-expressed in TNBC clinical samples and breast cancer cell lines compared to non-cancerous controls while miR-589-5p was down regulated in cancer cells. Suppression of HDAC3 decreased the cell viability, cell proliferation and colony formation. Similar results were observed after over-expression of the miR-589-5p. Dual-Luciferase reporter assay confirmed the direct targeting of HDAC3 by miR-589-5p. CONCLUSION: Our results showed that miR-589-5p mediates its anti-proliferative effects on breast cancer cells via targeting HDAC3. These findings suggest that the miR-589-5p/ HDAC3 axis could be considered as a possible therapeutic strategy in TNBC.

In Vitro Human Cancer Models for Biomedical Applications.

Cancer is one of the leading causes of death worldwide, and its incidence is steadily increasing. Although years of research have been conducted on cancer treatment, clinical treatment options for cancers are still limited. Animal cancer models have been widely used for studies of cancer therapeutics, but these models have been associated with many concerns, including inaccuracy in the representation of human cancers, high cost and ethical issues. Therefore, in vitro human cancer models are being developed quickly to fulfill the increasing demand for more relevant models in order to get a better knowledge of human cancers and to find novel treatments. This review summarizes the development of in vitro human cancer models for biomedical applications. We first review the latest development in the field by detailing various types of in vitro human cancer models, including transwell-based models, tumor spheroids, microfluidic tumor-microvascular systems and scaffold-based models. The advantages and limitations of each model, as well as their biomedical applications, are summarized, including therapeutic development, assessment of tumor cell migration, metastasis and invasion and discovery of key cancer markers. Finally, the existing challenges and future perspectives are briefly discussed.

The role of histone deacetylase 3 in breast cancer.

It has been recently revealed that Histone Deacetylase (HDAC) 3, a unique member of the HDACs family, can trigger and progress cancers by alternation in genes expression and proteins activity. Epigenetic modifications by HDACs have been studied well in various cancer cells. Recent studies have focused on the HDAC enzymes as a possible target in cancer therapy. There are significant documents on upregulation of HDAC3 in breast cancer (BC) cells which suggest an oncogenic role for this enzyme. Interestingly, some studies showed that HDAC3 inhibition could be considered as a promising target in breast cancer therapy, and thus far, several inhibitors from different nature have been introduced. In this review, we discussed the function and highlight the existing inhibitors of HDAC3 in BC pathogenesis and therapy.

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.

Unraveling the Effect of Breast Cancer Patients' Plasma on the Targeting Ability of Folic Acid-Modified Chitosan Nanoparticles.

The formation of protein corona (PC) around nanoparticles (NPs) has been reported inside biological conditions. This effect can alter delivery capacity toward the targeted tissues. Here, we synthesized folic acid-modified chitosan NPs (FA-CS NPs) using different concentrations of folic acid (5, 10, and 20%). FA-CS NPs were exposed to plasmas of breast cancer patients and healthy donors to evaluate the possibility of PC formation. We also monitored uptake efficiency in in vitro conditions after incubation with human breast cancer cell line MDA-MB-231 and monocyte/macrophage-like Raw264.7 cells. Data showed that the formation of PC around FA-CS NPs can change physicochemical properties coincided with the rise in NP size and negative surface charge. SDS-PAGE electrophoresis revealed differences in the type and content rate of plasma proteins attached to NP surface in a personalized manner. Based on MTT data, the formation of PC around NPs did not exert cytotoxic effects on MDA-MB-231 cells while this phenomenon reduced uptake rate. Fluorescence imaging and flow cytometry analyses revealed reduced cellular internalization rate in NPs exposed to patients' plasma compared to the control group. In contrast to breast MDA-MB-231 cells, Raw264.7 cells efficiently adsorbed the bare and PC-coated NPs from both sources, indicating the involvement of ligand-receptor-dependent and independent cellular engulfment. These data showed that the PC formed on the FA-CS NPs is entirely different in breast cancer patients and healthy counterparts. PC derived from patients' plasma almost abolishes the targeting efficiency of FA-CS NPs even in different mechanisms, while this behavior was not shown in the control group. Surprisingly, Raw264.7 cells strongly adsorbed the PC-coated NPs, especially when these particles were in the presence of patients' sera. It is strongly suggested that the formation of PC around can affect delivering capacity of FA-CS NPs to cancer cells. It seems that the PC-coated FA-CS NPs can be used as an efficient delivery strategy for the transfer of specific biomolecules in immune system disorders.

