Search Results (270)

Background: Boiling histotripsy (BH) uses high-amplitude, short-pulse focused ultrasound to disrupt tissue mechanically. Oncolytic virotherapy using reovirus has shown modest clinical benefit in pancreatic cancer patients. Here, reovirus and BH were used to treat pancreatic tumours, and their effects on the immune transcriptome of these tumours were characterised. Methods: Orthotopic syngeneic murine pancreatic KPC tumours grown in immune-competent subjects, were allocated to control, reovirus, BH and combined BH and reovirus treatment groups. Acoustic cavitation was monitored using a passive broadband cavitation sensor. Treatment effects were assessed histologically with hematoxylin and eosin staining. Single-cell multi-omics combining whole-transcriptome analysis with the expression of surface-expressed immune proteins was used to assess the effects of treatments on tumoural leukocytes. Results: Acoustic cavitation was detected in all subjects exposed to BH, causing cellular disruption in tumours 6 h after treatment. Distinct cell clusters were identified in the pancreatic tumours 24 h post-treatment. These included neutrophils and cytotoxic T cells overexpressing genes associated with an N2-like and an exhaustion phenotype, respectively. Reovirus decreased macrophages, and BH decreased regulatory T cells compared to controls. The combined treatments increased neutrophils and the ratio of various immune cells to Treg. All treatments overexpressed genes associated with an innate immune response, while ultrasound treatments downregulated genes associated with the transporter associated with antigen processing (TAP) complex. Conclusions: Our results show that the combined BH and reovirus treatments maximise the overexpression of genes associated with the innate immune response compared to that seen with each individual treatment, and illustrate the anti-immune phenotype of key immune cells in the pancreatic tumour microenvironment. Full article

Background: Inflammation and oxidative stress are key mechanisms in underlying skin conditions like psoriasis and eczema. While many plants, including Australian native plants, are proposed to target these pathways due to their phytochemical content, studies on whole extracts and their synergistic effects remain limited. Objectives: This study aimed to investigate individual and combined effects of whole plant extracts on skin protection and healing, focusing on their anti-inflammatory and antioxidant properties. Methods: The antioxidant potential of the individual and combined plant extracts were investigated on 2,2-diphenyl-1-picrylhydrazyl (DPPH) and reactive oxygen species (ROS) assay followed by luciferase assay in MCF-7 AREc32 cells for nuclear factor erythroid 2-related factor 2 (Nrf2) activation. The anti-inflammatory activities were investigated on lipopolysaccharide (LPS)-induced RAW 264.7 murine macrophages for the inhibition of nitric oxide (NO), tumour necrosis factor (TNF)-α, and interleukin (IL)-6. Synergistic interaction was determined by the combination index model (CI < 1). Combination(s) showing synergistic and optimal activity were further investigated on LPS-induced human dermal fibroblasts (HDF) cells for IL-6 inhibition and wound healing activity. Results: Three of the tested Australian native plant extracts demonstrated prominent antioxidant and anti-inflammatory activities including bitter orange, mountain pepper berry and native river mint. In particular, their three-way combination (1:1:1, w/w) showed prominent synergistic (CI < 1) in reducing NO and IL-6, along with enhanced Nrf2 activation. In LPS-inflamed HDF cells, the combination maintained synergistic inhibition of IL-6 levels and promoted wound healing response. Conclusions: These findings highlight the therapeutic potential of Australian native plant as a whole extract for skin protection and repair attributed to antioxidant and anti-inflammatory activities. The observed synergistic anti-inflammatory and antioxidant effects support their use in the development of new cosmetic formulations for skin. Full article

Cognitive problems are associated with impaired learning ability and memory dysfunction. Neuroinflammation has been identified as an important factor in the progression of anxiety and depressive disorders. Zingerone is a phenolic alkanone derived from ginger (Zingiber officinale Roscoe), which is known for its antioxidant and anti-inflammatory properties. A number of studies have investigated the effect of zingerone on neuroinflammation and cognitive impairment. However, this evidence has not been systematically reviewed. This study sought to systematically review the effect of zingerone on neuroinflammation and neurobehavioural changes associated with memory and learning impairment and anxiety-like and depressive-like behaviours. A systematic review was conducted using pre-defined search criteria on Google Scholar, Scopus and Web of Science. The records obtained were screened based on inclusion criteria, and data was extracted from the included studies. Out of the 482 studies that were identified, only 9 studies met the inclusion criteria. Neuroinflammatory markers such as interleukin 1β (IL-1β), interleukin 6 (IL-6), tumour necrosis factor-alpha (TNF-α) and ionized calcium binding adaptor molecule (IBA-1), as well as behavioural parameters including Morris water maze, Y-Maze, recognition test, passive avoidance test, elevated plus maze, sucrose preference test and forced swimming test were measured. Zingerone exhibited anti-neuroinflammatory effects by improving IL-1β, IL-6 and TNF-α levels. However, zingerone did not show any significant changes on activated microglia. The anti-neuroinflammatory mechanisms of zingerone were linked to the inhibition of nuclear factor kappa B (NF-kB) activation and the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, as well as the reduction in neuronal nitric oxide synthase (nNOS). The anxiolytic and anti-depressive effects of zingerone were also associated with an improvement in cortical cholinergic transmission, the mitigation of oxidative stress and the upregulation of neurotransmitters such as serotonin and dopamine. This review provides scientific evidence on the cognitive enhancing and neuroprotective mechanisms of zingerone, which may be beneficial for future experimental investigations. Full article

