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Background: Cancer and diabetes mellitus are quite common diseases found together worldwide. A considerable amount of evidence is available for the rapid development and presentation of various types of cancer in the type 2 diabetes mellitus (DM2) population as compared with the population without diabetes. The objective of the study is to formulate and evaluate 5-fluorouracil (5-FU) and metformin (MET) nanoparticles (NPs) and to establish the characteristic features of the biodegradable NPs. 5-FU and MET NPs with chitosan as a biodegradable polymer were formulated by the ionotropic cross-linking method. 0.25 gm of MET and 0.25 gm of 5-FU were dissolved in 100 ml of distilled water, and stock solution was prepared. 5 ml of stock solution was slowly mixed into the chitosan solution to obtain the mixture of drugs and chitosan. The tripolyphosphate reserve liquid was dripped slowly into the chitosan solution with constant stirring until the opaline appearance was noticed in the mixture, then filtered, and dried. The NPs were evaluated for their physical properties and drug release kinetics. Cell proliferation assay was done using human colorectal carcinoma cell line (HCT 116). Results: The formulation composed of 1.5 w/v of chitosan, 0.25 w/v of MET, and 5-FU had an average particle diameter of 198.7 nm. The polydispersity index was 0.757. Thermal and infrared spectroscopy results indicated the drugs and polymers selected for the formulation were unique without any identifiable interaction. The NPs were spherical in appearance, with numerous pours on the surface, which was evident when microscopically examined. Uniformity in drug release was observed, and the formulation demonstrated excellent release kinetics. HTC 116 cell line confirmed that the maximum percentage of cell death and minimum viability of cells were observed while using the combination of MET and 5-FU-NPs as compared to the pure MET or 5-FU alone. Conclusion: MET and 5-FU-loaded chitosan NPs were found to have excellent physiochemical properties, particle size, and drug release from the polymer in a controlled manner. Half-maximal inhibitory concentration value (IC50) of MET and 5-FU-NPs was found to be significantly less as compared to MET and 5-FU alone or the combination. [ABSTRACT FROM AUTHOR]

Purpose: The transmembrane serine protease 4 (TMPRSS4) gene is upregulated in various human cancers. However, its biological functions in pancreatic ductal adenocarcinoma remain unclear. We examined the expression of TMPRSS4 in pancreatic ductal adenocarcinoma tissues and its correlation with clinicopathological parameters in patients with pancreatic ductal adenocarcinoma who underwent surgery. Methods: The TMPRSS4 expression was immunohistochemically examined in 81 PDAC patients with pancreatic ductal adenocarcinoma. We analyzed the association between the TMPRSS4 expression and clinicopathological factors, the recurrence-free survival (RFS), and the overall survival (OS) and examined the effect of TMPRSS4 expression on cell migration and sensitivity to 5-fluorouracil. Results: The expression rate of TMPRSS4 in the samples was 62.9% (51/81). The TMPRSS4 expression was not correlated with any clinicopathological feature. The five-year overall and recurrence-free survival rates were significantly lower in the TMPRSS4-positive group than in the TMPRSS4-negative group. On a multivariate analysis, TMPRSS4 positivity, poorly differentiated histology, and non-adjuvant chemotherapy predicted a poor OS, while TMPRSS4 positivity and poorly differentiated histology predicted a poor RFS. TMPRSS4-silenced pancreatic ductal adenocarcinoma cells showed higher sensitivity to 5- fluorouracil than did the control siRNA-transfected cells. Conclusions: TMPRSS4 can be considered a prognostic factor and therapeutic target for pancreatic ductal adenocarcinoma. [ABSTRACT FROM AUTHOR]

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Ecofriendly organically modified bentonite based on curcumin-extracted compounds was applied as a catalytic carrier for green ZnO particulates (Zn@CU/BEN). The composite developed was evaluated as a cost-effective, highly efficient, and versatile photocatalyst for improving the oxidation of 5-fluorouracil (5-FU) residues in water resources. The ZnO@CU/BEN blend, with a dose of 0.5 g/L, exhibits notable catalytic characteristics, leading to the full oxidation of 5-FU at a concentration of 25 mg/L within 80 min. The kinetic assessment reflects the high fitness of the Firs order model with best rate constant value of 0.0156 and quantum yield (ɸ) value of 2.9 × 10–7. Nevertheless, the total reduction in organic carbon (TOC) was identified only after 160 min, indicating the existence of considerable byproducts of intermediates. The secondary compounds that were detected, alongside the establishment of hydroxyl radicals as the crucial oxidizing agent, revealed a degradation path consisting of two steps: hydroxylation and defluorination reactions. The toxicity characteristics of untreated pollutants and their resulting oxidized products were evaluated by measuring the inhibitory effects of the solutions on Vibrio fischeri at various time intervals. The sample that underwent partial oxidation during the first period exhibited a greater degree of toxicity compared to the unprocessed 5-FU. Nevertheless, the sample that underwent treatment for 200 min exhibited noteworthy characteristics of biosafety and non-toxicity. The synergistic effect of bentonite and organo-modified bentonite with curcumin extracts improves both the retention and oxidation activities of green ZnO. [ABSTRACT FROM AUTHOR]

5-Fluorouracil (5-FU) is a clinically established anticancer drug effective in treating various solid tumors, including colorectal, breast, and pancreatic cancers. However, its therapeutic efficacy is often hindered by rapid metabolism and the development of drug resistance. This study investigates a nanocomposite comprising chitosan (CS), agarose (Aga), carbon quantum dots (CQDs), and titanium dioxide (TiO2_CQDs) as a potential nanocarrier (NC) to enhance 5-FU delivery. A CS/Aga hydrogel was synthesized through physical cross-linking to improve biocompatibility. Subsequently, the drug-loaded nanocomposite (CS/Aga/TiO2_CQDs@5-FU) was prepared using a W/O/W double emulsion process. A comprehensive characterization of the NC and 5-FU incorporation was conducted. X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR) were employed to evaluate the crystalline properties of the nanoparticles (NPs) and confirm 5-FU integration. Dynamic light scattering (DLS) and zeta potential measurements assessed the stability and particle size distribution of the drug-loaded nanocomposites, confirming the formation of stable NPs. Field emission scanning electron microscopy (FE-SEM) verified the uniform dispersion of NPs, characterized by smooth and nearly spherical structures. Drug release kinetics were evaluated under controlled conditions. The encapsulation efficiency (EE) and loading efficiency (LE) were determined to be 86% and 47.25%, respectively, indicating the nanocomposite's high drug-carrying capacity. An MTT assay on U-87 MG and L929 cell lines demonstrated the biocompatibility of the fabricated NC. Notably, the drug-loaded nanocomposite exhibited lower cytotoxicity compared to pure 5-FU. These findings suggest that the nanocomposite holds promise as a drug delivery system, particularly for overcoming challenges associated with brain cancer treatment. [ABSTRACT FROM AUTHOR]

Primary cilia are crucial for neurogenesis, and cilium-related genes are involved in the closure of neural tubes. Inositol polyphosphate-5-phosphatase (Inpp5e) was enriched in primary cilia and closely related to the occurrence of neural tube defects (NTDs). However, the role of Inpp5e in the development of NTDs is not well-known. To investigate whether Inpp5e gene is associated with the neural tube closure, we established a mouse model of NTDs by 5-fluorouracil (5-FU) exposure at gestational day 7.5 (GD7.5). The Inpp5e knockdown (Inpp5e-/-) mouse embryonic stem cells (mESCs) were produced by CRISPR/Cas9 system. The expressions of Inpp5e and other cilium-related genes including intraflagellar transport 80 (Ift80), McKusick-Kaufman syndrome (Mkks), and Kirsten rat sarcoma viral oncogene homolog (Kras) were determined, utilizing quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), western blot, PCR array, and immunofluorescence staining. The result showed that the incidence of NTDs was 37.10% (23 NTDs/62 total embryos) and significantly higher than that in the control group (P < 0.001). The neuroepithelial cells of neural tubes were obviously disarranged in NTD embryos. The mRNA and protein levels of Inpp5e, Ift80, Mkks, and Kras were significantly decreased in NTD embryonic brain tissues, compared to the control (P < 0.05). Knockdown of the Inpp5e (Inpp5e-/-) reduced the expressions of Ift80, Mkks, and Kras in mESCs. Furthermore, the levels of α-tubulin were significantly reduced in NTD embryonic neural tissue and Inpp5e-/- mESCs. These results suggested that maternal 5-FU exposure inhibited the expression of Inpp5e, which resulted in the downregulation of cilium-related genes (Ift80, Mkks, and Kras), leading to the impairment of primary cilium development, and ultimately disrupted the neural tube closure. [ABSTRACT FROM AUTHOR]

