DOCSLIB.ORG

Design and Synthesis of Selective Estrogen Receptor Β Agonists and Their Hp Armacology K

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Design and Synthesis of Selective Estrogen Receptor Β Agonists and Their Hp Armacology K Marquette University e-Publications@Marquette Dissertations (2009 -) Dissertations, Theses, and Professional Projects Design and Synthesis of Selective Estrogen Receptor β Agonists and Their hP armacology K. L. Iresha Sampathi Perera Marquette University Recommended Citation Perera, K. L. Iresha Sampathi, "Design and Synthesis of Selective Estrogen Receptor β Agonists and Their hP armacology" (2017). Dissertations (2009 -). 735. https://epublications.marquette.edu/dissertations_mu/735 DESIGN AND SYNTHESIS OF SELECTIVE ESTROGEN RECEPTOR β AGONISTS AND THEIR PHARMACOLOGY by K. L. Iresha Sampathi Perera, B.Sc. (Hons), M.Sc. A Dissertation Submitted to the Faculty of the Graduate School, Marquette University, in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Milwaukee, Wisconsin August 2017 ABSTRACT DESIGN AND SYNTHESIS OF SELECTIVE ESTROGEN RECEPTOR β AGONISTS AND THEIR PHARMACOLOGY K. L. Iresha Sampathi Perera, B.Sc. (Hons), M.Sc. Marquette University, 2017 Estrogens (17β-estradiol, E2) have garnered considerable attention in influencing cognitive process in relation to phases of the menstrual cycle, aging and menopausal symptoms. However, hormone replacement therapy can have deleterious effects leading to breast and endometrial cancer, predominantly mediated by estrogen receptor-alpha (ERα) the major isoform present in the mammary gland and uterus. Further evidence supports a dominant role of estrogen receptor-beta (ERβ) for improved cognitive effects such as enhanced hippocampal signaling and memory consolidation via estrogen activated signaling cascades. Creation of the ERβ selective ligands is challenging due to high structural similarity of both receptors. Thus far, several ERβ selective agonists have been developed, however, none of these have made it to clinical use due to their lower selectivity or considerable side effects. The research in this dissertation involved the design of non-steroidal ERβ selective agonists for hippocampal memory consolidation. The step-wise process to achieve the ultimate goal of this research includes: (1) design and synthesis of (4- hydroxyphenyl)cyclohexyl or cycloheptyl derivatives, (2) in vitro biological evaluation of synthesized compounds to identify highly potent and selective candidates, and (3) in vivo biological evaluation of selected candidates for hippocampal memory consolidation. Several (4-hydroxyphenyl)cyclohexyl or cycloheptyl derivatives were synthesized having structural alterations on both aromatic and cyclohexyl/heptyl ring scaffolds. ERβ agonist potency was initially evaluated in TR-FRET ERβ ligand binding assay and compounds having high potency were re-evaluated in functional cell based assays for potency and ERβ vs. ERα selectivity. Two compounds from each series, ISP 163-PK4 and ISP 358-2 were identified as most selective ERβ agonists. Both compounds revealed high metabolic stability, solubility and no cross reactivity towards other nuclear receptors. In vivo efficiency of ISP 358-2 was evaluated in ovariectomized mice (C57BL/6) with object recognition (OR) and object placement (OP) tasks. The results indicate improved memory consolidation at 100 pg/ hemisphere and 0.5 mg/Kg via DH infusion and IP injection respectively. The information learned from this project serves as a foundation for development of other cycloheptyl/hexyl based ERβ agonists or antagonists having acceptable pharmacological profiles. i ACKNOWLEDGMENTS K. L. Iresha Sampathi Perera, B.Sc. (Hons), M.Sc. Since my journey as a PhD candidate is coming to an end, it is time to reminisce the people who stood by me along the way. This is my sincere gratitude to those wonderful souls, who helped in making my story a success. I am ever grateful to my advisor Professor William A. Donaldson for the wonderful opportunity he gave me to join his research group. I can’t thank him enough for his valuable guidance and input during the whole course my research which improved me as a researcher in leaps and bounds. The most special