Publications by authors named "Toru Suzuki"

333 Publications

An Myh11 single lysine deletion causes aortic dissection by reducing aortic structural integrity and contractility.

Sci Rep 2022 May 25;12(1):8844. Epub 2022 May 25.

Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.

Pathogenic variants in myosin heavy chain (Myh11) cause familial thoracic aortic aneurysms and dissections (FTAAD). However, the underlying pathological mechanisms remain unclear because of a lack of animal models. In this study, we established a mouse model with Myh11 K1256del, the pathogenic variant we found previously in two FTAAD families. The Myh11 aorta showed increased wall thickness and ultrastructural abnormalities, including weakened cell adhesion. Notably, the Myh11 mice developed aortic dissections and intramural haematomas when stimulated with angiotensin II. Mechanistically, integrin subunit alpha2 (Itga2) was downregulated in the Myh11 aortas, and the smooth muscle cell lineage cells that differentiated from Myh11 induced pluripotent stem cells. The contractility of the Myh11 aortas in response to phenylephrine was also reduced. These results imply that the suboptimal cell adhesion indicated by Itga2 downregulation causes a defect in the contraction of the aorta. Consequently, the defective contraction may increase the haemodynamic stress underlying the aortic dissections.
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http://dx.doi.org/10.1038/s41598-022-12418-8DOI Listing
May 2022

The Gut Axis Involvement in Heart Failure: Focus on Trimethylamine N-oxide.

Cardiol Clin 2022 May;40(2):161-169

Department of Cardiovascular Sciences, NIHR Leicester Cardiovascular Biomedical Research Centre, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK. Electronic address:

A novel pathophysiological model of interest is the association between heart failure (HF) and the gastrointestinal system, the 'gut hypothesis'. The choline and carnitine metabolic by-product, Trimethylamine N-oxide (TMAO) is one of the more prominent molecules associated with the link between HF and the gut. Indeed, TMAO levels are increased in HF populations and higher TMAO levels are associated with poor prognosis, whereas low TMAO levels either at baseline/follow up confer better prognosis. Considering that TMAO levels seem not to be affected by guideline-HF treatment, this model could represent a novel and independent therapeutic target for HF.
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http://dx.doi.org/10.1016/j.ccl.2021.12.004DOI Listing
May 2022

Development of Low-Molecular-Weight Compounds Targeting the Cancer-Associated KLF5 Transcription Factor.

ACS Med Chem Lett 2022 Apr 28;13(4):687-694. Epub 2022 Mar 28.

Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.

Krüppel-like factor 5 (KLF5) is a potential target for anticancer drugs. However, as an intrinsically disordered protein (IDP) whose tertiary structure cannot be solved, innovative strategies are needed. We focused on its hydrophobic α-helix structure, defined as an induced helical motif (IHM), which is a possible interface for protein-protein interaction. Using mathematical analyses predicting the α-helix's structure and hydrophobicity, a 4-amino-acid site (V-A-I-F) was identified as an IHM. Low-molecular-weight compounds that mimic the main chain conformation of the α-helix with the four side chains of V-A-I-F were synthesized using bicyclic pyrazinooxadiazine-4,7-dione. These compounds selectively suppressed the proliferation and survival of cancer cells but not noncancer cells and decreased the protein but not mRNA levels of KLF5 in addition to reducing proteins of Wnt signaling. The compounds further suppressed transplanted colorectal cancer cells without side effects. Our approach appears promising for developing drugs against key IDPs.
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http://dx.doi.org/10.1021/acsmedchemlett.1c00721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9014505PMC
April 2022

Insulin-like growth factor-1 (IGF-1) as predictor of cardiovascular mortality in heart failure patients: data from the T.O.S.CA. registry.

Intern Emerg Med 2022 Apr 21. Epub 2022 Apr 21.

Department of Translational Medical Sciences, Federico II University, Naples, Italy.

Introduction: Data from the "Trattamento Ormonale nello Scompenso CArdiaco" (T.O.S.CA) registry showed that heart failure (HF) represents a complex clinical syndrome with different hormonal alterations. Renal failure represents a frequent complication in HF. We evaluated the relationship between renal function and insuline-like growth factor-1 (IGF-1) deficiency and its impact on cardiovascular mortality (CVM) in patients enrolled in the T.O.S.CA. registry.

Methods: At the enrolment, all subjects underwent chemistry examinations, including circulating hormones and cardiovascular functional tests. COX regression analysis was used to evaluate factors related to CVM during the follow-up period in all populations, in high-risk patients and in the young-adult population. Also, we evaluate the effects of renal function on the CVM.

Results: 337 patients (41 deceased) were analyzed. CVM was related to severe renal dysfunction (HR stages IV-V = 4.86), high-risk conditions (HR 2.25), serum IGF-1 (HR 0.42), and HF etiology (HR 5.85 and HR 1.63 for valvular and ischemic etiology, respectively). In high-risk patients, CVM was related to IGF-1 levels, severe renal dysfunction and valvular etiology, whereas in young patients CMV was related to the high-risk pattern and serum IGF-1 levels.

Conclusions: Our study showed the clinical and prognostic utility of the IGF-1 assay in patients with HF.
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http://dx.doi.org/10.1007/s11739-022-02980-4DOI Listing
April 2022

Surrogate markers of gut dysfunction are related to heart failure severity and outcome-from the BIOSTAT-CHF consortium.

Am Heart J 2022 Jun 10;248:108-119. Epub 2022 Mar 10.

Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Leicester, UK; The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Electronic address:

Background: The contribution of gut dysfunction to heart failure (HF) pathophysiology is not routinely assessed. We sought to investigate whether biomarkers of gut dysfunction would be useful in assessment of HF (eg, severity, adverse outcomes) and risk stratification.

