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Novel diabetes therapeutic

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https://www.readbyqxmd.com/read/28230206/mirna-21-mediates-the-antiangiogenic-activity-of-metformin-through-targeting-pten-and-smad7-expression-and-pi3k-akt-pathway
#1
Mao Luo, Xiaoyong Tan, Lin Mu, Yulin Luo, Rong Li, Xin Deng, Ni Chen, Meiping Ren, Yongjie Li, Liqun Wang, Jianbo Wu, Qin Wan
Metformin, an anti-diabetic drug commonly used for type 2 diabetes therapy, is associated with anti-angiogenic effects in conditions beyond diabetes. miR-21 has been reported to be involved in the process of angiogenesis. However, the precise regulatory mechanisms by which the metformin-induced endothelial suppression and its effects on miR-21-dependent pathways are still unclear. Bioinformatic analysis and identification of miR-21 and its targets and their effects on metformin-induced antiangiogenic activity were assessed using luciferase assays, quantitative real-time PCR, western blots, scratch assays, CCK-8 assays and tubule formation assays...
February 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28228082/recent-advances-in-protein-tyrosine-phosphatase-1b-targeted-drug-discovery-for-type-ii-diabetes-and-obesity
#2
Neelesh Maheswari, Chandrabose Karthikeyan, Piyush Trivedi, N S Hari Narayana Moorthy
Protein tyrosine phosphatase 1B (PTP1B) is an important therapeutic target for type II diabetes and obesity because of its pivotal role as a negative modulator in both insulin and leptin signalling pathways. Consequently, the discovery of PTP1B inhibitors has been the focus of researchers in both academia and pharmaceutical industry over the last two decades. Though, intense pharmaceutical research in this area has resulted in many potent PTP1B inhibitors, a vast majority of them possessed pTyr mimetic group such as phosphonates, carboxylic acids and sulphamic acids, which led to poor PTP1B selectivity and insufficient in vivo efficacy due to low cell permeability and bioavailability...
February 22, 2017: Current Drug Targets
https://www.readbyqxmd.com/read/28223045/crystal-structures-reveal-a-new-and-novel-foxo1-binding-site-within-the-human-glucose-6-phosphatase-catalytic-subunit-1-gene-promoter
#3
Puja Singh, Eun Hee Han, James A Endrizzi, Richard M O'Brien, Young-In Chi
Human glucose-6-phosphatase plays a vital role in blood glucose homeostasis and holds promise as a therapeutic target for diabetes. Expression of its catalytic subunit gene 1 (G6PC1) is tightly regulated by metabolic-response transcription factors such as FoxO1 and CREB. Although at least three potential FoxO1 binding sites (insulin response elements, IREs) and one CREB binding site (cAMP response element, CRE) within the proximal region of the G6PC1 promoter have been identified, the interplay between FoxO1 and CREB and between FoxO1 bound at multiple IREs has not been well characterized...
February 18, 2017: Journal of Structural Biology
https://www.readbyqxmd.com/read/28220836/nucleobindin-1-binds-to-multiple-types-of-pre-fibrillar-amyloid-and-inhibits-fibrillization
#4
Alessandra Bonito-Oliva, Shahar Barbash, Thomas P Sakmar, W Vallen Graham
During amyloid fibril formation, amyloidogenic polypeptides misfold and self assemble into soluble pre-fibrillar aggregates, i.e., protofibrils, which elongate and mature into insoluble fibrillar aggregates. An emerging class of chaperones, chaperone-like amyloid binding proteins (CLABPs), has been shown to interfere with aggregation of particular misfolded amyloid peptides or proteins. We have discovered that the calcium-binding protein nuclebindin-1 (NUCB1) is a novel CLABP. We show that NUCB1 inhibits aggregation of islet-amyloid polypeptide associated with type 2 diabetes mellitus, a-synuclein associated with Parkinson's disease, transthyretin V30M mutant associated with familial amyloid polyneuropathy, and Aβ42 associated with Alzheimer's disease by stabilizing their respective protofibril intermediates...