Background: Drug resistance in colorectal cancer (CRC) is modulated by multiple molecular factors, which can be ascertained through genetic investigation. Single nucleotide polymorphisms (SNPs) within key genes have the potential to impair the efficacy of chemotherapeutic agents such as 5-fluorouracil (5-FU). Therefore, the identification of SNPs linked to drug resistance can significantly contribute to the advancement of tailored therapeutic approaches and the enhancement of treatment outcomes in patients with CRC. Material and Method: To identify dysregulated genes in 5-FU-based chemotherapy responder or non-responder CRC patients, a meta-analysis was performed. Next, the protein–protein interaction (PPI) network of the identified genes was analyzed using the STRING database. The most significant module was chosen for further analysis. In addition, a literature review was conducted to identify drug resistance-related genes. Enrichment analysis was conducted to validate the main module genes and the genes identified from the literature review. The associations between SNPs and drug resistance were investigated, and the consequences of missense variants were assessed using in silico tools. Result: The meta-analysis identified 796 dysregulated genes. Then, to conduct PPI analysis and enrichment analysis, we were able to discover 23 genes that are intricately involved in the cell cycle pathway. Consequently, these 23 genes were chosen for SNP analysis. By using the dbSNP database and ANNOVAR, we successfully detected and labeled SNPs in these specific genes. Additionally, after careful exclusion of SNPs with allele frequencies below 0.01, we evaluated 6 SNPs from the HDAC1, MCM2, CDK1, BUB1B, CDC14B, and CCNE1 genes using 8 bioinformatics tools. Therefore, these SNPs were identified as potentially harmful by multiple computational tools. Specifically, rs199958833 in CDK1 (Val124Gly) was predicted to be damaging by all tools used. Our analysis strongly indicates that this specific SNP could negatively affect the stability and functionality of the CDK1 protein. Conclusion: Based on our current understanding, the evaluation of CDK1 polymorphisms in the context of drug resistance in CRC has yet to be undertaken. In this investigation, we showed that rs199958833 variant in the CDK1 gene may favor resistance to 5-FU-based chemotherapy. However, these findings need validation in an independent cohort of patients. [ABSTRACT FROM AUTHOR]

Background: Among the three most used anticancer drugs, cyclophosphamide, Adriamycin, and 5-Fluorouracil (CAF), the most significant outcome is chemobrain, caused by increased oxidative stress, inflammatory insult, and mitochondrial dysfunction. Objective: In this study, endogenous antioxidant coenzyme Q10 (CoQ10) was evaluated for its neuroprotective effects in CICI. Materials and methods: The chemobrain was induced in Swiss albino female mice by administering CAF (40 + 4 + 25 mg/kg) intraperitoneal (i.p.) in three cycles (single injection per week) followed by treatment with CoQ10 (40 mg/kg; p.o.) for up to 3 weeks followed by behavioral, biochemical, molecular and histopathological analysis. Results: Treatment with CoQ10 significantly improved cognition by improving exploring time in novel objects recognition test followed by increasing the time spent in the target quadrant in MWM test as compared to CAF-treated animals. Moreover, CoQ10 demonstrated antioxidant properties by reducing the expression of LPO while increasing levels of GSH, SOD, and catalase as compared to CAF-treated animals. While the levels of AChEs were significantly reduced after CoQ10 treatment in CAF-treated animals. In terms of its mechanism, it effectively counteracted the pro-inflammatory substances (TNF-α and IL-1β) triggered by CAF while also enhancing the levels of anti-inflammatory markers (IL-10 and Nrf2). Moreover, CoQ10 showed mitochondrial enhancers and it improved the level of Complex (I, II, and IV). Besides that, mitochondrial morphological analysis was done by TEM, and neuronal morphology along with quantification analysis was performed by H&E staining using Image J software to confirm the neuroprotective effect of CoQ10 over CAF-induced cognitive impairment. Conclusion: This study suggests CoQ10 can protect the mitochondria by imposing antioxidant, and anti-inflammatory properties, which could be a potential therapy for CICI. [ABSTRACT FROM AUTHOR]

Background: 5-Fluorouracil (5-FU) has been used as a standard first-line treatment for colorectal cancer (CRC) patients. Although 5-FU-based chemotherapy and immune checkpoint blockade (ICB) have achieved success in treating CRC, drug resistance and low response rates remain substantial limitations. Thus, it is necessary to construct a 5-FU resistance-related signature (5-FRSig) to predict patient prognosis and identify ideal patients for chemotherapy and immunotherapy. Methods: Using bulk and single-cell RNA sequencing data, we established and validated a novel 5-FRSig model using stepwise regression and multiple CRC cohorts and evaluated its associations with the prognosis, clinical features, immune status, immunotherapy, neoadjuvant therapy, and drug sensitivity of CRC patients through various bioinformatics algorithms. Unsupervised consensus clustering was performed to categorize the 5-FU resistance-related molecular subtypes of CRC. The expression levels of 5-FRSig, immune checkpoints, and immunoregulators were determined using quantitative real-time polymerase chain reaction (RT‒qPCR). Potential small-molecule agents were identified via Connectivity Map (CMap) and molecular docking. Results: The 5-FRSig and cluster were confirmed as independent prognostic factors in CRC, as patients in the low-risk group and Cluster 1 had a better prognosis. Notably, 5-FRSig was significantly associated with 5-FU sensitivity, chemotherapy response, immune cell infiltration, immunoreactivity phenotype, immunotherapy efficiency, and drug selection. We predicted 10 potential compounds that bind to the core targets of 5-FRSig with the highest affinity. Conclusion: We developed a valid 5-FRSig to predict the prognosis, chemotherapeutic response, and immune status of CRC patients, thus optimizing the therapeutic benefits of chemotherapy combined with immunotherapy, which can facilitate the development of personalized treatments and novel molecular targeted therapies for patients with CRC. [ABSTRACT FROM AUTHOR]

Highlights: The goal is to optimize the microsponge drug delivery system's preparation. Scaling up ensures product repeatability. FTIR, DSC, and SEM confirmed the drug-loaded microsponge particles' compatibility and porous shape. The final gel dosage had shear-thinning rheology, suggesting dermal use. Ultimately, it supports and advances the UN's sustainable development goals and G20. In 1987, Won invented the solid-phase porous microsphere (MS), which stores bioactive compounds in many interconnected voids. Spherical particles (5–300 μm), MS, may form clusters of smaller spheres, resulting in many benefits. The current investigation focussed on gel-encased formulation, which can be suitable for dermal usage. First, quasi-emulsion (w/o/w) solvent evaporation was used to prepare 5-fluorouracil (5 FU) MS particles. The final product was characterized (SEM shows porous structure, FTIR and DSC showed drug compatibility with excipients, and gel formulation is shear-thinning) and further scaled up using the 8-fold method. Furthermore, CCD (Central Composite Design) was implemented to obtain the optimized results. After optimizing the conditions, including the polymer (600 mg, ethyl cellulose (EC), eudragit RS 100 (ERS)), stirring speed (1197 rpm), and surfactant concentration (2% w/v), we achieved the following results: optimal yield (63%), mean particle size (152 µm), drug entrapment efficiency (76%), and cumulative drug release (74.24% within 8 h). These findings are promising for industrial applications and align with the objectives outlined in UN Sustainable Development Goals 3, 9, and 17, as well as the goals of the G20 initiative. [ABSTRACT FROM AUTHOR]

Our current study reports the successful synthesis of thiolated chitosan-based nanoparticles for targeted drug delivery of 5-Fluorouracil. This process was achieved through the ionic gelation technique, aiming to improve the efficacy of the chemotherapeutic moiety by modifying the surface of the nanoparticles (NPs) with a ligand. We coated these NPs with hyaluronic acid (HA) to actively target the CD44 receptor, which is frequently overexpressed in various solid malignancies, including breast cancer. XRD, FTIR, SEM, and TEM were used for the physicochemical analysis of the NPs. These 5-Fluorouracil (5-FU) loaded NPs were evaluated on MDA-MB-231 (a triple-negative breast cell line) and MCF-10A (normal epithelial breast cells) to determine their in vitro efficacy. The developed 5-FU-loaded NPs exhibited a particle size within a favorable range (< 300 nm). The positive zeta potential of these nanoparticles facilitated their uptake by negatively charged cancer cells. Moreover, they demonstrated robust stability and achieved high encapsulation efficiency. These nanoparticles exhibited significant cytotoxicity compared to the crude drug (p < 0.05) and displayed a promising release pattern consistent with the basic diffusion model. These traits improve the pharmacokinetic profile, efficacy, and ability to precisely target these nanoparticles, offering a potentially successful anticancer treatment for breast cancer. However, additional in vivo assessments of these formulations are obligatory to confirm these findings. [ABSTRACT FROM AUTHOR]

Paclitaxel (PTX), methotrexate (MTX), and 5-fluorouracil (5-FU) are commonly-used small molecule anti-tumor drugs for breast cancer. Unfortunately, drug resistance occurs with long-term treatment or excessive use, and the high concentrations of PTX, MTX, and 5-FU in patients may lead to side effects with dose-limiting toxicities, such as myelosuppression, hepatotoxicity, and peripheral neuropathy. Therefore, concentration monitoring of PTX, MTX, and 5-FU in clinical treatment is very important. We prepared highly sensitive and specific monoclonal antibodies using several haptens, and established a multiple paper-based sensor utilizing optical signals of gold nanoparticles, which simultaneously detected PTX, MTX, and 5-FU in human plasma or urine with 10 min. A portable scanner for quantitative detection in plasma and urine samples was used, and the calculated limit of detection (cLOD) values were 0.002 and 0.142 µg/mL for PTX, 0.187 and 0.976 ng/mL for MTX, and 0.057 and 0.128 µg/mL for 5-FU, respectively. In the recovery test, the recovery rates and the coefficient of variation were 85.84%–108.81% and 1.23%–8.80%, respectively, indicating the reliability and accuracy of the multiple gold immunochromatographic strip (GIS). In addition, for the determination of collected clinical plasma samples, the correlation between the test data of the multiple GIS and liquid chromatography–tandem mass spectrometry (LC–MS/MS) was good. Therefore, the developed multiple GIS could be applied to the rapid detection of PTX, MTX, and 5-FU in different clinical samples. [ABSTRACT FROM AUTHOR]