This article presents the accurate and current state of knowledge regarding the process of angiogenesis in neoplastic cells and its importance for tumour development. It provides a detailed review of the different types of angiogenesis with a brief discussion of individual angiogenic factors. Pathological angiogenesis in tumour tissues and the production of angiogenic factors have been recognised as key features responsible for cancerous development and distant metastasis formation since 1971. A phenomenon known as an angiogenic switch allows neoplasm to transform from an avascular to a vascular phase. The emerging new network of blood vessels allows cancer cells to efficiently exchange gases, provide nutrients and eliminate metabolic waste products. The main factors stimulating the angiogenesis process are VEGF, FGF, EGF, PDGF, and TGF-β1. To date, the most specific, strongest and most widely studied factor is VEGF. It is regarded as the main mitogen for vascular endothelial cells, stimulating their proliferation, and it is therefore referred to as a survival factor for cancer cells. Several mechanisms of new blood-vessel formation in cancerous tissue have also been identified. The three dominant processes include vascular sprouting, intussusceptive angiogenesis and vessel co-option. Angiogenesis in cancer tissues remains a subject of numerous scientific studies. A thorough understanding of the mechanism of oncogenesis and tumour expansion appears to be the starting point for future research aimed at finding effective anti-cancer therapy. Full article

Probiotics have been revealed in various studies to modulate the gut microbiome and have a substantial impact on cancers, comprising oesophageal, lung, liver, and colorectal cancer. These properties are endorsed by a diverse mechanism, including the modulation of the gut microbiome; preventing the metabolism of carcinogenic substances; exertion of anti-inflammatory action, immunopotentiator properties, and antioxidant activities; prevention of tumour growth; and decreasing the adverse effects of chemotherapy. There are promising perspectives regarding the new and developing field of probiotic research in relation to cancer treatment. This review demonstrates the recent findings of probiotics efficacy in cancer prevention and treatment and organ-specific impact along with protection from chemotherapy-induced side effects. The present evidence specifies that strategic probiotics application may be an effective complementary approach for the management of numerous kinds of cancer; still, additional studies and clinical trials are required to comprehend the relationships between cancer and probiotics. Full article

Lidocaine, a widely used local anaesthetic, has been shown to possess anti-inflammatory and immunomodulatory properties with applications in surgery. During a surgical procedure, inflammation is a natural response of the body, triggered by the release of inflammatory mediators and the activation of the immune system. However, an excessive response can lead to serious postoperative complications. Lidocaine modulates inflammation through mechanisms beyond its anaesthetic action. It reduces the activation of neutrophils and macrophages, decreases the release of pro-inflammatory cytokines and prostaglandins, and preserves endothelial integrity, helping to control excessive inflammatory responses. Additionally, its perioperative use has shown benefits such as reduced postoperative pain, lower opioid consumption, and faster intestinal recovery. Furthermore, studies have suggested that lidocaine may have an anti-metastatic effect by inhibiting the migration of tumour cells and the activation of inflammatory pathways related to cancer spread. Although its use in surgery is promising, further research is needed to determine optimal dosages and its long-term clinical impact. Full article