Methods: A panel of gut-related biomarkers including metabolites of the choline/carnitine- pathway (acetyl-L-carnitine, betaine, choline, γ-butyrobetaine, L-carnitine and trimethylamine-N-oxide [TMAO]) and the gut peptide, Trefoil factor-3 (TFF-3), were investigated in 1,783 patients with worsening HF enrolled in the systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) cohort and associations with HF severity and outcomes, and use in risk stratification were assessed.

Results: Metabolites of the carnitine-TMAO pathway (acetyl-L-carnitine, γ-butyrobetaine, L-carnitine, and TMAO) and TFF-3 were associated with the composite outcome of HF hospitalization or all-cause mortality at 3 years (hazards ratio [HR] 2.04-2.93 [95% confidence interval {CI} 1.30-4.71] P≤ .002). Combining the carnitine-TMAO metabolites with TFF-3, as a gut dysfunction panel, showed a graded association; a greater number of elevated markers was associated with higher New York Heart Association class (P< .001), higher plasma concentrations of B-type natriuretic peptide (P< .001), and worse outcome (HR 1.90-4.58 [95% CI 1.19-6.74] P≤ 0.008). Addition of gut dysfunction biomarkers to the contemporary BIOSTAT HF risk model also improved prediction for the aforementioned composite outcome (C-statistics P≤ .011, NRI 13.5-21.1 [95% CI 2.7-31.9] P≤ .014).

Conclusions: A panel of biomarkers of gut dysfunction showed graded association with severity of HF and adverse outcomes. Biomarkers as surrogate markers are potentially useful for assessment of gut dysfunction to HF pathophysiology and in risk stratification.
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http://dx.doi.org/10.1016/j.ahj.2022.03.002DOI Listing
June 2022

Dysfunction of parvalbumin-expressing cells in the thalamic reticular nucleus induces cortical spike-and-wave discharges and an unconscious state.

Brain Commun 2022 28;4(2):fcac010. Epub 2022 Jan 28.

Department of Neuropsychiatry, Keio University School of Medicine, Tokyo 160-8582, Japan.

Spike-and-wave discharges and an accompanying loss of consciousness are hallmarks of absence seizure, which is a childhood generalized epilepsy disorder. In absence seizure, dysfunction of the cortico-thalamo-cortico circuitry is thought to engage in abnormal cortical rhythms. Previous studies demonstrated that the thalamic reticular nucleus has a critical role in the formation of normal cortical rhythms; however, whether thalamic reticular nucleus dysfunction leads directly to abnormal rhythms, such as epilepsy, is largely unknown. We found that expressing the inhibitory opsin, archaerhodopsin, including in the thalamic reticular nucleus, caused abnormal cortical rhythms in -tetracycline transactivator::tetO-ArchT (PV-ArchT) double transgenic mice. We validated the PV-ArchT line as a new mouse model of absence seizure through physiological and pharmacological analyses, as well as through examining their behavioural features. We then discovered that archaerhodopsin expression exclusively in thalamic reticular nucleus parvalbumin-positive neurons was sufficient to induce cortical spike-and-wave discharges using adeno-associated virus-mediated thalamic reticular nucleus targeting. Furthermore, we found that archaerhodopsin expression impaired rebound burst firing and T-current in thalamic reticular nucleus parvalbumin-positive cells by slice physiology. Although T-current in the thalamic reticular nucleus was impaired, the T-current blocker ethosuximide still had a therapeutic effect in PV-ArchT mice, suggesting a gain of function of T-type calcium channels in this absence seizure model. However, we did not find any over- or misexpression of T-type calcium channel genes in the thalamus or the cortex. Thus, we demonstrated that thalamic reticular nucleus dysfunction led to an absence seizure-like phenotype in mice. In a final set of experiments, we showed that the archaerhodopsin-mediated absence seizure-like phenotype disappeared after the removal of archaerhodopsin by using a time-controllable transgenic system. These data may provide a hint as to why many absence seizures naturally regress.
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http://dx.doi.org/10.1093/braincomms/fcac010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8887905PMC
January 2022

Deficiency of the kidney tubular angiotensin II type1 receptor-associated protein ATRAP exacerbates streptozotocin-induced diabetic glomerular injury via reducing protective macrophage polarization.

Kidney Int 2022 05 1;101(5):912-928. Epub 2022 Mar 1.

Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Although activation of the renin-angiotensin system and of its glomerular components is implicated in the pathogenesis of diabetic nephropathy, the functional roles of the tubular renin-angiotensin system with AT1 receptor signaling in diabetic nephropathy are unclear. Tissue hyperactivity of the renin-angiotensin system is inhibited by the angiotensin II type 1 receptor-associated protein ATRAP, which negatively regulates receptor signaling. The highest expression of endogenous ATRAP occurs in the kidney, where it is mainly expressed by tubules but rarely in glomeruli. Here, we found that hyperactivation of angiotensin II type 1 receptor signaling in kidney tubules exacerbated diabetic glomerular injury in a mouse model of streptozotocin-induced diabetic nephropathy. These phenomena were accompanied by decreased expression of CD206, a marker of alternatively activated and tissue-reparative M2 macrophages, in the kidney tubulointerstitium. Additionally, adoptive transfer of M2- polarized macrophages into diabetic ATRAP-knockout mice ameliorated the glomerular injury. As a possible mechanism, the glomerular mRNA levels of tumor necrosis factor-α and oxidative stress components were increased in diabetic knockout mice compared to non-diabetic knockout mice, but these increases were ameliorated by adoptive transfer. Furthermore, proximal tubule-specific ATRAP downregulation reduced tubulointerstitial expression of CD206, the marker of M2 macrophages in diabetic mice. Thus, our findings indicate that tubular ATRAP-mediated functional modulation of angiotensin II type 1 receptor signaling modulates the accumulation of tubulointerstitial M2 macrophages, thus affecting glomerular manifestations of diabetic nephropathy via tubule-glomerular crosstalk.
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http://dx.doi.org/10.1016/j.kint.2022.01.031DOI Listing
May 2022

Association of gut-related metabolites with respiratory symptoms in COVID-19: A proof-of-concept study.