aspect was the faith he showed in me during my research to achieve the results and the kind motivating words whenever I found myself challenged. I haven’t got enough words to thank him for being the motivator and mentor in bringing my research to a high-quality level. I could not have imagined having a better advisor for my Ph.D. study. Thank you again for your amazing support. I would like to thank the rest of my dissertation committee: Prof. Daniel Sem, Prof. James Kincaid and Dr. Christopher Dockendorff for their valuable time and effort in reviewing my dissertation. Further, their insightful comments during the committee meetings incented me to widen my research from various perspectives. Additionally, Dr. Christopher Dockendorff deserves a special mention on granting me access to their laboratory facilities which helped me immensely throughout my research. ii I am also very much thankful to Professor Daniel Sem, Professor Karyn Frick for the fantastic opportunity to work with them on an interesting project. I gained invaluable research experience from the monthly meetings I attended and the insightful suggestions and comments undoubtedly helped me to improve my research work. I also would like to mention Alicia Schulz and Jaekyoon Kim for their support during the collaboration. Thank you for giving me the opportunity to be a part of a fantastic team of researchers. I am also grateful to Department of Chemistry for providing me unrestricted facilities during my stay as a graduate student. I would like to convey my sincere gratitude to Dr. Sergey Lindeman and Dr. Sheng Cai for helping me with X-ray crystallographic and NMR studies. I would like to mention, Dr. Sandra Lukaszewski-Rose for the support she rendered to me during my tenure as a teaching assistant. I will always fondly remember the numerous functions you organized for students and the enjoyment I had. My acknowledgement would be incomplete without a word on Mr. Mark Bartelt. I am utterly grateful to him for all the technical supports on my research work. A very special mention to Prof. Isiah Warner at Louisiana State University for helping me in during my masters. I can’t thank you enough for the support you gave me during my time at Louisiana State University. Your encouraging words made me stronger to believe in myself and pursue my goals. Also, I would like to thank Prof. Chieu D. Tran, who was my first advisor at Marquette for his valuable guidance and help. I would also like to pay gratitude to the Chemistry department at University of Colombo where I took first steps as a researcher during my bachelors. I should specially thank my undergraduate thesis advisor Prof. Ramani Wijesekara for her immense help and guidance. iii I thank all past and present members of Donaldson and Dockendorff groups for their invaluable support. The groups have been a source of friendship as well as good advice. I wish all of you success in all your endeavors. Many thanks to Dr. Ajith Wijenayake and his family who helped me immensely when I moved to Milwaukee and my friends in Milwaukee for supporting me at all times. Further, to all my friends in Sri Lanka, U.S. and all around the world; I appreciate your encouragement and love I received. I love you all. Most importantly, my family was with me at every step of the way in this long journey. My Father Ariyasena Perera and My mother Hema Jayakody were the two pillars of strength whenever I was challenged. Their unconditional love made me stronger to thrive in what I do. I thank to my in-laws, especially my father in-law Mr. Jinadasa Nanayakkara for his encouragement. My brother and his family, my aunties, and my relatives for their lovely support. Finally, my loving husband Muditha Nanayakkara who listened, believed and taught me to be strong and being there for me whenever I needed the most. I love you so much. iv DEDICATION This dissertation is dedicated with love to My parents Hema and Ariyasena Perera My brother Erandha Perera My aunt Buddhi Jayakody and My loving husband Muditha Nanayakkara for supporting, encouraging and believing me in all endeavors…….. v TABLE OF CONTENTS ACKNOWLEDGEMENT....................................................................................................