8,969 research outputs found
Vascular Endothelial Growth Factor (VEGF) ROLE IN ENDOTHELIAL DYSFUNCTION MECHANISMS AND ARTERIAL PRESSURE CONTROL
No full textLo scopo principale della tesi è valutare l’effetto del Vascular Endothelial Growth Factor (VEGF) e di alcune sostante e/o farmaci, che interagiscono sulla via di segnale cellulare da esso attivato (ossido nitrico dipendente), sulla funzione vascolare e in particolare sull’endotelio, sul microcircolo e sull’elasticità arteriosa. Inoltre intendiamo esplorare l’eventuale ruolo del VEGF nello sviluppo di disfunzione endoteliale, danno del microcircolo o dei grossi vasi potenzialmente implicati nell’insorgenza dell’ipertensione arteriosa. La tesi è stata suddivisa in 3 studi:1) scopo del primo studio: è dunque valutare il ruolo di alcuni componenti (licopene e TCMPs) contenuti nel frutto del pomodoro sulle cellule endoteliali. L’obiettivo primario del presente studio è valutare in cellule HUVEC i potenziali effetti di queste due componenti del pomodoro, in particolare considerare i loro effetti sulla sintesi di NO da cui dipende sia la funzione endoteliale che l’angiogenesi.Materiali e metodi. HUVECs incubate con licopene, TCMPs ed altre sostanze note quali VEGF e L-NAME sono state osservate al microscopio confocale valutando l’NO in termini d’intensità di fluorescenza. Risultati. Il licopene ha mostrato di modulare positivamente la produzione di NO intracellulare, mentre le TCMPs hanno mostrato un effetto inibitorio sia da sole che quando associate a stimolo con VEGF.Conclusioni. Lo studio evidenzia che i componenti del pomodoro hanno proprietà biologiche importanti, il licopene preserverebbe la funzione endoteliale mentre le TCMPs attenuerebbero una tappa critica dell’angiogenesi.2)copo della tesi era valutare l’effetto sulla funzione vascolare della salsa di pomodoro (80 grammi al giorno per sette giorni) confrontata con una dieta priva di pomodoro in volontari sani prima e dopo il consumo di un pasto ricco di grassi accompagnato o meno da ulteriori 80 grammi di salsa di pomodoro. Lo studio presenta un disegno a cross-over con un periodo di wash out di almeno 4 settimane tra le due fasi. I test vascolari a cui abbiamo sottoposto i pazienti sono stati: (i) la funzione endoteliale mediata da flusso (FMD) mediante metodica ecografica; (ii) lo “stiffness index” (SI) ed il reflection index (RI) mediante tecnica fortopletismografica; (iii) la distensibilità e la compliance carotidee mediante un sistema ecografico. Abbiamo incluso 19 maschi sani di età compresa tra 21 e 32 anni. Tutte le misure vascolari effettuate al basale nella prima giornata di studio non sono risultate significativamente diverse nei soggetti a seconda che avessero assunto o meno il pomodoro nella settimana precedente. Dopo il pasto grasso invece tutti i soggetti indipendentemente dall’assunzione o meno del pomodoro hanno mostrato una riduzione del RI (61,95 ± 9,18 % rispetto a 73,45 ± 10,05 % nei soggetti che avevano assunto il pomodoro; 64,83 ± 9,70 % rispetto a 70,73 ± 10,19 % nei soggetti che non avevano assunto pomodoro; P<0.001), indice di relativa vasodilatazione. Inoltre, solo i soggetti che avevano assunto pomodoro hanno mostrato rispetto al basale un incremento del diametro dell’arteria brachiale (4,25 ± 0,45 mm rispetto a 4,08 ± 0,39 mm, P<0.05), una riduzione della pressione diastolica (69,79 ± 7,28 mmHg rispetto a 73,07 ± 6,63 mmHg, P<0.05) ed un incremento della frequenza cardiaca (65,21 ± 8,41 bpm rispetto a 61,68 ± 9,73 bpm, P<0.05) 120 minuti dopo il pasto. Invece, i soggetti che non avevano assunto pomodoro hanno mostrato un incremento significativo dello SI 210 minuti dopo il pasto rispetto al basale (6,98 ± 1,24 m/sec rispetto a 6,58 ± 1,31 m/sec, P<0.05). Non abbiamo osservato modificazioni significative della FMD in tutti i punti dello studio. I nostri dati sono compatibili con un effetto del pomodoro in acuto, in aggiunta al pasto grasso, nel modificare alcuni indici emodinamici e in particolare di rigidità arteriosa. La nostra intenzione è di ampliare la casistica in modo da consolidare i risultati ottenuti, effettuare il dosaggio di metaboliti dell’ossido nitrico e del licopene per tentare di chiarire la fisiopatologia di questo fenomeno. 