Nutrition 2022 04 5;96:111585. Epub 2022 Jan 5.

Department of Cardiovascular Sciences, University of Leicester, Leicester, National Institute for Health Research Leicester Biomedical Research Centre, Leicester, United Kingdom; The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Electronic address:

Gut-related metabolites have been linked with respiratory disease. The crosstalk between the gut and lungs suggests that gut health may be compromised in COVID-19. The aims of the present study were to analyze a panel of gut-related metabolites (acetyl-L-carnitine, betaine, choline, L-carnitine, trimethylamine, and trimethylamine N-oxide) in patients with COVID-19, matched with healthy individuals and patients with non-COVID-19 respiratory symptoms. As results, metabolites from this panel were impaired in patients with COVID-19 and were associated with the symptoms of breathlessness and temperature, and it was possible to differentiate between COVID-19 and asthma. Preliminary results showed that lower levels of betaine appeared to be associated with poor outcomes in patients with COVID-19, suggesting betaine as a marker of gut microbiome health.
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http://dx.doi.org/10.1016/j.nut.2021.111585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8730784PMC
April 2022

Regulation of CCR4-NOT complex deadenylase activity and cellular responses by MK2-dependent phosphorylation of CNOT2.

RNA Biol 2022 31;19(1):234-246. Epub 2021 Dec 31.

Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Onna, Japan.

CCR4-NOT complex-mediated mRNA deadenylation serves critical functions in multiple biological processes, yet how this activity is regulated is not fully understood. Here, we show that osmotic stress induces MAPKAPK-2 (MK2)-mediated phosphorylation of CNOT2. Programmed cell death is greatly enhanced by osmotic stress in CNOT2-depleted cells, indicating that CNOT2 is responsible for stress resistance of cells. Although wild-type (WT) and non-phosphorylatable CNOT2 mutants reverse this sensitivity, a phosphomimetic form of CNOT2, in which serine at the phosphorylation site is replaced with glutamate, does not have this function. We also show that mRNAs have elongated poly(A) tails in CNOT2-depleted cells and that introduction of CNOT2 WT or a non-phosphorylatable mutant, but not phosphomimetic CNOT2, renders their poly(A) tail lengths comparable to those in control HeLa cells. Consistent with this, the CCR4-NOT complex containing phosphomimetic CNOT2 exhibits less deadenylase activity than that containing CNOT2 WT. These data suggest that CCR4-NOT complex deadenylase activity is regulated by post-translational modification, yielding dynamic control of mRNA deadenylation.
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http://dx.doi.org/10.1080/15476286.2021.2021676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820811PMC
March 2022

Microbiomes in physiology: insights into 21st-century global medical challenges.

Exp Physiol 2022 04 14;107(4):257-264. Epub 2022 Feb 14.

Quadram Institute Bioscience, Food Innovation and Health & Gut Microbes in Health and Disease Programmes, Quadram Institute Bioscience, Norwich, UK.

New Findings: What is the topic of this review? The role of the gut microbiome in physiology and how it can be targeted as an effective strategy against two of the most important global medical challenges of our time, namely, metabolic diseases and antibacterial resistance. What advances does it highlight? The critical roles of the microbiome in regulating host physiology and how microbiome analysis is useful for disease stratification to enable informed clinical decisions and develop interventions such as faecal microbiota transplantation, prebiotics and probiotics. Also, the limitations of microbiome modulation, including the potential for probiotics to enhance antimicrobial resistance gene reservoirs, and that currently a 'healthy microbiome' that can be used as a biobank for transplantation is yet to be defined.

Abstract: The human gut microbiome is a key factor in the development of metabolic diseases and antimicrobial resistance, which are among the greatest global medical challenges of the 21st century. A recent symposium aimed to highlight state-of-the-art evidence for the role of the gut microbiome in physiology, from childhood to adulthood, and the impact this has on global disease outcomes, ageing and antimicrobial resistance. Although the gut microbiome is established early in life, over time the microbiome and its components including metabolites can become perturbed due to changes such as dietary habits, use of antibiotics and age. As gut microbial metabolites, including short-chain fatty acids, secondary bile acids and trimethylamine-N-oxide, can interact with host receptors including G protein-coupled receptors and can alter host metabolic fluxes, they can significantly affect physiological homoeostasis leading to metabolic diseases. These metabolites can be used to stratify disease phenotypes such as irritable bowel syndrome and adverse events after heart failure and allow informed decisions on clinical management and treatment. While strategies such as use of probiotics, prebiotics and faecal microbiota transplantation have been proposed as interventions to treat and prevent metabolic diseases and antimicrobial resistance, caution must be exercised, first due to the potential of probiotics to enhance antimicrobial resistance gene reservoirs, and second, a 'healthy gut microbiome' that can be used as a biobank for transplantation is yet to be defined. We highlight that sampling other parts of the gastrointestinal tract may produce more representative data than the faecal microbiome alone.
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http://dx.doi.org/10.1113/EP090226DOI Listing
April 2022

Downregulation of Bdnf Expression in Adult Mice Causes Body Weight Gain.

Neurochem Res 2022 Jan 4. Epub 2022 Jan 4.

Division of Brain Sciences, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan.

