The document discusses the role of nuclear receptors in controlling liver fibrosis. It describes several nuclear receptors expressed in hepatic stellate cells, including PPARβ/γ, PXR, FXR, and SHP. Activation of these receptors reduces stellate cell proliferation and the expression of fibrotic markers. Studies show that ligands for PPARγ, FXR, and PXR decrease liver fibrosis in rodent models by inducing a phenotypic switch in stellate cells from an activated to quiescent state.
Farnesoid x receptor (fxr) and intestinal mucosa - Stefano FiorucciAttività scientifica
Bile acids activated receptors regulate the integrity of gastrointestinal mucosafocus on FXR.
Stefano Fiorucci,
MD Department of Surgical and Biomedical Sciences
University of Perugia
For The Japanese Society of Gastroenterology (JSGE) COI Disclosure
The slides describe the relation between bile acids, intetsinal microbiota and bile acid activated receptors. Nuclear receptors and G-protein coupled receptors
Farnesoid x receptor (fxr) and intestinal mucosa - Stefano FiorucciAttività scientifica
Bile acids activated receptors regulate the integrity of gastrointestinal mucosafocus on FXR.
Stefano Fiorucci,
MD Department of Surgical and Biomedical Sciences
University of Perugia
For The Japanese Society of Gastroenterology (JSGE) COI Disclosure
The slides describe the relation between bile acids, intetsinal microbiota and bile acid activated receptors. Nuclear receptors and G-protein coupled receptors
Stable infected HEK293 OATP Cells for Transporter Analysis. A model system for the assay of drug uptake.
The knowledge of drug affinity and drug-drug interaction (DDI) and the role of organic anion transporting polypeptides (OATPs) and other transporter proteins like P-glycoprotein (MDR1, P-gp, ABCB1) is a basic requirement in drug development and is also recommended by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
OATPs of the SLCO (former SLC21) superfamily are of fundamental importance in the transport of drugs across cell membranes, e.g. in intestine, liver, kidney, brain, skeleton muscle and placenta.
Hepatic OATPs (OATP1B1, OATP1B3, OATP2B1) but also the sodium taurocholate co-transporting polypeptide (NTCP) are expressed at the sinusoidal membrane of human hepatocytes and transport several compounds into hepatocytes for biotransformation. In intestine, absorption of several compounds is mediated by e.g. OATP2B1 and the bile acid transporter ASBT (apical sodium-dependent bile salt transporter) which both are expressed at the brush border membrane.
PRIMACYT utilizes well characterized stable transfected human embryonic kidney cells (HEK293) expressing different transporter proteins to study uptake of drugs and chemicals in vitro.
Small molecule inhibitors of PI4 KinaseDavid Andrews
Potent, selective small molecule inhibitors of type III phosphatidylinositol-4-kinase α- and β- and their effects on phosphatidylinositol signalling. The importance of small molecule probes to help us understand cellular pathways in cancer
In Vitro Metabolic, CYP and Transporter Characterization of PTI-125, a Novel ...Covance
ISSX 2019 -- PTI-125 is an oral, small molecule drug candidate in clinical development for the treatment of AD. PTI-125 binds and reverses an altered conformation of filamin A to suppress multiple AD pathologies. The present study aimed to determine metabolic stability in mouse, rat, dog and human hepatic microsomes and assess potential drug-drug interactions for PTI-125.
A novel publication form stefano fiorucci lab demonstrates a role for bile acids in regulating arterial vasodilation.
The foinding might have relevance in designing novel ddrug to treat hypertension and metabolic syndrome.
Poster demonstrating the results from the development/verification project for the quantitation of pyridoxal 5-phosphate and 4-pyridoxic acid in human plasma.
Turn Back the Cellular Clock with NutrigenomicsAdducoMedia
The idea is simple: produce new, more powerful mitochondria so you can feel younger and more energetic from the inside out. The new NRF1 Synergizer formula from Lifevantage is a new breakthrough in nutrigenomics that wakes up your body's ability to make more mitochondria, protect the ones you have, and restore youth to your body at the cellular level.