Background/Objectives: Melanoma has a rising incidence worldwide. Current treatments are effective, although the development of resistance is common. A novel anti-cancer treatment using checkpoint kinase 1 inhibitor (CHK1i), SRA737, in combination with low-dose hydroxyurea (LDHU), has been demonstrated to effectively kill tumour cells and promote an anti-tumour immune response through the treatment-induced release of pro-inflammatory chemokines and cytokines. These chemokines/cytokines modify the tumour microenvironment from an immunosuppressive to an inflamed state to recruit anti-tumour immune cells. Methods: A panel of human melanoma cell lines was assessed using a panel of chemokines and cytokine expression, and the mechanism of their regulation was investigated. Results: We demonstrate that SRA737 + LDHU upregulates pro-inflammatory chemokines in human melanoma cells in response to SRA737 + LDHU through the ATM-NF-κB signalling pathway. The increased chemokine expression corresponded to the increase in secretion of pro-inflammatory chemokines from tumour cells following SRA737 + LDHU treatment. However, inhibiting NF-κB and ATM did not affect SRA737 + LDHU-induced cell killing. Increased expression of non-NF-κB target genes with SRA737 + LDHU suggests that other transcriptional pathways are also activated and may contribute to the increasing cytokine/chemokine gene expression in response to treatment. Conclusions: SRA737 + LDHU upregulates pro-inflammatory chemokine expression through an ATM-NF-κB-dependent mechanism. Full article

Brazilian propolis is a natural bee product with a unique and diverse chemical composition. It is especially rich in phenols and terpenoids that show a range of significant biological properties. Due to the growing scientific interest, its strong anti-inflammatory and anticancer activity has been highlighted. In vitro and in vivo studies demonstrate its potential to modulate inflammatory pathways by inhibiting pro-inflammatory cytokines, such as tumour necrosis factor (TNF-α) and interleukin 6 (IL-6), as well as by regulating oxidative stress. Additionally, active compounds in Brazilian propolis have the potential to inhibit tumour cell proliferation, induce apoptosis and modulate the tumour microenvironment. Depending on the botanical source and region of occurrence, different types of Brazilian propolis are distinguished, including green, red and brown, which differ in composition and biological activity. Green propolis, rich in artepilin C and phenolic acids, shows strong anti-inflammatory and anticancer properties. Red propolis contains isoflavones and quercetin that enhance its antioxidant and immunomodulatory activities. Brown propolis, rich in cinnamic acids and benzophenones, exerts cytotoxic effects against certain lines of cancer cells. This article discusses the current state of knowledge on the mechanisms of action of different types of Brazilian propolis and their potential uses as supportive therapy in inflammatory and cancerous diseases in combination with nanotechnology. Full article

Background: Induction of apoptosis is an important strategy for the treatment of prostate cancer. DR5 is a member of the death receptor superfamily and targeting DR5 is an effective way to induce apoptosis. Pyripyropene O is a natural compound isolated from the marine fungus Aspergillus fumigatus SCSIO 41220. We found it has anti-prostate cancer potential by inducing apoptosis; Methods: The effects of pyripyropene O on the viability, proliferation, cell cycle, apoptosis and migration of prostate cancer cells were investigated by MTT assay, plate clone formation assay, 3D cell sphere assay, flow cytometry and real-time cell analysis. Transmission electron microscopy was used to observe the changes in the internal structure of prostate cancer cells after treatment with pyripyropene O. After determining the mode of cell death, the mechanism of action of pyripyropene O on prostate cancer was further investigated using apoptotic protein microarray, western blot, qPCR, molecular docking, cellular immunofluorescence staining and cellular thermal shift assay. After explaining the mechanism of action of pyriproxyfen O, the in vivo absorption, distribution, metabolism, excretion and potential toxicity of pyriproxyfen O were investigated using ADMETLab 2.0 software. Finally, a zebrafish xenograft tumour model was developed to evaluate the anti-prostate cancer effects of pyriproxyfen O in vivo; Results: The experimental results at the cellular level showed that pyripyropene O inhibited the survival, proliferation and migration of prostate cancer cells, and also showed that pyripyropene O blocked the prostate cancer cell cycle at the G2/M phase and induced apoptosis. At the molecular level, pyripyropene O binds to the transcription factor YY1, promotes YY1 nuclear translocation, regulates the transcription level of DR5, a target gene of YY1, and upregulates the expression of DR5 mRNA and protein. The in vivo results showed that pyripyropene O effectively inhibited the development of prostate cancer in zebrafish; Conclusions: Pyripyropene O has a clear anti-prostate cancer effect at both cellular and animal levels, inhibiting the survival and proliferation of prostate cancer cells by binding to the transcription factor YY1 to activate the expression of DR5 to promote apoptosis, thus exerting an inhibitory effect on prostate cancer. Full article

