Search Results (480)

Objectives: Parental exposure to tobacco smoke is a significant public health concern, with over 1.1 billion smokers worldwide. The aim of this systematic review was to evaluate the impact of maternal, paternal, and dual-parental cigarette smoke exposure on offspring reproductive health. Methods: Original human clinical and animal research studies were included; titles and abstracts were manually scanned for relevance to the effect of parental smoking on offspring reproductive outcomes (Date of search:18/03/2025). Results: This systematic review incorporates 30 studies identified from three databases (PubMed, Web of Science, and Scopus). The results indicate that male offspring exhibit reduced spermatogenic capacity, characterized by decreased testicular size, lower sperm count, and impaired hormonal biosynthesis, with reductions of 30–40% in sperm production. Dual-parental smoking exacerbates these effects, with sperm counts averaging 85 million per ml in human male offspring from dual-smoking households, compared to 111 million per ml in single-smoking households. Animal studies provide mechanistic insights, revealing reduced testis weight in nicotine-exposed male rats and increased oxidative stress in offspring. Conclusions: This review highlights the dose-dependent and sex-specific effects of smoking on the fertility of offspring and underscores the need for standardized protocols to enhance the consistency and comparability of future research in both human and animal studies. Full article

Mycotoxins represent a group of highly toxic secondary metabolites produced by diverse fungal pathogens. Mycotoxin contaminations frequently occur in foods and feed and pose significant risks to human and animal health due to their carcinogenic, mutagenic, and immunosuppressive properties. Notably, deoxynivalenol, zearalenone, fumonisins (mainly including fumonisins B1, B2, and FB3), aflatoxin B1 (AFB1), and T-2/HT-2 toxins are the major mycotoxin contaminants in foods and feed. Undoubtedly, exposure to these mycotoxins can disrupt gut health, particularly damaging the intestinal epithelium in humans and animals. In this review, we summarized the detrimental effects caused by these mycotoxins on the intestinal health of humans and animals. The fundamental molecular mechanisms, which cover the induction of inflammatory reaction and immune dysfunction, the breakdown of the intestinal barrier, the triggering of oxidative stress, and the intestinal microbiota imbalance, were explored. These signaling pathways, such as MAPK, Akt/mTOR, TNF, TGF-β, Wnt/β-catenin, PKA, NF-kB, NLRP3, AHR, TLR2, TLR4, IRE1/XBP1, Nrf2, and MLCK pathways, are implicated. The abnormal expression of micro-RNA also plays a critical role. Finally, we anticipate that this review can offer new perspectives and theoretical foundations for controlling intestinal health issues caused by mycotoxin contamination and promote the development of prevention and control products. Full article

In hormone-dependent cancers, front-line treatment options include surgery and therapies that target hormone dependance. These therapies are effective initially but fail in tumors that recur, develop resistance or present at an advanced stage. Consequently, new therapeutic avenues are urgently needed. Increasing evidence implicates epigenetic modulators in tumor initiation, progression and therapeutic response, making them attractive biomarkers for patient stratification and targets for intervention. Over the past two decades, the discovery and development of small-molecule inhibitors directed against key epigenetic regulators have accelerated. This review provides a comprehensive overview of the major epigenetic targets, the inhibitors developed against them and the clinical trials currently underway in endocrine-related cancers. While epigenetic agents have shown limited benefits as monotherapies, their use in combination regimens is emerging as a strategy to overcome resistance and enhance the efficacy of existing treatments. We summarize the current landscape of combination trials, highlight early signs of clinical activity and discuss the opportunities and challenges inherent in integrating epigenetic drugs into the management of advanced endocrine-related cancers. Full article

In the management of cholangiocarcinoma, effective biliary drainage and accurate diagnosis are vital to allow further treatment. Confirmation of tissue diagnosis and molecular characterization is also required to guide future treatment options including surgery and chemotherapy as well as the possible use of personalized treatments that target specific mutations present within individual tumours. Initial CT or MRI scans may be followed by endoscopic ultrasound (EUS) or endoscopic retrograde cholangiopancreatography (ERCP) to obtain tissue samples. However, these methods often fall short due to difficulty in accessing entire bile duct strictures. SpyGlass cholangioscopy can improve diagnosis, yet may fail to provide sufficient tissue for molecular characterization. Here we present a perspective on the development of snake-like agile robots with integrated optical imaging and Raman spectroscopy. These robots could improve the mapping of the biliary tree and the precision of biopsy collection and allow tissue analysis in situ, as well as facilitating stenting to restore the flow of bile. A multidisciplinary approach that brings together clinicians, pathologists, and engineers is required to develop these new robotic technologies and improve patient outcomes. Full article

