Search Results (133)

Objectives: The aim of this work was to determine the phenolic composition of sweet wormwood (Artemisia annua L., Asteraceae) from controlled cultivation in Serbia and to assess the potential antioxidant effects and cytotoxicity. Methods: High-performance liquid chromatography was used to determine the phenolic composition of Artemisia annua ethanolic extract. The antioxidant activity was studied using in vitro tests of inhibition of the neutralization of 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl (OH), and nitroso (NO) radicals, as well as the process of inhibiting lipid peroxidation and the ferric reducing antioxidant power (FRAP). The cytotoxicity was evaluated by the effect on three cell lines (the rat pancreatic insulinoma cell line (Rin-5F), the rat hepatoma cell line (H4IIE), and human hepatocellular carcinoma (Hep G2)) using the MTT test of viability. Results: Ethanol extract showed the highest potency in inhibiting the DPPH radical, and the half maximal inhibitory concentration (IC₅₀) was 5.17 μg/mL. Chlorogenic acid was the dominant phenolic compound with an amount of 651 μg/g of dry extract. The results of the MTT viability test showed that the extract has the potential to inhibit the growth of the Rin-5F and Hep G2 cell lines, while no growth inhibition was observed on the H4IIE cell line. Conclusions: Undoubtedly, Artemisia annua is a powerful plant and a rich source of phenolic compounds. Inhibitory activity on causes of oxidative stress shows that the plant has a good antioxidant effect. Also, the anticancer activity shown through the inhibition of cell growth is not negligible. Full article

The Wnt signalling pathway plays a crucial role in tissue homeostasis and cancer biology due to its regulation of cellular processes, including proliferation, migration, and stem cell activity. Frizzled receptor 7 (FZD7) (a member of the F-class G protein-coupled receptors) has emerged as a key Wnt receptor within this pathway, which is elevated in several human malignancies. FZD7 is notably upregulated in gastrointestinal, breast, pancreatic, and hepatocellular carcinomas and transmits oncogenic Wnt signalling through canonical and non-canonical pathways. FZD7 promotes tumour initiation, and emerging evidence implicates FZD7 in cancer stem cell maintenance and epithelial–mesenchymal transition (EMT), reinforcing its role in metastasis. Therapeutic strategies targeting FZD7 have shown promise, including FZD7-specific monoclonal antibody-drug conjugates (ADCs), human single-chain fragment variable (scFVs) antibodies, and nanoparticles. Notably, our recent development of FZD7-ADC has demonstrated tumour-selective cytotoxicity with reduced off-target effects, positioning FZD7 as an attractive therapeutic target. Additionally, nanoparticle-based drug delivery systems have enhanced the precision of existing chemotherapies by targeting FZD7-expressing tumour cells. Despite significant advances, clinical translation remains a challenge due to potential on-target toxicity and the complexity of tumour microenvironments. Future research should focus on optimising delivery systems, refining antibody specificity, and conducting comprehensive preclinical and clinical trials. This review will focus on novel discoveries regarding FZD7 in cancer and provide an update on our original review on this subject in 2016. Additionally, we present new figures generated by our group using the publicly available Pan-Cancer Atlas RNAseq datasets, highlighting FZD7 expression patterns in patient samples. This integrated approach aims to provide updated insights into the function of FZD7 during cancer and its growing status as an attractive target for therapy. In summary, FZD7 stands out as a promising molecular target in cancer therapy due to its selective overexpression in tumours, functional role in Wnt-driven oncogenesis, and potential for innovative therapeutic applications. This review underscores the critical need for the continued exploration of FZD7-targeted therapies to improve patient outcomes in cancer treatment. Full article

