1) The document summarizes research on the biochemical properties of renin and prorenin binding to the (pro)renin receptor.
2) It finds that prorenin has higher binding affinity than renin for the receptor and that peptides from the prorenin prosegment can inhibit this binding.
3) The decoy and "hinge" peptides show potential as (pro)renin receptor blockers but more research is needed to validate their mechanisms and effects.
regulation of gene expression in eukaryotes is a complex mechanism involved many factors. out of many levels of regulations, chromosomal and transcription level of regulation are discussed in this slides.
This presentation is about Riboswitches and Riboswitches mediated regulation. Riboswitches are the small mRNA element that has tertiary structure and regulate the down stream genes in the same mRNA by interacting with small metabolites and metal ions.Various types of regulatory mechanism and structure and ligand binding of some important riboswitches are given here.Like TPP,PURINE AND FMN riboswitches. Also the role of some tandem and cooperative riboswitches are given here. Applications of Riboswitches are also given here like drug targets. Some future challenges are also given here.
A conserved Ser/Arg rich motif in PPZ orthologs from fungi is important for i...AnnuMinhas
Background - Ppz1 orthologs - novel family of
phosphatases - have unique N-terminal non
catalytic domain
Results – Ppz1 ortholog from halotolerant yeast
Debaryomyces hansenii plays important role in
salt tolerance, cell wall integrity and cell growth
in through distinct mechanism.
Conclusion – Short serine arginine rich motif in
non-catalytic domain is essential for its role in
salt tolerance.
Significance – This motif is conserved among
orthologs and functionally important.
regulation of gene expression in eukaryotes is a complex mechanism involved many factors. out of many levels of regulations, chromosomal and transcription level of regulation are discussed in this slides.
This presentation is about Riboswitches and Riboswitches mediated regulation. Riboswitches are the small mRNA element that has tertiary structure and regulate the down stream genes in the same mRNA by interacting with small metabolites and metal ions.Various types of regulatory mechanism and structure and ligand binding of some important riboswitches are given here.Like TPP,PURINE AND FMN riboswitches. Also the role of some tandem and cooperative riboswitches are given here. Applications of Riboswitches are also given here like drug targets. Some future challenges are also given here.
A conserved Ser/Arg rich motif in PPZ orthologs from fungi is important for i...AnnuMinhas
Background - Ppz1 orthologs - novel family of
phosphatases - have unique N-terminal non
catalytic domain
Results – Ppz1 ortholog from halotolerant yeast
Debaryomyces hansenii plays important role in
salt tolerance, cell wall integrity and cell growth
in through distinct mechanism.
Conclusion – Short serine arginine rich motif in
non-catalytic domain is essential for its role in
salt tolerance.
Significance – This motif is conserved among
orthologs and functionally important.
This presentation consists of topics related to oncogene, proto oncogene, Tumor suppresor gene, Ras gene family and structure and functions of tumor suppressor gene.
Validation of RNA interference by RNA-Seq: How to see the big picture - Brend...OECD Environment
10-12 April 2019: The OECD Conference on RNAi based pesticides provided an overview on the current status and future possibilities for the regulation of externally applied dsRNA-based products that are proposed for use as pesticides. The event facilitated exchanges between policy makers, academia, industry on their implications in health, environment, and regulation.
Similar to Biochemical properties of renin and prorenin binding (20)
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
263778731218 Abortion Clinic /Pills In Harare ,ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group of receptionists, nurses, and physicians have worked together as a teamof receptionists, nurses, and physicians have worked together as a team wwww.lisywomensclinic.co.za/
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...GL Anaacs
Contact us if you are interested:
Email / Skype : kefaya1771@gmail.com
Threema: PXHY5PDH
New BATCH Ku !!! MUCH IN DEMAND FAST SALE EVERY BATCH HAPPY GOOD EFFECT BIG BATCH !
Contact me on Threema or skype to start big business!!
Hot-sale products:
NEW HOT EUTYLONE WHITE CRYSTAL!!
5cl-adba precursor (semi finished )
5cl-adba raw materials
ADBB precursor (semi finished )
ADBB raw materials
APVP powder
5fadb/4f-adb
Jwh018 / Jwh210
Eutylone crystal
Protonitazene (hydrochloride) CAS: 119276-01-6
Flubrotizolam CAS: 57801-95-3
Metonitazene CAS: 14680-51-4
Payment terms: Western Union,MoneyGram,Bitcoin or USDT.
Deliver Time: Usually 7-15days
Shipping method: FedEx, TNT, DHL,UPS etc.Our deliveries are 100% safe, fast, reliable and discreet.
Samples will be sent for your evaluation!If you are interested in, please contact me, let's talk details.
We specializes in exporting high quality Research chemical, medical intermediate, Pharmaceutical chemicals and so on. Products are exported to USA, Canada, France, Korea, Japan,Russia, Southeast Asia and other countries.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Biochemical properties of renin and prorenin binding
1. Biochemical properties of renin
and prorenin binding
to the (pro)renin receptor
M.Prasad Naidu
MSc Medical Biochemistry,
Ph.D.Research Scholar
2. Introduction
Renin is the rate-limiting enzyme in RAS.
