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https://www.readbyqxmd.com/read/29792136/zinc-dependent-histone-deacetylase-inhibitors-in-cancer-therapeutics-recent-update
#1
Panagiotis I Georgianos, Maria Divani, Theodoros Eleftheriadis, Peter R Mertens, Vassilios Liakopoulos
BACKGROUND: Despite optimal management of diabetic kidney disease (DKD) with intensive glycemic control and administration of agents blocking the renin-angiotensin-aldosterone-system, the residual risk for nephropathy progression to end-stage-renal-disease (ESRD) remains high. Sodium-glucose co-transporter type 2 (SGLT-2)-inhibitors represent a newly-introduced anti-diabetic drug class with pleiotropic actions extending above their glucose-lowering efficacy. Herein, we provide an overview of preclinical and clinical-trial evidence supporting a protective effect of SGLT-2 inhibitors on DKD...
May 23, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29788881/novel-solid-lipid-nanocarrier-of-glibenclamide-a-factorial-design-approach-with-response-surface-methodology
#2
Sonia Pandey, Payal Patel, Arti Gupta
BACKGROUND: In the present investigation a factorial design approach attempt was applied to develop the solid lipid nanoparticles (SLN) of Glibenclamide (GLB) a poorly water-soluble drug (BCS -II) used in the treatment of type 2 diabetes. OBJECTIVES: Prime objectives of this experiment are to optimize the SLN formulation of Glibenclamide and improve the therapeutic effectiveness of the developed formulation. METHODS: Glibenclamide loaded SLNs (GLB-SLN) were fabricated by High speed homogenization technique...
May 21, 2018: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/29787756/fibronectin-type-iii-domain-containing-4-attenuates-hyperlipidemia-induced-insulin-resistance-via-suppression-of-inflammation-and-er-stress-through-ho-1-expression-in-adipocytes
#3
Wonjae Lee, Subin Yun, Geum Hee Choi, Tae Woo Jung
Although Fibronectin Type III Domain Containing 4 (FNDC4) has been reported to be involved in the modulation of inflammation in macrophages, its effects on inflammation and insulin resistance in adipose tissue are unknown. In the current study, we investigated the effects of FNDC4 on hyperlipidemia-mediated endoplasmic reticulum (ER) stress, inflammation, and insulin resistance in adipocytes via the AMP-activated protein kinase (AMPK)/heme oxygenase-1 (HO-1)-mediated pathway. Hyperlipidemia-induced nuclear factor κB (NFκB), inhibitory κBα (IκBα) phosphorylation, and pro-inflammatory cytokines such as TNFα and MCP-1 were markedly mitigated by FNDC4...
May 19, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29786745/histone-modifications-in-fatty-acid-synthase-modulated-by-carbohydrate-responsive-element-binding-protein-are-associated-with-non%C3%A2-alcoholic-fatty-liver-disease
#4
Can Cai, Huihong Yu, Guangming Huang, Xuan Du, Xiaoqing Yu, Youping Zhou, Wei Shen
Non‑alcoholic fatty liver disease (NAFLD) is a manifestation of metabolic syndrome in the liver and is closely associated with diabetes; however, its pathogenesis remains to be elucidated. Carbohydrate responsive element binding protein (ChREBP), the hub of glucolipid metabolism, regulates the induction of fatty acid synthase (FASN), the key enzyme of de novo lipogenesis, by directly binding to carbohydrate response element (ChoRE) in its promoter. Investigations of histone modifications on NAFLD remain in their infancy...
May 22, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29785241/an-in-vivo-zebrafish-model-for-interrogating-ros-mediated-pancreatic-%C3%AE-cell-injury-response-and-prevention
#5
Abhishek A Kulkarni, Abass M Conteh, Cody A Sorrell, Anjali Mirmira, Sarah A Tersey, Raghavendra G Mirmira, Amelia K Linnemann, Ryan M Anderson
It is well known that a chronic state of elevated reactive oxygen species (ROS) in pancreatic β -cells impairs their ability to release insulin in response to elevated plasma glucose. Moreover, at its extreme, unmitigated ROS drives regulated cell death. This dysfunctional state of ROS buildup can result both from genetic predisposition and environmental factors such as obesity and overnutrition. Importantly, excessive ROS buildup may underlie metabolic pathologies such as type 2 diabetes mellitus. The ability to monitor ROS dynamics in β -cells in situ and to manipulate it via genetic, pharmacological, and environmental means would accelerate the development of novel therapeutics that could abate this pathology...