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.

Interplay between MAPK/ERK signaling pathway and MicroRNAs: A crucial mechanism regulating cancer cell metabolism and tumor progression.

Mitogen-activated protein kinase (MAPK) signal transduction, as a highly conserved signaling pathway, is reported to be involved in various biological events, including metabolic reprogramming, cell proliferation, survival, and differentiation. Mutations in key molecules involved in MAPK/ERK signaling and dysregulation of this pathway are very common events in various human malignancies, which make the MAPK signaling a crucial signaling pathway participating in the regulation of glucose uptake by malignant cells and tumorigenesis. MicroRNAs (miRNAs), as small non-coding RNAs, are critical regulators of gene expression that play key roles in cancer initiation and progression. On the other hand, these small RNAs mutually regulate the MAPK signaling which is often overexpressed in the case of cancer progression; suggesting that crosstalk between miRNAs and this signaling pathway plays a pivotal role in the development of human cancers. Some miRNAs such as miR-20b, miR-34c-3p, miR-152, miR-181a, and miR-302b through inhibiting MAPK signaling, and miR-193a-3p, miR-330-3p, and miR-592 by activating this signaling pathway, play imperative roles in tumorigenesis. Therefore, in this review, we aimed to focus on the interplay between miRNAs and MAPK signaling in the various steps of tumorigenesis, including metabolic regulation, cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance.

MicroRNA-124-3p suppresses PD-L1 expression and inhibits tumorigenesis of colorectal cancer cells via modulating STAT3 signaling.

Programmed death ligand 1 (PD-L1) plays a significant role in colorectal tumorigenesis through induction of regulatory T cells (Tregs) and suppression of antitumor immunity. Furthermore, microRNAs (miRNAs) as the posttranscriptional regulators of gene expression show considerable promise as a therapeutic target for colorectal cancer (CRC) treatment. Considering this, in vitro effects of miRNA-124 (miR-124-3p) on CRC cell tumorigenesis and Tregs differentiation via targeting PD-L1 were investigated in the current study. Functional analysis showed that miR-124 is significantly downregulated in CRC tissues as compared with marginal normal samples (p < .0001), and its downregulation was negatively correlated with PD-L1 expression. Moreover, a specific region in PD-L1 3'-untranslated region was predicted as the miR-124 target and validated using the luciferase assay. Further investigation showed that transfection of HT29 and SW480 cells with miR-124 mimics significantly reduced PD-L1 mRNA, protein, and cell surface expression, and inhibited Tregs in coculture models via modulating interleukin [IL]-10, IL-2, tumor necrosis factor α, transforming growth factor beta, and interferon gamma expression levels. Besides, miR-124 overexpression decreased CRC cell proliferation and arrested cell cycle at the G1 phase through downregulation of c-Myc and induced apoptosis in CRC cells via upregulation of both intrinsic and extrinsic pathways. Also, miR-124 exogenous overexpression could reduce colony and spheroid formation ability of CRC cells via downregulating CD44 mRNA expression. miR-124 also diminished MMP-9 expression and subsequently suppressed cell migration and invasion. We also illustrated that STAT3 signaling was repressed by miR-124 in CRC cells. Taken together, our findings imply that considering the involvement of miR-124 in the regulation of PD-L1 through colorectal tumorigenesis and its remarkable antitumor effects, this miRNA could be regarded as the promising target for the development of therapeutic approaches for colorectal cancer.

Fever and breast cancer: A critical review of the literature and possible underlying mechanisms.

Fever is a common feature in various pathological conditions that manifests a series of molecular events in the internal milieu. Much less attention has been paid to the clinical importance and the management of fever in breast cancer patients. However, several studies have reported an association between postoperative fever and poor treatment outcomes in breast cancer patients. The fever is a side effect of chemotherapy and a manifestation of cancer recurrence. The postmenopausal breast cancer patients experience another body temperature disturbance that is known as a hot flashes. Here, we reviewed the literature regarding postoperative fever and the possible underlying molecular and cellular mechanisms. Then the efficacy of non-steroidal anti-inflammatory drugs was discussed as a therapeutic option to control postoperative fever. Finally, we reviewed the chemotherapy-induced neutropenic fever and cancer vaccination-induced fever.