February 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28220624/cardio-protective-effects-of-pectin-insulin-patch-in-streptozotocin-induced-diabetic-rats-beneficial-effects-of-insulin-patch
#5
Ntethelelo Sibiya, Phikelelani Ngubane, Musa Mabandla
PURPOSE: Cardiovascular complications are amongst the leading causes of morbidity and mortality in diabetes mellitus. Despite the beneficial effects of subcutaneous insulin administration, reports suggest that the therapy itself precipitates cardiovascular risks due to the high insulin concentration administered. It is therefore necessary to seek alternative insulin administration routes that may bypass the undesirable effects associated with high plasma insulin concentration. Accordingly, the study investigated the effect of a novel transdermal pectin-insulin patch on selected cardiovascular function markers in diabetes...
February 20, 2017: Journal of Diabetes
https://www.readbyqxmd.com/read/28215166/seaweed-polysaccharides-new-therapeutic-insights-against-the-inflammatory-response-in-diabetic-nephropathy
#6
Vaishnu Devi Da, Pragasam Viswanathan
BACKGROUND: The higher risk of diabetic nephropathy (DN) leads to end stage renal diseases in worldwide, which is associated with chronic inflammation. Currently, the available treatments are limited, lack of efficacy and safety. Therefore, we are in need of novel targets and advanced treatments to reduce the necessity for the renal replacement therapy and burden of this disease management. In this review, we performed through an inflammatory mechanism that contribute to DN, will provide a key point to the finding off novel therapeutic agents...
February 16, 2017: Anti-inflammatory & Anti-allergy Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28197794/therapeutic-options-in-refractory-diabetic-macular-oedema
#7
Sanket U Shah, Raj K Maturi
Diabetic macular oedema (DMO) results from alterations of several biochemical pathways in diabetic eyes. Centre-involving DMO is an important cause of visual loss in diabetes. Anti-vascular endothelial growth factor agents are now the mainstay of centre-involving DMO treatment. Oedema that does not achieve optimal response to these agents occurs in a sizeable proportion of eyes and is called refractory or persistent DMO. Management of refractory DMO is challenging. In this paper, the pathophysiology of DMO, and the definitions used in various studies are summarised...
February 15, 2017: Drugs
https://www.readbyqxmd.com/read/28197316/design-and-synthesis-of-novel-selective-gpr40-agopams
#8
Christopher W Plummer, Matthew J Clements, Helen Chen, Murali Rajagopalan, Hubert Josien, William K Hagmann, Michael Miller, Maria E Trujillo, Melissa Kirkland, Daniel Kosinski, Joel Mane, Michele Pachanski, Boonlert Cheewatrakoolpong, Andrew F Nolting, Robert Orr, Melodie Christensen, Louis-Charles Campeau, Michael J Wright, Randal Bugianesi, Sarah Souza, Xiaoping Zhang, Jerry Di Salvo, Adam B Weinglass, Richard Tschirret-Guth, Ravi Nargund, Andrew D Howard, Steven L Colletti
GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28192136/inhibition-of-glycation-and-aldose-reductase-activity-using-dietary-flavonoids-a-lens-organ-culture-studies
#9
Kapil K Patil, Rajesh N Gacche
On the eve of increasing incidence of diabetes mellitus and related complications, the search for novel, safe and alternatives therapeutic approaches are evolving. In the present investigation, a panel of ten dietary flavonoids such as 4'-methoxyflavanone, formononetin, hesperetin, hesperidin, naringenin, naringin, rutin, diadzin, silibinin and silymarin was evaluated as possible inhibitors of sugar induced cataractogenesis using bovine lens organ culture studies. The effect of selected flavonoids was observed on glycation induced lens opacity, AGE fluorescence, carbonyl group formation (a biomarker of glycation), protein aggregation and aldose reductase (AR) inhibition...
February 10, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28190392/pi3k-akt-pathway-a-potential-therapeutic-target-for-chronic-pain
#10
Shu-Ping Chen, Ya-Qun Zhou, Dai-Qiang Liu, Wen Zhang, Anne Manyande, Xue-Hai Guan, Yu-Ke Tian, Da-Wei Ye, Deeq Mohamed Omar
Chronic pain is among the most disabling and costly disorders, with prevalence ranging from 10% to 55%. However, current therapeutic strategies for chronic pain are unsatisfactory due to our poor understanding of its mechanisms. Thus, novel therapeutic targets need to be found in order to improve these patients' quality of life. PI3K and its downstream Akt are widely expressed in the spinal cord, particularly in the laminae I-IV of the dorsal horn, where nociceptive C and Aδ fibers of primary afferents principally terminate...