Objective: To study the efficacy and side-effect profile of topical 5-Fluorouracil (5-FU) in the treatment of ocular surface squamous neoplasia (OSSN). Methods: Retrospective study of 101 eyes of 100 patients treated with 5-FU with one week on and 3 weeks off regimen. Results: Of the 100 patients (101 eyes), the mean age at diagnosis of OSSN was 49 (median, 52 years; range, 11–87 years). History of prior intervention was noted in 6 (6%) eyes. Tumor epicenter included bulbar conjunctiva (n = 54; 53%), limbus (n = 27; 27%), and cornea (n = 20;20%). Mean number of cycles of topical 5-FU administered was 3 (median, 3; range, 1–8). Complete tumor regression was achieved with topical 5-FU in 89 (88%) eyes with a mean number of 2 cycles (median, 2; range, 1–6) of 5-FU. The remaining 12 (12%) lesions underwent additional treatment including excisional biopsy (n = 7), extended enucleation (n = 3), and topical Interferon alpha 2b (n = 2) for complete tumor control. Over a mean follow-up period of 6 months (median, 5 months; range, 1–36 months) following treatment, tumor recurrence was noted in 2 (2%) patients, and side-effects were noted in 7 (7%) eyes including conjunctival hyperemia (n = 1), punctal stenosis (n = 1), sterile keratitis (n = 4), and limbal stem cell deficiency (n = 1). Conclusion: Topical 5-FU is an effective non-invasive therapy for OSSN with a minimal side-effect profile. [ABSTRACT FROM AUTHOR]

The transdermal route is an important delivery system for the delivery of both systemic and local effects. The effectiveness of therapy is based on adherence of transdermal dosage form to the skin and physiochemical properties of the drug during therapy. Transdermal Film-Forming Gels when applied to the skin after adherence form a thin film and provide the delivery of drug to the body tissues. Novel 5-Fluorouracil loaded Film-Forming Gels was prepared by utilizing natural polymer (chitosan) with variable concentration of penetration enhancers i.e. oleic acid and tween 80 which further affects the drug release. Prepared Film-Forming Gels were subjected to pH determination, viscosity measurement, homogeneity determination and FTIR analysis. Drying test showed film-forming gel was dried within 15 min after application. Moreover, in-vitro release study confirmed the 83% release over 180 min and the ex-vivo release of FFG9 displayed 81.45% release. This novel system would be an effective dosage form for the delivery of drugs. [ABSTRACT FROM AUTHOR]

Background: The early diagnosis of gastric cancer (GC) and overcoming chemotherapy resistance is challenging. The aberrant expression of zinc finger protein 281 (ZNF281) and the over-activation of the Wnt/β-catenin pathway are oncogenic factors and confer tumor chemoresistance. ZNF281 modulates the Wnt/β-catenin pathway to influence malignant tumor behavior. However, the role of ZNF281 in GC chemotherapy and the relationship with the Wnt/β-catenin pathway have not been elucidated by researchers. Methods: We explored differences in ZNF281 expression in Pan-cancer and normal tissues, the effect of its expression on prognosis of patients treated with 5-fluorouracil (5-FU). Cox regression was utilized to determine whether ZNF281 is an independent prognostic factor. Enrichment analysis was performed to explore the mechanism underlying ZNF281’s role in 5-FU treatment. We assessed the relationship between ZNF281 and the tumour microenvironment (TME) and combined bulk-RNA and single-cell RNA data to analyse the relationship between ZNF281 and immune infiltration. In vitro experiments verified the effects of ZNF281 knockdown on proliferation, invasion, migration, apoptosis, DNA damage of GC cells with 5-FU treated and the Wnt/β-catenin pathway proteins. Results: ZNF281 was highly expressed in seven cancers and correlates with the prognosis. It is an independent prognostic factor in 5-FU treatment. ZNF281 correlates with TME score, CD8T cell abundance. ZNF281 is primarily associated with DNA repair and the Wnt/β-catenin pathway. ZNF281 knockdown enhanced the effect of 5-FU on phenotypes of GC cells. Conclusion: We identified and verified ZNF281 as one of the potential influencing factors of 5-FU treatment in GC and may be associated with the Wnt/β-catenin pathway. Low ZNF281 may contribute to improved 5-FU sensitivity in GC patients. [ABSTRACT FROM AUTHOR]

Background: 5-fluorouracil (5-FU) is conventionally used in chemotherapy for colon adenocarcinomas. Acquired resistance of 5-FU remains a clinical challenge in colon cancer, and efforts to develop targeted agents to reduce resistance have not yielded success. Protosappanin B (PSB), the main component of Lignum Sappan extract, is known to exhibit anti-tumor effects. However, whether and how PSB could improve 5-FU resistance in colon cancer have not yet been established. In this study, we aimed to explore the effects and underlying mechanisms of PSB in 5-FU-induced chemoresistance in colon adenocarcinoma. Methods: Forty-seven paired colon cancer tissue samples from patients who received 5-FU chemotherapy were collected as clinical samples. Two 5-FU resistant colon cancer cell lines were established for in vitro experiments. Reverse transcription-quantitative PCR (RT-qPCR) was performed to determine the mRNA and microRNA (miRNA) expression levels in colon adenocarcinoma tissues and cell lines. Cell Counting Kit-8 (CCK-8) and flow cytometry assays were performed to evaluate cell proliferation and apoptosis, respectively. Results: LINC00612 was highly expressed in colon adenocarcinoma samples and 5-FU resistant colon cancer cells. LINC00612 knockdown enhances 5-FU chemosensitivity in 5-FU resistant cells. Notably, PSB treatment attenuated LINC00612 expression in 5-FU resistant colon adenocarcinoma cells. Moreover, PSB treatment reversed the increase in LINC00612-induced 5-FU resistance. Mechanistically, LINC00612 specifically bound to miR-590-3p, which promoted 5-FU resistance in colon adenocarcinoma cells and attenuated the inhibitory effect of LINC00612 on GOLPH3 expression. Conclusion: PSB attenuates 5-FU chemoresistance in colon adenocarcinoma by regulating the LINC00612/miRNA-590-3p/GOLPH3 axis. Highlights: LINC00612 is highly expressed in 5-FU resistant colon cancer cells and LINC00612 knockdown enhances 5-FU chemosensitivity in 5-FU resistant cells. PSB reverses the elevated LINC00612-induced 5-FU resistance. PSB attenuates 5-FU chemoresistance in colon adenocarcinoma by regulating the LINC00612/miRNA-590-3p/GOLPH3 axis. [ABSTRACT FROM AUTHOR]

Macrophage polarization is closely associated with the inflammatory processes involved in the development and chemoresistance of colorectal cancer (CRC). M2 macrophages, the predominant subtype of tumor-associated macrophages (TAMs) in a wide variety of malignancies, have been demonstrated to promote the resistance of CRC to multiple chemotherapeutic drugs, such as 5-fluorouracil (5-FU). In our study, we investigated the potential of 23-Hydroxybetulinic Acid (23-HBA), a significant active component of Pulsatilla chinensis (P. chinensis), to inhibit the polarization of M2 macrophages induced by IL-4. Our results showed that 23-HBA reduced the expression of M2 specific marker CD206, while downregulating the mRNA levels of M2 related genes (CD206, Arg1, IL-10, and CCL2). Additionally, 23-HBA effectively attenuated the inhibitory effects of the conditioned medium from M2 macrophages on apoptosis in colorectal cancer SW480 cells. Mechanistically, 23-HBA prevented the phosphorylation and nuclear translocation of the STAT6 protein, resulting in the inhibition of IL-10 release in M2 macrophages. Moreover, it interfered with the activation of the IL-10/STAT3/Bcl-2 signaling pathway in SW480 cells, ultimately reducing M2 macrophage-induced resistance to 5-FU. Importantly, depleting STAT6 expression in macrophages abolished the suppressive effect of 23-HBA on M2 macrophage polarization, while also eliminating its ability to decrease M2 macrophage-induced 5-FU resistance in cancer cells. Furthermore, 23-HBA significantly diminished the proportion of M2 macrophages in the tumor tissues of colorectal cancer mice, simultaneously enhancing the anti-cancer efficacy of 5-FU. The findings presented in this study highlight the capacity of 23-HBA to inhibit M2 macrophage polarization, a process that contributes to reduced 5-FU resistance in colorectal cancer. [ABSTRACT FROM AUTHOR]

