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treating to new targets

Shivaji Thadke, J Dinithi R Perera, V M Hridya, Kirti Bhatt, Ashif Yasin Shaikh, Wei-Che Hsieh, Mengshen David Chen, Chakicherla Gayathri, Roberto R Gil, Gordon S Rule, Arnab Mukherjee, Charles A Thornton, Danith H Ly
We report the development of a new class of nucleic acid ligands that is comprised of Janus bases and MPPNA backbone and is capable of binding rCAG-repeats in a sequence-specific and selective manner via, inference, bivalent H-bonding interactions. Individually, the interactions between ligands and RNA are weak and transient. However, upon the installation of C-terminal thioester and N-terminal cystine and the reduction of disulfide bond, they undergo template-directed native chemical ligation to form concatenated oligomeric products that bind tightly to the RNA template...
March 21, 2018: Biochemistry
Riccardo Moia, Fary Diop, Chiara Favini, Ahad Ahmed Kodipad, Gianluca Gaidano
Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease. Deregulation of apoptosis is a major pathogenetic feature, and represents a therapeutic target. TP53 disrupted patients are categorized as high risk patients and are treated with novel target therapies. Among these new drugs, venetoclax, an orally bioavailable BCL2 inhibitor, has shown high efficacy also in relapsed/refractory CLL with TP53 disruption. Venetoclax has also been tested in combination with other drugs without compromising venetoclax dose and with a good safety profile...
March 21, 2018: Expert Review of Hematology
Adel Schwertani, Hong Y Choi, Jacques Genest
PURPOSE OF REVIEW: Plasma levels of HDL cholesterol are a biomarker of cardiovascular health but not a therapeutic target, as demonstrated by the failure of pharmacological modulation of HDL cholesterol to prevent or treat atherosclerotic cardiovascular disease. In health, HDL particles exert pleiotropic effects against atherosclerosis, including cholesterol removal from foam cells, vasodilatory effects through vascular endothelial cell nitric oxide production, decreased vascular inflammation and oxidative damage, endothelial cell proliferation and antiapoptotic effects...
March 19, 2018: Current Opinion in Cardiology
Nicolette Kapp, Xiao X Stander, Barend A Stander
This project investigated the in-vitro effects of a glycolytic inhibitor, 3-bromopyruvate (3-BrP), in combination with and a new in silico-designed inhibitor of the bromodomain-4 (BRD-4) protein, ITH-47, on the U937 acute myeloid leukemia cell line. 3-BrP is an agent that targets the altered metabolism of cancer cells by interfering with glucose metabolism in the glycolytic pathway. ITH-47 is an acetyl-lysine inhibitor that displaces bromdomain 4 proteins from chromatin by competitively binding to the acetyl-lysine recognition pocket of this bromodomain and extraterminal (BET) BRD protein, thereby preventing transcription of cancer-associated genes and further cell growth...
March 20, 2018: Anti-cancer Drugs
Rajiv Gandhi Govindaraj, Misagh Naderi, Manali Singha, Jeffrey Lemoine, Michal Brylinski
Rare, or orphan, diseases are conditions afflicting a small subset of people in a population. Although these disorders collectively pose significant health care problems, drug companies require government incentives to develop drugs for rare diseases due to extremely limited individual markets. Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning...
2018: NPJ Systems Biology and Applications
Nannan Pan, Yongxin Yang, Xin Du, Xin Qi, Guijin Du, Yang Zhang, Xiaodong Li, Quan Zhang
With the development of the Internet, an increasing number of adolescents play online game excessively, which leads to adverse effects on individuals and society. Previous studies have demonstrated altered gray-matter volume (GMV) in individuals with Internet gaming disorder (IGD), but the relationship between the tendency to IGD and the GMV across whole brain is still unclear in adolescents. In the present study, anatomical imaging with high resolution was performed on 67 male adolescents who played online game; and Young's Internet addiction test (IAT) was conducted to test the tendency to IGD...
2018: Frontiers in Psychiatry
Guo Nan Yin, Hai-Rong Jin, Min-Ji Choi, Anita Limanjaya, Kalyan Ghatak, Nguyen Nhat Minh, Jiyeon Ock, Mi-Hye Kwon, Kang-Moon Song, Heon Joo Park, Ho Min Kim, Young-Guen Kwon, Ji-Kan Ryu, Jun-Kyu Suh
Penile erection requires well-coordinated interactions between vascular and nervous system. Penile neurovascular dysfunction is a major cause of erectile dysfunction (ED) in patients with diabetes, which causes poor response to oral phosphodiesterase-5 inhibitors. Dickkopf2 (DKK2), a Wnt antagonist, is known to promote angiogenesis. Here, using DKK2-Tg mice or DKK2 protein administration, we demonstrate that overexpression of DKK2 in diabetic mice enhances penile angiogenesis and neural regeneration and restores erectile function...
