antiossidanti e sistema immunitario
Post on 29-Dec-2021
9 Views
Preview:
TRANSCRIPT
ANTIOSSIDANTI E SISTEMA IMMUNITARIO.
Dott. Alexander BertuccioliMedico Chirurgo
Biologo nutrizionista perfezionato in nutrizione in condizioni fisiologiche
Chimico farmaceutico ind. Prodotti Salutistici
Professore (a.c.) Scienze e tecniche dietetiche applicate
Professore (a.c.) Laboratorio di valutazione antropometrica
Dipartimento di Scienze Biomolecolari - DISB - Scuola di Scienze Biomediche, Università degli Studi di Urbino "Carlo Bo"
Comitato scientifico – FIF – AIFeM – AIPT – AWI – Fisioclinics - VL Medical Lab ESNS Fellows
Programma
• Quercetina
• Alfa glucani
• Glutatione
• Coenzima Q10
• Vitamina C
Quercetina
OH
OH
OH
OH
Si tratta di uno dei flavonoidi più comuni in quanto è isolabile da numerose specie vegetali: ippocastano, calendula, biancospino, camomilla, iperico e Ginkgo biloba.
Alimenti particolarmente ricchi di quercetina sono:
• il cappero• il levistico• l'uva rossa• il vino rosso• la cipolla rossa• il tè verde• il mirtillo• la mela• la propoli• il sedano.
Quercetina:componente agliconica di vari glicosidi
tra cui la rutina, quercitrina, isoquercitrina
ingresso
sfruttamento
assemblaggio
Bachmetov L, Gal-Tanamy M, Shapira A, et al.Suppression of hepatitis C virus by the flavonoid quercetin is mediated by inhibition of NS3 protease activity.J Viral Hepat. 2012;19(2):e81-e88.
DOCKING MOLECOLARE IN SILICO NEI CONFRONTI DELLE PROTEASI PLpro E 3CLpro
Cmax: 15 μg/L di quercetina libera
Cmax: 450 μg/L di quercetina coniugata
x2/x3 voltecon diverse formulazioni
Di Pierro F, Khan A, Bertuccioli A et al.Quercetin phytosome® as a potential drug for covid-19.Minerva Gastroenterol Dietol 2020. In press.
reduced USE OF MEDICATIONS
reduction of oxidative stress
EFFECTS ON PERFORMANCE and RECOVERY
EFFECTS ON OXIDATIVE STRESS
Alfa-Glucani
Funghi medicinali
Shiitake (Lentinula edodes)Maitake (Grifola frondosa)
Reishi (Ganoderma lucidum)
Corpofruttifero
Micelio
Estrazione con acqua caldao miscele acqua/etanolo
per ottenere beta-glucani(Shiitake, Maitake, Reishi)
AHCC
18 compresse
AHCC
oncologia
virologia
microbiologia
vaccini
epatologia
veterinaria
IBD
AHCC in microbiologia
- Riduce carica microbica- Sinergizza con antibiotici
- Aumenta la sopravvivenza durante infezione- Promuove risposta immune contro batteri, funghi e protozoi
- Riduce rilascio ormoni immuno-soppressori
AHCC
oncologia
virologia
microbiologia
vaccini
epatologia
veterinaria
IBD
1. Derivato da micelio primario di L. edodes standarizzato in α-glucani (anche acetilati) (titolo: 20%)
2. > 100 pubblicazioni su PubMed
3. Profilo di sicurezza elevatissimo (cellule, animali, uomo)
4. Dimostrate attività in oncologia (add-on alla chemioterapia; prognosi migliore, minori effetti collaterali)
5. Dimostrate attività in microbiologia (batteri, funghi, protozoi e virus)
6. Migliora nell’uomo la risposta al vaccino dell’influenza
7. Determina la clearance virale totale dei ceppi hr-HPV (in vitro e in vivo)
8. Nel soggetto oncologico o con infezione stimola cellule T, cellule NK, cellule NK-T, cellule LAK e γδ-Tincrementando le risposte sostenute da IFN-γ
9. Da un punto di vista molecolare e a livello linfocitario aumenta la trascrizione del gene LATe di altri geni apparentemente capaci di «ipertrofia» linfocitaria
10. Nel soggetto sano stimola solo le cellule dendritiche, subset DC1 (pro-Th1)
Glutatione
Il glutatione o GSH è un tri-peptide con proprietà antiossidanti, costituito da cisteina e glicina, legate da un normale legame peptidico, e glutammato, che invece è legato alla cisteina con un legame peptidico atipico tra il gruppo carbossilico della catena laterale del glutammato e il gruppo amminico della cisteina
Quando mi accorgo di una carenza di GSH?
