Novel pharmacologic inhibition of lysine-specific demethylase 1 as a potential therapeutic for glioblastoma.

Lysine-specific demethylase 1 (LSD1/KDM1A) is a pivotal epigenetic enzyme that contributes to several malignancies including malignant glioma. LSD1 is a flavin adenine dinucleotide dependent histone demethylase that specifically targets histone H3 lysine (K) 4 mono- (me1) and di-methylation (me2) and H3K9me1/2 for demethylation. Herein we report the development of an LSD inhibitor, S2172, which efficiently penetrates the blood-brain barrier.

Ureteral cancer successfully treated with laparoscopic nephroureterectomy with temporary intraoperative occlusion of the internal iliac artery for pelvic arteriovenous malformation.

Introduction: Pelvic arteriovenous malformation is often a source of intraoperative bleeding. Here, we report our experience with a case of ureteral cancer with pelvic arteriovenous malformation treated using laparoscopic nephroureterectomy with temporary intraoperative occlusion of the internal iliac artery.

Case Presentation: A 75-year-old man presented to our hospital with asymptomatic macro-hematuria.

Maternal Broccoli Powder Intake Ameliorates Insulin Resistance and Inflammation via AMPK/mTOR Pathway in the Livers of High-Fructose-Fed Male Rat Offspring Exposed to Maternal Protein Restriction.

Scope: Sub-optimal prenatal conditions such as maternal undernutrition during pregnancy and lactation posit high risks of adult metabolic diseases. High fructose intake causes insulin resistance and liver inflammation contributing to metabolic diseases. However, food-based preventive measure for these metabolic diseases in the offspring is under-researched.

Impact of home-based exercise on residual kidney function in patients initiating peritoneal dialysis: A feasibility multicenter randomized controlled trial.

Background: Although the impact of aerobic exercise (AE) and resistance training (RT) on peritoneal dialysis (PD) patients is well established, the impact of exercise programs on residual kidney function (RKF) has not been elucidated.

Methods: Patients were randomly assigned to either the exercise (= 25) or control groups (= 30). Patients in the exercise group performed AE three times a week and RT twice a week at home for 24 weeks.

Melinjo ( L) Extract Attenuates Colonic Inflammation in a Mouse Colitis Model by Regulating the AMPK/NFκB/Sirt1 Pathway.

Ulcerative colitis (UC) is a subtype of inflammatory bowel disease affecting the colon with idiopathic origin. Melinjo endosperm extract (MeE) contains polyphenolic compounds that have antioxidative and anticancer properties. We examined the effect of MeE on inflammation and mucin expression in the colons of UC of mice treated with dextran sulfate sodium (DSS).

Structural analyses of the GI.4 norovirus by cryo-electron microscopy and X-ray crystallography revealing binding sites for human monoclonal antibodies.

Unlabelled: Noroviruses are major causative agents of acute nonbacterial gastroenteritis in humans. There are neither antiviral therapeutic agents nor vaccines for noroviruses at this time. To evaluate the potential usefulness of two previously isolated human monoclonal antibody fragments, CV-1A1 and CV-2F5, we first conducted a single-particle analysis to determine the cryo-electron microscopy structure of virus-like particles (VLPs) from the genogroup I genotype 4 (GI.

Epigenetic mechanisms to propagate histone acetylation by p300/CBP.

Histone acetylation is important for the activation of gene transcription but little is known about its direct read/write mechanisms. Here, we report cryogenic electron microscopy structures in which a p300/CREB-binding protein (CBP) multidomain monomer recognizes histone H4 N-terminal tail (NT) acetylation (ac) in a nucleosome and acetylates non-H4 histone NTs within the same nucleosome. p300/CBP not only recognized H4NTac via the bromodomain pocket responsible for reading, but also interacted with the DNA minor grooves via the outside of that pocket.

Discovery of Novel Substrate-Competitive Lysine Methyltransferase G9a Inhibitors as Anticancer Agents.

Identification of structurally novel inhibitors of lysine methyltransferase G9a has been a subject of intense research in cancer epigenetics. Starting with the high-throughput screening (HTS) hit - obtained from the chemical library of the University of Tokyo Drug Discovery Initiative, the structure-activity relationship of the unique substrate-competitive inhibitors was established with the help of X-ray crystallography and fragment molecular orbital (FMO) calculations for the ligand-protein interaction. Further optimization of the characteristics and drug metabolism and pharmacokinetics (DMPK) properties led to the identification of (RK-701), which is a structurally distinct potent inhibitor of G9a/GLP (IC = 27/53 nM).

Curcumin intake during lactation suppresses oxidative stress through upregulation of nuclear factor erythroid 2-related factor 2 in the kidneys of fructose-loaded female rat offspring exposed to maternal protein restriction.

Background: A high-fructose diet causes the progression of chronic kidney disease. Maternal malnutrition during pregnancy and lactation increases oxidative stress, leading to chronic renal diseases later in life. We investigated whether curcumin intake during lactation could suppress oxidative stress and regulate NF-E2-related factor 2 (Nrf2) expression in the kidneys of fructose-loaded female rat offspring exposed to maternal protein restriction.

Mechanical Thrombectomy for Acute Common Carotid Artery Occlusion.

Mechanical thrombectomy (MT) is the standard treatment for acute large occlusion of the cerebral artery. Evidence for the success of this procedure was based on the treatment of patients with internal carotid artery and middle cerebral artery thrombi. There are a few reports on thrombi extending to the common carotid artery (CCA).