February 10, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28186649/bone-morphogenetic-protein-7-bmp-7-augments-insulin-sensitivity-in-mice-with-type-ii-diabetes-mellitus-by-potentiating-pi3k-akt-pathway
#11
Tandrika Chattopadhyay, Rajiv Ranjan Singh, Sarika Gupta, Avadhesha Surolia
A direct link between development of insulin resistance and the presence of chronic inflammation, in case of obesity exists, with cytokines playing an important role in glucose metabolism. Members of TGF-β superfamily, including bone morphogenetic proteins (BMPs), have been shown to be involved in islet morphogenesis, establishment of β-cell mass and adipose cell fate determination. Here, we demonstrate a novel and direct role of BMP-4 and -7 in the regulation of glucose homeostasis and insulin resistance...
February 10, 2017: BioFactors
https://www.readbyqxmd.com/read/28183360/fat-mass-and-fat-distribution-are-associated-with-low-back-pain-intensity-and-disability-results-from-a-cohort-study
#12
Sultana Monira Hussain, Donna M Urquhart, Yuanyuan Wang, Jonathan E Shaw, Dianna J Magliano, Anita E Wluka, Flavia M Cicuttini
BACKGROUND: Determining the association between body composition and low back pain (LBP) will improve our understanding of the mechanisms by which obesity affects LBP, and inform novel approaches to managing LBP. The aim of this study was to examine the relationship between body composition and LBP intensity and disability. METHODS: A total of 5058 participants (44% men) of the Australian Diabetes, Obesity and Lifestyle Study were assessed for LBP intensity and disability using the Chronic Pain Grade Questionnaire (2013-2014)...
February 10, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28183033/diabetic-nephropathy-a-potential-savior-with-rotten-egg-smell
#13
REVIEW
George J Dugbartey
Diabetic nephropathy (DN) is currently the leading cause of end-stage renal disease. Despite optimal management, DN is still a major contributor to morbidity and mortality of diabetic patients worldwide. The major pathological alterations in DN include excessive accumulation and deposition of extracellular matrix, leading to expansion of mesangial matrix, thickening of glomerular basement membrane and tubulointerstitial fibrosis. At the molecular level, accumulating evidence suggests that hyperglycemia or high glucose mediates renal injury in DN via multiple molecular mechanisms such as induction of oxidative stress, upregulation of renal transforming growth factor beta-1 expression, production of proinflammatory cytokines, activation of fibroblasts and renin angiotensin system, and depletion of adenosine triphosphate...
November 11, 2016: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/28181104/apigenin-attenuates-streptozotocin-induced-pancreatic-%C3%AE-cell-damage-by-its-protective-effects-on-cellular-antioxidant-defense
#14
Ning Wang, Wen Jing Yi, Lu Tan, Jia Hui Zhang, Jiamin Xu, Yi Chen, Mengting Qin, Shuang Yu, Jing Guan, Rui Zhang
Pancreatic beta cells are very sensitive to oxidative stress, which is one of the major causes of cell damages in diabetes. Growing interest has focused on the development of effective therapeutics to protect pancreatic cells from oxidative stress and searching for potentially protective antioxidants for treating diabetes. Apigenin, a plant-derived flavonoid, was investigated to determine whether it could protect rat insulinoma cell lines (RINm5F pancreatic beta cells) against streptozotocin (STZ)-induced oxidative damages and the mechanisms implicated...
February 8, 2017: In Vitro Cellular & Developmental Biology. Animal
https://www.readbyqxmd.com/read/28178698/dipeptidyl-peptidase-4-inhibitors-in-chronic-kidney-disease-a-systematic-review-of-randomized-clinical-trials
#15
Simon R Walker, Paul Komenda, Suhail Khojah, Wafa Al-Tuwaijri, Kerry MacDonald, Brett Hiebert, Neil Tangri, Stewart W D Nadurak, Thomas W Ferguson, Claudio Rigatto, Navdeep Tangri
BACKGROUND: Chronic kidney disease (CKD) is common in patients with type 2 diabetes mellitus (T2DM) and limits therapeutic options. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a novel class of oral glucose-lowering agents and are known to be safe and effective in the general population. METHODS: We searched Cochrane, EMBASE, and PubMed from the time of their inception until March 2015. We included randomized controlled trials analyzing the efficacy (change in hemoglobin A1C [HbA1C]) and safety of DPP-4 agents in individuals with reduced kidney function (estimated glomerular filtration rate <60 mL/min/1...