Gain or loss of appetite and resulting body weight changes are commonly observed in major depressive disorders (MDDs). Brain-derived neurotrophic factor (BDNF) is broadly expressed in the brain and is thought to play a role in the pathophysiology of MDDs and obesity. Congenital loss of function of BDNF causes weight gain in both humans and rodents; however, it is not clear whether acquired loss of function of BDNF also affects body weight. Thus, we exploited mutant mice in which the Bdnf expression level is regulated by the tetracycline-dependent transcriptional silencer (tTS)-tetracycline operator sequence (tetO) system. Time-controlled Bdnf expression using this system allowed us to establish congenital and acquired loss of function of Bdnf in mice. We demonstrated that changes in Bdnf expression influenced body weight during not only the developmental stage but also the adult stage of mice. Although it is still unclear whether acquired Bdnf loss of function in rodents mimics the pathology of MDD, our findings may bridge the mechanistic gap between MDDs and body weight gain in line with BDNF dysfunction.
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http://dx.doi.org/10.1007/s11064-021-03523-7DOI Listing
January 2022

Machine learning assisted optimization of blending process of polyphenylene sulfide with elastomer using high speed twin screw extruder.

Sci Rep 2021 Dec 15;11(1):24079. Epub 2021 Dec 15.

Research Institute for Chemical Process Technology, National Institute of Advanced Industrial Science and Technology (AIST), Higashi 1-1-1, Tsukuba, Ibaraki, 305-8565, Japan.

Random forest regression was applied to optimize the melt-blending process of polyphenylene sulfide (PPS) with poly(ethylene-glycidyl methacrylate-methyl acrylate) (E-GMA-MA) elastomer to improve the Charpy impact strength. A training dataset was constructed using four elastomers with different GMA and MA contents by varying the elastomer content up to 20 wt% and the screw rotation speed of the extruder up to 5000 rpm at a fixed barrel temperature of 300 °C. Besides the controlled parameters, the following measured parameters were incorporated into the descriptors for the regression: motor torque, polymer pressure, and polymer temperatures monitored by infrared-ray thermometers installed at four positions (T1 to T4) as well as the melt viscosity and elastomer particle diameter of the product. The regression without prior knowledge revealed that the polymer temperature T1 just after the first kneading block is an important parameter next to the elastomer content. High impact strength required high elastomer content and T1 below 320 °C. The polymer temperature T1 was much higher than the barrel temperature and increased with the screw speed due to the heat of shear. The overheating caused thermal degradation, leading to a decrease in the melt viscosity and an increase in the particle diameter at high screw speed. We thus reduced the barrel temperature to keep T1 around 310 °C. This increased the impact strength from 58.6 kJ m as the maximum in the training dataset to 65.3 and 69.0 kJ m at elastomer contents of 20 and 30 wt%, respectively.
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http://dx.doi.org/10.1038/s41598-021-03513-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8674312PMC
December 2021

Effects of tumor necrosis factor-α inhibition on kidney fibrosis and inflammation in a mouse model of aristolochic acid nephropathy.

Sci Rep 2021 12 8;11(1):23587. Epub 2021 Dec 8.

Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Japan.

Tumor necrosis factor (TNF)-α is a potent mediator of inflammation and is involved in the pathophysiology of chronic kidney disease (CKD). However, the effects of TNF-α inhibition on the progression of kidney fibrosis have not been fully elucidated. We examined the effects of TNF-α inhibition by etanercept (ETN) on kidney inflammation and fibrosis in mice with aristolochic acid (AA) nephropathy as a model of kidney fibrosis. C57BL/6 J mice were administered AA for 4 weeks, followed by a 4-week remodeling period. The mice exhibited kidney fibrosis, functional decline, and albuminuria concomitant with increases in renal mRNA expression of inflammation- and fibrosis-related genes. The 8-week ETN treatment partially but significantly attenuated kidney fibrosis and ameliorated albuminuria without affecting kidney function. These findings were accompanied by significant suppression of interleukin (IL)-1β, IL-6, and collagen types I and III mRNA expression. Moreover, ETN tended to reduce the AA-induced increase in interstitial TUNEL-positive cells with a significant reduction in Bax mRNA expression. Renal phosphorylated p38 MAPK was significantly upregulated by AA but was normalized by ETN. These findings indicate a substantial role for the TNF-α pathway in the pathogenesis of kidney fibrosis and suggest that TNF-α inhibition could become an adjunct therapeutic strategy for CKD with fibrosis.
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http://dx.doi.org/10.1038/s41598-021-02864-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8654826PMC
December 2021

Aristolochic Acid Induces Renal Fibrosis and Senescence in Mice.

Int J Mol Sci 2021 Nov 18;22(22). Epub 2021 Nov 18.

Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.

The kidney is one of the most susceptible organs to age-related impairments. Generally, renal aging is accompanied by renal fibrosis, which is the final common pathway of chronic kidney diseases. Aristolochic acid (AA), a nephrotoxic agent, causes AA nephropathy (AAN), which is characterized by progressive renal fibrosis and functional decline. Although renal fibrosis is associated with renal aging, whether AA induces renal aging remains unclear. The aim of the present study is to investigate the potential use of AAN as a model of renal aging. Here, we examined senescence-related factors in AAN models by chronically administering AA to C57BL/6 mice. Compared with controls, the AA group demonstrated aging kidney phenotypes, such as renal atrophy, renal functional decline, and tubulointerstitial fibrosis. Additionally, AA promoted cellular senescence specifically in the kidneys, and increased renal p16 mRNA expression and senescence-associated β-galactosidase activity. Furthermore, AA-treated mice exhibited proximal tubular mitochondrial abnormalities, as well as reactive oxygen species accumulation. Klotho, an antiaging gene, was also significantly decreased in the kidneys of AA-treated mice. Collectively, the results of the present study indicate that AA alters senescence-related factors, and that renal fibrosis is closely related to renal aging.
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http://dx.doi.org/10.3390/ijms222212432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618437PMC
November 2021

Chemerin Regulates Epithelial Barrier Function of Mammary Glands in Dairy Cows.

Animals (Basel) 2021 Nov 9;11(11). Epub 2021 Nov 9.

Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-0842, Japan.