2018: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29784660/interleukin-6-reduces-%C3%AE-cell-oxidative-stress-by-linking-autophagy-with-the-antioxidant-response
#6
Michelle R Marasco, Abass M Conteh, Christopher A Reissaus, John E Cupit V, Evan M Appleman, Raghavendra G Mirmira, Amelia K Linnemann
Production of reactive oxygen species (ROS) is a key instigator of β-cell dysfunction in diabetes. The pleiotropic cytokine IL-6 has previously been linked to β-cell autophagy but has not been studied in the context of β-cell antioxidant response. We used a combination of animal models of diabetes and analysis of cultured human islets and rodent β-cells to study how IL-6 influences antioxidant response. We show that IL-6 couples autophagy to antioxidant response to reduce β-cell and human islet ROS. β cell-specific loss of IL-6 signaling in vivo renders mice more susceptible to oxidative damage and cell death by the selective β-cell toxins streptozotocin and alloxan...
May 21, 2018: Diabetes
https://www.readbyqxmd.com/read/29784015/induction-of-multiple-myeloma-cancer-stem-cell-apoptosis-using-conjugated-anti-abcg2-antibody-with-epirubicin-loaded-microbubbles
#7
Fangfang Shi, Miao Li, Jing Wang, Di Wu, Meng Pan, Mei Guo, Jun Dou
BACKGROUND: Multiple myeloma (MM) currently remains largely incurable. Cancer stem cells (CSCs) are believed to be responsible for drug resistance and eventual relapse. In this study, we exploited a novel agent to evaluate its inhibitory effect on MM CSCs. METHODS: Epirubicin (EPI)-loaded lipid microbubbles (MBs) conjugated with anti-ABCG2 monoclonal antibody (EPI-MBs + mAb) were developed and their effect on MM 138- CD34- CSCs isolated from human MM RPMI 8226 cell line plus ultrasound exposure in vitro and in vivo in a nonobese diabetic/severe combined immunodeficient mouse model were assessed...
May 21, 2018: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/29783787/plasma-pharmacokinetic-determination-of-canagliflozin-and-its-metabolites-in-a-type-2-diabetic-rat-model-by-uplc-ms-ms
#8
Song-Tao Dong, Hui-Min Niu, Yin Wu, Jia-Lei Jiang, Ying Li, Kun-Yu Jiang, Xin Wang, Mao-Fan Zhang, Ming-Feng Han, Sheng-Nan Meng
Canagliflozin is a novel, orally selective inhibitor of sodium-dependent glucose co-transporter-2 (SGLT2) for the treatment of patients with type 2 diabetes mellitus. In this study, a sensitive and efficient UPLC-MS/MS method for the quantification of canagliflozin and its metabolites in rat plasma was established and applied to pharmacokinetics in a type 2 diabetic rat model. We firstly investigated the pharmacokinetic changes of canagliflozin and its metabolites in type 2 diabetic rats in order to use canagliflozin more safely, reasonably and effectively...
May 20, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29782892/a-glp-1-cck-fusion-peptide-harnesses-the-synergistic-effects-on-metabolism-of-cck-1-and-glp-1-receptor-agonism-in-mice
#9
David C Hornigold, Emma Roth, Victor Howard, Sarah Will, Stephanie Oldham, Matthew P Coghlan, Clemence Blouet, James L Trevaskis
Combination approaches for the treatment of metabolic diseases such as obesity and diabetes are becoming increasingly relevant. Co-administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist with a cholecystokinin receptor-1 (CCKR1) agonist exert synergistic effects on weight loss in obese rodents. Here, we report on the effects of a novel fusion peptide (C2816) comprised of a stabilized GLP-1R agonist, AC3174, and a CCKR1-selective agonist, AC170222. C2816 was constructed such that AC3174 was linked to the N-terminus of AC170222, thus preserving the C-terminal amide of the CCK moiety...
May 18, 2018: Appetite
https://www.readbyqxmd.com/read/29781744/endurance-training-alters-ykl40-perm1-and-hsp70-skeletal-muscle-protein-contents-in-men-with-type-2-diabetes-mellitus
#10
Christian Brinkmann, Anika Kuckertz, Thorsten Schiffer, Wilhelm Bloch, Hans-Georg Predel, Klara Brixius
BACKGROUND: The fight against type 2 diabetes mellitus (T2DM) is tremendously challenging. This pilot study investigates whether endurance training (3 times per week for 3 months, moderate intensity) can change the skeletal muscle protein contents of chitinase-3-like protein-1 (YKL40), peroxisome proliferator-activated receptor y coactivator-1 and estrogen-related receptor-induced regulator in muscle-1 (PERM1) and heat-shock protein-70 (HSP70), which have been discussed as novel therapeutically relevant targets...
