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1.
PRMT1 Sustains De Novo Fatty Acid Synthesis by Methylating PHGDH to Drive Chemoresistance in Triple-Negative Breast Cancer.
Yamamoto, T, Hayashida, T, Masugi, Y, Oshikawa, K, Hayakawa, N, Itoh, M, Nishime, C, Suzuki, M, Nagayama, A, Kawai, Y, et al
Cancer research. 2024;(7):1065-1083
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Abstract
UNLABELLED Triple-negative breast cancer (TNBC) chemoresistance hampers the ability to effectively treat patients. Identification of mechanisms driving chemoresistance can lead to strategies to improve treatment. Here, we revealed that protein arginine methyltransferase-1 (PRMT1) simultaneously methylates D-3-phosphoglycerate dehydrogenase (PHGDH), a critical enzyme in serine synthesis, and the glycolytic enzymes PFKFB3 and PKM2 in TNBC cells. 13C metabolic flux analyses showed that PRMT1-dependent methylation of these three enzymes diverts glucose toward intermediates in the serine-synthesizing and serine/glycine cleavage pathways, thereby accelerating the production of methyl donors in TNBC cells. Mechanistically, PRMT1-dependent methylation of PHGDH at R54 or R20 activated its enzymatic activity by stabilizing 3-phosphoglycerate binding and suppressing polyubiquitination. PRMT1-mediated PHGDH methylation drove chemoresistance independently of glutathione synthesis. Rather, activation of the serine synthesis pathway supplied α-ketoglutarate and citrate to increase palmitate levels through activation of fatty acid synthase (FASN). Increased palmitate induced protein S-palmitoylation of PHGDH and FASN to further enhance fatty acid synthesis in a PRMT1-dependent manner. Loss of PRMT1 or pharmacologic inhibition of FASN or protein S-palmitoyltransferase reversed chemoresistance in TNBC. Furthermore, IHC coupled with imaging MS in clinical TNBC specimens substantiated that PRMT1-mediated methylation of PHGDH, PFKFB3, and PKM2 correlates with chemoresistance and that metabolites required for methylation and fatty acid synthesis are enriched in TNBC. Together, these results suggest that enhanced de novo fatty acid synthesis mediated by coordinated protein arginine methylation and protein S-palmitoylation is a therapeutic target for overcoming chemoresistance in TNBC. SIGNIFICANCE PRMT1 promotes chemoresistance in TNBC by methylating metabolic enzymes PFKFB3, PKM2, and PHGDH to augment de novo fatty acid synthesis, indicating that targeting this axis is a potential treatment strategy.
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The Effects of Black Tea Consumption on Intestinal Microflora-A Randomized Single-Blind Parallel-Group, Placebo-Controlled Study.
Tomioka, R, Tanaka, Y, Suzuki, M, Ebihara, S
Journal of nutritional science and vitaminology. 2023;69(5):326-339
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Plain language summary
Tea from the leaves of the tea plant (Camelia sinensis) is consumed around the world. Tea has many health benefits, and in part, this is due to its rich content in compounds classed as polyphenols. Through the fermentation process, black tea is particularly high in polyphenols. Previous studies around respiratory infections indicated that regular consumption of black tea appeared to improve immune defence mechanisms that protect mucous membranes, called mucosal immunity. As this mucosal immunity is closely influenced by gut bacteria, the authors speculated whether the previously seen impact of improved mucosal immunity is related to the ability of black tea to also modulate bacteria in the gut. A previously run randomised single-blinded, placebo-controlled trial with 72 Japanese participants who consumed three cups of black tea (2g) or a placebo of barley tea for 12 weeks provided the data for this study. Data gathered included gut flora analysis, short-chain fatty acids (SCFAs) levels - fats that play a role in maintaining gut health, and saliva IgA (SIgA) concentrations - which are antibodies made in the lymph tissue of the gut. The results showed that black tea consumption led to a significant increase in the abundance of Prevotella bacteria, which mediate SCFA production and are involved in normalising immune function. Furthermore, tea increased butyrate-producing bacteria. Butyrate is associated with improved barrier function of the gut walls but also helps to manage pathogens and immune responses. Black tea consumption also increased salivary SIgA concentration - a type of antibody on the mucous membranes that prevents pathogens from entering the body -, and a decrease in stool acetic acid concentration, which may be due to the increase in butyrate-producing bacteria which use acetic acid to make butyrate. Notably, participants with low salivary SIgA levels at the start had a more pronounced positive change in total bacteria, after consuming black tea compared to the placebo group. The authors concluded that regular consumption of black tea may help to improve mucosal immunity by increasing the abundance of beneficial bacteria in the gut.