February 9, 2017: Nephron
https://www.readbyqxmd.com/read/28176628/diabetes-type-4-a-paradigm-shift-in-the-understanding-of-glaucoma-the-brain-specific-diabetes-and-the-candidature-of-insulin-as-a-therapeutic-agent
#16
M A Faiq, T Dada
The present analytical anecdote aims at construing the probable mechanism and ensuing applications of the "Brain Diabetes Hypothesis of Glaucoma" proposed by our research group in early 2014. Here we go a step further to look into many important mechanisms that serve to bridge conceptual gaps to fill up the mosaic of a picture revealing that glaucoma indeed is brain specific diabetes and more appropriately "Diabetes Type 4". Based on this conceptual substance, we weave a novel idea of insulin being a potential remedy for glaucoma...
February 6, 2017: Current Molecular Medicine
https://www.readbyqxmd.com/read/28176274/microglial-function-during-glucose-deprivation-inflammatory-and-neuropsychiatric-implications
#17
Matthew A Churchward, Devan R Tchir, Kathryn G Todd
Inflammation is increasingly recognized as a contributor to the pathophysiology of neuropsychiatric disorders, including depression, anxiety disorders and autism, though the factors leading to contextually inappropriate or sustained inflammation in pathological conditions are yet to be elucidated. Microglia, as the key mediators of inflammation in the CNS, serve as likely candidates in initiating pathological inflammation and as an ideal point of therapeutic intervention. Glucose deprivation, as a component of the pathophysiology of ischemia or occurring transiently in diabetes, may serve to modify microglial function contributing to inflammatory injury...
February 7, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28173848/inhibition-of-dynamin-related-protein-1-protects-against-myocardial-ischemia-reperfusion-injury-in-diabetic-mice
#18
Mingge Ding, Qianqian Dong, Zhenghua Liu, Zheng Liu, Yinxian Qu, Xing Li, Cong Huo, Xin Jia, Feng Fu, Xiaoming Wang
BACKGROUND: Many cardioprotective pharmacological agents failed to exert their protective effects in diabetic hearts subjected to myocardial ischemia/reperfusion (MI/R). Identify the molecular basis linking diabetes with MI/R injury is scientifically important and may provide effective therapeutic approaches. Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission plays an important role in MI/R injury under non-diabetic conditions. Importantly, recent studies indicated that Drp1-mediated mitochondrial fission is enhanced in the myocardium of diabetic mice...
February 7, 2017: Cardiovascular Diabetology
https://www.readbyqxmd.com/read/28164571/establishment-of-a-novel-myelodysplastic-syndrome-mds-xenotransplantation-model
#19
Ling Ma, Xia Zhang, Zhiqiong Wang, Yan Chen, Jia Wei, Lihua Hu
BACKGROUND: Myelodysplastic syndrome (MDS) is a clonal disease of the elderly characterized by chronic cytopenia, dysplasia, and a high risk of progression to acute myeloid leukemia (AML). Up until now, few animal models that fully recapitulate clinical features of this disease have been available. METHODS: This study aimed to establish a new MDS xenograft model utilizing a human MDS-derived cell line with heterozygous Y641C mutation of EZH2 (SKM-1). 1 x 107 SKM-1 cells were inoculated into anti-mouse CD122 monoantibody conditioned nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice by intravenous injection...
September 1, 2016: Clinical Laboratory
https://www.readbyqxmd.com/read/28149671/macrophage-tgf-%C3%AE-1-and-the-proapoptotic-extracellular-matrix-protein-bigh3-induce-renal-cell-apoptosis-in-prediabetic-and-diabetic-conditions
#20
Robert J Moritz, Richard G LeBaron, Clyde F Phelix, Rajesha Rupaimoole, Hong Seok Kim, Andrew Tsin, Reto Asmis
Metabolically stressed kidney is in part characterized by infiltrating macrophages and macrophage-derived TGF-β1 that promote the synthesis of various ECM molecules. TGF-β1 strongly enhances the expression of the gene TGFBI that encodes a cell-adhesion class, proapoptotic ECM protein called BIGH3. We hypothesized that in a diabetic environment a relationship between infiltrating macrophages, macrophage-derived TGF-β1, and BIGH3 protein promotes renal cell death. To investigate this hypothesis, we used our mouse model of diabetic complications...
July 2016: International Journal of Clinical Medicine
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