і DEDICATION....................................................................................................................iv LIST OF TABLES............................................................................................................vііi LIST OF FIGURES……………………………………………………………………….ix LIST OF SCHEMES ………………………………………………………………..…...xii LIST OF ABBREVIATIONS AND SYMBOLS..............................................................xiv CHAPTER 1. Background and Goals of Research………………………………………...1 1.1 Discovery of Estrogen Receptors.......................................................................1 1.2 Estrogen Receptors and Human Disease…………………………...……….....2 1.2.1 Estradiol, the Hippocampus and Memory…………………………...5 1.2.2 Estrogen Decrease in Menopause and Hormone Replacement Therapy……………………………………………………………………9 1.3 Estrogen Receptor Structure and Mechanism of Action……………………...11 1.4 Important Interactions within the Ligand Binding Domain…………………..15 1.5 Estrogen Receptor – Agonists, Antagonist and Selective Estrogen Receptor Modulators……………………………………………………………………….17 1.6 Review of ERβ Subtype Selective Ligands……………………………….….23 1.6.1 Design of Non-Steroidal ERβ Selective Agonists………………….24 1.7 Design of 4-Cyclohexyl or Cycloheptyl Phenolic Derivatives as
Load more

Recommended publications
  • And Active-Controlled Phase 3 Study of Postmenopausal Women with Osteoporosis
    Christiansen et al. BMC Musculoskeletal Disorders 2010, 11:130 http://www.biomedcentral.com/1471-2474/11/130 RESEARCH ARTICLE Open Access SafetyResearch article of bazedoxifene in a randomized, double-blind, placebo- and active-controlled phase 3 study of postmenopausal women with osteoporosis Claus Christiansen*1, Charles H Chesnut III2, Jonathan D Adachi3, Jacques P Brown4, César E Fernandes5, Annie WC Kung6, Santiago Palacios7, Amy B Levine8, Arkadi A Chines8 and Ginger D Constantine8 Abstract Background: We report the safety findings from a 3-year phase 3 study (NCT00205777) of bazedoxifene, a novel selective estrogen receptor modulator under development for the prevention and treatment of postmenopausal osteoporosis. Methods: Healthy postmenopausal osteoporotic women (N = 7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. Safety and tolerability were assessed by adverse event (AE) reporting and routine physical, gynecologic, and breast examination. Results: Overall, the incidence of AEs, serious AEs, and discontinuations due to AEs in the bazedoxifene groups was not different from that seen in the placebo group. The incidence of hot flushes and leg cramps was higher with bazedoxifene or raloxifene compared with placebo. The rates of cardiac disorders and cerebrovascular events were low and evenly distributed among groups. Venous thromboembolic events, primarily deep vein thromboses, were more frequently reported in the active treatment groups compared with the placebo group; rates were similar with bazedoxifene and raloxifene. Bazedoxifene showed a neutral effect on the breast and an excellent endometrial safety profile. The incidence of fibrocystic breast disease was lower with bazedoxifene 20 and 40 mg versus raloxifene or placebo.
    [Show full text]
  • Memorandum Date: June 6, 2014
    DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Memorandum Date: June 6, 2014 From: Bisphenol A (BPA) Joint Emerging Science Working Group Smita Baid Abraham, M.D. ∂, M. M. Cecilia Aguila, D.V.M. ⌂, Steven Anderson, Ph.D., M.P.P.€* , Jason Aungst, Ph.D.£*, John Bowyer, Ph.D. ∞, Ronald P Brown, M.S., D.A.B.T.¥, Karim A. Calis, Pharm.D., M.P.H. ∂, Luísa Camacho, Ph.D. ∞, Jamie Carpenter, Ph.D.¥, William H. Chong, M.D. ∂, Chrissy J Cochran, Ph.D.¥, Barry Delclos, Ph.D.∞, Daniel Doerge, Ph.D.∞, Dongyi (Tony) Du, M.D., Ph.D. ¥, Sherry Ferguson, Ph.D.∞, Jeffrey Fisher, Ph.D.∞, Suzanne Fitzpatrick, Ph.D. D.A.B.T. £, Qian Graves, Ph.D.£, Yan Gu, Ph.D.£, Ji Guo, Ph.D.¥, Deborah Hansen, Ph.D. ∞, Laura Hungerford, D.V.M., Ph.D.⌂, Nathan S Ivey, Ph.D. ¥, Abigail C Jacobs, Ph.D.∂, Elizabeth Katz, Ph.D. ¥, Hyon Kwon, Pharm.D. ∂, Ifthekar Mahmood, Ph.D. ∂, Leslie McKinney, Ph.D.∂, Robert Mitkus, Ph.D., D.A.B.T.€, Gregory Noonan, Ph.D. £, Allison O’Neill, M.A. ¥, Penelope Rice, Ph.D., D.A.B.T. £, Mary Shackelford, Ph.D. £, Evi Struble, Ph.D.€, Yelizaveta Torosyan, Ph.D. ¥, Beverly Wolpert, Ph.D.£, Hong Yang, Ph.D.€, Lisa B Yanoff, M.D.∂ *Co-Chair, € Center for Biologics Evaluation & Research, £ Center for Food Safety and Applied Nutrition, ∂ Center for Drug Evaluation and Research, ¥ Center for Devices and Radiological Health, ∞ National Center for Toxicological Research, ⌂ Center for Veterinary Medicine Subject: 2014 Updated Review of Literature and Data on Bisphenol A (CAS RN 80-05-7) To: FDA Chemical and Environmental Science Council (CESC) Office of the Commissioner Attn: Stephen M.