Abstract
We previously reported that black tea consumption for 12 wk reduced the risk of acute upper respiratory tract inflammation, and improved secretory capacity in individuals with low salivary SIgA levels (Tanaka Y et al. 2021. Jpn Pharmacol Ther 49: 273-288). These results suggested that habitual black tea consumption improves mucosal immunity. Therefore, in this study we evaluated the effect of black tea intake on gut microbiota, which is known to be involved in mucosal immunity, by analyzing the bacterial flora and the short-chain fatty acids (SCFAs) concentration of feces collected during the above clinical study. The clinical design was a randomized, single-blind, parallel-group, placebo-controlled study with 72 healthy Japanese adult males and females, who consumed three cups of black tea (Black Tea Polymerized Polyphenols 76.2 mg per day) or placebo per day for 12 wk. In all subjects intake of black tea significantly increased abundance of Prevotella and decreased fecal acetic acid concentration. Particularly in the subjects with low salivary SIgA levels, the change over time of total bacteria, Prevotella, and butyrate-producing bacteria, which are involved in normalizing immune function, were higher in the black tea group than in the placebo group. In subjects with low abundance of Flavonifractor plautii a butyrate-producing bacteria, black tea consumption significantly increased salivary SIgA concentration and the absolute number of Flavonifractor plautii. In conclusion, our results suggest that improvement of mucosal immunity via an increase in butyrate-producing bacteria in the gut may partly contribute to the suppressive effect of black tea consumption on acute upper respiratory tract inflammation observed in our previous report.
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Correlation of toxicities and efficacies of pemetrexed with clinical factors and single-nucleotide polymorphisms: a prospective observational study.
Takeda, Y, Naka, G, Katsuya, Y, Kobayashi, K, Suzuki, M, Hashimoto, M, Hirano, S, Uemura, Y
BMC cancer. 2023;(1):800
Abstract
BACKGROUND Pemetrexed is an efficacious multi-targeted antifolate with acceptable toxicity for non-squamous non-small cell lung cancer (non-Sq NSCLC) and malignant pleural mesothelioma. Vitamin B12 and folic acid as premedication can reduce the frequency of severe toxicities of pemetrexed chemotherapy. However, adverse effects are frequent in clinical settings. In this study, we aimed to identify the clinical factors and single-nucleotide polymorphisms (SNPs) associated with the toxicity and efficacy of pemetrexed chemotherapy. METHODS This observational study was conducted from October 2012 to December 2019; we evaluated the toxicities and efficacies of pemetrexed chemotherapy using multivariate logistic or Cox regression analysis. In total, 106 patients received pemetrexed chemotherapy. SNPs were analyzed for four patients with malignant pleural mesothelioma and 67 with non-Sq NSCLC. RESULTS The median progression-free survival (PFS) and overall survival of 63 patients with non-Sq NSCLC, excluding four in the adjuvant setting, were 6.8 and 33.3 months, respectively. Per propensity-score-adjusted multivariate Cox analyses, favorable factors for PFS were folic acid level ≥ 9.3 ng/mL before premedication, platinum combination, bevacizumab combination, vitamin B12 level < 1136 pg/mL before chemotherapy, A/A + A/G of BHMT (742 G > A), and A/A + A/C of DHFR (680 C > A). Favorable prognostic factors included good performance status, low smoking index, body mass index ≥ 20.66 kg/m2, folic acid level ≥ 5.55 ng/mL before premedication, higher retinol-binding protein before chemotherapy, and A/G of MTRR (66 A > G). Among the 71 patients who were analyzed for SNPs, the frequencies of hematologic toxicities and non-hematologic toxicities in Grades 3-4 were 38% and 36.6%, respectively. Per propensity-score-adjusted multivariate logistic analyses, risk factors for Grades 3-4 hematologic toxicities were vitamin B12 level < 486 pg/mL before premedication, leucocyte count < 6120 /µL before chemotherapy, folic acid level < 15.8 ng/mL before chemotherapy, status with a reduced dose of chemotherapy, and C/T + T/T of MTHFR (677 C > T). Risk factors for Grades 2-4 non-hematologic toxicities were homocysteine levels ≥ 11.8 nmol/mL before premedication, transthyretin level < 21.5 mg/dL before chemotherapy, C/C + T/T of MTHFR (677 C > T), and A/A + G/G of SLC19A1 [IVS2 (4935) G > A]. CONCLUSION The information on metabolites and SNPs of the folate and methionine cycle will help predict the toxicities and efficacies of pemetrexed. TRIAL REGISTRATION This trial was retrospectively registered with the University hospital Medical Information Network (UMIN000009366) on November 20, 2012.