In this study, a novel molecularly imprinted polymer (MIP) was synthesized with attapulgite (ATP) and acrylamide (AM) and ethyl methacrylate (MMA) for controlled release carrier of 5-fluorouracil (5-FU). The MIPs (PAM-PMMA) were characterized by XRD, FESEM, HRTEM, and FTIR. The drug loading and in vitro controlled release ability of MIP on 5-FU was investigated by adsorption property analysis and in vitro release analysis. MIPs (PAM-PMMA) reached a maximum drug loading of 12 mg/g and a maximum release of 80% at an ATP dosage of 0.2 g (0.4%), an initial concentration of 5-FU of 100 mg/L, and an adsorption time of 240 min. Cytotoxicity analysis showed that the maximum inhibition of cells could reach 25% at 72 h of cell culture time under the above conditions. The results showed that MIPs synthesized with ATP as the substrate and AM and MMA as the functional monomers were successfully synthesized and could be used as a drug delivery system for 5-FU. [ABSTRACT FROM AUTHOR]

5-Fluorouracil (5-FU) is an effective chemotherapy drug in the treatment of colorectal cancer (CRC). However, auxiliary or alternative therapies must be sought due to its resistance and potential side effects. Certain probiotic metabolites exhibit anticancer properties. In this study evaluated the anticancer and potential therapeutic activities of cell extracts potential probiotic strains, Limosilactobacillus fermentum and Lactiplantibacillus plantarum isolated from the mule milk and the standard probiotic strain Lacticaseibacillus rhamnosus GG (LGG) against the human colon cancer cell line (HT-29) and the normal cell line (HEK-293) alone or in combination with 5-FU. In this study, L. plantarum and L. fermentum, which were isolated from mule milk, were identified using biochemical and molecular methods. Their probiotic properties were investigated in vitro and compared with the standard probiotic strain of the species L. rhamnosus GG. The MTT assay, acridine orange/ethidium bromide (AO/EB) fluorescent staining, and flow cytometry were employed to measure the viability of cell lines, cell apoptosis, and production rates of Th17 cytokines, respectively. The results demonstrated that the combination of lactobacilli cell extracts and 5-FU decreased cell viability and induced apoptosis in HT-29 cells. Furthermore, this combination protected HEK-293 cells from the cytotoxic effects of 5-FU, enhancing their viability and reducing apoptosis. Moreover, the combination treatment led to an increase in the levels of IL-17A, IFN-γ, and TNF-α, which can enhance anti-tumor immunity. In conclusion, the cell extracts of the lactobacilli strains probably can act as a potential complementary anticancer therapy. [ABSTRACT FROM AUTHOR]

Background: Drug combination studies help to improve new treatment approaches for colon cancer. Tumor spheroids (3D) are better models than traditional 2-dimensional cultures (2D) to evaluate cellular responses to chemotherapy drugs. The cultivation of cancer cells in 2D and 3D cultures affects the apoptotic process, which is a major factor influencing the response of cancer cells to chemotherapeutic drugs. In this study, the antiproliferative effects of 5-fluorouracil (5-FU) and doxorubicin (DOX) were investigated separately and in combination using 2D and 3D cell culture models on two different colon cancer cell lines, HT-29 (apoptosis-resistant cells) and Caco-2 2 (apoptosis-susceptible cells). Methods: The effect of the drugs on the proliferation of both colon cancer cells was determined by performing an MTT assay in 2D culture. The apoptotic effect of 5-FU and DOX, both as single agents and in combination, was assessed in 2D and 3D cultures through quantitative real-time polymerase chain reaction analysis. The expression of apoptotic genes, such as caspases, p53, Bax, and Bcl-2, was quantified. Results: It was found that the mRNA expression of proapoptotic genes was significantly upregulated, whereas the mRNA expression of the antiapoptotic Bcl-2 gene was significantly downregulated in both colon cancer models treated with 5-FU, DOX, and 5-FU + DOX. Conclusion: The results indicated that the 5-FU + DOX combination therapy induces apoptosis and renders 5-FU and DOX more effective at lower concentrations compared to their alone use. This study reveals promising results in reducing the potential side effects of treatment by enabling the use of lower drug doses. [ABSTRACT FROM AUTHOR]

Recently, nanoparticle (NP)-based drugs have been developed to increase the efficiency of existing cancer treatment approaches; however, how NPs interact with cellular systems is still uncertain. In this study, we have examined the ability of Se–FA NPs to enhance the chemotherapeutic effect of 5-fluorouracil (5-FU) in human AGS gastric cancer cells as well as their ability alone and in combination with 5-FU to modulate autophagy. The prepared NPs were characterized using Fourier-transform infrared spectroscopy, dynamic light scattering, and scanning electron microscope. Cytotoxicity and autophagy-modulating activity of NPs were determined using MTT, q-PCR, and western blot methods. The size and surface charge of NPs were determined to be ~ 90.4 nm and − 53.8 mV, respectively. Se–FA NPs enhance the cytotoxicity of 5-FU (up to 4.1-fold) and consequently inhibit autophagy flux in AGS cells. These findings confirm the therapeutic potential of combining Se–FA NPs with 5-FU in an in vitro gastric cancer model and may suggest an approach to overcome chemotherapy resistance in cancer. [ABSTRACT FROM AUTHOR]

The electrospinning process was used to successfully encapsulate an anticancer drug, 5-fluorouracil (5-FU), into poly(ε-caprolactone)/gelatin (Gel) nanofiber mats (5-FU-PCL/Gel NFs). Nanofibers are recognized to be potential carriers for the delivery of anticancer drugs. One of the safest solvent systems for making PCL/Gel NF mats is the formic acid/acetic acid (FA/AA) solvent system. A compound solution jet was drawn from a customized coaxial spinneret using a high potential electric field of 20 kV. The loading of 5-FU with three different concentrations (5, 10, and 15 wt.%) improved PCL stabilization in the FA/AA system. The miscibility of the blended polymers in the electrospun nanofibers mats and 5-FU being well distributed in the nanofiber matrix was investigated using X-ray diffraction (XRD). In vitro 5-FU release from electrospun PCL/Gel NF mats revealed sustained release from the nanofiber mats, whereas slower release was found when higher concentrations of 5-FU were used. The produced electrospun PCL/Gel NF mats were studied by SEM, FTIR, TGA, and DSC. According to a study on drug release kinetics, 5-FU was released from PCl/Gel NFs in a diffusion-controlled pattern. [ABSTRACT FROM AUTHOR]

This case report describes an 80-year-old man who presented with a growing erythematous nodule with erosion, measuring 0.6 cm × 0.6 cm, on his right temple. This lesion was later diagnosed as atypical fibroxanthoma (AFX). Instead of undergoing Mohs surgery, the gold standard treatment, the patient opted to pursue a topical treatment regimen because of financial costs associated with surgical removal and repair. This topical regimen consisted of tazarotene cream, imiquimod cream, and 5-fluorouracil solution, applied for 30 days. The patient was directed to use this combination 5 days per week for 6 weeks. The specified dosage for each medication was a fifth of a packet of imiquimod 5% cream, an equivalent amount of tazarotene 0.1% cream, and a single drop of 5-fluorouracil 2% solution. These were combined on a bandage and placed on the lesion overnight. Following the treatment, a 3-week post-application examination revealed an erosion, 1.0 cm × 0.9 cm, amidst erythema. A subsequent incisional biopsy with histopathology and stains for CD10 and CD99, 3 weeks after treatment, and three punch biopsies with histopathology and stains for CD10 and CD99, 1-year post-treatment, confirmed the absence of AFX. AFX is a superficial variant of pleomorphic dermal sarcoma (PDS), which shares histologic similarities, yet the exact relationship between AFX/PDS and undifferentiated pleomorphic sarcoma is still not well understood. Previous studies have indicated a genomic similarity between AFX/PDS and cutaneous squamous cell carcinoma (cSCC), which suggests the potential efficacy of cSCC-targeted treatments for AFX/PDS. This case marks the first recorded instance of successful topical medical treatment of AFX, offering an alternative for patients who may opt out of surgical intervention. Continued research to assess the broader efficacy of this approach is encouraged. [ABSTRACT FROM AUTHOR]

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Targeting critical pathways of cancer cells using combination drugs is gaining significant importance as drug resistance is lowered and drug efficacy is improved even at low concentrations. Docetaxel and 5-fluorouracil are chemotherapeutic drugs prescribed for patients with solid tumours. While coated polymeric nanoparticles can combat drug resistance by sequential release of drugs, this paper proposes to encapsulate docetaxel and 5-fluorouracil in chitosan nanoparticles. To further improve the solubility of chitosan nanoparticles, they are crosslinked with polyethylene glycol using formaldehyde as crosslinker. Various techniques were used to characterize the nanoparticles. HR-SEM images indicated the formation of nanoparticles, drug loading into the chitosan nanoparticles and crosslinking of polyethylene glycol to chitosan nanoparticles. The experimental strategies were designed to evaluate the synergistic combination of the drugs in nanoparticles against AGS cell lines. It was found that the drugs loaded in chitosan nanoparticles synergistically inhibited the cell viability of AGS cells with a combination effect at 0.414. The combined effect of the drugs was even more effective, with value at 0.23 in the case of polyethylene glycol crosslinked-drug-loaded chitosan nanoparticles. The DPPH scavenging activity of drugs encapsulated in polyethylene glycol crosslinked chitosan nanoparticles was more effective at 57.39% compared to drug-alone counter parts. To further confirm the synergistic efficacy of the drugs loaded in nanoparticles in inducing apoptosis, changes were observed using acridine orange /ethidium bromide staining. Results indicated that combination effect of drugs in nanoparticles was much higher in AGS cells when compared to drug-alone incubated groups. [ABSTRACT FROM AUTHOR]