This enzyme is secreted into the blood
stream only from the juxtaglomerular cells of
the kidney in response to cellular stimuli.
Prorenin, the inactive precursor of renin.
3. Sources of Prorenin
Prorenin has been found to synthesize not only in the
juxtaglomerular cells but also in many other tissues such as
1)The collecting duct,
2)Adrenal , Zona glomerulosa,
3)Eye,
4)Muller cells, Mast cells,
5)Ovary, Thecal cells,
6)Uterus, Myometrium/Decidual cells, Placenta, Chorionic
cells,
7)Testis and Leydig cells, and
8)Submandibular gland.
Prorenin is secreted from these tissues into the blood
constitutively and its level in the circulation is 10 times higher
than that of mature renin .
4. Activation of Prorenin
The precursor of renin is inactive, because
the prosegment region with 43 amino acid
residues covers the active site of renin with
339–341 residues.
Activation of prorenin can take place either
proteolytically or non-proteolytically .
The non-proteolytic activation of prorenin has
been shown under acidic pH or low
temperature (cryo-activation) that reversibly
alter the stereo structure of intact prorenin
molecule into a catalytically active form .
5. contd
Also, the ‘gate’ (T7pFKR10p) and ‘handle’
(I11pFLKR15p) regions in the prorenin
prosegment were indicated in vitro to be
accountable for the non-proteolytic
activation of prorenin molecules through
protein–protein interaction .
Proteolytic activation has been observed
in vitro by treatments of some
proteases, thereby, irreversibly removing the
prosegment.
6. THE INTERACTION OF
RENIN/PRORENIN WITH THE (P)RR
The (pro)renin receptor,(P)RR, a new player
in the RAS components, binds both renin and
prorenin .
(Pro)renin receptor binds renin, thereby
locally increases angiotensin production.
After binding to the (P)RR, prorenin
undergoes a conformational change in the
prosegment region, thus opening the active
site accessible to the substrate
angiotensinogen .
7. contd
The (P)RR mRNA has been reported to express in
many organs,
for example :
Kidney,
Heart,
Brain,
Eye,
Adipose tissue and
vascular smooth muscle cells ,
thus it may help to accumulate renin and prorenin
locally in tissues even though lacking components
of RAS, that is, in the heart and vasculature wall .
8. contd
Receptor-associated renin and prorenin have been
proposed to potentially activate tissue-specific RAS
in an angiotensin-II-dependent manner.
As plasma prorenin level is higher than renin, thus
it is suggested that prorenin may have a major role
in tissue specific RAS activation .
Binding of renin and prorenin to the receptor
possibly triggers their own intracellular signaling
pathways independent of RAS that is angiotensin –
II – independent manner .
9.
10. contd
Both renin and prorenin stimulates p42/p44
mitogen activated protein kinase (MAPK)
activation and transforming growth factor-b1
release in mesangial cells in the presence of
renin and ACE inhibitors and/or AT1 receptor
antagonists .
Moreover, prorenin also activates p38
mitogen-activated protein kinase and
simultaneously phosphorylate heat-shock
protein 27 in cardiomyocytes.
11. contd
Prorenin stimulated extracellular signal -
related protein kinase phosphorylation is
through (P)RR-mediated activation of tyrosine
kinase.
The transcription factor promyelocytic
leukemia zinc-finger protein as a direct
protein interaction partner of the C-terminal
domain of the (P)RR, which is translocated
into the nucleus and represses transcription
of the (P)RR itself, thereby creating a very
short negative feedback loop.
12. BINDING PROPERTIES OF RENIN &
PRORENIN TO THE (P)RR
Studies are showing higher binding affinity of
rat prorenin for the (P)RR compared with that
of rat renin molecule in vitro using rat
recombinant (P)RR expressed in the
baculovirus expression system.
13. contd
Binding experiments of these molecules
were carried out using immobilized receptors
at different conditions for example:
(a) at 4 C on the synthetic plastic surfaces ,
(b) at 25 C on the CM5 sensor chip for
BIAcore analyses and
(c) at 37 C on the COS-7 cell membrane.
14.
15.
16.
17.
18. contd
Receptor-bound rat and human prorenin
showed 30 and 40% activity, respectively, in
comparison with the activity of trypsinized
prorenin molecules.
Batenburg et al. found a similar activation of
human prorenin by binding to the human
(P)RR with 6.0nmol / L of KD, using the
receptor expressed in smooth muscle cells of
transgenic rat for this receptor.