Stable infected HEK293 OATP Cells for Transporter Analysis. A model system for the assay of drug uptake.
The knowledge of drug affinity and drug-drug interaction (DDI) and the role of organic anion transporting polypeptides (OATPs) and other transporter proteins like P-glycoprotein (MDR1, P-gp, ABCB1) is a basic requirement in drug development and is also recommended by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
OATPs of the SLCO (former SLC21) superfamily are of fundamental importance in the transport of drugs across cell membranes, e.g. in intestine, liver, kidney, brain, skeleton muscle and placenta.
Hepatic OATPs (OATP1B1, OATP1B3, OATP2B1) but also the sodium taurocholate co-transporting polypeptide (NTCP) are expressed at the sinusoidal membrane of human hepatocytes and transport several compounds into hepatocytes for biotransformation. In intestine, absorption of several compounds is mediated by e.g. OATP2B1 and the bile acid transporter ASBT (apical sodium-dependent bile salt transporter) which both are expressed at the brush border membrane.
PRIMACYT utilizes well characterized stable transfected human embryonic kidney cells (HEK293) expressing different transporter proteins to study uptake of drugs and chemicals in vitro.
Small molecule inhibitors of PI4 KinaseDavid Andrews
Potent, selective small molecule inhibitors of type III phosphatidylinositol-4-kinase α- and β- and their effects on phosphatidylinositol signalling. The importance of small molecule probes to help us understand cellular pathways in cancer
In Vitro Metabolic, CYP and Transporter Characterization of PTI-125, a Novel ...Covance
ISSX 2019 -- PTI-125 is an oral, small molecule drug candidate in clinical development for the treatment of AD. PTI-125 binds and reverses an altered conformation of filamin A to suppress multiple AD pathologies. The present study aimed to determine metabolic stability in mouse, rat, dog and human hepatic microsomes and assess potential drug-drug interactions for PTI-125.
A novel publication form stefano fiorucci lab demonstrates a role for bile acids in regulating arterial vasodilation.
The foinding might have relevance in designing novel ddrug to treat hypertension and metabolic syndrome.
Poster demonstrating the results from the development/verification project for the quantitation of pyridoxal 5-phosphate and 4-pyridoxic acid in human plasma.
Turn Back the Cellular Clock with NutrigenomicsAdducoMedia
The idea is simple: produce new, more powerful mitochondria so you can feel younger and more energetic from the inside out. The new NRF1 Synergizer formula from Lifevantage is a new breakthrough in nutrigenomics that wakes up your body's ability to make more mitochondria, protect the ones you have, and restore youth to your body at the cellular level.
This presentation introduces a brief and rapid review for an important research area (oxidative stress) and its relation to liver fibrosis.
Liver fibrosis is very important for us as we are facing a very dangerous and continuously growing problem in Egypt, HEPATIC PATIENTS COMPLICATIONS.
regeneration
Proliferative Capacities of Tissues
Stem Cells
REPAIR BY CONNECTIVE TISSUE
Angiogenesis
Migration of Fibroblasts and ECM Deposition (Scar Formation)
PATHOLOGIC ASPECTS OF REPAIR
Detecting Early Liver Fibrosis - A Nutshell for Primary CareJarrod Lee
This presentation summarizes the latest technologies for detecting early liver fibrosis and their role in healthcare today. It is aimed at primary care doctors, to help them better utilize these new developments for their patients.
Revisión del artículo "PlcRa, a new quorum-sensing regulator from Bacillus cereus, plays a role in oxidative stress responses and cysteine metabolism in stationary phase", de Eugénie Huillet, et. al.