The Atacama Desert, an unexplored habitat, offers intriguing potential for natural product chemistry due to the unique adaptations of microorganisms to aridity, extreme salinity, and high UV radiation. Over several years, soil samples were collected from various locations across the desert, leading to the isolation of diverse microorganisms. This paper presents the isolation and structural characterisation of two new 10-membered lactones, curvulalide B and C (3 and 4). These compounds are epimers of each other and are produced by one of the fungi isolated from the samples collected, using LC–MS and 1D and 2D NMR techniques. The compounds were tested against the ESKAPE pathogens, bovine mastitis pathogens, and Cryptococcus neoformans but were inactive against them. Full article

The aim of this systematic review was to evaluate the current evidence for the involvement of epithelial-derived extracellular vesicles (EVs) in Immunoglobulin E (IgE)-mediated allergic sensitisation. Original clinical and research studies specifically examining the effect of epithelial-derived EVs in IgE-mediated allergic sensitisation were included. Non-IgE mediated allergies, abstracts and review articles were excluded. A total of 18 publications were identified from three databases (EMBASE, Web of Science and PubMed) that indicate epithelial-derived EVs have the potential to promote tolerance or allergic sensitisation. For example, epithelial-derived EVs have the potential to promote IgE-mediated allergic sensitisation by delivering mRNAs that promote T helper 2 (Th2) polarisation and cytokine secretion, or promote tolerance through the induction of T regulatory (Treg) cells. The results also indicate that the potential role of epithelial-derived EVs in IgE-mediated allergic sensitisation may be dependent on the barrier, with all publications related to intestinal epithelium driving tolerance, but publications on nasal and bronchial/alveolar epithelia gaving mixed effects. No publications were found on cutaneous epithelia. Taken together, the literature suggests that epithelial-derived EVs play a key role in influencing IgE-mediated allergic sensitisation. Further research examining all epithelial barriers, using both robust human in vitro models that give more biologically relevant information, as well as clinical studies, are required to further characterise the role of epithelial-derived EVs in IgE-mediated allergic sensitisation. Full article

Osteosarcoma (OSA) is the most prevalent bone malignancy in people and dogs. Current survival rates show the need for advances in novel therapies to help overcome the growth, survival and metastatic progression of the cancer. Canine models are often used to advance prognostic and treatment opportunities for OSA due to the similarities in the disease between species. This study focusses on the genetic and molecular similarities of OSA between human and canine specimens. Differentially expressed genes (DEGs) were compared and identified in canine and human OSA tumours, revealing 86 common genes, 36 having high and 50 having low expression. Further immunohistochemical analysis of the corresponding proteins of three identified DEGs (ASPN, STK3, BAMBI) allowed for the visualisation of protein expression in canine OSA tissues (n = 19). Overall nuclear and cytoplasmic H-scores were generated, and nuclear and cytoplasmic scores in males and females and in different anatomical locations (axial versus appendicular) were also investigated, presenting unique opportunities to understand the expression in this cancer type. This study contributes to a deeper knowledge of genetic pathways changes and identifies avenues for the diagnosis, prognosis and treatment of OSA in people and dogs, whilst encompassing the One Health concept in medicine. Full article

This study investigated the protective effects of corynoxeine, a natural alkaline compound, on colistin-caused nephrotoxicity using a murine model. Forty mice were divided randomly into control, corynoxeine-only (20 mg/kg/day, intraperitoneal injection), colistin-only (20 mg/kg/day, intraperitoneal injection), and colistin (20 mg/kg/day) + corynoxeine (5 and 20 mg/kg/day) groups (8 mice in each group). All treatments were maintained for seven consecutive days. Results showed that colistin treatment at 20 mg/kg/day for seven days significantly increased serum urea nitrogen and creatinine levels and induced the loss and degeneration of renal tubular epithelial cells, which were markedly ameliorated by corynoxeine co-treatment at 5 or 20 mg/kg/day. Corynoxeine supplementation also markedly attenuated colistin-induced increases in malondialdehyde levels and decreases in reduced glutathione levels and superoxide dismutase and catalase activities in the kidneys. Furthermore, corynoxeine supplementation significantly decreased the expression of transforming growth factor β (TGF-β) and nicotinamide adenine dinucleotide phosphate hydrogen oxidase 4 (NOX4) proteins and nuclear factor kappa B (NF-κB), interleukin-1beta (IL-1β), IL-6, and tumor necrosis factor-α mRNAs, while it significantly increased the expression of erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins in the kidneys. In conclusion, these results reveal that corynoxeine can protect against colistin-induced nephrotoxicity in mice by inhibiting oxidative stress and inflammation, which may partly be attributed to its ability on the activation of the Nrf2/HO-1 pathway and the inhibition of the TGF-β/NOX4 and NF-κB pathways. Full article

