Melatonin is a naturally occurring molecule secreted by the pineal gland and known as a gatekeeper of circadian clocks. Mounting evidence indicates that melatonin, employing multiple and interrelated ...mechanisms, exhibits a variety of oncostatic properties in a myriad of tumors during different stages of their progression. Tumor metastasis, which commonly occurs at the late stage, is responsible for the majority of cancer deaths; metastases lead to the development of secondary tumors distant from a primary site. In reference to melatonin, the vast majority of investigations have focused on tumor development and progression at the primary site. Recently, however, interest has shifted toward the role of melatonin on tumor metastases. In this review, we highlight current advances in understanding the molecular mechanisms by which melatonin counteracts tumor metastases, including experimental and clinical observations; emphasis is placed on the impact of both cancer and non‐neoplastic cells within the tumor microenvironment. Due to the broad range of melatonin's actions, the mechanisms underlying its ability to interfere with metastases are numerous. These include modulation of cell–cell and cell–matrix interaction, extracellular matrix remodeling by matrix metalloproteinases, cytoskeleton reorganization, epithelial–mesenchymal transition, and angiogenesis. The evidence discussed herein will serve as a solid foundation for urging basic and clinical studies on the use of melatonin to understand and control metastatic diseases.
Toxoplasma gondii and Neospora caninum are intracellular protozoan parasites that cause reproductive disorders in ruminants and humans. Information on the risk factors of T. gondii and N. caninum ...infections in goats is very limited in Taiwan. The aim of the study was to investigate the epidemiology and identify the risk factors of these two infections in goats. A total of 630 caprine sera were collected from 42 dairy goat farms and the owners were interviewed by a structured questionnaire. The apparent seroprevalences of T. gondii in farm- and individual- levels were respectively 88.1% and 32.22%, while those of N. caninum were 19.05% and 2.54%, respectively. Toxoplasma gondii B1 gene was identified in 7 feed samples and 8 from the water samples whereas N. caninum was not found. Wooden flooring was the main risk factor for T. gondii infection while the frequency of visits by staff to other farms and the breed of goat were risk factors for N. caninum. The improvement of flooring materials or thorough cleaning, periodic disinfection and maintenance of dryness on the floor are highly recommended for the prevention of T. gondii infection in farmed goats. In addition, unnecessary visits to other farms should be limited to prevent the spread of N. caninum. These factors should be highlighted for the prevention of T. gondii and N. caninum in goats, particularly when raised in intensive housing system with flooring on height.
The safety of newer xanthine oxidase inhibitor febuxostat compared to allopurinol remains unclear. To compare the risks of allopurinol hypersensitivity and febuxostat hypersensitivity and ...cardiovascular diseases (CVDs) in Asians, we conducted a population‐based cohort study enrolling patients receiving allopurinol or febuxostat from Chang Gung Memorial Hospital Health System across Taiwan during 2012–2016 and further performed a meta‐analysis incorporating two recent studies. Among the 61,539 users, a corresponding 12,007 and 5,680 patients were identified as new users. The overall incidence of febuxostat hypersensitivity was significantly lower than allopurinol hypersensitivity (0.2 vs. 2.7 per 1,000 new users; P < 0.001). There were 33 allopurinol‐hypersensitivity reactions (including 18 severe cutaneous adverse drug reactions), and only one patient developed febuxostat‐maculopapular exanthema. Moreover, febuxostat did not statistically increase the risk of CVD (hazard ratio (HR), 1.16; P = 0.152) and related death (HR, 1.49; P = 0.496) compared to allopurinol. The result of the meta‐analysis also showed a consistent result. In conclusion, the incidence and severity of febuxostat‐hypersensitivity are lower than with allopurinol. Febuxostat did not show an increased risk of CVD and related death.
Background
Childhood asthma is a multifactorial inflammatory condition of the airways, associated with specific changes in respiratory microbiome and circulating metabolome.
Methods
To explore the ...functional capacity of asthmatic microbiome and its intricate connection with the host, we performed shotgun sequencing of airway microbiome and untargeted metabolomics profiling of serum samples in a cohort of children with mite‐sensitized asthma and non‐asthmatic controls.