Structure-Activity Relationship and Evaluation of - and -PCPA-Derived Inhibitors of LSD1 and LSD2.

-2-Phenylcycloproylamine (-PCPA) has been used as the scaffold to develop covalent-binding inhibitors against lysine-specific demethylase 1 (LSD1/KDM1A), a therapeutic target for several cancers. However, the effects of different structural moieties on the inhibitory activity, selectivity, and reactivity of these derivatives, including the isomers, against LSD1 and its paralogue LSD2/KDM1B are not fully understood. Here we synthesized 65 - and -PCPA derivatives and evaluated their inhibitory activity against LSD1 and LSD2.

Changes of cortico-cortical neural connections associated with motor functional recovery after stroke.

Objectives: During functional recovery after stroke, some neural connections in the brain are augmented and new neural networks are constructed to compensate for impaired neurological functions. Recently, it was reported that the extent of cortico-cortical neural connections can be estimated by correlation analysis based on electroencephalography (EEG). The purpose of this study was to investigate changes of correlation coefficients in the cerebral cortex with motor functional recovery after stroke.

Rocuronium versus saline for effective facemask ventilation during anesthesia induction: a double-blinded randomized placebo-controlled trial.

Background: Mask ventilation progressively improves after loss of consciousness during anesthesia induction possibly due to progression of muscle paralysis. This double-blinded randomized placebo-controlled study aimed to test a hypothesis that muscle paralysis improves mask ventilation during anesthesia induction.

Methods: Forty-four adults patients including moderate to severe obstructive sleep apnea undergoing scheduled surgeries under elective general anesthesia participated in this study.

Design and Synthesis of Tranylcypromine-Derived LSD1 Inhibitors with Improved hERG and Microsomal Stability Profiles.

Lysine-specific demethylase 1 (LSD1/KDM1A) is a promising therapeutic target for the treatment of cancers. Several derivatives of tranylcypromine (2-phenylcyclopropylamine) have been developed as LSD1 inhibitors. One such derivative is ; however, this compound has a high hERG channel inhibitory activity and a low microsomal stability, making it unsuitable as a drug candidate.

Effect of angioembolization for isolated complex pelvic injury: A post-hoc analysis of a nationwide multicenter trauma database in Japan.

Background And Importance: Complex pelvic injuries are among the types of trauma with the highest mortality. Treatment strategies should be based on the hemodynamic status, the anatomical type of fracture, and the associated injuries. Combination therapies, including preperitoneal pelvic packing, temporary mechanical stabilization, resuscitative endovascular balloon occlusion of the aorta, and angioembolization, are recommended for pelvic injuries.

Photocatalytic reactor design and its application in real wastewater treatment using TiO coated on the stainless-steel mesh.

The application of wastewater treatment using TiO coated on the stainless-steel mesh is promising for disintegrating organic pollutants in wastewater. This research successfully coated TiO particles on stainless-steel mesh for the photocatalyst process by using the dip-coating method. This method was selected due to its simplicity and low cost, as well as its extensive application prospects in wastewater treatment.

Above-ordering-temperature large anomalous Hall effect in a triangular-lattice magnetic semiconductor.

While anomalous Hall effect (AHE) has been extensively studied in the past, efforts for realizing large Hall response have been mainly limited within intrinsic mechanism. Lately, however, a theory of extrinsic mechanism has predicted that magnetic scattering by spin cluster can induce large AHE even above magnetic ordering temperature, particularly in magnetic semiconductors with low carrier density, strong exchange coupling, and finite spin chirality. Here, we find out a new magnetic semiconductor EuAs, where Eu ions with large magnetic moments form distorted triangular lattice.

Association between mortality and age among mechanically ventilated COVID-19 patients: a Japanese nationwide COVID-19 database study.

Background: Only a few studies have reported the association between age and mortality in COVID-19 patients who require invasive mechanical ventilation (IMV). We aimed to evaluate the effect of age on COVID-19-related mortality among patients undergoing IMV therapy.

Methods: This cohort study was conducted using the COVID-19 Registry Japan database, a nationwide multi-centre study of hospitalized patients with laboratory-confirmed COVID-19.

Ultra-Early Induction of General Anesthesia for Reducing Rebleeding Rates in Patients with Aneurysmal Subarachnoid Hemorrhage.

Objective: Rebleeding of aneurysmal subarachnoid hemorrhage (aSAH) is one of the significant risk factors for poor clinical outcome. The rebleeding risk is the highest during the acute phase with an approximate rebleeding rate of 9-17% within the first 24 h. Theoretically, general anesthesia can stabilize a patient's vital signs; however, its effectiveness as initial management for preventing post-aSAH rebleeding remains unclear.

Structure-Based Identification of Potent Lysine-Specific Demethylase 1 Inhibitor Peptides and Temporary Cyclization to Enhance Proteolytic Stability and Cell Growth-Inhibitory Activity.

Peptides are attractive drug candidates, but their utility is greatly limited by their inherent susceptibility to proteolytic degradation and their inability to pass through the cell membrane. Here, we employ a strategy of temporary cyclization to develop a cell-active lysine-specific demethylase 1 (LSD1/KDM1A) inhibitor peptide. We first identified a highly potent LSD1-inhibitory linear peptide, with the assistance of X-ray crystal structure data of inhibitor peptide-bound LSD1·CoREST.