Engineered scaffold-based proteins that bind to concrete targets with high affinity offer significant advantages over traditional antibodies in theranostic applications. Their development often relies on display methods, where large libraries of variants are physically contacted with the desired target protein and pools of binding variants can be selected. Herein, we use a novel combined artificial intelligence/physics-based computational framework and phage display approach to obtain ubiquitin based Affilin^® proteins targeting the human epidermal growth factor receptor 3 (HER3) extracellular domain, a relevant tumor target. As traditional antibodies against the receptor have failed so far, we sought to provide molecules in a smaller more versatile format to cover the medical need in HER3 related diseases. We demonstrate that the developed in silico pipeline can generate de novo Affilin^® proteins binding the biochemical HER3 target using a small training set of <1000 sequences. The classical phage display yielded primary candidates with low nanomolar affinities to the biochemical target and HER3-expressing cells. The latter could be further optimized by phage display and computational maturation alike. These combined efforts resulted in four HER3 ligands with high affinity, cell binding, and serum stability with theranostic potential. Full article

Sponges in the verongiid genus Pseudoceratina Carter are well-known producers of bioactive secondary metabolites. Chemical screening of a Tongan P. cf. verrucosa Bergquist using NMR highlighted the presence of aromatic natural products. Subsequent extraction and purification of P. cf. verrucosa yielded a new bromotyrosine, purpuramine R (1), that exhibits moderate (MIC 16 µg/mL) antibacterial activity against Gram-positive Staphylococcus aureus. The E-geometry of the oxime was confirmed using a combination of NMR and computational approaches. Additionally, computational conformational analysis indicates that purpuramine R adopts a hairpin orientation, stabilized by intramolecular hydrogen and halogen bonds. Knowledge of this stabilized conformation can inform synthetic approaches to make analogues of the purpuramines for future SAR studies. Full article

Resistance to platinum-based chemotherapy is a major clinical problem in ovarian cancers. The development of predictive biomarkers and therapeutic approaches is an area of unmet need. p73, a member of the p53 family of transcription factors, has essential functions during DNA repair, proliferation, invasion, and apoptosis. The role of p73 in ovarian cancer pathogenesis and response to therapy is largely unknown. The clinicopathological significance of p73 protein expression was evaluated in 278 human ovarian cancers. TP73 transcripts were investigated in publicly available clinical data sets (n = 522) and bioinformatics analysis was completed in the ovarian TCGA cohort (n = 182). Preclinically, p73 was overexpressed in A2780 platinum-sensitive ovarian cancer cells or depleted in platinum-resistant A2780cis cells and investigated for aggressive phenotypes, as well as platinum sensitivity. High p73 protein expression was linked with high grade (p < 0.001), advanced-stage disease (p = 0.002), and shorter progression-free survival (p < 0.0001). TP73 transcripts were significantly higher in tumours compared to normal tissue (p < 0.0001) and linked with shorter PFS (p = 0.047). Preclinically, p73 overexpression in A2780 cells increased proliferation, invasion, spheroid formation, and DNA repair capacity, and was associated with the upregulation of multiple DNA repair and platinum resistance-associated genes. In contrast, p73 deletion in A2780cis led to reduced proliferation and enhanced sensitivity to cisplatin, along with DNA double-strand break accumulation, G2/M cell cycle arrest, and increased apoptosis. We conclude that p73 is a predictor of platinum resistance. p73 can be exploited for targeted ovarian cancer therapy. Full article

Background: Glutathione (GSH) is an essential antioxidant that protects against oxidative stress, but its oral bioavailability is below 1% due to enzymatic degradation and poor gastrointestinal absorption. Improving the oral bioavailability of GSH could significantly enhance its therapeutic efficacy. Methods: This study synthesised GSH analogues with chemical modifications to improve bioavailability. Seven GSH derivatives were designed: three analogues with altered stereochemistry (1.62, 1.63, and 1.64) and three N-methylated derivatives (1.65, 1.70, and 1.71), alongside a native GSH (1.61). The analogues were synthesised via Fmoc-solid-phase peptide synthesis, and they were characterised using reverse-phase high-performance liquid chromatography (RP-HPLC), electrospray ionisation mass spectrometry (ESI-MS), Fourier-transform infrared spectroscopy (FTIR), and nuclear magnetic resonance (NMR) spectroscopy. Their toxicity was assessed on Caco-2 cells for viability, and their antioxidant activity was assessed on UVA-irradiated fibroblast cells, enzymatic resistance, and interactions with GSH-metabolising enzymes. Results: Among the tested analogues, the N-methylated cysteine Compound (1.70) emerged as the most promising candidate. Compound 1.70 demonstrated superior resistance to enzymatic degradation, as well as showing enhanced cell viability and improved antioxidant activity. In vivo studies revealed a 16.8-fold increase in plasma half-life (t½) and a 16.1-fold increase in oral bioavailability compared to native GSH. Conclusions: Chemical modification strategies, particularly the N-methylation of GSH, present a viable approach to enhancing oral bioavailability. Compound 1.70 showed significant potential for therapeutic applications, warranting further investigation and development in clinical settings. Full article