March 20, 2018: Diabetes
Sara Clemenza, Flavia Sorbi, Ivo Noci, Tommaso Capezzuoli, Irene Turrini, Carlo Carriero, Nicolò Buffi, Massimiliano Fambrini, Felice Petraglia
Endometriosis is a chronic disease, and a lifelong management plan should be developed by using pharmacological treatment and surgical procedures. The pathogenesis of endometriosis is complicated and has not been definitively established. The mechanisms involved are numerous, and their understanding is constantly evolving. Currently, the first-line drugs act by blocking ovarian function, creating an hypoestrogenic environment. The blockade of estrogen secretion and receptor activity and the activation of progesteron receptors are the main target of several current drugs, as well as those under development...
February 15, 2018: Best Practice & Research. Clinical Obstetrics & Gynaecology
Alba Di Pardo, Vittorio Maglione
Huntington's disease (HD) is a single-gene inheritable neurodegenerative disorder with an associated complex molecular pathogenic profile that renders it the most 'curable incurable' brain disorder. Continuous effort in the field has contributed to the recent discovery of novel potential pathogenic mechanisms. Findings in preclinical models of the disease as well as in human post-mortem brains from affected patients demonstrate that alteration of the sphingosine-1-phosphate (S1P) axis may represent a possible key player in the pathogenesis of the disease and may act as a potential actionable drug target for the development of more targeted and effective therapeutic approaches...
March 17, 2018: Trends in Pharmacological Sciences
Gabriela Basile Carballo, Jéssica Ribeiro Honorato, Giselle Pinto Farias de Lopes, Tania Cristina Leite de Sampaio E Spohr
Hedgehog (Hh) signaling pathway plays an essential role during vertebrate embryonic development and tumorigenesis. It is already known that Sonic hedgehog (Shh) pathway is important for the evolution of radio and chemo-resistance of several types of tumors. Most of the brain tumors are resistant to chemotherapeutic drugs, consequently, they have a poor prognosis. So, a better knowledge of the Shh pathway opens an opportunity for targeted therapies against brain tumors considering a multi-factorial molecular overview...
March 20, 2018: Cell Communication and Signaling: CCS
Erhao Zhang, Jieyi Gu, Jianpeng Xue, Chenyu Lin, Chen Liu, Mengwei Li, Jingchao Hao, Sarra Setrerrahmane, Xiaowei Chi, Weiyan Qi, Jialiang Hu, Hanmei Xu
BACKGROUND: Chimeric antigen receptors (CARs) presented on T cell surfaces enable redirection of T cell specificity, which has enormous promise in antitumor therapy. However, excessive activity and poor control over such engineered T cells cause significant safety challenges, such as cytokine release syndrome and organ toxicities. To enhance the specificity and controllable activity of CAR-T cells, we report a novel switchable dual-receptor CAR-engineered T (sdCAR-T) cell and a new switch molecule of FITC-HM-3 bifunctional molecule (FHBM) in this study...
March 20, 2018: Journal of Hematology & Oncology
Zsolt Zador, Andrew T King, Nophar Geifman
BACKGROUND: Atypical meningiomas are common central nervous system neoplasms with high recurrence rate and poorer prognosis compared to their grade I counterparts. Surgical excision and radiotherapy remains the mainstay therapy but medical treatments are limited. We explore new drug candidates using computational drug repurposing based on the gene expression signature of atypical meningioma tissue with subsequent analysis of drug-generated expression profiles. We further explore possible mechanisms of action for the identified drug candidates using ingenuity pathway analysis (IPA)...
2018: PloS One
Frederick A Rubino, Sujeet Kumar, Natividad Ruiz, Suzanne Walker, Daniel Kahne
MurJ, the flippase that exports the bacterial cell wall mon-omer Lipid II to the periplasm, is a target for new antibiot-ics, which are desperately needed to treat Gram-negative infections. Quantitative methods to monitor MurJ activity are required to characterize inhibitors but are challenging to develop because the lipid-linked substrate is not chemi-cally altered in a flippase reaction. Here we show that MurJ inhibition can be quantified by measuring the accu-mulation of intracellular Lipid II using a biotin-tagging strategy...