3) Lo scopo della tesi è di valutare in soggetti con carcinoma renale metastatizzato, l’effetto di farmaci oncologici anti-angiogenetici sui valori di pressione cercando di valutare se l ́andamento degli stessi sia associato alla disfunzione endoteliale, alla riduzione dell ́elasticitá vasale e/o al danno microcircolatorio. Lo studio ha coinvolto 19 soggetti di età compresa tra 59 e 77 anni, seguiti per un periodo di 3 mesi. Gli incontri si sono svolti in 3 tempi: il giorno di inizio della terapia (T0), a un mese (T1) e a tre mesi (T2) dal primo incontro. I test a cui abbiamo sottoposto i soggetti ad ogni visita sono stati: misurazione della pressione arteriosa con apparecchio elettronico oscillometrico (3 misurazioni a distanza di 5 minuti con il paziente sdraiato), misurazione della funzione endoteliale tramite la tecnica ecografica della vasodilatazione mediata da flusso (FMD: flow mediated dilatation), misurazione della distensibilità carotidea tramite ecografia dei tronchi sovraortici, studio ecocardiografico, capillaroscopia periungueale e raccolta delle urine. L’analisi dei dati ha mostrato un aumento della pressione arteriosa difforme nei pazienti: già dopo il primo mese di terapia anti-angiogenetica, nove pazienti hanno fatto registrare un incremento significativo dei valori di pressione (sia PAS che PAD) per cui è stato necessario incrementare/introdurre la terapia antipertensiva.La concentrazione di nitrati urinari, indice della produzione endogena di ossido nitrico, è risultata ridotta al basale nei sei pazienti con peggioramento pressorio rispetto ai pazienti che si sono mantenuti stabili . Ad un mese i valori di distensibilitá carotidea (DC) erano inferiori nei pazienti con peggioramento dei valori pressori rispetto ai pazienti stabili. Non abbiamo osservato modificazioni significative degli altri parametri emodinamici analizzati nei due gruppi né a 1 mese né a tre mesi. Abbiamo altresí osservato una correlazione inversa tra incremento dei valori di PAS (∆-PAS) e la riduzione dei valori di distensibilitá carotidea (∆-DC) ad un mese (r=-0,52; p<0,05). All’indagine capillascopica basale nessun soggetto presentava alterazioni capillariche senza apparente relazione con le modifiche dei valori pressori. Alla Tomografia Computerizzata (TC) a 6 mesi, 7 soggetti presentavano un quadro di progressione di malattia non correlata ai parametri vascolari. I nostri dati sono compatibili con un effetto dei farmaci anti-angiogenetici nel modificare la pressione arteriosa in pazienti “sensibili”. I dati raccolti suggeriscono un possibile ruolo dell ́ossido nitrico o di altri fattori vasoattivi nelle modifiche della pressione arteriosa.Aims of the study: evaluating the Vascular Endhitelial Growth Factor (VEGF) effect on systemic blood preassure and machanisms of regulation oxid nitric induced. 3 studies were been conducted:1) Aims of the first study: evaluating in vitro role of VEGF and lycopene, present in tomato fruit, on endothelial cells, using Human umbilical vein endothelial cells (HUVECs).Materials and methods: HUVECs were been incubated with lycopene (2μM), VEGF and L-NAME were observed by confocal microscopy the NO production in terms of fluorescence intensity (DAF) have been evaluated. Results: the DAF was higher in HUVECS incubated with lycopene (381,1 ± 126,99, p < 0,05 , n = 24 ) compared with control (292,6 ± 107,24 , n = 24); when cells were incubated with VEGF (10ng/ml) the intensity of fluorescence significantly increased (449,7 ± 115,64 p <0,05 , n=8). The supernatant of HUVECs incubated with lycopene showed the highest amounts of nitrate–nitrit. Conclusions: The study shows that the main component of tomato has important biological properties such as preservere endothelial function. Lycopene has been shown to positively