We have generated a vector that enables the removal of plasmids coding for truncated proteins. This vector expresses a protein of interest in the yeast Saccharomyces cerevisiae from a galactose-inducible promoter. The gene of interest is fused in-frame to a downstream sequence coding for phosphoribosylanthranilate isomerase (PRAI), which catalyses the third step in tryptophan biosynthesis. As a consequence, only the full-length protein of interest renders the host cell tryptophan prototrophic, allowing for selection against cells expressing truncated proteins. Our proof-of-principle study demonstrates that PRAI is functional when fused C-terminally to a protein, robustly rendering cells tryptophan prototrophic. The N-terminal GST tag and C-terminal myc tag allow for tag-mediated protein purification, co-precipitation studies, determination of relative expression levels, as well as validation of full-length expression of the protein via Western blotting. Full article

Lysine, butyric acid, and zinc play important roles in skin homeostasis, which involves aging, inflammation, and prevention of skin barrier disruption. This bioactivity spectrum is not replicated by any one topical compound currently in use. Our purpose in this study was to characterize a novel compound, zinc dibutyroyllysinate (ZDL), consisting of zinc with lysine and butyric acid moieties. We used RNA-seq to evaluate its effect on gene expression in a full-thickness skin model. We show that lysine alone has minimal effects on gene expression, whereas ZDL had greater transcriptional bioactivity. The effects of ZDL included an increased expression of genes promoting epidermal differentiation and retinol metabolism, along with a decreased expression of microphthalmia-associated transcription factor (MITF) and other melanogenesis genes. These effects were not replicated by an alternative salt compound (i.e., calcium dibutyroyllysinate). ZDL additionally led to a dose-dependent increase in skin fibroblast extracellular matrix proteins, including collagen I, collagen IV, and prolidase. Loss of melanin secretion was also seen in ZDL-treated melanocytes. These results provide an initial characterization of ZDL as a novel topical agent. Our findings support a rationale for the development of ZDL as a skincare ingredient, with potential applications for diverse conditions, involving melanocyte hyperactivity, pigmentation, inflammation, or aging. Full article

Microorganisms play a significant role in biofouling and biocorrosion within the maritime industry. Addressing these challenges requires an innovative and integrated approach utilizing marine natural products with beneficial properties. A comprehensive screening of 173 non-toxic EtOAc and H₂O extracts derived from diverse marine organisms collected in Indonesian waters was conducted using a robust panel of assays. These included antimicrobial tests and classical biosurfactant assays (drop collapse and oil displacement), as well as anti-quorum-sensing (QS) and anti-biofilm assays. These screening efforts identified five active extracts with promising activities. Among these, EtOAc extracts of the marine tunicate Sigilina cf. signifera (0159-22e) and the marine sponge Lamellodysidea herbacea (0194-24c) demonstrated significant anti-biofouling activity against Perna indica and anti-biocorrosion performance (mpy 10.70 ± 0.70 for S. cf. signifera; 7.87 ± 0.86 for L. herbacea; 13.60 ± 1.70 for positive control Tetracorr CI-2915). Further chemical analyses of the active extracts, including LC-HR-MS/MS, MS-based molecular networking, and chemoinformatics, revealed the presence of both known and new bioactive compounds. These included tambjamines and polybrominated diphenyl ethers (PBDEs), which are likely contributors to the observed bioactivities. Subsequent investigations uncovered new anti-QS and anti-biofilm properties in synthetic and natural PBDEs 1–12 previously derived from L. herbacea. Among these, 8 exhibited the most potent anti-QS activity, with an IC₅₀ value of 15 µM, while 4 significantly reduced biofilm formation at a concentration of 1 µM. This study highlights the potential of marine-derived compounds in addressing biofouling and biocorrosion challenges in a sustainable and effective manner. Full article