Background: Docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy is reportedly an effective treatment strategy for squamous cell carcinoma of the anus (SCCA). However, studies regarding its use in Japanese patients remain scarce. Case presentation: Here, we present the case of an 82-year-old woman with SCCA, cStage IIIB. Chemoradiotherapy was initiated after colostomy of the anorectal mass; however, para-aortic lymph node recurrence was observed 3 months after treatment completion. Five courses of DCF chemotherapy were subsequently administered, resulting in a complete response (CR). Two years and 1 month later, the aortic lymph node was enlarged again, and the patient achieved CR again after radiotherapy. Nine months later, local recurrence was detected in the anal canal, and laparoscopic perineal rectal amputation was performed. The patient remains progression-free 5 years and 10 months after the initial treatment and 1 year and 7 months after the final treatment. Conclusions: Our findings suggest that complementary treatment after DCF chemotherapy may be efficacious in Japanese patients with SCCA and help achieve CR. Despite occasional local recurrences, this approach may help achieve long-term progression-free survival. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is one of the world's largest health concerns with growing global incidence and mortality. The potential value of the neurokinin-1 receptor as a therapeutic target has been reported in several tumor types, including CRC. Here we examined the potential anti-tumor effects of a clinically approved neurokinin-1 receptor antagonist, aprepitant, alone and its combination with 5-Fluorouracil (5-FU) as a first choice CRC chemotherapeutic drug, in both in vitro and in vivo models of CRC. Methods: MTT assay was employed for assessing cell proliferation. mRNA expression levels were determined by quantitative real-time PCR (qRT-PCR). Flow cytometric analysis of apoptosis was performed using an Annexin-V/propidium iodide assay kit. We finally conducted an in vivo experiment in a mouse model of CRC to confirm the in vitro antiproliferative activity of aprepitant and 5-FU. Results: We found that aprepitant and 5-FU significantly reduced CRC cell viability. The combination of drugs exhibited potent synergistic growth inhibitory effects on CRC cells. Moreover, aprepitant and 5-FU induced apoptosis and altered the levels of apoptotic genes (up-regulation of Bax, and p53 along with downregulation of Bcl-2). Importantly, the aprepitant and 5-FU combination showed a more pronounced impact on apoptosis and associated genes than either of the agents alone. Furthermore, aprepitant reduced tumor growth in vivo and led to significantly longer survival time, and this effect was more prominent when using the aprepitant and 5-FU combination. Conclusions: Collectively, combinatory treatment with aprepitant and 5-FU potentially exerts synergistic growth inhibition and apoptosis induction in CRC, deserving further consideration as a novel strategy for CRC patients. [ABSTRACT FROM AUTHOR]

Stimuli-responsive polymers can be used for various purposes due to their amazing properties within the context of controlled release systems. In this study, the aim was to prepare hydrogels that are stimulus-responsive to temperature and pH and utilize them in drug release investigations. N-Vinyl caprolactam-based polymers were synthesized and optimized based on the swelling ratio data. Both temperature and pH sensitivity, along with their respective transition values, were determined. The best sample was selected based on 5-FU encapsulation efficiency. To enhance the swelling ratio and encapsulation values, different amounts of poly-(ethylene glycol) were added to improve water swelling ratio and 5-FU release properties. All obtained samples were characterized using water swelling ratio, SEM, FTIR, and DSC analyses. Additionally, the encapsulation and release of the 5-FU drug from the hydrogels were studied. According to the results, it was understood that it could release the 5-FU drug approximately 14% when below the transition temperature and pH value, and approximately 99% when above the transition temperature and pH value. The kinetics of the drug release were thoroughly examined. The results of thekinetic study revealed a drug release pattern consistent with Fick's law. [ABSTRACT FROM AUTHOR]

5-Fluorouracil is a chemotherapeutic agent used for the treatment of different kinds of cancers and Amlodipine Besylate is a vasodilator used to cure hypertension and angina. In order to improve different properties of drugs like drug solubility, mask bitter taste, prevent photodegradation, and for controlled drug delivery, the host–guest, solid inclusion complexes of 5-flurouracil (5-FU) and Amlodipine Besylate (ABS) with beta-cyclodextrin (β-CD) were utilized for different studies in this manuscript which were prepared through traditional methods and microwave-prompted technique. Different parameters such as apparent molar volume (Vϕ), partial molar volume at infinite dilution (Vϕ0), apparent molar isentropic compression (Kϕ,s), partial molar isentropic compression at infinite dilution (K0ϕ,s) were obtained from experimental density and speed of sound data. The partial molar volume at infinite dilution (Vϕ0 × 106/m3 mol−1) values of β-CD in aqueous solution of drug ABS was found 79.83, 80.32 and 80.64 at 305.15, 310.15 and 315.15 K, respectively. The partial molar volume at infinite dilution (Vϕ0 × 106/m3 mol−1) values of β-CD in aqueous solution of drug 5-FU was found − 252.61, − 246.42 and − 255.74 at 305.15, 310.15 and 315.15 K, respectively. The value of solubility constant (Ks) was found to be 74.3822 ± 4 M−1 for 5-FU and 204.0811 ± 4.75 M−1 for ABS in phase solubility studies. The inclusion complexes (ICs) were incorporated into the hybrid polymer networks (HPNs) of chitosan and gelatin to explore drug release studies. A comparison of directly loaded drug into the HPNs was made with the cyclodextrin-mediated release. The ICs prepared by different methods were also compared for the drug release. [ABSTRACT FROM AUTHOR]

5-fluorouracil (5-FU) forms the basis of many chemotherapy regimens and is one of the most common preferred chemotherapeutic drugs. In this study, the synthesis of temperature and pH responsive hydrogels in the release of 5-fluorouracil (5-FU) was studied to prevent drug release during blood circulation and uncontrolled overdose drug concentration at the tumor site. In this regard, the synthesis of temperature sensitive polymer Poly(N-vinylcaprolactam) PNVCL, temperature and pH sensitive polymers P(NVCL-co-VIm) and P(NVCL-co-VIm)/PVP hydrogels was carried out by the free radical polymerization method. DSC analysis revealed that as a result of copolymerization of PNVCL with hydrophilic 1-vinylimidazole (VIm) and polyvinylpyrrolidone (PVP), the lower critical solution temperature (LCST) increased and was close to the human body temperature. In addition, it was concluded from pH sensitivity analysis that the swelling ratios of the hydrogels changed with the medium pH. Additionally, hydrogels swelled in the acidic medium but shrunk in the alkaline medium. Accordingly, 5-FU release was investigated in different temperatures (25 °C and 37 °C) and pH (pH 5.5 and 7.4) medium and approximately 96% drug release was reached at 37 °C and pH 7.4. Consequently, P(NVCL-co-VIm)/PVP hydrogels at different pH and temperature mediums could be beneficially utilized as a material with the potential to be used in targeted drug delivery systems. [ABSTRACT FROM AUTHOR]

Chemoresistance and severe toxicities represent major drawbacks of chemotherapy. Natural extracts, including the essential oils of Pistacia lentiscus (PLEO), exhibit substantial anticancer and anti-inflammatory activities where different cancers are reported to dramatically recess following targeting with PLEO. PLEO has promising antimicrobial, anticancer, and anti-inflammatory properties. However, the therapeutic properties of PLEO are restricted by limited stability, bioavailability, and targeting ability. PLEO nanoformulation can maximize their physicochemical and therapeutic properties, overcoming their shortcomings. Hence, PLEO was extracted and its chemical composition was determined by GC–MS. PLEO and 5-Fluorouracil (5FU) were electrospun into poly-ε-caprolactone nanofibers (PCL-NFs), of 290.71 nm to 680.95 nm diameter, to investigate their anticancer and potential synergistic activities against triple-negative breast cancer cells (MDA-MB-231), human adenocarcinoma breast cancer cells (MCF-7), and human skin melanoma cell line (A375). The prepared nanofibers (NFs) showed enhanced thermal stability and remarkable physical integrity and tensile strength. Biodegradability studies showed prolonged stability over 42 days, supporting the NFs use as a localized therapy of breast tissues (postmastectomy) or melanoma. Release studies revealed sustainable release behaviors over 168 h, with higher released amounts of 5FU and PLEO at pH 5.4, indicating higher targeting abilities towards cancer tissues. NFs loaded with PLEO showed strong antioxidant properties. Finally, NFs loaded with either PLEO or 5FU depicted greater anticancer activities compared to free compounds. The highest anticancer activities were observed with NFs co-loaded with PLEO and 5FU. The developed 5FU-PLEO-PCL-NFs hold potential as a local treatment of breast cancer tissues (post-mastectomy) and melanoma to minimize their possible recurrence. [ABSTRACT FROM AUTHOR]