modulate the production of intracellular NO.2) Aims of second study: testing whether a 7-day period of tomato paste supplementation can improve some haemodynamic parameters in healthy volunteers (HV) before and after a standardized fat meal.Methods and results: We enrolled 19 male HV in a randomized, single-blind (operator), crossover design. HV maintained a diet poor in vegetables during the study periods, starting a week before randomization. They were randomized either to a supplementation arm (70 g tomato paste per day) for 7 days or to a control arm (no added tomato paste) with a two-week washout periods between the different periods. Flow-Mediated Dilatation (FMD) and Carotid Distendibility (CD) by ultrasounds, Stiffness Index (SI), Reflection Index (RI) by photopletismography and blood pressure (BP), were measured as an estimate of vascular function before and after (2 and 3.5 hours) the fat meal. In the direct comparison between the 2 arms, only the difference in SI was increased in the without-tomato-arm as compared to the tomato-arm both at 2 and 3.5h points (Δ-mean [95%CI]: +0.46m/sec [0.01/0.93] m/sec, +0.55 [0.03/1.07m/sec], P<0.05). After the fat meal, in both arms, HV showed a marked reduction in RI at 2h (-10.7%[-6.7/-14.7%] with tomato paste; -7.2%[-3.0/-11.4%] without tomato paste; P<0.01). Interestingly, only in the tomato-arm, some haemodynamic changes were detectable at 2h with respect to baseline: in particular an increase in brachial artery diameter (+0.20mm[0.06/0.33mm], P<0.01), a reduction in diastolic BP (-2.4 mmHg[0.1/4.7 mmHg], P<0.05) and an increase in heart rate (+3.9bpm [1.4/6.4bpm], P<0.01). The same parameters were not significantly changed in the without-tomato-arm even if they resulted not significantly different between the two arms. The nitrites were higher il tomato group vs placebo one (85, 7 ± 42,2 vs 122,5 ± 83,4 p= 0,05)Conclusion: Tomato supplementation modifies some haemodynamic parameters triggered by a high fat diet suggesting a possible beneficial effect in people assuming a diet rich in tomato.3) Aims of the third study: evaluating the effect of antiangiogenitic drugs (antiVEGF/VEGFR) used in first line therapy in clear cellular carcinoma (CCR) on BP incidence, endothelial function, arterial rigidity and microvascular enviroment. Methods and results: We enrolled 19 hypertensive controlled/normotensive patients candidated to use antiangiogionetic drugs. Vascular test (flow mediated dilatation, carotid distensibility, capillaroscopy and BP) were measured at baseline (time 0 or T0), after 1 month of therapy (Time 1 or T1) and after 3 months of therapy (Time 2 or T2). We demonstrated an increase of BP in 47% of patients at time T1. We divided the population in two groups (patients with no preassure increase at T1 and patients with pressure increase at T1). At baseline population present some differences in particular levels of preassure (PAS 141,5±14,2 vs 123,1 ±11,9 p=0,008 e PAD 87,4±8,6 vs 77,7±8,0; p= 0,002), nitrates (no BP T1 92,7±46 vs BP T1 125±92 uM/mmol) and PLTs (no BP T1 218±56,8 and BP T1442±273,5; p =0,016). We documented a linear correlation betwen preassure increase and riduction in carotid distensibility at T1 (r=-0,52; p<0,05). The capillaroscopy was modified in 53% of patients after 1 month of therapy but with no significant differences in the two groups. Conclusion: the antiVGF therapy in our population determined an increase in BP and a modification in vassels structure tested with capillaroscopy. Although there were no correlations between preassure and capillary modifications. All those mechanisms can explain the important role of VEGF in blood preassure control. No direct correlation was identified between vascular caratheristics and cancer evolution
Recent Developments in NAFLD
No full text: The aim of our Special Edition, entitled "Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights", is to point out recent developments in the area of NAFLD pathogenesis and treatment [...]