Cancer is the most common malignancy, with over 2 million new cases and nearly 1.8 million deaths worldwide annually. Non-small-cell lung cancer (NSCLC) is the predominant subtype, accounting for the majority of cases. Myeloid-derived suppressor cells (MDSCs), which originate from monocytes and typically differentiate into macrophages and granulocytes, possess potent immunosuppressive capabilities. MDSCs regulate immune responses in various pathological conditions and are strongly associated with poor prognosis in cancer patients. This study aims to elucidate the complex interplay between MDSCs, immune cells, and tumours in the NSCLC tumour microenvironment (TME). By integrating single-cell RNA sequencing (scRNA-seq) data with bulk RNA sequencing (Bulk RNA-seq) data, we identified MDSCs as the target cell population and used Monocle software (v2.22.0) to infer their developmental trajectories. We identified key genes associated with MDSCs differentiation processes and classified MDSCs into seven distinct states based on their functional roles. Furthermore, we constructed a prognostic risk model based on the impact of MDSCs differentiation on NSCLC prognosis, utilizing Elastic Net regression and multivariate Cox regression analysis of Bulk RNA-seq data. The model’s performance and accuracy were validated using both internal and external validation sets. Additionally, we compared risk scores with clinical pathological features and the relationship between risk scores and key immune cells in the immune microenvironment, demonstrating the model’s clinical predictive value. We also explored how prognostic genes contribute to poor prognosis in NSCLC. Moreover, small molecule compounds targeting these prognostic genes were screened, and their anti-tumour effects were evaluated as potential therapeutic strategies for NSCLC treatment. This study not only reveals the complex regulatory mechanisms of MDSCs in the NSCLC immune microenvironment but also successfully constructs a prognostic risk model based on MDSCs differentiation states. The model demonstrates excellent clinical performance in predicting patient prognosis, effectively identifying high-risk patients and providing robust support for individualized treatment and immunotherapy decisions. Through association analyses with key immune cells in the immune microenvironment and clinical pathological features, our model can assist clinicians in formulating more precise treatment plans based on patients’ immune status and tumour characteristics. Furthermore, we identified small molecule compounds targeting these prognostic genes, providing novel and promising therapeutic targets for NSCLC, which could further enhance treatment efficacy and improve patients’ survival quality. Full article

Background: Human leukocyte antigen class I (HLA-I) plays a pivotal role in shaping anti-tumour immunity by influencing the functionality of T cells and natural killer (NK) cells within the tumour microenvironment. Methods: Here, we explored the transcriptional landscape of HLA-I molecules across various solid cancer transcriptomes from The Cancer Genome Atlas (TCGA) database and assessed the impact of HLA-I expression on the clinical significance of tumour-infiltrating CD56^dim and CD56^bright NK cells. Results: Our analysis revealed that high HLA-I expression correlated with reduced patient survival in the TCGA lower-grade glioma (LGG) cohort, with this association varying by histopathological subtype. We then estimated the relative abundance of 23 immune and stromal cell signatures in LGG transcriptomes using a cellular deconvolution approach, which revealed that LGG patients with low HLA-I expression and high CD56^dim NK cell abundance had better survival outcomes compared to those with high HLA-I expression and low CD56^dim NK cell abundance. Furthermore, HLA-I expression was positively correlated with various inhibitory NK cell receptors and negatively correlated with activating NK cell receptors, particularly those within the killer cell lectin-like receptor (KLR) gene family. High co-expression of HLA-E and NKG2A predicted poor survival outcomes in LGG patients, whereas low HLA-E and high NKG2C/E abundance predicted more favourable outcomes, suggesting a potential modulatory role of HLA-I on the tumour-infiltrating cytotoxic CD56^dim NK cell subset. Conclusions: Overall, our study unveils a potential role for deregulated HLA-I expression in modulating the clinical impact of glioma-infiltrating CD56^dim NK cells. These findings lay the foundation for future in-depth experimental studies to investigate the underlying mechanisms. Full article

Background: Grape pomace (GP), a by-product of winemaking, is a rich source of bioactive polyphenols known for their antioxidant and anti-inflammatory properties. While the cardiovascular benefits of red grape pomace have received significant scientific attention, the therapeutic potential of white grape pomace remains largely unexplored, particularly in glucocorticoid-induced hypertension. Given the rising prevalence of hypertension and the oxidative-inflammatory mechanisms underlying its progression, this study investigates the effects of white GP on blood pressure regulation, oxidative stress, and pro-inflammatory cytokine expression in an experimental model of dexamethasone (DEXA)-induced hypertension (HTN). By focusing on white GP, this research addresses a significant gap in current knowledge and proposes a novel, sustainable approach to managing hypertension through valorising winemaking by-products. Methods: The first concentration used, GP1, was 795 mg polyphenols/kg bw, while the second concentration, GP2, was 397.5 mg polyphenols/kg bw. Results: White GP polyphenols extract in the DEXA_GP1 group had reduced systolic and diastolic blood pressure. The extract with a higher content of polyphenols (GP1) prevented the elevation of serum levels of total oxidative stress (TOS), malondialdehyde (MDA), and oxidative stress index (OSI), while the extract with a lower content of polyphenols (GP2) slightly reduced serum levels of MDA. Both concentrations of GP increased serum levels of NO and Total Thiols, significantly higher (p < 0.05) than in the group treated with lisinopril. The serum levels of tumour necrosis factor-alpha (TNF-α) increased in all groups where HTN was induced. Both doses of GP extract prevented the elevation of TNF-α. Heart tissue levels of the studied cytokines (TNF-α, interleukin (IL)-1β, and IL-6 were not influenced (p > 0.05) by either the HTN induction or the treatment administered. Conclusions: These findings suggest that grape pomace may serve as a promising nutraceutical intervention for hypertension management, particularly in conditions associated with oxidative stress. Full article