May 21, 2018: Endocrine Research
https://www.readbyqxmd.com/read/29777802/derivation-and-characterization-of-a-ucp1-reporter-human-es-cell-line
#11
Suranjit Mukherjee, Tuo Zhang, Lauretta A Lacko, Lei Tan, Jenny Zhaoying Xiang, Jason M Butler, Shuibing Chen
Interest in human brown fat as a novel therapeutic target to tackle the growing obesity and diabetes epidemic has increased dramatically in recent years. While much insight into brown fat biology has been gained from murine cell lines and models, few resources are available to study human brown fat in vitro, which makes the need for new ways to derive and study human brown adipocytes imperative. Human ES cell based reporter systems present an excellent tool to identify, mark, and purify cell populations of choice...
April 22, 2018: Stem Cell Research
https://www.readbyqxmd.com/read/29775936/from-hit-to-lead-structure-based-discovery-of-naphthalene-1-sulfonamide-derivatives-as-potent-and-selective-inhibitors-of-fatty-acid-binding-protein-4
#12
Ding-Ding Gao, Hui-Xia Dou, Hai-Xia Su, Ming-Ming Zhang, Ting Wang, Qiu-Feng Liu, Hai-Yan Cai, Hai-Peng Ding, Zhuo Yang, Wei-Liang Zhu, Ye-Chun Xu, He-Yao Wang, Ying-Xia Li
Fatty acid binding protein 4 (FABP4) plays a critical role in metabolism and inflammatory processes and therefore is a potential therapeutic target for immunometabolic diseases such as diabetes and atherosclerosis. Herein, we reported the identification of naphthalene-1-sulfonamide derivatives as novel, potent and selective FABP4 inhibitors by applying a structure-based design strategy. The binding affinities of compounds 16dk, 16do and 16du to FABP4, at the molecular level, are equivalent to or even better than that of BMS309403...
May 9, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29775899/hispidulin-alleviates-high-glucose-induced-podocyte-injury-by-regulating-protective-autophagy
#13
Fengbo Wu, Sijia Li, Nan Zhang, Wei Huang, Xiang Li, Manyi Wang, Ding Bai, Bo Han
OBJECTIVES: Diabetic nephropathy (DN) is one of the most common complications in patients with diabetes, and the discovery of novel targeted therapeutic approaches for DN treatment still faces severe challenges. In the current study, we aimed to discover a novel natural product for potential DN treatment and determine its molecular mechanisms. MATERIALS AND METHODS: Methylthiazoltetrazolium (MTT) assay was employed to evaluate cell viability. Transmission electron microscopy, GFP-LC3 fluorescence fusion plasmid, and Annexin V/PI apoptosis assay were carried out to determine cellular autophagy and apoptosis...
May 15, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29774216/autophagic-regulation-of-lipid-homeostasis-in-cardiometabolic-syndrome
#14
Mingjie Yang, Yingmei Zhang, Jun Ren
As an important protein quality control process, autophagy is essential for the degradation and removal of long-lived or injured cellular components and organelles. Autophagy is known to participate in a number of pathophysiological processes including cardiometabolic syndrome. Recent findings have shown compelling evidence for the intricate interplay between autophagy and lipid metabolism. Autophagy serves as a major regulator of lipid homeostasis while lipid can also influence autophagosome formation and autophagic signaling...