Epithelial barrier function in the mammary gland acts as a forefront of the defense mechanism against mastitis, which is widespread and a major disorder in dairy production. Chemerin is a chemoattractant protein with potent antimicrobial ability, but its role in the mammary gland remains unelucidated. The aim of this study was to determine the function of chemerin in mammary epithelial tissue of dairy cows in lactation or dry-off periods. Mammary epithelial cells produced chemerin protein, and secreted chemerin was detected in milk samples. Chemerin treatment promoted the proliferation of cultured bovine mammary epithelial cells and protected the integrity of the epithelial cell layer from hydrogen peroxide (HO)-induced damage. Meanwhile, chemerin levels were higher in mammary tissue with mastitis. Tumor necrosis factor alpha (TNF-α) strongly upregulated the expression of the chemerin-coding gene () in mammary epithelial cells. Therefore, chemerin was suggested to support mammary epithelial cell growth and epithelial barrier function and to be regulated by inflammatory stimuli. Our results may indicate chemerin as a novel therapeutic target for diseases in the bovine mammary gland.
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http://dx.doi.org/10.3390/ani11113194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8614423PMC
November 2021

Tissue-specific expression of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2, in mouse models of chronic kidney disease.

Sci Rep 2021 08 19;11(1):16843. Epub 2021 Aug 19.

Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Elevated angiotensin-converting enzyme 2 (ACE2) expression in organs that are potential targets of severe acute respiratory syndrome coronavirus 2 may increase the risk of coronavirus disease 2019 (COVID-19) infection. Previous reports show that ACE2 alter its tissue-specific expression patterns under various pathological conditions, including renal diseases. Here, we examined changes in pulmonary ACE2 expression in two mouse chronic kidney disease (CKD) models: adenine-induced (adenine mice) and aristolochic acid-induced (AA mice). We also investigated changes in pulmonary ACE2 expression due to renin-angiotensin system (RAS) blocker (olmesartan) treatment in these mice. Adenine mice showed significant renal functional decline and elevated blood pressure, compared with controls. AA mice also showed significant renal functional decline, compared with vehicles; blood pressure did not differ between groups. Renal ACE2 expression was significantly reduced in adenine mice and AA mice; pulmonary expression was unaffected. Olmesartan attenuated urinary albumin excretion in adenine mice, but did not affect renal or pulmonary ACE2 expression levels. The results suggest that the risk of COVID-19 infection may not be elevated in patients with CKD because of their stable pulmonary ACE2 expression. Moreover, RAS blockers can be used safely in treatment of COVID-19 patients with CKD.
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http://dx.doi.org/10.1038/s41598-021-96294-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377123PMC
August 2021

Genomic imprinting in mouse blastocysts is predominantly associated with H3K27me3.

Nat Commun 2021 06 21;12(1):3804. Epub 2021 Jun 21.

Max Perutz Laboratories Vienna, University of Vienna, Vienna Biocenter, Vienna, Austria.

In mammalian genomes, differentially methylated regions (DMRs) and histone marks including trimethylation of histone 3 lysine 27 (H3K27me3) at imprinted genes are asymmetrically inherited to control parentally-biased gene expression. However, neither parent-of-origin-specific transcription nor imprints have been comprehensively mapped at the blastocyst stage of preimplantation development. Here, we address this by integrating transcriptomic and epigenomic approaches in mouse preimplantation embryos. We find that seventy-one genes exhibit previously unreported parent-of-origin-specific expression in blastocysts (nBiX: novel blastocyst-imprinted expressed). Uniparental expression of nBiX genes disappears soon after implantation. Micro-whole-genome bisulfite sequencing (µWGBS) of individual uniparental blastocysts detects 859 DMRs. We further find that 16% of nBiX genes are associated with a DMR, whereas most are associated with parentally-biased H3K27me3, suggesting a role for Polycomb-mediated imprinting in blastocysts. nBiX genes are clustered: five clusters contained at least one published imprinted gene, and five clusters exclusively contained nBiX genes. These data suggest that early development undergoes a complex program of stage-specific imprinting involving different tiers of regulation.
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http://dx.doi.org/10.1038/s41467-021-23510-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217501PMC
June 2021

Exercise Intolerance in Heart Failure with Preserved Ejection Fraction.

Heart Fail Clin 2021 Jul;17(3):397-413

Department of Translational Medical Sciences, Federico II University, Naples, Italy.

Exercise intolerance represents a typical feature of heart failure with preserved ejection fraction (HFpEF), and is associated with a poor quality of life, frequent hospitalizations, and increased all-cause mortality. The cardiopulmonary exercise test is the best method to quantify exercise intolerance, and allows detection of the main mechanism responsible for the exercise limitation, influencing treatment and prognosis. Exercise training programs improve exercise tolerance in HFpEF. However, studies are needed to identify appropriate type and duration. This article discusses the pathophysiology of exercise limitation in HFpEF, describes methods of determining exercise tolerance class, and evaluates prognostic implications and potential therapeutic strategies.
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http://dx.doi.org/10.1016/j.hfc.2021.03.004DOI Listing
July 2021

Ninjin'yoeito, a traditional Japanese Kampo medicine, suppresses the onset of anhedonia induced by dysfunction in the striatal dopamine receptor type 2-expressing medium spiny neurons.

Neuroreport 2021 07;32(10):869-874

Tsumura Kampo Research Laboratories, Tsumura & Co., Ibaraki.

Objective: Recent studies have suggested that ninjin'yoeito (NYT), a traditional Japanese Kampo medicine, improves diminished motivation in humans and animals, rendering it a novel therapeutic option for impaired motivation. To better characterize the effect of NYT on motivation, we examined its effect on motivated behaviors in mice.

Methods: Mouse models of neurodegeneration-related apathy, in which striatal dopamine receptor type 2-expressing medium spiny neurons (D2-MSNs) were progressively damaged by diphtheria toxin expression, were chosen.