Results
We observed higher gene counts and sample‐to‐sample dissimilarities in asthmatic microbiomes, indicating a more heterogeneous community structure and functionality among the cases than in controls. Moreover, we identified airway microbial species linked to changes in circulating metabolites and IgE responses of the host, including a positive correlation between Prevotella sp oral taxon 306 and dimethylglycine that were both decreased in patients. Several control‐enriched species (Eubacterium sulci, Prevotella pallens, and Prevotella sp oral taxon 306) were inversely correlated with total and allergen‐specific IgE levels. Genes related to microbial carbohydrate, amino acid, and lipid metabolism were differentially enriched, suggesting that changes in microbial metabolism may contribute to respiratory health in asthmatics. Pathway modules relevant to allergic responses were differentially abundant in asthmatic microbiome, such as enrichments for biofilm formation by Pseudomonas aeruginosa, membrane trafficking, histidine metabolism, and glycosaminoglycan degradation, and depletions for polycyclic aromatic hydrocarbon degradation. Further, we identified metagenomic and metabolomic markers (eg, Eubacterium sulci) to discriminate cases from the non‐asthmatic controls.
Conclusions
Our dual‐omics data reveal the connections between respiratory microbes and circulating metabolites perturbed in mite‐sensitized pediatric asthma, which may be of etiological and diagnostic implications.
This study demonstrates shotgun sequencing of airway microbiome and untargeted metabolomics profiling of serum samples in children with mite‐sensitized asthma and non‐asthmatic controls. Integrative analysis identifies specific airway dysbiosis at the species level and its associated functional shift in strong associations with circulating metabolites and IgE responses to mites. Overall, dual‐omics integration reveals microbe‐metabolite connections perturbed in mite‐sensitized pediatric asthma.
Abbreviations: KEGG, Kyoto Encyclopedia of Genes and Genomes; AUC, area under the receiver operating characteristic curve
Alterations in the gut microbiota composition and their associated metabolic dysfunction exist in psoriasis. However, the impact of biologics on shaping gut microbiota is not well known. This study ...aimed to determine the association of gut microorganisms and microbiome-encoded metabolic pathways with the treatment in patients with psoriasis. A total of 48 patients with psoriasis, including 30 cases who received an IL-23 inhibitor (guselkumab) and 18 cases who received an IL-17 inhibitor (secukinumab or ixekizumab) were recruited. Longitudinal profiles of the gut microbiome were conducted by using 16S rRNA gene sequencing. The gut microbial compositions dynamically changed in psoriatic patients during a 24-week treatment. The relative abundance of individual taxa altered differently between patients receiving the IL-23 inhibitor and those receiving the IL-17 inhibitor. Functional prediction of the gut microbiome revealed microbial genes related to metabolism involving the biosynthesis of antibiotics and amino acids were differentially enriched between responders and non-responders receiving IL-17 inhibitors, as the abundance of the taurine and hypotaurine pathway was found to be augmented in responders treated with the IL-23 inhibitor. Our analyses showed a longitudinal shift in the gut microbiota in psoriatic patients after treatment. These taxonomic signatures and functional alterations of the gut microbiome could serve as potential biomarkers for the response to biologics treatment in psoriasis.
The inhibitory effect of melatonin on cancer cell dissemination is well established, yet the functional involvement of lncRNAs in melatonin signaling remains poorly understood. In this study, we ...identified a melatonin‐attenuated lncRNA acting as a potential melatonin‐regulated oral cancer stimulator (MROS‐1). Downregulation of MROS‐1 by melatonin suppressed TPA‐induced oral cancer migration through replenishing the protein expression of prune homolog 2 (PRUNE2), which functioned as a tumor suppressor in oral cancer. Melatonin‐mediated MROS‐1/PRUNE2 expression and cell motility in oral cancer were regulated largely through the activation of JAK‐STAT pathway. In addition, MROS‐1, preferentially localized in the nuclei, promoted oral cancer migration in an epigenetic mechanism in which it modulates PRUNE2 expression by interacting with a member of the DNA methylation machinery, DNA methyltransferase 3A (DNMT3A). Higher methylation levels of PRUNE2 promoter were associated with nodal metastases and inversely correlated with PRUNE2 expression in head and neck cancer. Collectively, these findings suggest that MROS‐1, serving as a functional mediator of melatonin signaling, could predispose patients with oral cancer to metastasize and may be implicated as a potential target for antimetastatic therapies.
