The human microbiome plays an essential role in the human immune system, food digestion, and protection from harmful bacteria by colonizing the human intestine. Recently, although the human ...microbiome affects colorectal cancer (CRC) treatment, the mode of action between the microbiome and CRC remains unclear. This study showed that propionate suppressed CRC growth by promoting the proteasomal degradation of euchromatic histone-lysine N-methyltransferase 2 (EHMT2) through HECT domain E3 ubiquitin protein ligase 2 (HECTD2) upregulation. In addition, EHMT2 downregulation reduced the H3K9me2 level on the promoter region of tumor necrosis factor α-induced protein 1 (TNFAIP1) as a novel direct target of EHMT2. Subsequently, TNFAIP1 upregulation induced the apoptosis of CRC cells. Furthermore, using Bacteroides thetaiotaomicron culture medium, we confirmed EHMT2 downregulation via upregulation of HECTD2 and TNFAIP1 upregulation. Finally, we observed the synergistic effect of propionate and an EHMT2 inhibitor (BIX01294) in 3D spheroid culture models. Thus, we suggest the anticancer effects of propionate and EHMT2 as therapeutic targets for colon cancer treatment and may provide the possibility for the synergistic effects of an EHMT2 inhibitor and microbiome in CRC treatment.
In South Korea, a November 2021 outbreak caused by severe acute respiratory syndrome coronavirus 2 Omicron variant originated from 1 person with an imported case and spread to households, ...kindergartens, workplaces, restaurants, and hospitals, resulting in 11 clusters within 3 weeks. An epidemiologic curve indicated rapid community transmission of the Omicron variant.
To determine optimal quarantine duration, we evaluated time from exposure to diagnosis for 107 close contacts of severe acute respiratory syndrome coronavirus 2 Omicron variant case-patients. Average ...time from exposure to diagnosis was 3.7 days; 70% of diagnoses were made on day 5 and 99.1% by day 10, suggesting 10-day quarantine.
Human pluripotent stem cell (hPSC)-derived intestinal organoids (hIOs) form 3D structures organized into crypt and villus domains, making them an excellent in vitro model system for studying human ...intestinal development and disease. However, hPSC-derived hIOs still require in vivo maturation to fully recapitulate adult intestine, with the mechanism of maturation remaining elusive. Here, we show that the co-culture with human T lymphocytes induce the in vitro maturation of hIOs, and identify STAT3-activating interleukin-2 (IL-2) as the major factor inducing maturation. hIOs exposed to IL-2 closely mimic the adult intestinal epithelium and have comparable expression levels of mature intestinal markers, as well as increased intestine-specific functional activities. Even after in vivo engraftment, in vitro-matured hIOs retain their maturation status. The results of our study demonstrate that STAT3 signaling can induce the maturation of hIOs in vitro, thereby circumventing the need for animal models and in vivo maturation.
More than half of the adult population worldwide is overweight or obese, while excess adiposity has been linked to chronic low-grade inflammation, contributing to the development of chronic diseases. ...Recent studies have showed that diet-induced alterations to the gut microbiota composition play a pivotal role in the development of obesity. However, the cause-effect relationship between obesity and gut microbiota composition is not yet fully understood. In this study, we investigated the short-term responses of gut microbiota composition to diets with different fat contents and their associations with inflammatory biomarkers.
Sixty male C57BL/6 J mice were fed a normal diet (ND; 15% fat) or a high-fat diet (HFD; 45% fat) for 10 or 20 weeks. The relative proportion of the phylum Actinobacteria was elevated by the HFD and was positively associated with body weight and proinflammatory cytokines including TNF-α, IL-1β, and IL-6. The proportion of the phylum Firmicutes increased with aging and was also positively correlated with proinflammatory cytokines. The proportions of Actinobacteria and Firmicutes were inversely associated with tight junction proteins claudin-1 and E-cadherin, respectively. The proportions of the class Clostridia and the family Ruminococcaceae within the phylum Firmicutes were affected by both diet and age. In addition, the proportions of the phylum Bacteroidetes, the family Bacteroidaceae, and the genus Bacteroides decreased with aging and were inversely correlated with colonic proinflammatory cytokines representing a positive association with tight junction proteins.
Host age and dietary fat intake are important elements that induce proportional changes in gut microbiota, and these changes are also associated with systemic inflammation. This study provides evidence that diet affects the gut microbiota composition within a short period of time.
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•Pluripotent stem cell (PSC)-derived expandable human hepatocyte-like liver organoids were generated.•PSC-derived human hepatic organoids are capable of long-term expansion with ...competent liver functionality.•PSC-derived human hepatic organoids provide a robust hepatic model for toxicity prediction and drug screening.
The development of hepatic models capable of long-term expansion with competent liver functionality is technically challenging in a personalized setting. Stem cell-based organoid technologies can provide an alternative source of patient-derived primary hepatocytes. However, self-renewing and functionally competent human pluripotent stem cell (PSC)-derived hepatic organoids have not been developed.
We developed a novel method to efficiently and reproducibly generate functionally mature human hepatic organoids derived from PSCs, including human embryonic stem cells and induced PSCs. The maturity of the organoids was validated by a detailed transcriptome analysis and functional performance assays. The organoids were applied to screening platforms for the prediction of toxicity and the evaluation of drugs that target hepatic steatosis through real-time monitoring of cellular bioenergetics and high-content analyses.
Our organoids were morphologically indistinguishable from adult liver tissue-derived epithelial organoids and exhibited self-renewal. With further maturation, their molecular features approximated those of liver tissue, although these features were lacking in 2D differentiated hepatocytes. Our organoids preserved mature liver properties, including serum protein production, drug metabolism and detoxifying functions, active mitochondrial bioenergetics, and regenerative and inflammatory responses. The organoids exhibited significant toxic responses to clinically relevant concentrations of drugs that had been withdrawn from the market due to hepatotoxicity and recapitulated human disease phenotypes such as hepatic steatosis.