Treatments for NAFLD: State of Art
No full textNon‐alcoholic fatty liver disease (NAFLD) is to date the most common chronic liver dis‐ ease in clinical practice and, consequently, a major health problem worldwide. It affects approxi‐ mately 30% of adults in the general population and up to 70% of patients with type 2 diabetes (T2DM). Despite the current knowledge of the epidemiology, pathogenesis, and natural history of NAFLD, no specific pharmacological therapies are until now approved for this disease and, con‐ sequently, general strategies have been proposed to manage it. They include: (a) lifestyle change in order to promote weight loss by diet and physical activity, (b) control of the main cardiometabolic risk factors, (c) correction of all modifiable risk factors leading the development and progression of advanced forms of NAFLD, and (d) prevention of hepatic and extra‐hepatic complications. In the last decade, several potential agents have been widely investigated for the treatment of NAFLD and its advanced forms—shedding some light but casting a few shadows. They include some glu‐ cose‐lowering drugs (such as pioglitazone, glucagon‐like peptide‐1 (GLP‐1) receptor agonists, so‐ dium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors), antioxidants (such as vitamin E), statins or other lipid lowering agents, bile and non‐bile acid farnesoid X activated receptor (FXR) agonists, and others. This narrative review discusses in detail the different available approaches with the potential to prevent and treat NAFLD and its advanced forms
Glucose-lowering agents and reduced risk of incident non-alcoholic fatty liver disease: new insights
No full textMaybe, given the multiple pathways involved in the NAFLD pathogenesis and the single response from single- agent therapies (that stands from 30% to 50%) observed in the RCTs published so far (3), the combination of different agents with various mechanisms of action may be the best way to treat NAFLD and its advanced forms (11). In this regard, for instance, the GLP-1 RA, semaglutide, is being investigated in combination with the nonsteroidal Farnesoid X receptor (FXR) agonist, cilofexor, and with the acetyl- CoA carboxylase inhibitor, firsocostat, in a phase 2 proof- of-concept trial (NCT03987074). Semaglutide is also being investigated in combination with empagliflozin (gliflozin) in a placebo-controlled, double-blind, randomized, 3-arm parallel group trial (NCT04639414). Moreover, considering the heterogeneity of NAFLD patients, it might be even more suitable to identify specific individuals for a definite therapeutic strategy (11). However, the research on this topic is still at the beginning and further studies are needed to improve our understanding for intercepting NAFLD patients who would have a higher probability of treatment response with a specific agent as monotherapy or, better, with a combination therapy (3)
Coronavirus disease 2019 and prevalence of chronic liver disease: A meta-analysis
No full textAt present, there is scarce information regarding the global prevalence of chronic liver disease in individuals with coronavirus disease 2019 (COVID-19) disease, which is becoming a global pandemic. The aim of this study was to assess the overall prevalence of chronic liver disease among patients with COVID-19 disease by meta-analysing data in observational studies and to investigate the relationship between liver damage and COVID-19 disease. We included 11 observational studies for a total of 2034 adult individuals (median age 49 years [IQR 45-54], 57.2% men). The overall prevalence of chronic liver disease at baseline was 3% (95% CI 2%-4%; I-2 = 29.1%). Individuals with severe COVID-19 disease had relevant alterations of liver enzymes and coagulative profile, probably due to the innate immune response against the virus. Further studies are needed to better investigate the causes of liver injury in patients with COVID-19 disease and the effect of treatment for COVID-19 on the liver