March 20, 2018: Journal of the American Chemical Society
Karin Kosulin, Elena Lam, Albert Heim, Thomas Dobner, Estefanía Rodríguez
BACKGROUND: Human adenoviral (HAdV) infections are usually mild and self-limited, however, some infections from species A, B, C, D and E, can cause severe illnesses, which have raised public health concerns over the past few years. Current available antiviral therapies have limited efficacy and severe toxicity; therefore, finding new targets for specific anti-adenoviral drug design is urgently needed. Our previous work showed that the small molecule compound, HBX, inhibits HAdV type 5 (species C, HAdV-C5) replication and oncogenic transformation through inhibition of the cellular pro-viral factor ubiquitin-specific protease 7 (USP7)...
March 20, 2018: Antiviral Therapy
Seynabou Sougoufara, Omar Thiaw, Aurélie Cailleau, Nafissatou Diagne, Myriam Harry, Charles Bouganali, Pape M Sembène, Souleymane Doucoure, Cheikh Sokhna
The implementation of long-lasting insecticidal-treated bed nets (LLINs) has contributed to halving the mortality rate due to malaria since 2000 in sub-Saharan Africa. These tools are highly effective against indoor-feeding malaria vectors. Thus, to achieve the World Health Assembly's new target to reduce the burden of malaria over the next 15 years by 90%, it is necessary to understand how the spatiotemporal dynamics of malaria vectors and human exposure to bites is modified in the context of scaling up global efforts to control malaria transmission...
March 19, 2018: American Journal of Tropical Medicine and Hygiene
Md Saiful Islam Roney, Song-Kyu Park
Cancer is one of the deadliest diseases in the world. Despite extensive studies, treating metastatic cancers remains challenging. Years of research have linked a rare set of cells known as cancer stem cells (CSCs) to drug resistance, leading to the suggestion that eradication of CSCs might be an effective therapeutic strategy. However, few drug candidates are active against CSCs. New drug discovery is often a lengthy process. Drug screening has been advantageous in identifying drug candidates. Current understanding of cancer biology has revealed various clues to target cancer from different points of view...
March 19, 2018: Archives of Pharmacal Research
Casey M Theriot
Over the past 10 years, microbiome research has focused on defining the structures associated with different disease states in multiple systems, but has fallen short on showing causation. Prior omic studies have generated many new hypotheses, but moving forward we need to start dissecting the function of each bacterium alone and in concert with complex bacterial communities in well-characterized systems. Over the next 5 years, we need a merging of new omic technologies for exploratory studies with classical bacterial genetics, bacterial physiology, protein engineering, and biochemistry to further define the biochemical mechanisms of the gut microbiota...
March 2018: MSystems
Monia Cito, Silvia Pellegrini, Lorenzo Piemonti, Valeria Sordi
The experience in the field of islet transplantation shows that it is possible to replace β cells in a patient with type 1 diabetes (T1D), but this cell therapy is limited by the scarcity of organ donors and by the danger associated to the immunosuppressive drugs. Stem cell therapy is becoming a concrete opportunity to treat various diseases. In particular, for a disease like T1D, caused by the loss of a single specific cell type that does not need to be transplanted back in its originating site to perform its function, a stem cell-based cell replacement therapy seems to be the ideal cure...
March 2018: Endocrine Connections
Ming Zhang, Xiaoming Chi, Na Qu, CongYing Wang
Non-alcoholic fatty liver disease and steatohepatitis (NAFLD and NASH) account for the majority of liver disease in industrialized countries. However, the pathogenesis still unclear. Long non-coding RNAs (lncRNAs) has been reported to be involved in various pathophysiological processes. Here, we reported a novel role of lncARSR in hepatic lipogenesis in NAFLD. The expression of lncARSR was induced both in NAFLD patients and mouse model, as well as in hepatocytes treated with fatty acid. Moreover, overexpression of lncARSR enhanced while knockdown of lncARSR ameliorated hepatic lipid accumulation in vivo and in vitro...
March 16, 2018: Biochemical and Biophysical Research Communications
Adriely Goes, Gregor Fuhrmann
Biogenic and biomimetic therapeutics are a relatively new class of systems that are of physiological origin and/or take advantage of natural pathways, or aim at mimicking these to improve selective interaction with target tissue. The number of biogenic and bioengineered avenues for drug therapy and diagnostics has multiplied over the past years for many applications, indicating the high expectations associated with this biological route. Nevertheless, the use of "bio"-related approaches for treating or diagnosing infectious diseases is still rare...
March 19, 2018: ACS Infectious Diseases
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