Results: The decrease in effort-based operant responding for rewards (sucrose pellets), indicative of the mouse's motivated behavior, in the affected mice was not suppressed by chronic treatment with NYT suspended in drinking water at 1% (w/v). Mice were then subjected to a sucrose preference test, wherein they freely chose to ingest tap water and a sucrose solution without being required to exert effort. The affected mice showed a decline in preference for sucrose over tap water, relative to nonaffected controls, indicating anhedonia-like traits. In contrast to the diminished operant behavior, the anhedonic behavior in the affected mice was prevented by the NYT administration. Furthermore, NYT did not affect the size of Drd2 mRNA disappearance in the striatum of affected mice, suggesting that the NYT effect was unrelated to DTA-mediated neurodegeneration.

Conclusion: These results demonstrate that the beneficial effect of NYT on motivation is mediated, at least in part, through the potentiation of hedonic capacity by certain neuromodulatory pathways.
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http://dx.doi.org/10.1097/WNR.0000000000001667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240642PMC
July 2021

RNA decay machinery safeguards immune cell development and immunological responses.

Trends Immunol 2021 05 12;42(5):447-460. Epub 2021 Apr 12.

Laboratory for Immunogenetics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Onna, Okinawa 904-0495, Japan.

mRNA decay systems control mRNA abundance by counterbalancing transcription. Several recent studies show that mRNA decay pathways are crucial to conventional T and B cell development in vertebrates, in addition to suppressing autoimmunity and excessive inflammatory responses. Selective mRNA degradation triggered by the CCR4-NOT deadenylase complex appears to be required in lymphocyte development, cell quiescence, V(D)J (variable-diversity-joining) recombination, and prevention of inappropriate apoptosis in mice. Moreover, a recent study suggests that mRNA decay may be involved in preventing human hyperinflammatory disease. These findings imply that mRNA decay pathways in humans and mice do not simply maintain mRNA homeostatic turnover but can also precisely regulate immune development and immunological responses by selectively targeting mRNAs.
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http://dx.doi.org/10.1016/j.it.2021.03.008DOI Listing
May 2021

Evaluation of an 8-Week Vegan Diet on Plasma Trimethylamine-N-Oxide and Postchallenge Glucose in Adults with Dysglycemia or Obesity.

J Nutr 2021 07;151(7):1844-1853

Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, United Kingdom.

Background: Trimethylamine N-oxide (TMAO), a metabolite generated by the gut in response (in part) to meat consumption, is linked to poor cardiometabolic health.

Objectives: We investigate the effect of an 8-week vegan diet, followed by a 4-week period of unrestricted diet, on glucose tolerance and plasma TMAO in human omnivores with obesity or dysglycemia.

Methods: This interventional single-group prospective trial involved 23 regular meat eaters with dysglycemia [glycated hemoglobin ≥ 5.7% and ≤8% (39-64 mmol/mol)], or obesity (ΒΜΙ ≥ 30 kg/m2) aged 57.8 ± 10.0 years. Participants [14 men (60.9%) and 9 women (39.1%)] were supported in following a vegan diet for 8 weeks, followed by 4 weeks of unrestricted diet. The primary outcomes (plasma TMAO and glucose) were assessed at baseline, during the vegan diet (weeks 1 and 8), and after the unrestricted diet period (week 12). TMAO was assessed after fasting and glucose was measured as a time-averaged total AUC using a 180-minute oral-glucose-tolerance test. Generalized estimating equation models with an exchangeable correlation structure were used to assess changes from baseline, adjusting for age, sex, ethnicity, and weight.

Results: TMAO levels (marginal mean) were reduced after weeks 1 and 8 of a vegan diet compared to baseline, from 10.7 (97.5% CI, 6.61-17.3) μmol/L to 5.66 (97.5% CI, 4.56-7.02) μmol/L and 6.38 (97.5% CI, 5.25-7.74) μmol/L, respectively; however, levels rebounded at week 12 after resumption of an unrestricted diet (17.5 μmol/L; 97.5% CI, 7.98-38.4). Postprandial glucose levels (marginal means) were reduced after weeks 1 and 8 compared to baseline, from 8.07 (97.5% CI, 7.24-8.90) mmol/L to 7.14 (97.5% CI, 6.30-7.98) mmol/L and 7.34 (97.5% CI, 6.63-8.04) mmol/L, respectively. Results for glucose and TMAO were independent of weight loss. Improvements in the lipid profile and markers of renal function were observed at week 8.

Conclusions: These findings suggest that a vegan diet is an effective strategy for improving glucose tolerance and reducing plasma TMAO in individuals with dysglycemia or obesity. This study was registered at clinicaltrials.gov as NCT03315988.
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http://dx.doi.org/10.1093/jn/nxab046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245890PMC
July 2021

Multiple hormonal and metabolic deficiency syndrome predicts outcome in heart failure: the T.O.S.CA. Registry.

Eur J Prev Cardiol 2021 12;28(15):1691-1700

Clinical Medicine and Surgery Department, Federico II University, Naples, Italy.

Aims: Recent evidence supports the occurrence of multiple hormonal and metabolic deficiency syndrome (MHDS) in chronic heart failure (CHF). However, no large observational study has unequivocally demonstrated its impact on CHF progression and outcome. The T.O.S.CA. (Trattamento Ormonale nello Scompenso CArdiaco; Hormone Treatment in Heart Failure) Registry has been specifically designed to test the hypothesis that MHDS affects morbidity and mortality in CHF patients.