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Body fluid regulation via chronic inhibition of sodium-glucose cotransporter-2 in patients with heart failure: a post hoc analysis of the CANDLE trial.
Fujiki, S, Tanaka, A, Imai, T, Shimabukuro, M, Uehara, H, Nakamura, I, Matsunaga, K, Suzuki, M, Kashimura, T, Minamino, T, et al
Clinical research in cardiology : official journal of the German Cardiac Society. 2023;(1):87-97
Abstract
BACKGROUND In patients with chronic heart failure (CHF) and type 2 diabetes (T2D), sodium-glucose cotransporter-2 (SGLT2) inhibition improves cardiorenal outcomes, but details of the effects on distinct subsets of body fluid volume remain incomplete. METHODS This was a post hoc analysis of patients with CHF and T2D in the CANDLE trial (UMIN000017669), an investigator-initiated, multi-center, randomized open-label trial that compared the effect of canagliflozin (100 mg, n = 113) with glimepiride (starting dose: 0.5 mg, n = 120) on changes in N-terminal pro-brain natriuretic peptide. The estimated plasma volume (ePV, calculated with the Straus formula) and estimated extracellular volume (eEV, determined by the body surface area) were compared between treatment groups at weeks 4, 12, and 24. RESULTS Among 233 patients analyzed, 166 (71.2%) had an ejection fraction (EF) > 50%. Reductions in ePV and eEV were observed only in the canagliflozin group until week 12 (change from baseline at week 12, ePV; - 7.63%; 95% confidence interval [CI], - 10.71 to - 4.55%, p < 0.001, eEV; - 123.15 mL; 95% CI, - 190.38 to - 55.92 mL, p < 0.001). While ePV stopped falling after week 12, eEV continued to fall until week 24 ([change from baseline at week 24] - [change from baseline at week 12], ePV; 1.01%; 95%CI, - 2.30-4.32%, p = 0.549, eEV; - 125.15 mL; 95% CI, - 184.35 to - 65.95 mL, p < 0.001). CONCLUSIONS Maintenance of a modest reduction in ePV and continuous removal of eEV via chronic SGLT2 inhibition suggests that favorable body fluid regulation contributes to the cardiorenal benefits of SGLT2 inhibitors in patients with CHF, irrespective of EF. TRIAL REGISTRATION UMIN000017669.
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Diagnosis and prevalence of sarcopenic obesity in patients with colorectal cancer: A scoping review.
Saino, Y, Kawase, F, Nagano, A, Ueshima, J, Kobayashi, H, Murotani, K, Inoue, T, Nagami, S, Suzuki, M, Maeda, K
Clinical nutrition (Edinburgh, Scotland). 2023;(9):1595-1601
Abstract
BACKGROUND & AIMS Sarcopenic obesity (SO) is associated with worse outcomes in patients with colorectal cancer (CRC); however, the diagnostic methods and prevalence of SO vary among studies. Therefore, we conducted this scoping review to investigate the diagnosis of SO in CRC, identify the associated problems, and determine its prevalence. METHODS A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews reporting guidelines. A literature search was performed by two independent reviewers on studies that diagnosed SO in CRC using the MEDLINE, EMBASE, CINAHL, CENTRAL, Web of Science, and Ichushi-Web (in Japanese) databases. Observational, longitudinal, cross-sectional, and clinical trials written in English or Japanese as of July 2022 were included. Studies that did not define SO were excluded from the analysis. The study protocol was pre-registered in Figshare. RESULTS In total, 670 studies were identified, 22 of which were included. Eighteen studies used sarcopenia in combination with obesity to diagnose SO. Sarcopenia was mainly diagnosed using skeletal muscle mass index (SMI), and only one combined with grip strength or gait speed. Obesity was diagnosed based on the body mass index (BMI; n = 11), followed by visceral fat area (VFA; n = 5). The overall prevalence of SO in patients with CRC was 15% (95%CI, 11-21%). The prevalence of SO in surgical resection and colorectal cancer liver metastases was 18% (95%CI, 12-25%) and 11% (95%CI, 3-36%), respectively. CONCLUSIONS SO in patients with CRC was mainly diagnosed based on a combination of SMI and BMI, and muscle strength and body composition were rarely evaluated. The prevalence of SO was approximately 15%, depending on the diagnostic methods used. Since SO in patients with CRC is associated with poor prognosis, further research on diagnostic methods for the early detection of SO and its clinical outcomes is needed.