    [Show full text]
  • Selective Estrogen Receptor Modulators Enhance CNS Remyelination Independent of Estrogen Receptors
    This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Cellular/Molecular Selective estrogen receptor modulators enhance CNS remyelination independent of estrogen receptors Kelsey A. Rankin1, Feng Mei1, Kicheol Kim1, Yun-An A. Shen1, Sonia R. Mayoral1, Caroline Desponts2, Daniel S. Lorrain2, Ari J. Green1, Sergio E. Baranzini1, Jonah R. Chan1 and Riley Bove1 1University of California, San Francisco, Weill Institute for Neurosciences, Department of Neurology 2Inception Sciences, San Diego, CA https://doi.org/10.1523/JNEUROSCI.1530-18.2019 Received: 11 June 2018 Revised: 17 January 2019 Accepted: 20 January 2019 Published: 29 January 2019 Author contributions: K.R., Y.-A.A.S., A.J.G., J.R.C., and R.B. designed research; K.R., F.M., K.K., Y.- A.A.S., S.R.M., C.D., D.S.L., and S.B. performed research; K.R. analyzed data; K.R. wrote the first draft of the paper; K.R., J.R.C., and R.B. edited the paper; K.R. wrote the paper; F.M. and J.R.C. contributed unpublished reagents/analytic tools. Conflict of Interest: The authors declare no competing financial interests. We would like to thank the Innovation Program for Remyelination and Repair at the Weill Institute for Neurosciences at the University of California, San Francisco (UCSF). This work was supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01NS062796, R01NS097428, R01NS095889, R01NS088155], the National Multiple Sclerosis Society [RG5203A4], The Adelson Medical Research Foundation: ANDP (A130141), the Heidrich Family and Friends and the Rachleff Family Endowments.
    [Show full text]
  • Estroquench™ Hormone Specific Formulation™
    PRODUCT DATA DOUGLAS LABORATORIES® 08/2014 1 EstroQuench™ Hormone Specific Formulation™ DESCRIPTION EstroQuench™ is a Hormone Specific Formulation™ of ingredients that have documented anti-aromatase activity as well as androgenic adaptogens which support the function of endogenous aromatase inhibitors. Collectively these herbs promote minimal production and function of estrogens, while promoting testosterone function, including optimal sexual function in both genders. This formulation is designed to quench excessive production of estrogens and aberrant functions of them while supporting optimal function of androgens by maintaining the health of androgen producing glands.† Hormone Specific Formulation™ provided by Douglas Laboratories® and formulated by Dr. Joseph J Collins is created to support the optimal function of specific hormones through the use of hormone specific adaptogens, hormone specific agonists and hormone specific functional mimetics. This formulation may be used as part of a hormone health program with dietary and nutrient support. In addition, this formulation may be used by clinicians as an adjuvant to support optimal hormone health in patients who have been prescribed bioidentical hormone therapies. FUNCTIONS Aromatase (a cytochrome P450 enzyme {CYP19}) is the enzyme that controls the conversion of androgens to estrogens. More specifically, aromatase is the enzyme responsible for catalyzing the biosynthesis of androstenedione into estrone, and the biosynthesis of testosterone to estradiol. Estrogens include the broad range of aromatized hormones created form androgens. The specific attribute of estrogens that separate them from progestogens, androgens and corticoids is that estrogens are the only aromatized steroid hormones. Estradiol, the most potent endogenous estrogen, is biosynthesized by aromatization from androgens by aromatase (which is also called estrogen synthase).