Methods And Results: The T.O.S.CA. Registry is a prospective, multicentre, observational study involving 19 Italian centres. Thyroid hormones, insulin-like growth factor-1, total testosterone, dehydropianoandrosterone sulfate, insulin resistance, and the presence of diabetes were evaluated. A MHDS was defined as the presence of ≥2 hormone deficiencies (HDs). Primary endpoint was a composite of all-cause mortality and cardiovascular hospitalizations. Four hundred and eighty heart failure patients with ejection fraction ≤45% were enrolled. MHDS or diabetes was diagnosed in 372 patients (77.5%). A total of 271 events (97 deaths and 174 cardiovascular hospitalizations) were recorded, 41% in NO-MHDS and 62% in MHDS (P < 0.001). Median follow-up was of 36 months. MHDS was independently associated with the occurrence of the primary endpoint [hazard ratio 95% (confidence interval), 1.93 (1.37-2.73), P < 0.001] and identified a group of patients with a higher mortality [2.2 (1.28-3.83), P = 0.01], with a graded relation between HDs and cumulative events (P < 0.01).

Conclusion: MHDS is common in CHF and independently associated with increased all-cause mortality and cardiovascular hospitalization, representing a promising therapeutic target.

Trial Registration: ClinicalTrials.gov identifier: NCT023358017.
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http://dx.doi.org/10.1093/eurjpc/zwab020DOI Listing
December 2021

Targeting the gut microbiome in coronary artery disease.

Am Heart J 2021 06 23;236:1-3. Epub 2021 Feb 23.

University of Leicester and NIHR Leicester Biomedical Research Centre, Leicester, United Kingdom.

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http://dx.doi.org/10.1016/j.ahj.2021.02.017DOI Listing
June 2021

Physical and structural characteristics of starch-based and conventional cookies: Water sorption, mechanical glass transition, and texture properties of their crust and crumb.

J Texture Stud 2021 06 4;52(3):347-357. Epub 2021 Feb 4.

Program of Food and AgriLife Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan.

The physical properties of starch-based cookie (gluten free and low fat) were compared with those of conventional cookie in consideration for the difference between crust and crumb parts. The internal porosity of the samples was measured by X-ray computed tomography. The starch-based cookie had a higher porosity (0.61) than the conventional cookie (0.42). The mechanical glass-transition temperature (T ) of the samples was evaluated by the thermal rheological analysis. The anhydrous mechanical T of the starch-based cookie was much lower than that of the conventional cookie. The T -depression of the starch-based cookie induced by water sorption was more gradual than that of the conventional cookie. For both types of cookie, the crust components were more resistant to water plasticizing than crumb components because of the difference of the equilibrium water contents at each water activity. For the texture analysis of crust components, the whole samples were fractured. The starch-based cookie had a lower fracture force, distance, and energy than the conventional cookie at each water activity point. For the texture analysis of crumb components, a portion of the crust was removed from the whole samples, and the exposed crumb was compressed by a plunger. From the texture profile, a normalized linear length was evaluated. The normalized linear length for the starch-based cookie was higher than that for the conventional cookie. These results were corresponded to the differences in the undeveloped gluten and fat contents.
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http://dx.doi.org/10.1111/jtxs.12585DOI Listing
June 2021

Association of gut-related metabolites with outcome in acute heart failure.

Am Heart J 2021 04 14;234:71-80. Epub 2021 Jan 14.

Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Leicester, United Kingdom. Electronic address:

Background: Trimethylamine N-oxide (TMAO), a gut-related metabolite, is associated with heart failure (HF) outcomes. However, TMAO is the final product of a complex metabolic pathway (ie, choline/carnitine) that has never been entirely investigated in HF. The present study investigates a panel of metabolites involved in the TMAO-choline/carnitine metabolic pathway for their associations with outcome in acute HF patients.

Methods: In total, 806 plasma samples from acute HF patients were analyzed for TMAO, trimethyllysine, L-carnitine, acetyl-L-carnitine, γ-butyrobetaine, crotonobetaine, trimethylamine, betaine aldehyde, choline, and betaine using a developed liquid chromatography-tandem mass spectrometry method. Associations with outcome of all-cause mortality (death) and a composite of all-cause mortality and/or rehospitalization caused by HF (death/HF) at 30 days and 1 year were investigated.

Results: TMAO, trimethyllysine, L-carnitine, acetyl-L-carnitine, and γ-butyrobetaine were associated with death and death/HF at 30 days (short term; hazard ratio 1.30-1.49, P≤ .021) and at 1 year (long term; hazard ratio 1.15-1.25, P≤ .026) when adjusted for cardiac risk factors. L-carnitine and acetyl-L-carnitine were superior for short-term outcomes whereas TMAO was the superior metabolite for association with long-term outcomes. Furthermore, acetyl-L-carnitine and L-carnitine were superior for in-hospital mortality and improved risk stratification when combined with current clinical risk scores (ie, Acute Decompensated HEart Failure National REgistry, Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure, and Get With The Guidelines-Heart Failure; odds ratio (OR) ≥ 1.52, P≤ .020).

Conclusions: Carnitine-related metabolites show associations with adverse outcomes in acute HF, in particular L-carnitine and acetyl-L-carnitine for short-term outcomes, and TMAO for long-term outcomes. Further studies are warranted to investigate the role and implications of carnitine metabolites including intervention in the pathogenesis of HF.
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http://dx.doi.org/10.1016/j.ahj.2021.01.006DOI Listing
April 2021

Tissue xanthine oxidoreductase activity in a mouse model of aristolochic acid nephropathy.

FEBS Open Bio 2021 02 1;11(2):507-518. Epub 2021 Feb 1.

Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.

