| 1. |
- Arsura, Marcello, et al.
(författare)
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Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis : implications in liver tumor formation.
- 2003
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 22:3, s. 412-425
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Tidskriftsartikel (refereegranskat)abstract
- NF-kappaB has been implicated in the regulation of apoptosis, a key mechanism of normal and malignant growth control. Previously, we demonstrated that inhibition of NF-kappaB activity by TGF-beta1 leads directly to induction of apoptosis of murine B-cell lymphomas and hepatocytes. Thus, we were surprised to determine that NF-kappaB is transiently activated in response to TGF-beta1 treatment. Here we elucidate the mechanism of TGF-beta1-mediated regulation of NF-kappaB and induction of apoptosis in epithelial cells. We report that TGF-beta1 activates IKK kinase, which mediates IkappaB-alpha phosphorylation. In turn, the activation of IKK following TGF-beta1 treatment is mediated by the TAK1 kinase. As a result of NF-kappaB activation, IkappaB-alpha mRNA and protein levels are increased leading to postrepression of NF-kappaB and induction of cell death. Inhibition of NF-kappaB following TGF-beta1 treatment increased AP-1 complex transcriptional activity through sustained c-Jun phosphorylation, thereby potentiating AP-1/SMADs-mediated cell killing. Furthermore, TGF-beta1-mediated upregulation of Smad7 appeared independent of NF-kappaB. In hepatocellular carcinomas of TGF-beta1 or TGF-alpha/c-myc transgenic mice, we observed constitutive activation of NF-kappaB that led to inhibition of JNK signaling. Overall, our data illustrate an autocrine mechanism based on the ability of IKK/NF-kappaB/IkappaB-alpha signaling to negatively regulate NF-kappaB levels thereby permitting TGF-beta1-induced apoptosis through AP-1 activity.
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| 2. |
- Correale, Michele, et al.
(författare)
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Circulating biomarkers in pulmonary arterial hypertension : an update
- 2024
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Ingår i: Biomolecules. - : MDPI. - 2218-273X. ; 14:5
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Forskningsöversikt (refereegranskat)abstract
- Pulmonary arterial hypertension (PAH) is a rare subtype of group 1 pulmonary hypertension (PH) diseases, characterized by high pulmonary artery pressure leading to right ventricular dysfunction and potential life-threatening consequences. PAH involves complex mechanisms: vasoconstriction, vascular remodeling, endothelial dysfunction, inflammation, oxidative stress, fibrosis, RV remodeling, cellular hypoxia, metabolic imbalance, and thrombosis. These mechanisms are mediated by several pathways, involving molecules like nitric oxide and prostacyclin. PAH diagnosis requires clinical evaluation and right heart catheterization, confirming a value of mPAP ≥ 20 mmHg at rest and often elevated pulmonary vascular resistance (PVR). Even if an early and accurate diagnosis is crucial, PAH still lacks effective biomarkers to assist in its diagnosis and prognosis. Biomarkers could contribute to arousing clinical suspicion and serve for prognosis prediction, risk stratification, and dynamic monitoring in patients with PAH. The aim of the present review is to report the main novelties on new possible biomarkers for the diagnosis, prognosis, and treatment monitoring of PAH.
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| 3. |
- Dini, Frank L., et al.
(författare)
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Patient phenotype profiling using echocardiography and natriuretic peptides to personalise heart failure therapy
- 2024
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Ingår i: Heart Failure Reviews. - : Springer. - 1382-4147 .- 1573-7322. ; 29, s. 367-378
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Forskningsöversikt (refereegranskat)abstract
- Heart failure (HF) is a progressive condition with a clinical picture resulting from reduced cardiac output (CO) and/or elevated left ventricular (LV) filling pressures (LVFP). The original Diamond-Forrester classification, based on haemodynamic data reflecting CO and pulmonary congestion, was introduced to grade severity, manage, and risk stratify advanced HF patients, providing evidence that survival progressively worsened for those classified as warm/dry, cold/dry, warm/wet, and cold/wet. Invasive haemodynamic evaluation in critically ill patients has been replaced by non-invasive haemodynamic phenotype profiling using echocardiography. Decreased CO is not infrequent among ambulatory HF patients with reduced ejection fraction, ranging from 23 to 45%. The Diamond-Forrester classification may be used in combination with the evaluation of natriuretic peptides (NPs) in ambulatory HF patients to pursue the goal of early identification of those at high risk of adverse events and personalise therapy to antagonise neurohormonal systems, reduce congestion, and preserve tissue/renal perfusion. The most benefit of the Guideline-directed medical treatment is to be expected in stable patients with the warm/dry profile, who more often respond with LV reverse remodelling, while more selective individualised treatments guided by echocardiography and NPs are necessary for patients with persisting congestion and/or tissue/renal hypoperfusion (cold/dry, warm/wet, and cold/wet phenotypes) to achieve stabilization and to avoid further neurohormonal activation, as a result of inappropriate use of vasodilating or negative chronotropic drugs, thus pursuing the therapeutic objectives. Therefore, tracking the haemodynamic status over time by clinical, imaging, and laboratory indicators helps implement therapy by individualising drug regimens and interventions according to patients' phenotypes even in an ambulatory setting.
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| 4. |
- Dini, Frank L., et al.
(författare)
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Right ventricular failure in left heart disease : from pathophysiology to clinical manifestations and prognosis
- 2023
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Ingår i: Heart Failure Reviews. - : Springer Netherlands. - 1382-4147 .- 1573-7322. ; 28:4, s. 757-766
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Forskningsöversikt (refereegranskat)abstract
- Right heart failure (RHF) is a clinical syndrome in which symptoms and signs are caused by dysfunction and/or overload of the right heart structures, predominantly the right ventricle (RV), resulting in systemic venous hypertension, peripheral oedema and finally, the impaired ability of the right heart to provide tissue perfusion. Pathogenesis of RHF includes the incompetence of the right heart to maintain systemic venous pressure sufficiently low to guarantee an optimal venous return and to preserve renal function. Virtually, all myocardial diseases involving the left heart may be responsible for RHF. This may result from coronary artery disease, hypertension, valvular heart disease, cardiomyopathies and myocarditis. The most prominent clinical signs of RHF comprise swelling of the neck veins with an elevation of jugular venous pressure and ankle oedema. As the situation worsens, fluid accumulation becomes generalised with extensive oedema of the legs, congestive hepatomegaly and eventually ascites. Diagnosis of RHF requires the presence of signs of elevated right atrial and venous pressures, including dilation of neck veins, with at least one of the following criteria: (1) compromised RV function; (2) pulmonary hypertension; (3) peripheral oedema and congestive hepatomegaly. Early recognition of RHF and identifying the underlying aetiology as well as triggering factors are crucial to treating patients and possibly reversing the clinical manifestations effectively and improving prognosis.
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