1) Nei soggetti affetti da favismo l'assenza dell'enzima glucosio-6-fosfato deidrogenasi (G6PD) porta a una minore produzione di NADPH; le fave contengono sostanze ossidanti che conducono all'emolisi in quanto la carenza di NADPH limita la genesi di GSH a partire da GSSG. Il poco GSH non può contrastare il danno ossidativo di tali sostanze.
2) Nell’intossicazione da paracetamolo dove il GSH coniuga i metaboliti dell’antipiretico altrimenti epatotossici.
Sostanze esogene che aumentano la concentrazione di GSH?
Silimarina
EFFECT OF SILYMARIN ( 200 mg/kg/3 days)
ON THE REDUCED (GSH) AND OXIDISED GLUTATHIONE (GSSG)
CONTENT OF RAT LIVER
0.6
0.4
0.2
0
0 9
Control
Control
GSSG
content(µmoles/g protein)
6.0
0
8.0
1 2 3 4 5 6 7 8Days
4.0
2.0
GSH content(µmoles/g protein)
Each point represents the mean ± S.E. from 8 rats
Virol J. 2013 Aug 7;10(1):251.Oxidative stress and hepatitis C virus.Paracha UZ, Fatima K, Alqahtani M, Chaudhary A, Abuzenadah A, Damanhouri G, Qadri I.
The disproportionate imbalance between the systemic manifestation of reactive oxygen species and body'sability to detoxify the reactive intermediates is referred to as oxidative stress. Several biological processes aswell as infectious agents, physiological or environmental stress, and perturbed antioxidant response canpromote oxidative stress. Oxidative stress usually happens when cells are exposed to more electricallycharged reactive oxygen species (ROS) such as H2O2 or O2-. The cells' ability to handle such pro-oxidantspecies is impeded by viral infections particularly within liver that plays an important role in metabolismand detoxification of harmful substances. During liver diseases (such as hepatocellular or cholestaticproblems), the produced ROS are involved in transcriptional activation of a large number of cytokines andgrowth factors, and continued production of ROS and Reactive Nitrogen Species (RNS) feed into thevicious cycle. Many human viruses like HCV are evolved to manipulate this delicate pro- and antioxidantbalance; thus generating the sustainable oxidative stress that not only causes hepatic damage but alsostimulates the processes to reduce treatment of damage. In this review article, the oxidant and antioxidantpathways that are perturbed by HCV genes are discussed. In the first line of risk, the pathways of lipidmetabolism present a clear danger in accumulation of viral induced ROS. Viral infection leads todecrease in cellular concentrations of glutathione (GSH) resulting in oxidation of importantcomponents of cells such as proteins, DNA and lipids as well as double strand breakage of DNA.These disorders have the tendency to lead the cells toward cirrhosis and hepatocellular carcinomain adults due to constant insult. We have highlighted the importance of such pathways and revealeddifferences in the extent of oxidative stress caused by HCV infection.
Infezioni viraleDeplezione GSH
Cascata ossidativaDanneggiamento membrane
Danneggiamento proteineDanneggiamento DNA
CirrosiEpato-carcinoma
Deficit di GSH ?
Infezioni virali
Alcolismo
Intossicazione da farmaci
Eur J Clin Pharmacol. 1992;43(6):667-9.
The systemic availability of oral glutathione.Witschi A, Reddy S, Stofer B, Lauterburg BH.
When the plasma glutathione concentration is low, such as in patients with HCV, HBV,HIV infection, alcohol abuse, and patients with cirrhosis, increasing the availability ofcirculating glutathione by oral administration might be of therapeutic benefit. To assessthe feasibility of supplementing oral glutathione we have determined the systemic availabilityof glutathione in 7 healthy volunteers. The basal concentrations of glutathione, cysteine, andglutamate in plasma were 6.2, 8.3, and 54 mumol.l-1 respectively. During the 270 min after theadministration of glutathione in a dose of 0.15 mmol.kg-1 the concentrations of glutathione,cysteine, and glutamate in plasma did not increase significantly, suggesting that the systemicavailability of glutathione is negligible in man. Because of hydrolysis of glutathione byintestinal and hepatic gamma-glutamyltransferase, dietary glutathione is not a majordeterminant of circulating glutathione, and it is not possible to increase circulatingglutathione to a clinically beneficial extent by the oral administration of a single doseof 3 g of glutathione.
Wien Klin Wochenschr. 2000 Jul 28;112(14):610-6.