19. HRP/DECOY AND ‘HINGE’ REGION
PEPTIDES ARE THE MOST
PROBABLE CANDIDATES FOR (P)RR
BLOCKER
The decoy peptide mimics the
R10pIFLKRMPSI19p region of prorenin
prosegment was first indicated by Ichihara et
al , who designed this peptide based on the
‘handle’ region peptide (HRP , I11pFLKR15p)
in prorenin prosegment reported by Suzuki et
al, Ichihara et al.
20. Contd
Decoy peptide administration demonstrated
complete inhibition of diabetic nephropathy in
the streptozotocin-induced diabetic rats.
Blockade of prorenin activation using decoy
peptide in spontaneously hypertensive rats
with high-salt diet has been reported by
Susic et al., who also showed reduction of
serum creatinine level, decreased left
ventricular mass and fibrosis, improved left
ventricular function by treating these rats
with the decoy.
21. Contd
Human HRP prevented the proteinuria and
glomerulosclerosis that developed in human
(P)RR transgenic rats .
In vitro study also showed that both decoy
and ‘handle’ region peptides from rat and
human inhibited the bindings of rat and
human prorenins to their respective (P)RR
on the membrane over expressed in COS-7
cells, with a Ki of 6.6 nmol /L
22. contd
Human HRP prevented prorenin-induced
activation of extracellular signal-related
protein kinase 1/2 in COS-7 cells expressing
the h(P)RR .
Rat HRP decrease not only mesangial cell
proliferation but also the expression of
transforming growth factor-b1 mRNA and
phosphorylation of extracellular signal-related
protein kinase 1/2.
23. contd
HRP inhibits the development of retinal
neovascularization through interfering non-
proteolytic activation of prorenin in
experimental retinopathy model of
prematurity .
HRP suppresses the pathological
angiogenesis, leukocyte accumulation and
intracellular adhesion molecule-1 with
vascular endothelial growth factor
expression; reduced retinal gene and protein
expression of inflammatory mediators.
24. contd
other investigators reported that HRP/decoy
peptide affected neither prorenin binding to
(P)RR expressed on the vascular smooth
muscle cells nor Ang-I generation .
These incompatible results with decoy
peptide containing HRP have led to further
investigate the effects of decoy peptide .
Not only renin/prorenin but also the decoy
containing HRP directly bound to the
recombinant (P)RR .
25. The binding experiments with other
peptides designed .
26. contd
I11pFLKR15p sequence show higher binding
affinity for the receptor .
Decoy peptide also inhibit the binding of
prorenin & renin to (P)RR.
Thus, these observations revealed that
prorenin has higher binding affinity for (P)RR
compared with that of mature renin and the
decoy sequence of the prosegment has been
suggested to have an essential role for the
prorenin binding
27. contd
The decoy binding with high affinity to (P)RR
explains the probable reason for high-affinity
binding of prorenin.
The binding inhibition of decoy for renin to
(P)RR still remain to be elucidated, as it is
lacking the prosegment sequence.
The decoypeptide blunted the interaction of
renin with (P)RR possibly by changing
specific space within the receptor.
28. contd
A new sequence S149QGVLKEDVF158 that
localizes in the flexible junctional region
between the N- and C-domains of
renin/prorenin termed as the ‘hinge’ has
recently been reported to have such pivotal
role for renin/prorenin binding to (P)RR .
The KD for the binding of the ‘hinge’ peptide
to (P)RR was five times higher than that of
the decoy and estimated to be 17nmol /L .
29. contd
Not only the decoy peptide but also the
‘hinge’ region peptide together accounted for
the higher binding affinity of prorenin and
hence, prorenin molecule has at least two
sites whereas renin has a single site through
which these molecules can interact with the
(P)RR.
30. EFFECTS OF
ALISKIREN,HRP/DECOY AND
‘HINGE’ PEPTIDES ON RENIN
ACTIVITY
Aliskiren, a new orally direct renin inhibitor, potently
inhibits the renin activity and thus lowers
angiotensin II generation in vivo.
Aliskiren did not blunt bindings of renin and
prorenin to (P)RR .
Significantly decreases, the mRNA expression of
(P)RR in the kidney cortex of diabetic hypertensive
Ren2 rats.
31. contd
The renin activity either in the soluble free
form or in the receptor-bound state of renin/
prorenin was not inhibited by the decoy
(11P–19P) and the ‘hinge’(149–158)
peptides at 80 nmol /L .
32. Perspectives
Many in vivo studies have demonstrated the
role of non-proteolytic activation of prorenin
mediated by the (P)RR in the pathogenesis of
diabetic nephropathy and retinopathy as well
as in the activation of tissue specific
RAS, which might lead to the onset of
hypertension.
Further studies may help to understand the
counter part of decoy peptide present in
(P)RR and its mode of action in blocking
renin/prorenin binding to this receptor.
33. contd
More studies are needed to
substantiate the fact that this ‘hinge’
region peptide, as a (P)RR blocker .
It is yet to be elucidated whether the
decoy and ‘hinge’ peptides can bind to
the recently reported shedded (P)RR
and thus attenuate the interaction of
renin/prorenin with this receptor .