A series of novel hydrazones bearing diphenylamine and 5-oxopyrrolidine moieties, along with benzene and naphthalene rings substituted with hydroxy, alkoxy, or carboxylic groups, were synthesized. Their anticancer activity was evaluated in vitro using both 2D (MTT and ‘wound healing’ assays) and 3D (cell spheroid) models against human melanoma IGR39 cells, the triple-negative breast cancer cell line MDA-MB-231, and pancreatic carcinoma Panc-1 cell line. Compounds 8 (2-hydroxybenzylidene derivative) and 12 (2-hydroxynaphthalenylmethylene derivative) demonstrated the highest cytotoxicity in both 2D and 3D assays, while compounds 4 (2,5-dimethoxybenzylidene derivative) and 6 (2,4,6-trimethoxybenzylidene derivative) were most effective at inhibiting cell migration. Notably, all compounds exhibited lower activity against the Panc-1 cancer cell line in a cell monolayer, but the effects on spheroid cell viability in 3D models were comparable across all tested cancer cell lines. Molecular docking studies of the most active hydrazones suggested that these compounds may act as multikinase inhibitors. In particular, 2-hydroxynaphthalenylmethylene derivative 12 showed high binding affinity values (−11.174 and −11.471 kcal/mol) to the active sites of two key protein kinases—a non-receptor TK (SCR) and STPK (BRAF)—simultaneously. Full article

Background/Objectives: MIDN (midnolin) is newly discovered method for critically regulating a ubiquitin-independent proteasomal degradation pathway. This study aims to examine the expression, prognostic value, genomic changes, interacting proteins, methylation status, and correlations with the tumor immune microenvironment of MIDN in various cancers. Methods: The GTEx, Depmap, GEPIA2, and Kaplan–Meier Plotter databases are applied to evaluate the MIDN level in tumor and normal tissues and the MIDN prognostic value in cancers. The genetic alterations of MIDN in cancers are investigated using the cBioPortal database. The STRING, GeneMANIA, DAVID, and Human Protein Atlas are harnessed to identify and analyze MIDN-interacted proteins. The Sangerbox 3.0 platform (a pan-cancer analysis module) is used to measure the correlations between the MIDN level and the tumor immune microenvironment, stemness, immune cell infiltration, tumor mutational burden, immune checkpoint genes, and RNA modification genes. Immunofluorescence, qRT-PCR, and Western blotting assays were used to evaluate the biological roles of MIDN in breast and gastric cancer cells. Results: MIDN expression was dysregulated in many cancers and associated with prognosis in several cancers, such as esophageal cancer. MIDN was mutated in 1.7% of cancers, and deep deletion was the dominant mutation type. NR4A1, PSMC1, and EGR1 were selected as MIDN-interacted proteins, and these four molecules were co-expressed in pancreatic cancer, liver cancer, urothelial cancer, melanoma, and breast cancer. MIDN expression was significantly correlated with the infiltration of CD8+ T cell, CD4+ T cell, B cell, macrophage, neutrophil, and DC both in prostate adenocarcinoma and liver hepatocellular carcinoma. The MIDN level was correlated with several immune checkpoint genes, such as VEGFA, and RNA modification genes such as YTHDF1, YTHDF2, YTHDF3, and YTHDC1 in cancers. Furthermore, in breast cancer cells, the downregulation of MIDN suppressed the colony formation abilities and lessened cell-cycle-associated and stemness-associated genes; in gastric cancer, the knockdown of MIDN diminished the mRNA levels of Nanog and LDHA. Strikingly, silence of MIDN upregulated FTO protein expression in both breast and gastric cancer cells. Conclusions: Our findings demonstrate the expression, prognostic value, mutation status, interacting proteins, methylation status, and correlations with the tumor immune microenvironment of MIDN. MIDN will be developed as a potential therapeutic target and a prognosis biomarker. Full article