New system compromising of chitosan nanoparticles encapsulated pre-synthesized selenium nanoparticles in the presence of 5-fluorouracil was successfully prepared and used for cancer antiproliferation. Selenium nanoparticles were synthesized using ascorbic acid as reducing agent under mild condition. Chitosan nanoparticles were prepared via ionic gelation technique using sodium tri-polyphosphate. Characterization of the prepared nanoparticles was carried out using FTIR, TEM, XRD, TGA and dynamic light scattering (DLS). The results displayed the formation of selenium nanoparticles with an average size 20 nm and chitosan nanoparticles with an average size 207 and 250 nm for neat nano-chitosan and chitosan incorporated 5-fluorouracil/selenium nanoparticles, respectively. The encapsulated nanocomposites were tested for treatment of cancer cell of human colorectal carcinoma (HCT-116), human liver carcinoma (HepG-2), and human breast adenocarcinoma MCF-7. The results indicated the potent cytotoxic activities of all nanocomposite toward the tested cells with enhanced anticancer activity rather than the single drug or neat selenium nanoparticle. All composites were tested against non-tumor fibroblast-derived cell line (BJ) and demonstrated very low cytotoxicity. [ABSTRACT FROM AUTHOR]

The reactivity of 5-fluoro-1H,3H-pyrimidine-2,4-dione (5-fluorouracil), which is widely used to treat cancer, toward superoxide radical anion (O2•−) and hydroperoxyl radical (HO2•) was investigated using density functional theory (DFT) calculations. 5-Fluorouracil is a pyrimidine analog with cytotoxic effects on cancer cells and potential ecotoxicology as a recalcitrant compound to the natural environment; therefore, clarifying its chemical degradation mechanism is difficult by way of in vivo and in vitro experiments but important for further usage. The DFT results clarified that the oxidation of 5-fluorouracil by O2•− or HO2• in water is feasible through a proton-coupled electron transfer (PCET) mechanism. In addition, a concerted PCET pathway between 5-fluorouracil and HO2• preformed via the protonation of O2•− is proposed. In this pathway, the amine group at the first position of 5-fluorouracil acts as a reaction site for the concerted PCET after forming a prereactive complex via a hydrogen bond. Considering that the actual oxidant along the PCET pathways is HO2• with a short lifetime, the biodegradability of 5-fluorouracil by O2•− (HO2•) is governed by the complex formation step and the concerted PCET. [ABSTRACT FROM AUTHOR]

Purpose: Hyperammonemia is a serious adverse effect of 5-fluorouracil (5FU) administration. Hemodialysis can be used for its management, but detailed data on the concentrations and removal rate of 5FU and its metabolites during hemodialysis remain unclear. Here, we present two cases of hemodialysis patients with end-stage renal disease who received concurrent 5FU infusion. Methods: Blood samples were collected from the hemodialysis circuit before and after the dialyzer during day 2 hemodialysis sessions, and from the internal shunt just before and after day 4 hemodialysis sessions. The serum levels of 5FU and its metabolites—α-fluoro-β-alanine (FBAL) and monofluoroacetate (FA)—were measured using liquid chromatography-tandem mass spectrometry. Results: Seven sets of blood samples were collected for case 1; the removal rates (mean ± standard deviation) of 5FU and FBAL by the dialyzer were 81.2 ± 23.2% and 96.1 ± 8.6%, respectively (p < 0.001). Three sets of blood samples were collected for case 2; the removal rates of 5FU and FBAL were 81.7 ± 3.9% and 94.8 ± 2.7%, respectively (p = 0.03). Twenty-seven sets of blood samples were collected for case 1; reductions in blood FBAL and FA levels were 49.3 ± 8.8% (p < 0.001) and 64.2 ± 30.3% (p = 0.04), respectively. Bayesian estimation yielded similar results. Three sets of blood samples were collected for case 2; reductions in the blood FBAL and FA levels were 49.9 ± 6.9% and 50.6 ± 33.0%, respectively. Conclusion: In this study, 5FU and its metabolite FBAL were directly removed from the blood by approximately 90% during hemodialysis, and the blood levels of FBAL and FA were reduced by approximately 50% with a single hemodialysis session. [ABSTRACT FROM AUTHOR]

The study investigated the use of 5-fluorouracil-loaded ZnO nanocomposites (5-FU/Gd-ZnO NCs) as a potential treatment for cancer. 5-FU is a commonly used drug for cancer treatment but has undesirable side effects. The materials were characterized using various techniques, including PXRD, FTIR, FESEM, TEM, DLS, £-potential, and AFM. The data showed that the nanocomposites had a plate-like agglomeration with particle diameters ranging from 317.6 to 120.1 nm. The IC50 value of 5-FU-ZnO, which inhibits cell growth, was found to be 1.85 ppm. The effects of 5-FU-ZnO on inflammatory markers were also examined. While 5-FU increased the levels of TNF-a and IL-1b, the nanocomposites were able to reduce these levels. Additionally, the 5-FU/Gd-ZnO-NCs group showed an increase in thiol levels and a decrease in catalase and superoxide dismutase levels. Flow cytometry results showed that 5-FU, ZnO-NCs, and 5-FU/Gd-ZnO-NCs did not have any additive or synergistic effects on the suppression or eradication of cancer cells. In vivo, experiments showed that the 5-FU/Gd-ZnO NCs had similar necrotic characteristics and reduced fibrosis and collagen deposition compared to the free medication. The nanocomposites also exhibited higher antioxidative activity and lower inflammatory responses compared to the 5-FU group. It was shown that 5-FU/Gd-ZnO-NCs successfully inhibit cell proliferation. The in vivo results were comparable to those obtained with free 5-FU, suggesting the potential of these nanocomposites as therapeutic agents. [ABSTRACT FROM AUTHOR]

Mucositis is a high-incidence side effect in cancer patients undergoing chemotherapy. Next-generation probiotics are emerging as new therapeutic tools for managing various disorders. Studies have demonstrated the potential of Akkermansia muciniphila to increase the efficiency of anticancer treatment and to mitigate mucositis. Due to the beneficial effect of A. muciniphila on the host, we evaluated the dose–response, the microorganism viability, and the treatment protocol of A. muciniphila BAA-835 in a murine model of chemotherapy-induced mucositis. Female Balb/c mice were divided into groups that received either sterile 0.9% saline or A. muciniphila by gavage. Mucositis was induced using a single intraperitoneal injection of 5-fluorouracil. The animals were euthanized three days after the induction of mucositis, and tissue and blood were collected for analysis. Prevention of weight loss and small intestine shortening and reduction of neutrophil and eosinophil influx were observed when animals were pretreated with viable A. muciniphila at 1010 colony-forming units per mL (CFU/mL). The A. muciniphila improved mucosal damage by preserving tissue architecture and increasing villus height and goblet cell number. It also improved the integrity of the epithelial barrier, decreasing intestinal permeability and bacterial translocation. In addition, the treatment prevented the expansion of Enterobacteriaceae. The immunological parameters were also improved by decreasing the expression of pro-inflammatory cytokines (IL6, IL1β, and TNF) and increasing IL10. In conclusion, pretreatment with 1010 CFU/mL of viable A. muciniphila effectively controlled inflammation, protected the intestinal mucosa and the epithelial barrier, and prevented Enterobacteriaceae expansion in treated mice. [ABSTRACT FROM AUTHOR]

Introduction: Seroma is a frequent complication that can affect the final result of reconstructive and cosmetic surgeries. Methodology: This study evaluated the effectiveness of 5-Fluorouracil and 75% hypertonic glucose in preventing seroma in a mastectomy rat model, as well as cellular and vascular events in adjacent tissues. A left mastectomy with lymphadenectomy was performed in 60 Wistar-Albino female rats. Animals randomly allocated to the control group (Group I; n = 20) were sutured right after mastectomy. The intervention groups received 1.0 mL of 75% hypertonic glucose (Group II; n = 20) or 1.0 mL of 5-Fluorouracil (Group III; n = 20) at the surgical site before suturing. The assessment of the presence of seroma was performed in all animals at 24, 48, and 72 h and on the 7th and 12th postoperative day. After the 12th day, a tissue sample was taken from the surgical site and sent for histological analysis. The occurrence of seroma was assessed using GEE. A significance level of 5% was adopted. Results: Differences in seroma formation over time were observed for both Control Group I (p=0.041) and Intervention Group II (p<0.001). In Intervention Group III, there was no difference in the percentage and volume of seroma across the assessment points (p=0.627). When both the Control and Intervention Group II were compared to Intervention Group III, we found a reduction in seroma formation in the last group. The reduction in the inflammatory process was more regular to Intervention Group III. Conclusion: In this animal model, 5-Fluorouracil was more effective in preventing seroma formation than 75% Hypertonic Glucose. No Level Assigned This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. [ABSTRACT FROM AUTHOR]