    [Show full text]
  • Test Report Comprehensive Hormone Insights™
    698814 COMPREHENSIVE HORMONE INSIGHTS™ TEST REPORT Dr. Maximus, N.D. E: [email protected] Date of Collection: P: 403-241-4500 Time of Collection: F: 403-241-4501 Date of Receipt: www.rmalab.com Reported On: CHI Accession: 698814 Healthcare Professional Patient Age: Dr. Maximus, N.D. Date of Birth: Gender: Male F: Relevant Medications Biometrics Curcumin Height (in) : 73 Weight (lb) : 180 BMI : 24 Waist (in) : 35 Hip (in) : 41 CHI Accession: 698814 SUMMARY HMUS01 How to read the graphs LEGEND: 50 66 Sex Steroid Hormones 50 66 Middle third of 33 33 84 reference population Hormone Start of 83 100 80 100 highest 16 Percentile Precursors 16 Percentile third of Sum of Androgens Sum of Estrogens 50 66 reference 0 0 population (T, DHT, α+β androstanediol) Listed in Interp Guide 33 84 End of 100 16 lowest Percentile00 50 66 50 66 third of 33 33 84 reference 0 population Patient’s percentile rank 81 100 95 100 compared to reference 16 Percentile 16 Percentile population (see summary) DHEA + Metabolites Sum of Progesterone Metabolites 0 (DHEA + A + E) 0 α+β Pregnanediol Cortisol Melatonin Oxidative Stress Free Cortisol Profile (ng/mg) 100 50 66 50 66 33 84 33 84 80 64 100 0 100 16 Percentile 16 Percentile 60 6-sulfatoxy 8-Hydroxy-2- 0 Melatonin 0 deoxyguanosine 40 (Overnight) (Overnight) 20 6-sulfatoxymelatonin provides 8-hydroxy-2-deoxyguanosine is Cortisol/Creatinine (ng/mg) insight into melatonin levels. a marker of oxidative stress 0 Morning Dinner Bedtime A B C 50 66 Free cortisol Cortisol Metabolites 33 84 profile is used to provides a general Testosterone Cortisol assess diurnal assessment of 16 100 cortisol rhythm adrenal cortisol 16 Percentile Cortisol production Cortisol Metabolites 0 (α+β THF + THE) Testosterone Cortisol/Testosterone provides insight into relative catabolic (cortisol) and anabolic (testosterone) states.
    [Show full text]
  • The Mechanisms and Managements of Hormone-Therapy Resistance in Breast and Prostate Cancers
    Endocrine-Related Cancer (2005) 12 511–532 REVIEW The mechanisms and managements of hormone-therapy resistance in breast and prostate cancers K-M Rau1,2*, H-Y Kang3,4*, T-L Cha1,5,6, S A Miller1 and M-C Hung1 1Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA 2Department of Hematology-Oncology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan 3Graduate Institute of Clinical Medical Sciences, Chang Gung University, Kaohsiung, Taiwan 4The Center for Menopause and Reproductive Medicine Research, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan 5Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA 6Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (Requests for offprints should be addressed to M-C Hung; Email: [email protected]) *(K-M Rau and H-Y Kang contributed equally to this work) Abstract Breast and prostate cancer are the most well-characterized cancers of the type that have their development and growth controlled by the endocrine system. These cancers are the leading causes of cancer death in women and men, respectively, in the United States. Being hormone-dependent tumors, antihormone therapies usually are effective in prevention and treatment. However, the emergence of resistance is common, especially for locally advanced tumors and metastatic tumors, in which case resistance is predictable. The phenotypes of these resistant tumors include receptor- positive, ligand-dependent; receptor-positive, ligand-independent; and receptor-negative, ligand- independent. The underlying mechanisms of these phenotypes are complicated, involving not only sex hormones and sex hormone receptors, but also several growth factors and growth factor re- ceptors, with different signaling pathways existing alone or together, and with each pathway possibly linking to one another.