Objective: We evaluate the immunotherapeutic potential of the yellow fever virus vaccine strain 17D (YFV 17D) for intratumoral therapy of pancreatic cancer in mice. Methods: The cytopathic effect of YFV 17D on mouse syngeneic pancreatic cancers cells were studied both in vitro and in vivo and on human pancreatic cancers cells in vitro. Results: YFV 17D demonstrated a strong cytopathic effect against human cancer cells in vitro. Although YFV 17D did not exhibit a lytic effect against Pan02 mouse cells in vitro, a single intratumoral administration of 17D caused a delay in tumor growth and an increase in median survival by 30%. Multiple injections of 17D did not further improve the effect on tumor growth; however, it notably extended the median survival. Furthermore, preliminary immunization with 17D enhanced its oncotherapeutic effect. Conclusions: Intratumoral administration of yellow fever virus vaccine strain 17D delayed tumor in a murine model of pancreatic cancer. The fact that YFV 17D in vitro affected human cancer cells much more strongly than mouse cancer cells appears promising. Hence, we anticipate that the in vivo efficacy of YFV-17D-based oncolytic therapy will also be higher against human pancreatic carcinomas compared to its effect on the mouse pancreatic tumor. Full article

Di(2-ethhylhexyl) phthalate (DEHP) is a common plastic rubberizer. DEHP leaches from plastic matrices and is under increasing scrutiny as numerous studies have linked it to negative human health manifestations. Coxsackievirus B3 (CVB) is a human pathogen that typically causes subclinical infections but can sometimes cause severe diseases such as pancreatitis, myocarditis, and meningoencephalitis. Though CVB infections are common, severe illness is relatively rare, and it is unclear what factors mediate disease severity. In this study, we sought to determine the effects that DEHP has on CVB infection in a variety of human cell types to evaluate whether this plastic-derived pollutant could represent a proviral environmental factor. Methods: HeLa cervical cancer cells, human induced pluripotent stem cell-derived brain-like endothelial cells (iBECs), and Caco-2 colon carcinoma cells were exposed to 40 µg/mL DEHP for 24 h prior to infecting with enhanced green fluorescent protein (EGFP)-expressing CVB. The severity of the infection was evaluated via fluorescence microscopy and flow cytometry-based viral EGFP detection, viral plaque assay on tissue culture media, and Western blotting to detect VP1 viral capsid protein. Interferon-associated proteins such as interferon regulatory factor (IRF) 3, IRF7, interferon-induced transmembrane (IFITM) 2, and IFITM3 were measured by Western blotting. The roles of IFITM2 and IFITM3 in the context of CVB infection were evaluated via siRNA silencing. Results: We found that DEHP drastically increased CVB infection in each of the cell types we tested, and, while the cellular processes underlying DEHP’s proviral properties were not entirely clear, we observed that DEHP may subvert CVB-induced interferon signaling and elevate levels of IFITMs, which appeared to bolster CVB infection. Conclusions: DEHP may represent a major environmental factor associated with the severity of CVB infection. Further understanding of how DEHP exacerbates infection may better elucidate its potential role as a proviral environmental factor. Full article

Leucine is an essential amino acid that cannot be produced endogenously in the human body and therefore needs to be obtained from dietary sources. Leucine plays a pivotal role in stimulating muscle protein synthesis, along with isoleucine and valine, as the group of branched-chain amino acids, making them one of the most popular dietary supplements for athletes and gym-goers. The individual effects of leucine, however, have not been fully clarified, as most of the studies so far have focused on the grouped effects of branched-chain amino acids. In recent years, leucine and its metabolites have been shown to stimulate muscle protein synthesis mainly via the mammalian target of the rapamycin complex 1 signaling pathway, thereby improving muscle atrophy in cancer cachexia. Interestingly, cancer research suggests that leucine may have either anti-cancer or pro-tumorigenic effects. In the current manuscript, we aim to review leucine’s roles in muscle protein synthesis, tumor suppression, and tumor progression, specifically summarizing the molecular mechanisms of leucine’s action. The role of leucine is controversial in hepatocellular carcinoma, whereas its pro-tumorigenic effects have been demonstrated in breast and pancreatic cancers. In summary, leucine being used as nutritional supplement for athletes needs more attention, as its pro-oncogenic effects may have been identified by recent studies. Anti-cancer or pro-tumorigenic effects of leucine in various cancers should be further investigated to achieve clear conclusions. Full article