Our organoids exhibit self-renewal (expandable and further able to differentiate) while maintaining their mature hepatic characteristics over long-term culture. These organoids may provide a versatile and valuable platform for physiologically and pathologically relevant hepatic models in the context of personalized medicine.
A functionally mature, human cell-based liver model exhibiting human responses in toxicity prediction and drug evaluation is urgently needed for pre-clinical drug development. Here, we develop a novel human pluripotent stem cell-derived hepatocyte-like liver organoid that is critically advanced in terms of its generation method, functional performance, and application technologies. Our organoids can contribute to the better understanding of liver development and regeneration, and provide insights for metabolic studies and disease modeling, as well as toxicity assessments and drug screening for personalized medicine.
The incidence of colitis-associated colorectal cancer (CAC) has increased due to a high-nutrient diet, increased environmental stimuli and inherited gene mutations. To adequately treat CAC, drugs ...should be developed by identifying novel therapeutic targets. E3 ubiquitin-protein ligase pellino homolog 3 (pellino 3; Peli3) is a RING-type E3 ubiquitin ligase involved in inflammatory signalling; however, its role in the development and progression of CAC has not been elucidated. In this study, we studied Peli3-deficient mice in an azoxymethane/dextran sulphate sodium-induced CAC model. We observed that Peli3 promotes colorectal carcinogenesis with increased tumour burden and oncogenic signalling pathways. Ablation of Peli3 reduced inflammatory signalling activation at the early stage of carcinogenesis. Mechanistic studies indicate that Peli3 enhances toll-like receptor 4 (TLR4)-mediated inflammation through ubiquitination-dependent degradation of interferon regulatory factor 4, a negative regulator of TLR4 in macrophages. Our study suggests an important molecular link between Peli3 and colonic inflammation-mediated carcinogenesis. Furthermore, Peli3 can be a therapeutic target in the prevention and treatment of CAC.
Colorectal cancer (CRC) is the third most common cancer, and is associated with a high percentage of cancer-related death globally. Furthermore, the success rate of therapeutic treatment for CRC ...patients mainly depends on the status of metastasis. Therefore, novel drugs or therapeutic techniques should be discovered for the treatment of metastatic CRC. In this study, we selected Astaxanthin (AXT), one of the most common carotenoids, as a novel metastasis inhibitor through high-throughput drug screening based on invadopodia staining, and confirmed the anti-migratory and anti-invasive activity of AXT. We demonstrated that AXT increases miR-29a-3p and miR-200a expression, and thereby suppresses the expression of MMP2 and ZEB1, respectively. As a result, AXT represses the epithelial-mesenchymal transition (EMT) of CRC cells. Through the mechanistic study, we identified that AXT shows anti-metastatic activity through the transcriptional repression of MYC transcription factor. Finally, we also confirmed that AXT suppresses the in vivo metastatic capacity of colon cancer cell using mouse model. Collectively, we uncovered the novel function of AXT in the inhibition of EMT and invadopodia formation, implicating the novel therapeutic potential for AXT in metastatic CRC patients.
Although the biological role of melatonin in osteogenic differentiation has been suggested, the mechanism of osteoblast differentiation remains unclear. Thus, the present study investigated the ...underlying molecular mechanisms based on osteoblast-specific transcription factors. We found that melatonin enhanced BMP-4-induced osteogenic differentiation and increased the expression of osteogenic markers, especially Osterix, which is an essential transcription factor for the differentiation of preosteoblasts into mature osteoblasts in the late stage of osteoblast differentiation. Melatonin treatment increased the expression of Osterix during osteoblast differentiation and stabilized its expression by the inhibition of ubiquitin-proteasome-mediated degradation of Osterix, leading to up-regulated Osterix transcriptional activity on the osteogenic promoter and promoting alkaline phosphatase activity and bone mineralization. Furthermore, treatment with protein kinase A (PKA) inhibitor H89 and protein kinase C (PKC) inhibitor Go6976 blocked the melatonin-induced transcriptional activity and phosphorylation of Osterix, indicating that melatonin regulates Osterix expression via the PKA and PKC signaling pathways. Overall, these findings suggest that melatonin directly regulates the late stage of osteoblast differentiation by enhancing Osterix expression; this provides further evidence of melatonin as a potent agent for treating osteoporosis.
Cancer was thought to be caused solely by genetic mutations in oncogenes and tumor suppressor genes. In the last 35 years, however, epigenetic changes have been increasingly recognized as another ...primary driver of carcinogenesis and cancer progression. Epigenetic deregulation in cancer often includes mutations and/or aberrant expression of chromatin-modifying enzymes, their associated proteins, and even non-coding RNAs, which can alter chromatin structure and dynamics. This leads to changes in gene expression that ultimately contribute to the emergence and evolution of cancer cells. Studies of the deregulation of chromatin modifiers in cancer cells have reshaped the way we approach cancer and guided the development of novel anticancer therapeutics that target epigenetic factors. There remain, however, a number of unanswered questions in this field that are the focus of present research. Areas of particular interest include the actions of emerging classes of epigenetic regulators of carcinogenesis and the tumor microenvironment, as well as epigenetic tumor heterogeneity. In this review, we discuss past findings on epigenetic mechanisms of cancer, current trends in the field of cancer epigenetics, and the directions of future research that may lead to the identification of new prognostic markers for cancer and the development of more effective anticancer therapeutics.
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