Cis-Regulatory divergence and expression of ryanodine receptor paralogues in ...TahaniBaakdhah
Ryanodine receptors (RyRs) are large homotetrameric proteins that in mammals are encoded by three genes: RyR1 in skeletal muscle; RyR2 in cardiac and smooth muscle; and RyR3 which is expressed in a diversity of cell types. RyR channels play a central role in the excitation-contraction (EC) coupling process by mediating Ca²+ release from the sarcoplasmic reticulum (SR). RyR1 paralogues are expressed in a fiber type-specific manner in fish skeletal muscles: RyR1a in slow-twitch skeletal muscle (red muscle) and RyR1b in fast-twitch skeletal muscle (white muscle). RyR1a and RyR1b are classic examples of spatial subfunctionalization, since they share an ancestral function, yet are expressed differentially in red and white muscle fibres respectively. Gene duplication and subsequent divergence in sequence, expression and interactions are considered to be one of the major driving forces in the evolution of diversity. After the upstream promoter regions, evolutionarily conserved introns are considered the second most important sites containing gene regulatory elements that control tissue-specific expression (gene enhancers or gene silencers). Using medaka (Oryzias latipes) as a model organism, I searched the noncoding sequences in medaka RyR1 and RyR3 genes to look for conserved noncoding elements for RyR co-orthologues and paralogues. The bioinformatic analyses revealed evidence of conservation of noncoding elements for RyR co-orthologues and divergence between RyR paralogues. I also analyzed the spatial and developmental expression of the RyR paralogues (RyR1a/RyR1b; RyR3a/RyR3b) in medaka. The expression analyses revealed conserved expression patterns for the RyR co-orthologues and divergent expression of the RyR paralogues.
Il punto sul microbiota e le malattie umane- Covegno scientifico Attività scientifica
Il microbiota e le patologie umane- Perugia 20 aprile 2018- Convegno a Perugia-
Probiotici e trattamento delle patologie umane
Microbiota intestinale e malattie infiammatorie
Giornata di studio sul microbiota e patologie umane- Esperti a confronto sul ruolo dl microbiota nelle patologie dell' apparato digerente Perugia 20 aprile 2018
Meeting sul microbiota umano 20 aprile 2018
Focus su microbiota intestinale e malattie infiammatorie ed epatiche- Probiotici: come valutare un probiotico?
These slides describe the pathophysiology and the management of patients with liver cirrhosis and portal hypertension. The slides are at the level of post-graduate students
GPBAR1 (TGR5) regulates il 10 production from intestinal macrophages Attività scientifica
Novel therapeutic approach to intestinal inflammation by targeting GPBAR1 (TGR5) stimulates release of anti-inflammatory cytokine IL-10.
Just published in J. Immunology June 2017
Nuovo website:
www.gastroenterologia.unipg.it
disponibile da oggi per aggiornamenti, didattica, blog ed informazioni sulla sezione di gastroenterologia di Perugia
BILE ACID ACTIVATED RECEPTORS: FROM MEDICINAL CHEMISTRY TO CLINICAL APPLICATIONSAttività scientifica
A scientific meeting on bile acids and their receptors and clinical applications in liver and metabolic disorders will be held on Feb 9, 2016 in Perugia. Attendance is free.
Inf: stefano.fiorucci@unipg.it
A seminar on nanotechnology at the Department of Surgical and Biomedical Science University of Perugia. The seminar will describe general concepts and biomedical applications of nanotechnologies.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
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.
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
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
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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
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.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
3. Metabolic NRs expressed in the
liver and gastrointestinal tract
Androstan Receptor (CAR)
Estrogen Related Receptor-α (ERR)
Farnesoid X Receptor (FXR)
Hepatocyte Nuclear Factor-4 (HNF-4)
Liver X Receptor (LXR)
Peroxisome Proliferator-Activated Receptor (PPAR)
Pregnane X Receptor (PXR)
Retinoid X Receptor (RXR)
Vitamin D Receptor (VDR)
4. Metabolic NRs expressed in the
liver and gastrointestinal tract
Androstan Receptor (CAR)
Estrogen Related Receptor-α (ERR)
Farnesoid X Receptor (FXR)
Hepatocyte Nuclear Factor-4 (HNF-4)
Liver X Receptor (LXR)
Peroxisome Proliferator-Activated Receptor (PPAR)
Pregnane X Receptor (PXR)
Retinoid X Receptor (RXR)
Vitamin D Receptor (VDR)
5. NRs general structure
AF1 AF2
A/B C D E F
NH2 DBD hinge LBD COOH
AF1 AF2
DIMERIZATION
6. NRs mode of action
HAT
HDAC
+ligands LX
N-CoR LL XL
Histones LXX L
Histones
AF2 AF2 De-Acetylation AF2 AF2 Acetylation
Bile acids
AF1 AF1 CDCA or INT-747 AF1 AF1 Ac Ac
Ac Ac
Ac Ac
DBD DBD DBD DBD
FXR RXR FXR RXR
9-cis RA Ac Ac
Ac Ac
Ac Ac
CDCA
INT-747
FXR RXR FXR RXR
9-cis RA
9-cis RA
IR-1 IR-1
9. PPARβ
PPARβ signaling contributes to enhanced
proliferation of HSC
• HSCs constitutively express high levels of PPARβ, which
become further induced during culture activation and in vivo
fibrogenesis.