Biological barriers remain a major obstacle for the development of innovative therapeutics. Depending on a disease’s pathophysiology, the involved tissues, cell populations, and cellular components, drugs often have to overcome several biological barriers to reach their target cells and become effective in a specific cellular compartment. Human biological barriers are incredibly diverse and include multiple layers of protection and obstruction. Importantly, biological barriers are not only found at the organ/tissue level, but also include cellular structures such as the outer plasma membrane, the endolysosomal machinery, and the nuclear envelope. Nowadays, clinicians have access to a broad arsenal of therapeutics ranging from chemically synthesized small molecules, biologicals including recombinant proteins (such as monoclonal antibodies and hormones), nucleic-acid-based therapeutics, and antibody-drug conjugates (ADCs), to modern viral-vector-mediated gene therapy. In the past decade, the therapeutic landscape has been changing rapidly, giving rise to a multitude of innovative therapy approaches. In 2018, the FDA approval of patisiran paved the way for small interfering RNAs (siRNAs) to become a novel class of nucleic-acid-based therapeutics, which—upon effective drug delivery to their target cells—allow to elegantly regulate the post-transcriptional gene expression. The recent approvals of valoctocogene roxaparvovec and etranacogene dezaparvovec for the treatment of hemophilia A and B, respectively, mark the breakthrough of viral-vector-based gene therapy as a new tool to cure disease. A multitude of highly innovative medicines and drug delivery methods including mRNA-based cancer vaccines and exosome-targeted therapy is on the verge of entering the market and changing the treatment landscape for a broad range of conditions. In this review, we provide insights into three different disease entities, which are clinically, scientifically, and socioeconomically impactful and have given rise to many technological advancements: acquired immunodeficiency syndrome (AIDS) as a predominant infectious disease, pancreatic carcinoma as one of the most lethal solid cancers, and hemophilia A/B as a hereditary genetic disorder. Our primary objective is to highlight the overarching principles of biological barriers that can be identified across different disease areas. Our second goal is to showcase which therapeutic approaches designed to cross disease-specific biological barriers have been promising in effectively treating disease. In this context, we will exemplify how the right selection of the drug category and delivery vehicle, mode of administration, and therapeutic target(s) can help overcome various biological barriers to prevent, treat, and cure disease. Full article

In this work, the synthesis, structural analysis and anticancer properties of 5-methyl-9-trifluoromethyl-12H-quino[3,4-b][1,4]benzothiazinium chloride (3) are described. Compound 3 was synthesized by reacting 1-methyl-4-butylthio-3-(benzoylthio)quinolinium chloride with 4-(trifluoromethyl)aniline, respectively. The structure of the resulting product was determined using ¹H-NMR and ¹³C-NMR spectroscopy as well as HR-MS spectrometry. The spatial geometry of agent 3 and the arrangement of molecules in the crystal (unit cell) were also confirmed using X-ray diffraction. The tetracyclic quinobenzothiazinium system is fairly planar because the dihedral angle between the planes formed by the benzene ring and the quinoline system is 173.47°. In order to obtain insight into the electronic charge distribution of the investigated molecule, electronic structure calculations employing the Density Functional Theory (DFT) were performed. Moreover, antiproliferative activity against a set of pancreatic cancer cell lines was tested, with compound 3 showing IC₅₀ values against human primary pancreatic adenocarcinoma BxPC-3 and human epithelioid pancreatic carcinoma Panc-1 of 0.051 µM and 0.066 µM, respectively. The IC₅₀ value of cytotoxicity/cell viability of the investigated compound assessed on normal human lung fibroblasts WI38 was 0.36 µM. Full article