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Genetic Variations of Vitamin A-Absorption and Storage-Related Genes, and Their Potential Contribution to Vitamin A Deficiency Risks Among Different Ethnic Groups.
Suzuki, M, Tomita, M
Frontiers in nutrition. 2022;:861619
Abstract
Vitamin A, an essential fat-soluble micronutrient, plays a critical role in the body, by regulating vision, immune responses, and normal development, for instance. Vitamin A deficiency (VAD) is a major cause of xerophthalmia and increases the risk of death from infectious diseases. It is also emerging that prenatal exposure to VAD is associated with disease risks later in life. The overall prevalence of VAD has significantly declined over recent decades; however, the rate of VAD is still high in many low- and mid-income countries and even in high-income countries among specific ethnic/race groups. While VAD occurs when dietary intake is insufficient to meet demands, establishing a strong association between food insecurity and VAD, and vitamin A supplementation is the primary solution to treat VAD, genetic contributions have also been reported to effect serum vitamin A levels. In this review, we discuss genetic variations associated with vitamin A status and vitamin A bioactivity-associated genes, specifically those linked to uptake of the vitamin in the small intestine and its storage in the liver, as well as their potential contribution to vitamin A deficiency risks among different ethnic groups.
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Developmental Origins of Metaflammation; A Bridge to the Future Between the DOHaD Theory and Evolutionary Biology.
Itoh, H, Ueda, M, Suzuki, M, Kohmura-Kobayashi, Y
Frontiers in endocrinology. 2022;:839436
Abstract
Metabolic syndrome refers to obesity-associated metabolic disorders that increase the risk of type 2 diabetes, coronary diseases, stroke, and other disabilities. Environmental imbalance during the early developmental period affects health and increases susceptibility to non-communicable diseases, including metabolic syndrome, in later life; therefore, the Developmental Origins of Health and Disease (DOHaD) theory was established. According to the DOHaD theory, the hypothesis of the energy-saving 'Thrifty Phenotype' in undernourished fetuses is one of the well-accepted schemes as a risk of developing metabolic syndrome. This phenotype is evolutionarily advantageous for survival of the fittest in a hangry environment after birth, a strong selection pressure, but increases the risk of developing metabolic syndrome under an obesogenic diet according to the 'Mismatch' hypothesis. Increasing evidences support that chronic inflammation pathophysiologically connects obesity to metabolic disorders in metabolic syndrome, leading to the concept of 'Metaflammation'. 'Metaflammation' in humans is proposed to originate from the evolutionary conservation of crosstalk between immune and metabolic pathways; however, few studies have investigated the contribution of evolutionary maladaptation to the pathophysiology of 'Metaflammation'. Therefore, it is promising to investigate 'Metaflammation' from the viewpoint of selective advantages and its 'Mismatch' to an unexpected environment in contemporary lifestyles, in consideration of the principal concept of evolutionarily conserved nutrient sensing and immune signaling systems.
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Effects of Timing of Medium-Chain Triglycerides (8:0 and 10:0) Supplementation during the Day on Muscle Mass, Function and Cognition in Frail Elderly Adults.
Abe, S, Ezaki, O, Suzuki, M
The Journal of frailty & aging. 2022;(1):100-108
Abstract
OBJECTIVES Supplementation with 6 g/day of medium-chain triglycerides (MCTs) at dinnertime increases muscle function and cognition in frail elderly adults relative to supplementation with long-chain triglycerides. However, suitable timing of MCT supplementation during the day is unknown. DESIGN We enrolled 40 elderly nursing home residents (85.9 ± 7.7 years) in a 1.5-month randomized intervention trial. Participants were randomly allocated to two groups: one received 6 g/day of MCTs at breakfast (breakfast group) as a test group and the other at dinnertime (dinner group) as a positive control group. MEASUREMENTS Muscle mass, strength, function, and cognition were monitored at baseline and 1.5 months after initiation of intervention. RESULTS Thirty-seven participants completed the study and were included in the analysis. MCT supplementation in breakfast and dinner groups respectively increased right arm muscle area from baseline by 1.1 ± 0.8 cm2 (P<0.001) and 1.6 ± 2.5 cm2 (P<0.001), left arm muscle area by 1.1 ± 0.7 cm2 (P<0.001) and 0.9 ± 1.0 cm2 (P<0.01), right knee extension time by 39 ± 42 s (P<0.01) and 20 ± 32 s (P<0.05), leg open and close test time by 1.74 ± 2.00 n/10 s (P<0.01) and 1.67 ± 2.01 n/10 s (P<0.01), and Mini-Mental State Examination score by 1.5 ± 3.0 points (P=0.06) and 1.0 ± 2.1 points (P=0.06). These increases between two groups did not differ statistically significantly. CONCLUSION Supplementation with 6 g MCTs/day for 1.5 months, irrespective of ingestion at breakfast or dinnertime, could increase muscle mass and function, and cognition in frail elderly adults.