• PPARβ activation by L165041 enhanced HSC proliferation.
• Treatment of rats with a single bolus of CCl4 in combination
with L165041 enhanced the expression of fibrotic markers.
Gastroenterology 2003 Jan;124(1):184-201
10. PPARγ
• Ligands of PPARγ modulate profibrogenic and
proinflammatory actions in HSCs.
• PPARγ ligands regulate adipogenic genes in
HSC.
• PPARγ induces a phenotypic switch from
activated to quiescent HSC.
• PPARγ ligands prevent hepatic steatosis,
fibrosis in rodent models of liver cirrhosis.
12. PPARγ transduction induces other adipogenic
transcription factors
She, H. et al. J. Biol. Chem. 2005;280:4959-4967
13. Expression of SREBP-1c induces other adipogenic
factors And HSCs quiescence
She, H. et al. J. Biol. Chem. 2005;280:4959-4967
14. PXR
Ligands
Rifampicin in humans, PCN in rodents, phenobarbital,
dexamethasone, LCA, statins, St. John's wort, clotrimazole,
possible UDCA
Molecular targets
MRP2/Mrp2, MRP3, Oatp1a4, MDR1, CYP3A4,
SULT2A1/Sult2a1, (indirectly) CYP7A1 UGT1A1
Biological effects
Induction of canalicular and alternative basolateral
bile acid excretion induction of phase I and II bile
acid and bilirubin detoxification systems indirect
repression of CYP7A1
15. PXR LIGANDS
PNAS | March 13, 2001 | vol. 98 | no. 6 | 3369-3374
Chemical structures of xenobiotics that bind to and activate PXR.
Hyperforin is a constituent of St. John's wort.
16. PXR
• Pregnenolone-16alpha-carbonitrile inhibits
rodent liver fibrogenesis via PXR
-dependent and PXR-independent
mechanisms.
Biochem J. 2005 May 1;387(Pt 3):601-8
• PXR activators inhibit human hepatic
stellate cell transdifferentiation in vitro
Gastroenterology. 2006 Jul;131(1):194-209
17. PXR
PXR is expressed in HSCs
Gastroenterology. 2006 Jul;131(1):194-209
20. Ntcp Bsep Mdr2
Na+
BS- X BS- PC
OA-
Ostαβ
X
BS-
X
OA-
OC+ Mrp3 & 4 Proximal Renal Tubule
BS -
BS-
Oatps Mrp2 Mdr1
Asbt
Cholangiocyte
X
Na+
Hepatocyte
BS-
Asbt Ostαβ ? OA-
Na+ Na+ BS-
Enterocyte
Bile Duct BS- BS- Mrp2 Ostαβ
Mrp4
OA-
+
? Mrp3 OC
BS-
OA- Mdr1 ? Mrp3
BS-
Na+ BS- Kidney
Mdr1
?
Asbt
X Mrp2 Adaptive changes in
transporter expression in
Intestine
cholestasis
Trauner & Boyer.