Hollow mesoporous silica nanoparticles (HMSNs) are promising drug carriers due to their large surface area, high porosity, and biocompatibility. In this study, a straightforward and adjustable synthesis strategy was developed for generating HMSNs with tunable hollow cavities and use them to deliver 5-fluorouracil, a common anticancer drug as model drug. This approach involves using solid SiO2 nanoparticles (sSiO2 NPs) and cetyltrimethylammonium bromide (CTAB) as templates. Remarkably, our study introduces the application of I-optimal design to optimize the size of sSiO2 NPs, subsequently impacting the internal cavity diameter and drug loading capacity of the resulting HMSNs. Dynamic light scattering (DLS), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), Brunauer Emmett-Teller (BET) analysis, Fourier-transform infrared (FTIR) spectroscopy and in vitro drug release were conducted to characterize the synthesized particles. Moreover, the blood compatibility and cytotoxicity were performed to demonstrate the biocompatibility of as-synthesized HMSNs. Notably, the investigation unveils that both the internal cavity size and shell thickness have discernible effects on drug loading and release behavior. Furthermore, it was observed that HMSNs particle size played a significant role in their hemocompatibility, while confirming that all synthesized HMSNs exhibited appropriate biocompatibility. Overall, these findings highlight the facile control and manipulation of drug loading and release characteristics within HMSNs through tuning the hollow cores. Additionally, these results demonstrate the potential for regulating hemocompatibility, thereby expanding the range of applications for these nanoparticles. This research provides an innovative and versatile methodology for the synthesis of HMSNs, emphasizing their potential application in drug delivery systems. [ABSTRACT FROM AUTHOR]

This work presents the synthesis and characterization of a composite made of superparamagnetic iron oxide and hydroxyapatite nanoparticles (SPION/HAp) with a well-developed surface for loading anticancer drugs and for use in magnetic hyperthermia and local chemotherapy. The proposed material was obtained by an easy one-pot co-precipitation method with a controlled ratio of SPION to HAp. The morphology was studied by SEM and TEM, indicating rod-like structures for high HAp content in the composite and granule-like structures with increasing SPION. Its crystallinity, elemental composition, and functional groups were determined by X-ray diffraction, EDS, and FT-IR, respectively. The nanocomposite was then stabilized with citrates (CA), polyethylene glycol (PEG), and folic acid (FA) as agents to improve intracellular absorption, while turbidimetric studies confirmed that only citrates effectively stabilized the magnetic carriers to form a colloidal suspension. Subsequently, 5-fluorouracil (5-FU) was loaded into the magnetic carriers and tested in vitro using the L-929 cell line. The studies showed no cytotoxicity of the citrate-stabilized suspension against fibroblasts and some cytotoxicity after 5-FU release. In addition to in vitro studies, the composite was also tested on biomimetic membranes made of DOPC, DOPE, cholesterol, and DOPS lipids using Langmuir trough. The results show that the resulting suspension interacts with biomimetic membranes, while magnetic hyperthermia studies confirm effective heat generation to achieve therapeutic 42–46 °C and improve drug release from magnetic carriers. [ABSTRACT FROM AUTHOR]

Background: 5-FU has multiple applications in various cancers but has limitations owing to its shorter half-life and rapid metabolism. In this study, injectable intratumoral gels were developed to enhance 5-FU concentrations in tumor vicinity. Sterile tunable poly (N-isopropylacrylamide)-based pH/thermo dual-sensitive self-assembled and in situ crosslinkable injectable depot gels with low viscous grade of chitosan (LVCS) were developed via cold and free radical polymerization method for localized and sustained delivery. Results: Rheological analysis confirmed the gelation temperature, sol–gel transitions and viscoelastic behavior of in situ gels. Swelling–deswelling–reswelling cycles established the effect of temperature on structural changes. Swelling tests and in vitro drug release conducted in various dissolution media at variable temperatures confirmed pH/thermal dual response of formulations. Methyl thiazolyl tetrazolium assay confirmed that the hydrogels have good cytocompatibility with above 85% cells viability in Vero cells. In vitro cytotoxicity assay against MCF-7 cells displayed that 5-fluorouracil has good anticancer activity in loaded gel form as compared to free 5-FU. The cytotoxic studies showed that IPLVCS-2 and IPLVCS-6 have the highest inhibition (IC50 = 47 ± 1 µg/ml, 34 ± 17 µg/ml) as compared to free 5-FU (IC50 = 52 ± 3 µg/ml). Conclusion: Current findings conclude that taking the advantage of physiologic environment acidic pH and high temperature of cancer cells, poly(NIPAAm)-g-LVCS formulations can effectively be used as intratumoral controlled depot of 5-FU. [ABSTRACT FROM AUTHOR]

The interaction of a PEGylated and non-PEGylated Fe3O4 nanoparticle drug-delivery system, with 5-fluorouracil (5-FU) as the chemotherapy drug, is investigated via atomistic molecular dynamics (MD). The induced pore formation in a dipalmitoylphosphatidylcholine (DPPC) bilayer phospholipid (BLPL) is studied, and the resulting hourglass-shaped pores with hydrophilic lipid headgroups lining the pores are observed. Furthermore, we optimize the required number of ligands that are required to allow for the formed pores to spontaneously reseal. Additionally, the number of water molecules that transverse through the water bridge is investigated. These results may be useful to design nanocarrier systems that will maintain the cellular osmotic pressure and stability, while the 5-FU is converted to the required metabolites inside the cell to serve its purpose as a chemotherapeutic drug. [ABSTRACT FROM AUTHOR]

Today, the disease treatment aims to increase the patient's quality of life, reduce the dose of drugs used, extend the dosing interval, and purify the patient from the side and harmful effects. Controlled drug release systems are the systems that respond best in this respect. In this study, the evaluation of the in vitro release of 5-fluorouracil for the transdermal delivery system of NaAlg/HPMC/TiO2 biocompatible membranes was investigated. The nanocomposite membrane was prepared by adding TiO2 nanoparticles to a mixture of sodium alginate and hydroxypropyl methylcellulose polymers. Membranes were analyzed by Fourier Transform Infrared, Scanning Electron Microscopy, Differential Scanning Calorimetry, X-Ray Diffraction, and Thermogravimetric analyses. In addition, water contact angles and mechanical tests of the membranes were carried out. The degree of swelling of the prepared membranes was examined; the highest swelling degree was obtained as 304.9% in pH 5.0 buffer. The effects of crosslinking time, nanoparticle amount, and temperature were investigated in the release studies of 5-FU. The highest drug release was found to be 65.3% at the end of 24 h in membranes containing 5% TiO2 and crosslinked for 1 h. The release kinetics of 5-FU were evaluated according to four kinetic models, and the release from NaAlg/HPMC/TiO2 membranes showed conformity with the Korsmeyer–Pappes model. [ABSTRACT FROM AUTHOR]

Background: Single-target inhibitors have not been successful in cancer treatment due to the development of drug resistance. Nevertheless, therapeutic agents capable of simultaneously inhibiting multiple targets have revealed encouraging results in inducing apoptosis and overcoming drug resistance in cancerous cells. Here, we designed a composite liposomal nano-carrier co-loading 5-Fluorouracil (5-FU) with all-trans retinoic acid (ATRA) to assess anticancer efficacy of the combined drugs in colorectal cancer (CRC). Methods: A PEGylated liposomal nano-carrier with phospholipid/cholesterol/DSPE-PEG (2000) was synthesized by the thin film hydration technique for co-delivery of ATRA and 5-FU. After characterizing, the role of 5-FU and ATRA co-loaded liposomal nano-carrier in proliferation, epithelial-mesenchymal transition (EMT), apoptosis, and cancer stem cells (CSCs) were investigated by using colony forming and MTT assay, RT-qPCR and Annexin V/PI kit. Results: The average size of liposomes (LPs) was < 150 nm with uniform size distribution. Drug release analyses indicated that both ATRA and 5-FU could simultaneously release from LPs in a sustained release manner. The synergistic inhibitory effects of ATRA and 5-FU loaded in LPs were verified with a combination index of 0.43. Dual drug LPs showed the highest cytotoxicity, enhanced inhibition of cell proliferation, increased apoptotic potential, decreased CSCs, and attenuated EMT-associated biomarkers. Also, dual drug LPs decreased β-catenin gene expression more than other liposomal formulations. Conclusion: These findings suggest that using LPs to achieve a synergistic effect of ATRA and 5-FU is an effectual approach to increase the therapeutic effect of 5-FU toward CRC cells. [ABSTRACT FROM AUTHOR]

5-fluorouracil (5-Fu) is a chemotherapy drug commonly used in various types of cancers, including lung cancer. However, in order to decrease its side effects, the drug had to be loaded onto a nanocarrier. In this work, ZnO nanoparticles are prepared via sedimentation of Zn(OAc)2·2H2O in absolute ethanol and specified by some analytical techniques. Then, 5-fluorouracil molecules are loaded onto the surface of nanomaterial and loading/ release properties of the mentioned drug are investigated under in vitro conditions. After that, the electronic sensitivity and effectiveness of ZnO nanocluster bearing 5-fluorouracil were investigated theoretically with the B3LYP/wB97XD density functional theory (DFT). Theoretical parameters including band gap energy (Eg), molecular electrostatic potential (MEP), adsorption energy (Ead), density of electronic states, and global hardness (η) are also analyzed and compared. Furthermore, an MTT experiment was planned to investigate cytocompatibility of the drug-loaded material on the lung cancer cells A549. This study confirmed that drug-loaded material has a higher antiproliferative activity compared to free drug against A549 cancer cells. [ABSTRACT FROM AUTHOR]