Both high-fidelity and mismatch-tolerant recombination, catalyzed by RAD51 and DMC1 recombinases, respectively, are indispensable for genomic integrity. Here, we use cryo-EM, MD simulation and ...functional analysis to elucidate the structural basis for the mismatch tolerance of DMC1. Structural analysis of DMC1 presynaptic and postsynaptic complexes suggested that the lineage-specific Loop 1 Gln244 (Met243 in RAD51) may help stabilize DNA backbone, whereas Loop 2 Pro274 and Gly275 (Val273/Asp274 in RAD51) may provide an open "triplet gate" for mismatch tolerance. In support, DMC1-Q244M displayed marked increase in DNA dynamics, leading to unobservable DNA map. MD simulation showed highly dispersive mismatched DNA ensemble in RAD51 but well-converged DNA in DMC1 and RAD51-V273P/D274G. Replacing Loop 1 or Loop 2 residues in DMC1 with RAD51 counterparts enhanced DMC1 fidelity, while reciprocal mutations in RAD51 attenuated its fidelity. Our results show that three Loop 1/Loop 2 residues jointly enact contrasting fidelities of DNA recombinases.
To develop a pre‐emptive genetic test that comprises multiple predisposing alleles for the prevention of phenytoin‐related severe cutaneous adverse reactions (SCARs), three sets of patients with ...phenytoin‐SCAR and drug‐tolerant controls from Taiwan, Thailand, and Japan, were enrolled for this study. In addition to cytochrome P450 (CYP)2C9*3, we found that HLA‐B*13:01, HLA‐B*15:02, and HLA‐B*51:01 were significantly associated with phenytoin hypersensitivity with distinct phenotypic specificities. Strikingly, we showed an increase in predictive sensitivity of concurrently testing CYP2C9*3/HLA‐B*13:01/HLA‐B*15:02/HLA‐B*51:01 from 30.5–71.9% for selecting the individuals with the risk of developing phenytoin‐SCAR in Taiwanese cohorts, accompanied by a specificity of 77.7% (combined sensitivity, 64.7%; specificity, 71.9% for three Asian populations). Meta‐analysis of the four combined risk alleles showed significant associations with phenytoin‐SCAR in three Asian populations. In conclusion, combining the assessment of risk alleles of HLA and CYP2C9 potentiated the usefulness of predictive genetic tests to prevent phenytoin hypersensitivity in Asians.
Nasopharyngeal carcinoma (NPC), a disease common in the South‐East Asian population, has high lymph node metastatic ability. Melatonin, an endogenously produced substance present in animals, plants, ...fungi, and bacteria, has oncostatic activity via several mechanisms. The molecular mechanisms involved in melatonin‐mediated tumor inhibitory potential are not completely defined. Here, we show that melatonin treatment inhibits TPA‐induced cell motility by regulating the matrix metalloproteinase‐9 (MMP‐9) expression in NPC. We also identified the signaling cascade through which melatonin inhibits MMP‐9 expression; this involves melatonin regulating the binding activity of the transcription factor specificity protein‐1 (SP‐1)‐DNA. Our mechanistic analysis further reveals that the c‐Jun N‐terminal kinase/mitogen‐activated protein kinase pathway is involved in the melatonin‐mediated tumor suppressor activity. Furthermore, the findings indicate a functional link between melatonin‐mediated MMP‐9 regulation and tumor suppressing ability and provide new insights into the role of melatonin‐induced molecular and epigenetic regulation of tumor growth. Thus, we conclude that melatonin suppresses the motility of NPC by regulating TPA‐induced MMP‐9 gene expression via inhibiting SP‐1‐DNA binding ability. The results provide a functional link between melatonin‐mediated SP‐1 regulation and the antimetastatic actions of melatonin on nasopharyngeal carcinoma.
Skin is the largest human organ, our protection against various environmental assaults and noxious agents. Accumulation of these stress events may lead to the formation of skin cancers, including ...both melanoma and non-melanoma skin cancers. Although modern targeted therapies have ameliorated the management of cutaneous malignancies, a safer, more affordable, and more effective strategy for chemoprevention and treatment is clearly needed for the improvement of skin cancer care. Phytochemicals are biologically active compounds derived from plants and herbal products. These agents appear to be beneficial in the battle against cancer as they exert anti-carcinogenic effects and are widely available, highly tolerated, and cost-effective. Evidence has indicated that the anti-carcinogenic properties of phytochemicals are due to their anti-oxidative, anti-inflammatory, anti-proliferative, and anti-angiogenic effects. In this review, we discuss the preventive potential, therapeutic effects, bioavailability, and structure-activity relationship of these selected phytochemicals for the management of skin cancers. The knowledge compiled here will provide clues for future investigations on novel oncostatic phytochemicals and additional anti-skin cancer mechanisms.
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