Phys. Rev 83:’03
21. FXR
Ligands
CDCA, DCA, CA, LCA possibly UDCA (weak ligand)
synthetic: GW4064,6 -ethyl-CDCA, fexaramines
Molecular targets
SHP, BSEP/Bsep, I-BABP, Mrp2, OATP1B3,
OSTαβ, Sult2a1, CYP3A4, UGT2B4, UGT2B7
Biological effects
Induction of canalicular and alternative basolateral
bile acid excretion induction of phase I and II bile
acid detoxification systems
22. SHP
Ligands
Molecular targets
CYP7A1/Cyp7a1, CYP8B1/Cyp8b1, CYP27A1, Ntcp, ASBT/Asbt
Biological effects
Repression of bile acid synthesis and basolateral bile acid uptake
23. FXR ligands & bile acid metabolism
Cholesterol
NTCP
CYP7A
NTCP
Portal Blood
CYP8B MR
P2
Bile
SHP bile acids BSEP canaliculus
3
MDR
MRP3
FXR RXR
MRP4
CYP3A4 Phase II
CYP7A cholesterol 7alpha-hydroxylase
CYP8B sterol 12 alpha-hydroxylase P450
24. FXR
• HSCs constitutively express high levels of FXR,
which become slightly induced during culture
activation and in vivo fibrogenesis.
• FXR activation by FXR ligands reduces HSC
proliferation.
• Treatment of rats with FXR ligands reduces the
expression of fibrotic markers in rodent models
of cirrhosis.
Fiorucci, et al. Gastroenterology 2004
35. Nuclear receptors cross talk
FXR ligands upregulates PPARα and PPARγ
expression/function1,2
Some of the metabolic effects of FXR ligands are
negatively modulated by PPARγ antagonists1,2
PXR is a target of farnesoid X receptor3
1. Mol Endocrinol. 2003 Feb;17(2):259-72
2. JPET 315:58–68, 2005
3. J Biol Chem. 2006 Jul 14;281(28):19081-91
36. Regulation of Transporter Expression
by NRs
SHP
RXRα RARα HNF-1
Ntcp
FXR PXR CAR
RARα RXRα
Mrp2
SP-1 SP-3 LRH-1
Mrp3
RXRα FXR
Bsep
RXRα FXR
Ostα/β
37. 6-ECDCA
7.0 4
Rosiglitazone *
6.5
α (I) collagen mRNA
6.0 **
*
PPAR-γ mRNA
5.5 3
Fold of basall 5.0
qRT-PCR
qRT-PCR
4.5
4.0 2
3.5 *
3.0 *
2.5 *
1
2.0
1.5 * *
1
1.0 * * *
e
*
on
0.5 0
.z
l
tro
os
0.0
µM
µM
µM
A M
on
R
C µ
C
+
D 1
0
5
.1
1
0.01 0.1 0.5 1.0 5.0 10.0
e
E C ne
A
0
on
C
A
6- o
D
C
az
az
FXR or PPAR- γ ligand
EC
D
lit
lit
EC
ig
ig
6-
os
os
(µ
6-
M)
R
R
7.5 * α 1 (I) collagen
α-SMA
α (I) collagen mRNA
*
qRT-PCR
5.0
**
** **
**
2.5
1
*** ***
0.0
Medium TGF β 1 ng/ml
1
Alone 6-ECDCA RGT 6-ECDCA
+RGT
0.1 µM 1µM
Fiorucci S., et al. JPET 315:58–68, 2005
38. FXR, PXR and PPARγ
Cross-talk between FXR, PXR and
PPARγ might contribute to the
antifibrotic activity of FXR ligands
in rodent models of liver cirrhosis
Fiorucci S., et al. JPET 315:58–68, 2005
39. Acknowledgements
Dipartimento di Medicina
Clinica e Sperimentale
(Università di Perugia)
Giovanni Rizzo
Barbara Renga
Piero Vavassori
Andrea Mencarelli GSK (NC, USA)
Moses di Sante Timothy M. Willson
Bryan Goodwin
Dipartimento di Chimica e Intercept Pharmaceuticals (New York)
Tossicologia del farmaco Mark Pruzanski
(Universià di Perugia)
Roberto Pellicciari
Emidio Camaioni
Gabriele Costantino
Antonio Macchiarulo
Antimo Gioiello
Bahman Sadeghpour
Udo Mayer