The antimetabolite drug 5-fluorouracil (5-Fu) is extensively applied to treat many cancerous tumors. However, in order to inhibit its severe side effects and maintain its clinical benefits and anticancer efficacy, this drug should be loaded onto a suitable nanovehicle. In this work, gold nanoparticles were synthesized using Turkevich reduction method, and then, the prepared particles coated with a thin layer of silver via re-reduction of a silver nitrate solution. XRD, EDS, DLS, TEM and UV–Visible measurements were performed to characterize gold and gold–silver nanoparticles. By taking the UV–Visible absorption spectrum, two plasmonic peaks found at 411 and 526 nm due to the localized surface plasmons of the spherical interfaces of the nanoparticles. By loading 5-fluorouracil molecules onto the surface of gold and fabrication of gold–silver nanocomposite, significant changes occurred in the TEM, DLS and UV–Vis outcomes that can be interpreted considering the re-decoration and aggregation of the nanoparticles. Moreover, both of the plasmonic peaks experienced a redshift. By adding different amounts of drug solution into the colloidal solution, a direct and meaningful relation was obtained between the absorption peaks and drug concentration, which can be used as a measuring tool to evaluate drug loading amount. This study revealed that 5-fluorouracil affects DLS and UV–Vis absorption characteristics of gold–silver nanocomposite and adsorption characteristics of the synthesized bimetallic Ag–Au nanocomposite leading to more suitable results compared to the single metal nanoparticles. It is concluded that measuring drug loading using gold–silver nanocomposite would be more precise than that of single metal nanoparticles. In addition, the drug release behavior of drug-loaded gold–silver nanocomposite was also investigated under in vitro conditions at pH 6.5 and 37 °C. This study revealed that ~ 72% of loaded drug was released after 70 h. Furthermore, the MTT assay was used to study the cytocompatibility of the loaded drug on the cancer cell line U251. This study showed that the drug-loaded nanoparticles have a higher anti-proliferative effect compared to that of the free drug against U251 glioma cancer cells. 5-Fluorouracil as an extensively used drug in the treatment of many cancers is delivered by gold–silver nanocomposite. Findings revealed that the bimetallic nanocomposite behaves much better than the corresponding single metal counterparts in the drug loading process. Loading of 5-fluorouracil molecules onto the surface of gold–silver nanoparticles significantly affects TEM, DLS and optical properties of the carrier, and therefore, a direct and meaningful relation can be obtained between the peak changes and drug concentration. In addition, the prepared nanoparticles showed acceptable anti-proliferative activity against the cancer cell line U251. [ABSTRACT FROM AUTHOR]

Chitosan and agarose were crosslinked to form a polymeric hydrogel and γ-alumina nanoparticles were incorporated within the hydrogel to obtain a nanocomposite for delivery of 5-fluorouracil (5-FU) (Chitosan/Agarose/γ-alumina/5-FU). The nanocomposite was entrapped in a water-in-oil-in-water emulsion system. The size of the nanoparticles was measured using the dynamic light scattering (DLS) method. The zeta potential value of the nanoparticles was measured for evaluating their stability. To determine the morphology of the nanocarrier, field emission scanning electron microscope (FESEM) was employed. Fourier transform infrared (FTIR) was applied to identify the bonds between the components of the nanocarrier and verify entrapment of 5-FU. X-ray diffraction (XRD) was performed to determine crystallinity of nanoparticles. To determine the influence of including inorganic nanoparticles on loading and encapsulation efficiency, the two parameters were calculated with and without the presence of γ-alumina. In vitro release experiment was performed in acidic and neutral environment through which the pH-sensitivity of the nanocarrier was revealed. MTT assay and flow cytometry using breast cancer cells (MCF-7) demonstrated superiority of 5-FU-loaded nanoemulsion compared to free 5-FU in eliminating cancerous cells. These results led to recognition of the fabricated nanomaterial as an efficient carrier for 5-FU and breast cancer therapy. [ABSTRACT FROM AUTHOR]

Purpose: 5-fluorouracil (5-FU) and its prodrug capecitabine are commonly prescribed anti-tumor medications. We aimed to establish physiologically based pharmacokinetic (PBPK) models of capecitabine-metabolites and 5-FU-metabolites to describe their pharmacokinetics in tumor and plasma of cancer patients with liver impairment. Methods: Models including the cancer compartment were developed in PK-Sim® and MoBi® and evaluated by R programming language with 25 oral capecitabine and 18 intravenous 5-FU studies for cancer patients with and without liver impairment. Results: The PBPK models were constructed successfully as most simulated Cmax and AUClast were within two-fold error of observed values. The simulated alterations of tumor 5-FU Cmax and AUClast in cancer patients with severe liver injury compared with normal liver function were 1.956 and 3.676 after oral administration of capecitabine, but no significant alteration was observed after intravenous injection of 5-FU. Besides, 5-FU concentration in tumor tissue increases with higher tumor blood flow but not tumor size. Sensitivity analysis revealed that dihydropyrimidine dehydrogenase (DPD) and other metabolic enzymes′ activity, capecitabine intestinal permeability and plasma protein scale factor played a vital role in tumor and plasma 5-FU pharmacokinetics. Conclusions: PBPK model prediction suggests no dosage adaption of capecitabine or 5-FU is required for cancer patients with hepatic impairment but it would be reduced when the toxic reaction is observed. Furthermore, tumor blood flow rate rather than tumor size is critical for 5-FU concentration in tumor. In summary, these models could predict pharmacokinetics of 5-FU in tumor in cancer patients with varying characteristics in different scenarios. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the recurrence rate of odontogenic keratocyst (OKC) after treatment with 5-fluoracil as an adjunctive therapy and to evaluate, as well, the efficacy of this medication in reducing the incidence of inferior alveolar nerve paresthesia associated with other chemotherapeutic agents. Material and methods: The research question (developed according to the patient/population, intervention, comparison, and outcomes [PICO] method) addressed was "Does the use of 5-fluorouracil as an adjunctive therapy in the treatment of OKC reduce both the recurrence rate and the incidence of inferior alveolar nerve paresthesia as compared with other chemotherapeutic agents?" A systematic review was performed by searching 4 databases: PubMed, EBSCO, Portal Evidencia, and Cochrane Reviews. Each search was conducted twice. Two independent reviewers evaluated the data. For each database, a search strategy was developed that included the following generic terms: Fluorouracil, 5-Fluorouracil, or liquid nitrogen and odontogenic cyst or odontogenic keratocyst. Three filters were applied to the searches, as well, consisting of the terms clinical trials, English papers, and Spanish papers. Results: Of the 74 papers retrieved. The titles and abstracts of the selected papers were reviewed to determine whether those papers were relevant to our research question; only 3 papers were selected for this systematic review: 2 retrospective cohort studies and 1 clinical trial. Assessments risk bias and the quality of evidence were performed. Conclusions: The risk of bias and quality of evidence in this systematic review are moderate due to the study's design, although the clinical results were excellent with respect to the reduction of both OKC recurrence and paresthesia associated with this kind of cyst. [ABSTRACT FROM AUTHOR]

Trans-ferulic acid (TFA) is a polyphenolic compound present in many dietary supplements. The aim of this study was to get better chemotherapeutic outcomes through treatment protocols for human hepatocellular carcinoma (HCC). This study focused on the exploration of the in vitro influence of a combination of TFA with 5-fluorouracil (5-FU), doxorubicin (DOXO), and cisplatin (CIS) on HepG2 cell line. Treatment with 5-FU, DOXO, and CIS alone down-regulated oxidative stress and alpha-fetoprotein (AFP), and decreased cell migration through the depression of metalloproteinases (MMP-3, MMP-9, and MMP-12) expression. Co-treatment with TFA synergized the effects of these chemotherapies by decreased MMP-3, MMP-9, and MMP-12 expression, and gelatinolytic activity of both MMP-9 and MMP-2 in cancer cells. TFA significantly reduced the elevated levels of AFP and NO, and depressed cell migration ability (metastasis) in HepG2 groups. Co-treatment with TFA elevated the chemotherapeutic potency of 5-FU, DOXO, and CIS in managing HCC. [ABSTRACT FROM AUTHOR]

Exosomes are biological nanovesicles that are intrinsically loaded with thousands of biomacromolecules and are principally responsible for cell-to-cell communication. Inspired by the natural payload, they have been extensively investigated as drug delivery vehicles; however, the drug distribution, whether into or onto exosomes, is still debatable. In the present work, we have tried to investigate it systemically by selecting 5-fluorouracil (5-FU) (hydrophilic) and paclitaxel (PAC) (hydrophobic), drugs with very different physicochemical characteristics, for the loading to the exosomes. Exosomes were obtained from bovine milk, and the drugs were loaded using three different methods: incubation, sonication, and triton x-100. The particle size was found to be approximately 100 nm in all the cases; however, the highest drug loading was found in the sonication method. Fluorescence spectrophotometer, EDX analysis, EDX mapping, XPS, and XRD analysis indicated the possible presence of more drugs over the surface in the case of the incubation method. Drugs loaded by the sonication method had more controlled release than simple incubation and triton x-100. The method of drug loading had an insignificant effect on the cytotoxicity while in line with our previous observation, the combination (PAC and 5-FU) exhibited synergism as evidenced by ROS assay, colony formation assay, and mitochondrial membrane potential assay. [ABSTRACT FROM AUTHOR]