2018: Frontiers in Cardiovascular Medicine
https://www.readbyqxmd.com/read/29774092/vorapaxar-treatment-reduces-mesangial-expansion-in-streptozotocin-induced-diabetic-nephropathy-in-mice
#15
Maaike Waasdorp, JanWillem Duitman, Sandrine Florquin, C Arnold Spek
Background: Twenty years after the onset of diabetes, up to 40% of patients develop diabetic nephropathy. Protease-activated receptor-1 (PAR-1) has recently been shown to aggravate the development of experimental diabetic nephropathy. PAR-1 deficient mice develop less albuminuria and glomerular lesions and PAR-1 stimulation induces proliferation and fibronectin production in mesangial cells in vitro . Vorapaxar is a clinically available PAR-1 inhibitor which is currently used for secondary prevention of ischemic events...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29773993/diabetic-cardiomyopathy-impact-of-biological-sex-on-disease-development-and-molecular-signatures
#16
REVIEW
Ryan Toedebusch, Anthony Belenchia, Lakshmi Pulakat
Diabetic cardiomyopathy refers to a unique set of heart-specific pathological variables induced by hyperglycemia and insulin resistance. Given that cardiovascular disease (CVD) is the leading cause of death in the world, and type 2 diabetes incidence continues to rise, understanding the complex interplay between these two morbidities and developing novel therapeutic strategies is vital. Two hallmark characteristics specific to diabetic cardiomyopathy are diastolic dysfunction and cardiac structural mal-adaptations, arising from cardiac cellular responses to the complex toxicity induced by hyperglycemia with or without hyperinsulinemia...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29769329/isolation-of-state-dependent-monoclonal-antibodies-against-the-12-transmembrane-domain-glucose-transporter-4-using-virus-like-particles
#17
David F Tucker, Jonathan T Sullivan, Kimberly-Anne Mattia, Christine R Fisher, Trevor Barnes, Manu N Mabila, Rona Wilf, Chidananda Sulli, Meghan Pitts, Riley J Payne, Moniquetta Hall, Duncan Huston-Paterson, Xiaoxiang Deng, Edgar Davidson, Sharon H Willis, Benjamin J Doranz, Ross Chambers, Joseph B Rucker
The insulin-responsive 12-transmembrane transporter GLUT4 changes conformation between an inward-open state and an outward-open state to actively facilitate cellular glucose uptake. Because of the difficulties of generating conformational mAbs against complex and highly conserved membrane proteins, no reliable tools exist to measure GLUT4 at the cell surface, follow its trafficking, or detect the conformational state of the protein. Here we report the isolation and characterization of conformational mAbs that recognize the extracellular and intracellular domains of GLUT4, including mAbs that are specific for the inward-open and outward-open states of GLUT4...
May 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29769238/strength-in-numbers-opportunities-for-enhancing-the-development-of-effective-treatments-for-type-1-diabetes-the-trialnet-experience
#18
Carla J Greenbaum, Cate Speake, Jeffrey Krischer, Jane Buckner, Peter A Gottlieb, Desmond A Schatz, Kevan C Herold, Mark A Atkinson
The early to mid-1980s were an inflection point in the history of type 1 diabetes research. Two landmark events occurred: the initiation of immune-based interventions seeking to prevent type 1 diabetes and the presentation of an innovative model describing the disorder's natural history. Both formed the basis for hundreds of subsequent studies designed to achieve a dramatic therapeutic goal-a means to prevent and/or reverse type 1 diabetes. However, the need to screen large numbers of individuals and prospectively monitor them using immunologic and metabolic tests for extended periods of time suggested such efforts would require a large collaborative network...
May 16, 2018: Diabetes
https://www.readbyqxmd.com/read/29764859/activation-of-nrf2-is-required-for-normal-and-chrebp%C3%AE-augmented-glucose-stimulated-%C3%AE-cell-proliferation
#19
Anil Kumar, Liora S Katz, Anna M Schulz, Misung Kim, Lee B Honig, Lucy Li, Bennett Davenport, Dirk Homann, Adolfo Garcia-Ocaña, Mark A Herman, Cole M Haynes, Jerry E Chipuk, Donald K Scott
Patients with both major forms of diabetes would benefit from therapies that increase β-cell mass. Glucose is a natural mitogen that drives adaptive β-cell mass expansion by promoting β-cell proliferation. We previously demonstrated that carbohydrate response element binding protein (ChREBPα) is required for glucose-stimulated β-cell proliferation, and that overexpression of ChREBPα amplifies the proliferative effect of glucose. Here we found that ChREBPα reprogrammed anabolic metabolism to promote proliferation...
May 15, 2018: Diabetes
https://www.readbyqxmd.com/read/29760587/the-role-of-adipokines-in-skeletal-muscle-inflammation-and-insulin-sensitivity
#20
REVIEW
Thomas Nicholson, Chris Church, David J Baker, Simon W Jones
Background: There is currently an unmet clinical need to develop better pharmacological treatments to improve glucose handling in Type II Diabetes patients with obesity. To this end, determining the effect of obesity-associated adipokines on skeletal muscle insulin sensitivity has emerged as an important area of drug discovery research. This review draws together the data on the functional role of adipokines on skeletal muscle insulin signalling, highlights several understudied novel adipokines and provides a perspective on the direction of future research...
2018: Journal of Inflammation
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