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The SEQC2 epigenomics quality control (EpiQC) study.
Foox, J, Nordlund, J, Lalancette, C, Gong, T, Lacey, M, Lent, S, Langhorst, BW, Ponnaluri, VKC, Williams, L, Padmanabhan, KR, et al
Genome biology. 2021;(1):332
Abstract
BACKGROUND Cytosine modifications in DNA such as 5-methylcytosine (5mC) underlie a broad range of developmental processes, maintain cellular lineage specification, and can define or stratify types of cancer and other diseases. However, the wide variety of approaches available to interrogate these modifications has created a need for harmonized materials, methods, and rigorous benchmarking to improve genome-wide methylome sequencing applications in clinical and basic research. Here, we present a multi-platform assessment and cross-validated resource for epigenetics research from the FDA's Epigenomics Quality Control Group. RESULTS Each sample is processed in multiple replicates by three whole-genome bisulfite sequencing (WGBS) protocols (TruSeq DNA methylation, Accel-NGS MethylSeq, and SPLAT), oxidative bisulfite sequencing (TrueMethyl), enzymatic deamination method (EMSeq), targeted methylation sequencing (Illumina Methyl Capture EPIC), single-molecule long-read nanopore sequencing from Oxford Nanopore Technologies, and 850k Illumina methylation arrays. After rigorous quality assessment and comparison to Illumina EPIC methylation microarrays and testing on a range of algorithms (Bismark, BitmapperBS, bwa-meth, and BitMapperBS), we find overall high concordance between assays, but also differences in efficiency of read mapping, CpG capture, coverage, and platform performance, and variable performance across 26 microarray normalization algorithms. CONCLUSIONS The data provided herein can guide the use of these DNA reference materials in epigenomics research, as well as provide best practices for experimental design in future studies. By leveraging seven human cell lines that are designated as publicly available reference materials, these data can be used as a baseline to advance epigenomics research.
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TLR Signals in Epithelial Cells in the Nasal Cavity and Paranasal Sinuses.
Suzuki, M, Cooksley, C, Suzuki, T, Ramezanpour, M, Nakazono, A, Nakamaru, Y, Homma, A, Vreugde, S
Frontiers in allergy. 2021;:780425
Abstract
The respiratory tract is constantly at risk of invasion by microorganisms such as bacteria, viruses, and fungi. In particular, the mucosal epithelium of the nasal cavity and paranasal sinuses is at the very forefront of the battles between the host and the invading pathogens. Recent studies have revealed that the epithelium not only constitutes a physical barrier but also takes an essential role in the activation of the immune system. One of the mechanisms equipped in the epithelium to fight against microorganisms is the Toll-like receptor (TLR) response. TLRs recognize common structural components of microorganisms and activate the innate immune system, resulting in the production of a plethora of cytokines and chemokines in the response against microbes. As the epithelia-derived cytokines are deeply involved in the pathogenesis of inflammatory conditions in the nasal cavity and paranasal sinuses, such as chronic rhinosinusitis (CRS) and allergic rhinitis (AR), the molecules involved in the TLR response may be utilized as therapeutic targets for these diseases. There are several differences in the TLR response between nasal and bronchial epithelial cells, and knowledge of the TLR signals in the upper airway is sparse compared to that in the lower airway. In this review, we provide recent evidence on TLR signaling in the upper airway, focusing on the expression, regulation, and responsiveness of TLRs in human nasal epithelial cells (HNECs). We also discuss how TLRs in the epithelium are involved in the pathogenesis of, and possible therapeutic targeting, for CRS and AR.