Both maternal obesity and postnatal consumption of obesogenic diets contribute to the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). However, there is no consensus as to whether diets that are high in fat or carbohydrates/sugars differentially influence the development of HCC. Moreover, the long-term effects of prenatal HF exposure on HCC and whether this is influenced by postnatal diet has not yet been evaluated. C57BL/6 dams were fed either a low-fat, high-carbohydrate control (C) or low-carbohydrate, high-fat (HF) diet. At weaning, male and female offspring were fed the C or HF diet, generating four diet groups: C/C, C/HF, HF/C and HF/HF. Tissues were collected at 16 months of age and livers were assessed for MASLD and HCC. Glucose regulation and pancreatic morphology were also evaluated. Liver tissues were assessed for markers of glycolysis and fatty acid metabolism and validated using a human HCC bioinformatic database. Both C/HF and HF/HF mice developed obesity, hyperinsulinemia and a greater degree of MASLD than C/C and HF/C offspring. However, despite significant liver and pancreas pathology, C/HF mice had the lowest incidence of HCC while tumour burden was highest in HF/C male offspring. The molecular profile of HCC mouse samples suggested an upregulation of the pentose phosphate pathway and a downregulation of fatty acid synthesis and oxidation, which was largely validated in the human dataset. Both pre-weaning HF diet exposure and post-weaning consumption of a high-carbohydrate diet increased the risk of developing spontaneous HCC in aged mice. However, the influence of pre-weaning HF feeding on HCC development appeared to be stronger in the context of post-weaning obesity. As rates of maternal obesity continue to rise, this has implications for the future incidence of HCC and possible dietary manipulation of offspring carbohydrate intake to counteract this risk. Full article

Long non-coding RNAs (lncRNAs) are well known for their oncogenic or anti-oncogenic roles in cancer development. AGAP2-AS1, a new lncRNA, has been extensively demonstrated as an oncogenic lncRNA in various cancers. Abundant experimental results have proved the aberrantly high level of AGAP2-AS1 in a great number of malignancies, such as glioma, colorectal, lung, ovarian, prostate, breast, cholangiocarcinoma, bladder, colon and pancreatic cancers. Importantly, the biological functions of AGAP2-AS1 have been extensively demonstrated. It could promote the proliferation, migration and invasion of cancer cells. Simultaneously, the clinical significances of AGAP2-AS1 were also illustrated. AGAP2-AS1 was exceptionally overexpressed in various cancer tissues. Clinical studies disclosed that the abnormal overexpression of AGAP2-AS1 was tightly connected with overall survival (OS), lymph nodes metastasis (LNM), clinical stage, tumor infiltration, high histological grade (HG), serous subtype and PFI times. However, to date, the biological actions and clinical significances of AGAP2-AS1 have not been systematically reviewed in human cancers. In the present review, the authors overviewed the biological actions, potential mechanisms and clinical features of AGAP2-AS1 according to the previous studies. In summary, AGAP2-AS1, as a vital oncogenic gene, is a promising biomarker and potential target for carcinoma prognosis and therapy. Full article

The functions of the gut are closely related to those of many other organs in the human body. Indeed, the gut microbiota (GM) metabolize several nutrients and compounds that, once released in the bloodstream, can reach distant organs, thus influencing the metabolic and inflammatory tone of the host. The main microbiota-derived metabolites responsible for the modulation of endocrine responses are short-chain fatty acids (SCFAs), bile acids and glucagon-like peptide 1 (GLP-1). These molecules can (i) regulate the pancreatic hormones (insulin and glucagon), (ii) increase glycogen synthesis in the liver, and (iii) boost energy expenditure, especially in skeletal muscles and brown adipose tissue. In other words, they are critical in maintaining glucose and lipid homeostasis. In GM dysbiosis, the imbalance of microbiota-related products can affect the proper endocrine and metabolic functions, including those related to the gut–liver–pancreas axis (GLPA). In addition, the dysbiosis can contribute to the onset of some diseases such as non-alcoholic steatohepatitis (NASH)/non-alcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), and type 2 diabetes (T2D). In this review, we explored the roles of the gut microbiota-derived metabolites and their involvement in onset and progression of these diseases. In addition, we detailed the main microbiota-modulating strategies that could improve the diseases’ development by restoring the healthy balance of the GLPA. Full article