The biomechanical properties of the extracellular matrix (ECM) including its stiffness, viscoelasticity, collagen architecture, and temperature constitute critical biomechanical cues governing breast cancer progression. Matrix metalloproteinase 13 (MMP13) is an important marker of breast cancer and plays important roles in matrix remodelling and cell metastasis. Emerging evidence highlights MMP13 as a dynamic modulator of the ECM’s physical characteristics through dual mechanoregulatory mechanisms. While MMP13-mediated collagen degradation facilitates microenvironmental softening, thus promoting tumour cell invasion, paradoxically, its crosstalk with cancer-associated fibroblasts (CAFs) and tumour-associated macrophages (TAMs) drives pathological stromal stiffening via aberrant matrix deposition and crosslinking. This biomechanical duality is amplified through feedforward loops with an epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) populations, mediated by signalling axes such as TGF-β/Runx2. Intriguingly, MMP13 exhibits context-dependent mechanomodulatory effects, demonstrating anti-fibrotic activity and inhibiting the metastasis of breast cancer. At the same time, angiogenesis and increased metabolism are important mechanisms through which MMP13 promotes a temperature increase in breast cancer. Targeting the spatiotemporal regulation of MMP13’s mechanobiological functions may offer novel therapeutic strategies for disrupting the tumour–stroma vicious cycle. Full article

Cancer significantly impacts human quality of life and life expectancy, with an estimated 20 million new cases and 10 million cancer-related deaths worldwide every year. Standard treatments including chemotherapy, radiotherapy, and surgical removal, for aggressive cancers, such as glioblastoma, are often ineffective in late stages. Glioblastoma, for example, is known for its poor prognosis post-diagnosis, with a median survival time of approximately 15 months. Novel therapies using local electric fields have shown anti-tumour effects in glioblastoma by disrupting mitotic spindle assembly and inhibiting cell growth. However, constant application poses risks like patient burns. Wireless stimulation via piezoelectric nanomaterials offers a safer alternative, requiring ultrasound activation to induce therapeutic effects, such as altering voltage-gated ion channel conductance by depolarising membrane potentials. This review highlights the piezoelectric mechanism, drug delivery, ion channel activation, and current technologies in cancer therapy, emphasising the need for further research to address limitations like biocompatibility in whole systems. The goal is to underscore these areas to inspire new avenues of research and overcome barriers to developing piezoelectric nanoparticle-based cancer therapies. Full article

Piper nigrum L. (PN), which contains various bioactive compounds, is a plant with homologous medicine and food. Sleep deprivation (SD) profoundly impacts cognitive function and emotional health. However, the mechanisms by which PN improves cognitive function and depressive mood induced by SD remain unclear. In our study, network pharmacology and molecular docking techniques were used to predict the potential mechanisms by which PN regulates SD. In this study, 220 compounds were identified in PN, and 10 core targets were screened through network pharmacology. Animal experiments showed that PN ameliorated depressive mood and cognitive deficits in sleep-deprived mice, upregulated the serum activities of superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT), and downregulated malondialdehyde (MDA) levels. The ELISA assay showed that PN significantly decreased the tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) levels. Histopathological staining of brain tissue demonstrated that PN mitigates SD-induced hippocampal damage, enables the hippocampus to produce more neurotransmitters, including 5-hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA), and dopamine (DA), and reduces glutamate (Glu) levels. RT-qPCR and WB analyses further indicated that PN could exert anti-SD effects by inhibiting the over-activation of the JAK1/STAT3 signalling pathway. In the PC12 cell model, PN could reduce inflammation and prevent apoptosis, exerting neuroprotective effects. In summary, PN has positive effects on alleviating depressive symptoms and cognitive dysfunction induced by SD. Full article