    [Show full text]
  • 2018 Apigenin Male Infertility (2).Pdf
    Original Article Thai Journal of Pharmaceutical Sciences Apigenin and baicalin, each alone or in low-dose combination, attenuated chloroquine induced male infertility in adult rats Amira Akilah, Mohamed Balaha*, Mohamed-Nabeih Abd-El Rahman, Sabiha Hedya Department of Pharmacology, Faculty of Medicine, Tanta University, Postal No. 31527, El-Gish Street, Tanta, Egypt Corresponding Author: Department of Pharmacology, ABSTRACT Faculty of Medicine, Tanta University, Postal No. 31527, Introduction: Male infertility is a worldwide health problem, which accounts for about 50% of all El-Gish Street, Tanta, Egypt. cases of infertility and considered as the most common single defined cause of infertility. Recently, Tel.: +201284451952. E-mail: apigenin and baicalin exhibited a powerful antioxidant and antiapoptotic activities. Consequently, in [email protected]. the present study, we evaluated the possible protective effect of apigenin and baicalin, either alone or Edu.Eg (M. Balaha). in low-dose combination, on a rat model of male infertility, regarding for its effects on the hormonal assay, testicular weight, sperm parameters, oxidative-stress state, apoptosis, and histopathological Received: Mar 06, 2018 changes. Material and methods: 12-week-old adult male Wister rats received 10 mg/kg/d Accepted: May 08, 2018 chloroquine orally for 30 days to induce male infertility. Either apigenin (30 or 15 mg/kg/d), baicalin Published: July 10, 2018 (100 or 50 mg/kg/d) or a combination of 15 mg/kg/d apigenin and 50 mg/kg/d baicalin received daily
    [Show full text]
  • Influence of Resveratrol Against Ovariectomy Induced Bone Loss In
    Reproductive Medicine; Endocrinology & Infertility Influence of Resveratrol Against Ovariectomy Induced Bone Loss in Rats: Comparison With Conjugated Equine Estrogen Tibolone and Raloxifene Önder ÇELİK1, Şeyma HASÇALIK1, Mustafa TAMSER2, Yusuf TÜRKÖZ3 Ersoy KEKİLLİ4, Cengiz YAĞMUR4, Mehmet BOZ1 Malatya, Turkey OBJECTIVE: We examined the effect of resveratrol, a phenolic compound found in the skins of most grapes, on bone loss in ovariectomized rats. STUDY DESIGN: A total of 42 young Wistar-albino rats, of which 35 animals were submitted to bilater- al oophorectomy, and 7 rats were submitted to the same surgical incision but without oophorectomy were studied. The rats were assigned to six groups of 7 animals each. For 35 consecutive days the fol- lowing treatments were given: Group 1, sham; group 2, ovariectomized (OVX); group 3, OVX plus resveratrol; group 4, OVX plus conjugated equine estrogen; group 5 OVX plus tibolone; group 6, OVX plus raloxifene. Immediately 40 days after the ovariectomy bone mineral density (BMD) of the lumbar spine and femur by using dual-energy X-ray absorptiometry. The BMD of lumbar region (R1), total femur region (R2) and three neighbor subregions of femur (R3, R4, R5) were drawn. RESULTS: There were no significant difference between OVX and resveratrol groups for R2, R3 and R4 values. Compared with the OVX group, CEE group had lower values for R3 but similar values for R2 and R4. Raloxifene group had significantly higher value than the OVX, resveratrol, CEE and tibolone groups for R2. For R3, raloxifene had significantly higher values than in the ones in resveratrol, CEE and tibolone. For R4 region, raloxifene had significantly higher values than CEE group.