Xanthine oxidoreductase (XOR) is a critical enzyme in purine metabolism and uric acid production, and its levels are reported to increase during stress, thereby promoting organ damage. Herein, we investigated the activity of XOR in a mouse model of aristolochic acid I (AA)-induced nephropathy, a type of nephrotoxic chronic kidney disease (CKD). A persistent decrease in renal function was observed in mice up to 4 weeks after 4 weeks of AA (2.5 mg kg ) administration. Renal histology revealed an increase in tubular interstitial fibrosis over time. Although AA administration did not change XOR activity in the plasma, heart, liver, or muscle, XOR activity was persistently increased in renal tissue. Our results suggest that the renal tissue-specific increase in XOR activity is involved in the progression of tubulo-interstitial disorders, specifically fibrosis.
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http://dx.doi.org/10.1002/2211-5463.13083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876505PMC
February 2021

[A case of Endocrine Active Retroperitoneal Ganglioneuroma, Difficult to Differentiate From Adrenal Pheochromocytoma].

Hinyokika Kiyo 2020 Dec;66(12):439-442

The Department of Surgical Pathology, Hyogo College of Medicine.

A 66-year-old woman who had been receiving medication for hypertension and hyperlipidemia was referred to our hospital for evaluation of a left adrenal tumor (12×8 mm) that was incidentally detected on computed tomography. Her 24-hour urinary catecholamine level was elevated, and metaiodobenzylguanidine (MIBG) scintigraphy revealed increased uptake in the area around the left adrenal gland, necessitating laparoscopic adrenalectomy for preoperative diagnosis of left adrenal pheochromocytoma. Intraoperatively, we detected a para-aortic tumor behind the adrenal gland, and this lesion was excised together with the adrenal gland. However, manipulation of the para-aortic tumor led to elevation in the blood pressure to 170 mmHg. Histopathological examination of the resected specimens revealed an adrenocortical adenoma and a para-aortic ganglioneuroma, consisting of ganglion cells, nerve fibers, and Schwann cells. The patient's blood pressure normalized immediately postoperatively, and MIBG scintigraphy revealed a negative result. Endocrine active ganglioneuromas are rare, and to our knowledge, currently only 8 cases (including ours) have been reported in the Japanese and English literature.
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http://dx.doi.org/10.14989/ActaUrolJap_66_12_439DOI Listing
December 2020

Cardiovascular and renal outcomes with SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and network meta-analysis.

Cardiovasc Diabetol 2021 01 7;20(1):14. Epub 2021 Jan 7.

Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3 Chome-9 Fukuura, Kanazawa Ward, Yokohama, Kanagawa, 236-0004, Japan.

Background: Emerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with decreased risk of cardiovascular and renal events in type 2 diabetes mellitus (DM) patients. However, no study to date has compared the effect of SGLT-2 inhibitors with that of GLP-1 RAs in type 2 DM patients with chronic kidney disease (CKD). We herein investigated the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients.

Methods: We performed a systematic literature search through November 2020. We selected randomized control trials that compared the risk of major adverse cardiovascular events (MACE) and a composite of renal outcomes. We performed a network meta-analysis to compare SGLT-2 inhibitors with GLP-1 RAs indirectly. Risk ratios (RRs) with corresponding 95% confidence intervals (CI) were synthesized.

Results: Thirteen studies were selected with a total of 32,949 patients. SGLT-2 inhibitors led to a risk reduction in MACE and renal events (RR [95% CI]; 0.85 [0.75-0.96] and 0.68 [0.59-0.78], respectively). However, GLP-1 RAs did not reduce the risk of cardiovascular or renal adverse events (RR 0.91 [0.80-1.04] and 0.86 [0.72-1.03], respectively). Compared to GLP-1 RAs, SGLT-2 inhibitors did not demonstrate a significant difference in MACE (RR 0.94 [0.78-1.12]), while SGLT-2 inhibitors were associated with a lower risk of renal events compared to GLP-1 RAs (RR 0.79 [0.63-0.99]). A sensitivity analysis revealed that GLP-1 analogues significantly decreased MACE when compared to placebo treatment (RR 0.81 [0.69-0.95]), while exendin-4 analogues did not (RR 1.03 [0.88-1.20]).

Conclusions: In patients with type 2 DM and CKD, SGLT-2 inhibitors were associated with a decreased risk of cardiovascular and renal events, but GLP-1 RAs were not. SGLT-2 inhibitors significantly decreased the risk of renal events compared to GLP-1 RAs. Among GLP-1 RAs, GLP-1 analogues showed a positive impact on cardiovascular and renal outcomes, while exendin-4 analogues did not.
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http://dx.doi.org/10.1186/s12933-020-01197-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792332PMC
January 2021

Regulation of Fetal Genes by Transitions among RNA-Binding Proteins during Liver Development.

Int J Mol Sci 2020 Dec 7;21(23). Epub 2020 Dec 7.

Center for Integrative Medical Sciences, Laboratory for Immunogenetics, RIKEN, Kanagawa 230-0045, Japan.

Transcripts of (), , and () genes are highly expressed in mouse fetal liver, but decrease drastically during maturation. While transcriptional regulation of these genes has been well studied, the post-transcriptional regulation of their developmental decrease is poorly understood. Here, we show that shortening of poly(A) tails and subsequent RNA decay are largely responsible for the postnatal decrease of , , and transcripts in mouse liver. IGF2 mRNA binding protein 1 (IMP1), which regulates stability and translation efficiency of target mRNAs, binds to these fetal liver transcripts. When IMP1 is exogenously expressed in mouse adult liver, fetal liver transcripts show higher expression and possess longer poly(A) tails, suggesting that IMP1 stabilizes them. IMP1 declines concomitantly with fetal liver transcripts as liver matures. Instead, RNA-binding proteins (RBPs) that promote RNA decay, such as cold shock domain containing protein E1 (CSDE1), K-homology domain splicing regulatory protein (KSRP), and CUG-BP1 and ETR3-like factors 1 (CELF1), bind to 3' regions of fetal liver transcripts. These data suggest that transitions among RBPs associated with fetal liver transcripts shift regulation from stabilization to decay, leading to a postnatal decrease in those fetal transcripts.
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http://dx.doi.org/10.3390/ijms21239319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731027PMC
December 2020
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