Therapeutic potential of glutathione.
Exner R, Wessner B, Manhart N, Roth E.
Reactive oxygen species, formed in various biochemical reactions, are normally scavenged byantioxidants. Glutathione in its reduced form (GSH) is the most powerful intracellular antioxidant,and the ratio of reduced to oxidised glutathione (GSH:GSSG) serves as a representative marker ofthe antioxidative capacity of the cell. Several clinical conditions are associated with reduced GSHlevels which as a consequence can result in a lowered cellular redox potential. GSH and the redoxpotential of the cell are components of the cell signaling system influencing the translocation ofthe transcription factor NF kappa B which regulates the synthesis of cytokines and adhesionmolecules. Therefore, one possibility to protect cells from damage caused by reactive oxygenspecies is to restore the intracellular glutathione levels. Cellular GSH concentration can beinfluenced by exogenous administration of GSH (as intravenous infusion or as aerosol), orof GSH precursors such as cysteine (in form of N-acetyl-L-cysteine). The modulation of GSHmetabolism might present a useful adjuvant therapy in many pathologies such as intoxication,diabetes, uremia, sepsis, inflammatory lung processes, coronary disease, cancer andimmunodeficiency states.
Soluzione: NAC
Expert Opin Biol Ther. 2008 Dec;8(12):1955-62.
N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility.Dodd S, Dean O, Copolov DL, Malhi GS, Berk M
BACKGROUND:Glutathione is an endogenous antioxidant and has a ubiquitous role in many of the body's defences.Treatment with N-acetylcysteine (NAC) has been shown to increase levels of glutathione. NAChas been proposed as a treatment for several illnesses.OBJECTIVES:The efficacy and tolerability of NAC was examined across a range of conditions to evaluate the evidencesupporting the use of NAC for each indication.METHODS:A literature search was conducted using PubMed. Information was also collected from other onlinesources including the websites of the Therapeutic Goods Administration of Australia and the FDA.RESULTS:Reports ranged from case studies to clinical trials. There is strong evidence to support the use of NACfor the treatment of paracetamol overdose and emerging evidence suggesting it has utility inpsychiatric disorders, particularly schizophrenia and bipolar disorder.NAC is safe and well tolerated when administered orally but has documented risks withintravenous administration.
Treat Respir Med. 2004;3(6):353-63.New insights into the pathogenesis of cystic fibrosis: pivotal role of glutathione system dysfunction and implicationsfor therapy.Hudson VM
The cystic fibrosis transmembrane regulator (CFTR) should no longer be viewed primarily as a 'chloride channel' but recognized asa channel that also controls the efflux of other physiologically important anions, such as glutathione (GSH) and bicarbonate. Moreeffective approaches to cystic fibrosis treatment may result from this reconceptualization of the CFTR by researchers andclinicians. For example, oxidant damage in cystic fibrosis has been assumed to be a significant part of the pathophysiology of thedisease. Generally speaking, antioxidant status in cystic fibrosis is compromised. However, until recently this was seen assecondary to the excessive chemoattraction of neutrophils in this disease caused by mutation of the CFTR protein, leading to ahigh oxidant burden. New findings suggest that the cystic fibrosis mutations in fact cause a primary dysfunction in the system ofone of the body's most important antioxidant and immune-signaling substances: the reduced GSH system. Cystic fibrosismutations significantly decrease GSH efflux from cells without redundant channels to the CFTR; this leads to deficiency of GSH inthe epithelial lining fluid of the lung, as well as in other compartments, including immune system cells and the gastrointestinaltract. This deficiency is exaggerated over time as the higher-than-normal oxidant burden of cystic fibrosis leads to successivelylarger decrements in GSH without the normal opportunity to fully recover physiologic levels. This GSH system dysfunction may bethe trigger for initial depletion of other antioxidants and may also play a role in initiating the over-inflammation characteristic ofcystic fibrosis. Proper GSH system functioning also affects immune system competence and mucus viscosity, both of relevance tocystic fibrosis pathophysiology. In a way, cystic fibrosis may be thought of as the first identified disease with GSH systemdysfunction.This overview provides a review of the most pertinent recent research findings in this area. Exogenous augmentationof GSH in the lung epithelial lining fluid is possible, and therapeutic approaches include administration of aerosolized bufferedGSH, intravenous GSH, and oral GSH. However, it is important to remember that the pathophysiology of cystic fibrosis ismultifactorial, and rectification of GSH system dysfunction in patients with cystic fibrosis will not eliminate all harmful effects ofthe disease. The promising results of two clinical trials of aerosolized buffered GSH in cystic fibrosis patients have been publishedor accepted for publication at the time of this writing. GSH depletion in lung epithelial lining fluid has also been noted inother respiratory diseases such as COPD, idiopathic pulmonary fibrosis, and adult respiratory distress syndrome, andtherapies to augment GSH may also be contemplated in these diseases.