    [Show full text]
  • TE INI (19 ) United States (12 ) Patent Application Publication ( 10) Pub
    US 20200187851A1TE INI (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No .: US 2020/0187851 A1 Offenbacher et al. (43 ) Pub . Date : Jun . 18 , 2020 ( 54 ) PERIODONTAL DISEASE STRATIFICATION (52 ) U.S. CI. AND USES THEREOF CPC A61B 5/4552 (2013.01 ) ; G16H 20/10 ( 71) Applicant: The University of North Carolina at ( 2018.01) ; A61B 5/7275 ( 2013.01) ; A61B Chapel Hill , Chapel Hill , NC (US ) 5/7264 ( 2013.01 ) ( 72 ) Inventors: Steven Offenbacher, Chapel Hill , NC (US ) ; Thiago Morelli , Durham , NC ( 57 ) ABSTRACT (US ) ; Kevin Lee Moss, Graham , NC ( US ) ; James Douglas Beck , Chapel Described herein are methods of classifying periodontal Hill , NC (US ) patients and individual teeth . For example , disclosed is a method of diagnosing periodontal disease and / or risk of ( 21) Appl. No .: 16 /713,874 tooth loss in a subject that involves classifying teeth into one of 7 classes of periodontal disease. The method can include ( 22 ) Filed : Dec. 13 , 2019 the step of performing a dental examination on a patient and Related U.S. Application Data determining a periodontal profile class ( PPC ) . The method can further include the step of determining for each tooth a ( 60 ) Provisional application No.62 / 780,675 , filed on Dec. Tooth Profile Class ( TPC ) . The PPC and TPC can be used 17 , 2018 together to generate a composite risk score for an individual, which is referred to herein as the Index of Periodontal Risk Publication Classification ( IPR ) . In some embodiments , each stage of the disclosed (51 ) Int. Cl. PPC system is characterized by unique single nucleotide A61B 5/00 ( 2006.01 ) polymorphisms (SNPs ) associated with unique pathways , G16H 20/10 ( 2006.01 ) identifying unique druggable targets for each stage .
    [Show full text]
  • New Insights for Hormone Therapy in Perimenopausal Women Neuroprotection
    Chapter 12 New Insights for Hormone Therapy in Perimenopausal Women Neuroprotection Manuela Cristina Russu and Alexandra Cristina Antonescu Additional information is available at the end of the chapter http://dx.doi.org/10.5772/intechopen.74332 Abstract Perimenopause is a mandatory period in women’s life, when the medical staff may initiate hormone therapy with sex steroids for the delay of brain aging and neurodegenerative diseases, during the so-called “window of opportunity.” Animals’ models are helpful to sustain the still controversial results of human clinical observational and/or randomized controlled studies. Estrogens, progesterone, and androgens, with their nuclear and mem- brane receptors, genes, and epigenetics, with their connections to cholinergic, GABAergic, serotoninergic, and glutamatergic systems are involved in women’snormalbrainorin brain’s pathology. The sex steroids are active through direct and/or indirect mechanisms to modulate and/or to protect brain plasticity, and vessels network, fuel metabolism—glucose, ketones, ATP, to reduce insulin resistance, and inflammation of the aging brain through blood-brain barrier disruption, microglial aberrant activation, and neural cell survival/loss. Keywords: perimenopause, “window” of opportunity, neuroprotection, sex steroid hormones 1. Introduction The months/years of perimenopause represent an important moment during women’saging, when sex steroids and their receptors decline are evident in the hippocampal and cortical neu- rons, after estrogen exposure during the reproductive years. The sex steroid hormones decline is associated/acts synergic to other factors as hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, vitamin B12/folate deficiency, depression, and traumatic brain injury to promote diverse pathological mechanisms involved in brain aging, memory impairment, and AD.