Oral squamous-cell and pancreatic carcinomas are aggressive cancers with a poor outcome. Photodynamic therapy (PDT) consists of the use of photosensitizer-induced cell and tissue damage that is activated by exposure to visible light. PDT selectively acts on cancer cells, which have an accumulation of photosensitizer superior to that of the normal surrounding tissues. 5-aminolevulinic acid (5-ALA) induces the production of protoporphyrin IX (PpIX), an endogenous photosensitizer activated in PDT. This study aimed to test the effect of a new gel containing 5% v/v 5-ALA (ALAD-PDT) on human oral CAL-27 and pancreatic CAPAN-2 cancer cell lines. The cell lines were incubated in low concentrations of ALAD-PDT (0.05%, 0.10%, 0.20%, 0.40%, 0.75%, 1.0%) for 4 h or 8 h, and then irradiated for 7 min with 630 nm RED light. The cytotoxic effects of ALAD-PDT were measured using the MTS assay. Apoptosis, cell cycle, and ROS assays were performed using flow cytometry. PpIX accumulation was measured using a spectrofluorometer after 10 min and 24 and 48 h of treatment. The viability was extremely reduced at all concentrations, at 4 h for CAPAN-2 and at 8 h for CAL-27. ALAD-PDT induced marked apoptosis rates in both oral and pancreatic cancer cells. Elevated ROS production and appreciable levels of PpIX were detected in both cell lines. The use of ALA-PDT as a topical or intralesional therapy would permit the use of very low doses to achieve effective results and minimize side effects. ALAD-PDT has the potential to play a significant role in complex oral and pancreatic anticancer therapies. Full article

Natural products contribute substantially to anticancer therapy; the plant kingdom provides an important source of molecules. Conofolidine is a novel Aspidosperma-Aspidosperma bisindole alkaloid isolated from the Malayan plant Tabernaemontana corymbosa. Herein, we report conofolidine’s broad-spectrum anticancer activity together with that of three other bisindoles—conophylline, leucophyllidine, and bipleiophylline—against human-derived breast, colorectal, pancreatic, and lung carcinoma cell lines. Remarkably, conofolidine was able to induce apoptosis (e.g., in MDA-MB-468 breast) or senescence (e.g., in HT-29 colorectal) in cancer cells. Annexin V-FITC/PI, caspase activation, and PARP cleavage confirmed the former while positive β-gal staining corroborated the latter. Cell cycle perturbations were evident, comprising S-phase depletion, accompanied by downregulated CDK2, and cyclins (A2, D1) with p21 upregulation. Confocal imaging of HCT-116 cells revealed an induction of aberrant mitotic phenotypes-membrane blebbing, DNA-fragmentation with occasional multi-nucleation. DNA integrity assessment in HCT-116, MDA-MB-468, MIAPaCa-2, and HT-29 cells showed increased fluorescent γ-H2AX during the G1 cell cycle phase; γ-H2AX foci were validated in HCT-116 and MDA-MB-468 cells by confocal microscopy. Conofolidine increased oxidative stress, preceding apoptosis- and senescence-induction in most carcinoma cell lines as seen by enhanced ROS levels accompanied by increased NQO1 expression. Collectively, we present conofolidine as a putative potent anticancer agent capable of inducing heterogeneous modes of cancerous cell death in vitro, encouraging further preclinical evaluations of this natural product. Full article

Pancreatic cancer is one of the most aggressive, heterogeneous, and fatal types of human cancer; therefore, more effective therapeutic drugs are urgently needed. Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been identified as a cornerstone in this pathology. The aim of this review is to identify HER2 membrane overexpression in relation to pancreatic cancer pathways that can be used in order to develop a targeted therapy. After searching the keywords, 174 articles were found during a time span of 10 years, between 2013 and 2023, but only twelve scientific papers were qualified for this investigation. The new era of biomolecular research found a significant relationship between HER2 overexpression and pancreatic cancer cells in 25–30% of cases. The variables are dependent on tumor-derived cells, with differences in receptor overexpression between PDAC (pancreatic ductal adenocarcinoma), BTC (biliary tract cancer), ampullary carcinoma, and PNETs (pancreatic neuroendocrine tumors). HER2 overexpression is frequently encountered in human pancreatic carcinoma cell lines, and the ERBB family is one of the targets in the near future of therapy, with good results in phase I, II, and III studies evaluating downregulation and tumor downstaging, respectively. Full article