Reply: Diagnostic accuracy of AGILE3+ score for advanced fibrosis in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis
No full textCould vitamin D supplements be a new therapy for heart failure? Possible pathogenic mechanisms from data of intervention studies
No full textVitamin D deficiency may play a role in the pathogenesis of chronic heart failure (HF), but whether giving patients supplements to raise vitamin D into the normal range improves their survival is not clear. It has been demonstrated that vitamin D deficiency is common in patients with HF, especially the elderly, in obese and in dark skinned people, and that low vitamin D levels are associated with adverse outcome. The epidemiological data have been confirmed by experimental data, which show that knockout mice for the vitamin D receptor developed myocardial hypertrophy and dysfunction. Data from interventional studies are scarce and discordant, and more research is urgently needed to confirm whether add-on supplementation therapy with vitamin D has a role in the management of patients with chronic HF
Looking for women in hepatology: Sex authorship differences in clinical practice guidelines and position statements
No full textFirst female authorship is slowly increasing in scientific publications, but it is still inconsistent and seems to vary across different medical disciplines and specialties. When looking at the authorship in gastroenterology and/or hepatology original papers, it was estimated that the proportion of first female authors increased from 9% in 1992 to 29% in 2012, whereas for last authors, the proportion of female authors increased from 5% in 1992 to 14% in 2012. However, clinical practice guidelines or position statements may potentially adopt different authorship rules when compared to original articles
Endothelial progenitor cells and aptoptosis in patients with heart failure
No full textObjective: One the main features of heart failure is endothelial disfunction and some authors claimed this is caused by endothelial cell apoptosis. Scope of the study is to evaluate in a group of patients with heart failure the number of EPC (endothelial progenitor cells) both ex vivo and in culture in parallel with the assessment of EPC apoptosis and the echocardiographic evaluation of systolic and diastolic left ventricular function.
Design and Method: We studied 30 patients with congestive heart failure (CHF) and 16 healthy control subjects CS) by measuring the number of EPC both ex vivo and after 4 days in culture. We measured also EPC apoptosis together with echocardiographic parameters of systolic and diastolic left ventricular function.
Results and Conclusion: The EPC count measured both ex vivo (CD34+/KDR+; M ± ES, CHF, 9.5 ± 1.1%, CS, 5.1 ± 0.8%, p < 0.02) and after culture (KDR+/CD34+; M ± ES, CHF, 51.2 ± 6.6%; CS, 23.5 ± 8.8%, p < 0.0001) was significantly increased in CHF patients as compared to CS. In CHF patients EPC number measured in culture is directly correlated with hs-CRP (p = 0.035, r = 0.497). The EPC apoptosis does not show any statistically difference between CHF patients and CS. In CHF patients the number of apoptotic EPC was inversely correlated with total (r = −0.418, p = 0.02) and LDL cholesterol (r = −0.399, p = 0.03). We hypnotize that the increased oxidative stress characterizing heart failure may explain the increased EPC number which may have a compensatory significance for endothelial dysfunction as EPC number is directly linked to a crucial flogistic parameter as CRP. EPC apoptosis is not altered in CHF patients and does not seem to be related with the increased EPC number. The inverse correlation between EPC apoptosis and LDL cholesterol may represent the clinical equivalent of the in vitro ability of oxidized LDL to inhibit the macrophage binding to apoptotic endothelial cells
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