    [Show full text]
  • Coumestrol Suppresses Proliferation of ES2 Human Epithelial Ovarian Cancer Cells
    W LIM, W JEONG and others Coumestrol inhibits progression 228:3 149–160 Research of EOC Coumestrol suppresses proliferation of ES2 human epithelial ovarian cancer cells Whasun Lim1,*, Wooyoung Jeong2,* and Gwonhwa Song1 1Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Correspondence Republic of Korea should be addressed 2Department of Animal Resources Science, Dankook University, Cheonan 330-714, to G Song Republic of Korea Email *(W Lim and W Jeong contributed equally to this work) [email protected] Abstract Coumestrol, which is predominantly found in soybean products as a phytoestrogen, Key Words has cancer preventive activities in estrogen-responsive carcinomas. However, effects and " ovary molecular targets of coumestrol have not been reported for epithelial ovarian cancer (EOC). " reproduction In the present study, we demonstrated that coumestrol inhibited viability and invasion and " reproductive tract induced apoptosis of ES2 (clear cell-/serous carcinoma origin) cells. In addition, immuno- " coumestrol reactive PCNA and ERBB2, markers of proliferation of ovarian carcinoma, were attenuated in " clear cell carcinoma their expression in coumestrol-induced death of ES2 cells. Phosphorylation of AKT, p70S6K, ERK1/2, JNK1/2, and p90RSK was inactivated by coumestrol treatment in a dose- and time- dependent manner as determined in western blot analyses. Moreover, PI3K inhibitors Journal of Endocrinology enhanced effects of coumestrol to decrease phosphorylation of AKT, p70S6K, S6, and ERK1/2. Furthermore, coumestrol has strong cancer preventive effects as compared to other conventional chemotherapeutics on proliferation of ES2 cells. In conclusion, coumestrol exerts chemotherapeutic effects via PI3K and ERK1/2 MAPK pathways and is a potentially novel treatment regimen with enhanced chemoprevention activities against progression of EOC.
    [Show full text]
  • Differences Between the Non-Steroidal Aromatase Inhibitors Anastrozole and Letrozole – of Clinical Importance?
    British Journal of Cancer (2011) 104, 1059 – 1066 & 2011 Cancer Research UK All rights reserved 0007 – 0920/11 www.bjcancer.com Minireview Differences between the non-steroidal aromatase inhibitors anastrozole and letrozole – of clinical importance? ,1 J Geisler* 1 Institute of Clinical Medicine, University of Oslo, Faculty Division at Akershus University Hospital, Sykehusveien 27, Lørenskog N-1478, Norway Aromatase inhibition is the gold standard for treatment of early and advanced breast cancer in postmenopausal women suffering from an estrogen receptor-positive disease. The currently established group of anti-aromatase compounds comprises two reversible aromatase inhibitors (anastrozole and letrozole) and on the other hand, the irreversible aromatase inactivator exemestane. Although exemestane is the only widely used aromatase inactivator at this stage, physicians very often have to choose between either anastrozole or letrozole in general practice. These third-generation aromatase inhibitors (letrozole/Femara (Novartis Pharmaceuticals, Basel, Switzerland) and anastrozole/Arimidex (AstraZeneca, Pharmaceuticals, Macclesfield, Cheshire, UK)), have recently demonstrated superior efficacy compared with tamoxifen as initial therapy for early breast cancer improving disease-free survival. However, although anastrozole and letrozole belong to the same pharmacological class of agents (triazoles), an increasing body of evidence suggests that these aromatase inhibitors are not equipotent when given in the clinically established doses. Preclinical and clinical evidence indicates distinct pharmacological profiles. Thus, this review focuses on the differences between the non-steroidal aromatase inhibitors allowing physicians to choose between these compounds based on scientific evidence. Although we are waiting for the important results of a still ongoing head-to-head comparison in patients with early breast cancer at high risk for relapse (Femara Anastrozole Clinical Evaluation trial; ‘FACE-trial’), clinicians have to make their choices today.
    [Show full text]