GSH depletion in lung epithelial lining fluid has also been noted in other
respiratory diseases such as COPD, idiopathic pulmonary fibrosis, and adult respiratory
distress syndrome, and therapies to augment GSH may also be contemplated in these
diseases
Cisteina-glicina-glutammato
Come rigenerare con grande efficienza il GSH?
Una soluzione dagli aminoacidi?
Coenzima Q10
CoQ10
Meccanismi anti-ossidativi
Catena di trasporto degli e-
NADH+H
+
Q10
Cit C
- -
-
-
+
--
+
+
+ + + +++
+ +++
++
+
+
+
+
+ +
++
FADH2
-
FAD
+ +
+
++
+
+
++
NADH+
- - --
½ O2 + 2 H+ H2O
4 H+ 4 H+
2 H+
2 e- 2 e- 2 e-
2 e-
COMPLESSO I NADH DEIDROGENASITrasferisce elettroni dal NADH al coenzima Q
COMPLESSO II SUCCINATO DEIDROGENASITrasferisce elettroni dal FADH2 al coenzima Q
COMPLESSO III UBICHINONE CITOCROMO C REDUTTASI trasferisce elettroni dal coenzima Q al citocromo C
COMPLESSO IV CITOCROMO OSSIDASI trasferisce elettroni dal citocromo C all O2
ATP SINTETASI sfruttando l’energia fornita dal gradiente di H+ permette di ottenere ATP a partire da ADP + P
CoQ10, ubichinone, ubidecarenone
L’ubichinone (CoQ10) è la forma attiva di CoQ10?
NO!
La forma attiva è detta ubichinoloè corrisponde alla forma ridotta
(cioè che quindi può ossidarsi) di CoQ10
Drug Deliv. 2015 Jul 25:1-14.Strategies for oral delivery and mitochondrial targeting of CoQ10.Zaki NM (University of Toronto, Ontario , Canada).
Coenzyme Q10 (CoQ10), also known as ubiquinone or ubidecarenone, is a powerful,endogenously produced, intracellularly existing lipophilic antioxidant. It combats reactiveoxygen species (ROS) known to be responsible for a variety of human pathological conditions.Its target site is the inner mitochondrial membrane (IMM) of each cell. In case of deficiencyand/or aging, CoQ10 oral supplementation is warranted. However, CoQ10 has low oralbioavailability due to its lipophilic nature, large molecular weight, regional differencesin its gastrointestinal permeability and involvement of multitransporters. Intracellulardelivery and mitochondrial target ability issues pose additional hurdles. To maximize CoQ10delivery to its biopharmaceutical target, numerous approaches have been undertaken. Thereview summaries the current research on CoQ10 bioavailability and highlights the headwaysto obtain a satisfactory intracellular and targeted mitochondrial delivery. Unresolvedquestions and research gaps were identified to bring this promising natural product to theforefront of therapeutic agents for treatment of different pathologies.
Alto peso molecolare
Estremamente lipofilo
E’ se lo rendiamo «solubile» in acqua?
Perché la forma «solubile»è più biodisponibile?
Come lo possiamo solubilizzare?
Con una procedura detta nano-emulsione (O/A)
Vitamina C
La vitamina C è una sostanza inodore, debolmente acida, che in natura trova un’ampia distribuzione e ricopre ruoli biologici di primaria importanza.
Fortemente solubile in acqua (e in ambiente acquosi) viene facilmente degradata dal calore, dall’esposizione all’aria e dal contatto con fero o rame (per esempio presenti in altri alimenti).
Il suo assorbimento è piuttosto rapido e avviene con una dinamica crescente a livello della bocca, dello stomaco e prevalentemente dell’intestino tenue.
Quali sono i ruoli fondamentali esercitati dalla Vitamina C?
• Sintesi di tessuto connettivo
• Sintesi di catecolammine
• Sintesi di ormoni peptidici
• Sintesi della carnitina
• Detossificazione e metabolismi dipendenti dal Citocromo P450
• Metabolismo del ferro, permettendone l’assorbimento e la mobilizzazione
• Azione contro i radicali liberi
• Azione vasodilatatrice favorendo il rilascio di ossido nitrico
• Prevenzione nella formazione delle nitrosammine
• Supporto della funzione immunitaria.
top related