196,225 research outputs found
Asthma and poly(ADP-ribose) polymerase inhibition: a new therapeutic approach
No full textRaffaela Zaffini, Giovanni Gotte, Marta Menegazzi Department of Neuroscience, Biomedicine and Movement Science, Biochemistry Section, University of Verona, Verona, Italy Abstract: Asthma is a chronic lung disease affecting people of all ages worldwide, and it frequently begins in childhood. Because of its chronic nature, it is characterized by pathological manifestations, including airway inflammation, remodeling, and goblet cell hyperplasia. Current therapies for asthma, including corticosteroids and beta-2 adrenergic agonists, are directed toward relieving the symptoms of the asthmatic response, with poor effectiveness against the underlying causes of the disease. Asthma initiation and progression depends on the T helper (Th) 2 type immune response carried out by a complex interplay of cytokines, such as interleukin (IL) 4, IL5, and IL13, and the signal transducer and activator of transcription 6. Much of the data resulting from different laboratories support the role of poly(ADP-ribose) polymerase (PARP) 1 and PARP14 activation in asthma. Indeed, PARP enzymes play key roles in the regulation and progression of the inflammatory asthma process because they affect the expression of genes and chemokines involved in the immune response. Consistently, PARP inhibition achievable either upon genetic ablation or by using pharmacological agents has shown a range of therapeutic effects against the disease. Indeed, in the last two decades, several preclinical studies highlighted the protective effects of PARP inhibition in various animal models of asthma. PARP inhibitors showed the ability to reduce the overall lung inflammation acting with a specific effect on immune cell recruitment and through the modulation of asthma-associated cytokines production. PARP inhibition has been shown to affect the Th1–Th2 balance and, at least in some aspects, the airway remodeling. In this review, we summarize and discuss the steps that led PARP inhibition to become a possible future therapeutic strategy against allergic asthma. Keywords: allergic airway disease, PARP1, PARP14, remodeling, STAT6, Th1–Th2 balance, Th2 respons
Role of the Ribonuclease ONCONASE in miRNA Biogenesis and tRNA Processing: Focus on Cancer and Viral Infections
No full textThe majority of transcribed RNAs do not codify for proteins, nevertheless they display crucial regulatory functions by affecting the cellular protein expression profile. MicroRNAs (miRNAs) and transfer RNA-derived small RNAs (tsRNAs) are effectors of interfering mechanisms, so that their biogenesis is a tightly regulated process. Onconase (ONC) is an amphibian ribonuclease known for cytotoxicity against tumors and antiviral activity. Additionally, ONC administration in patients resulted in clinical effectiveness and in a well-tolerated feature, at least for lung carcinoma and malignant mesothelioma. Moreover, the ONC therapeutic effects are actually potentiated by cotreatment with many conventional antitumor drugs. This review not only aims to describe the ONC activity occurring either in different tumors or in viral infections but also to analyze the molecular mechanisms underlying ONC pleiotropic and cellular-specific effects. In cancer, data suggest that ONC affects malignant phenotypes by generating tRNA fragments and miRNAs able to downregulate oncogenes expression and upregulate tumor-suppressor proteins. In cells infected by viruses, ONC hampers viral spread by digesting the primer tRNAs necessary for viral DNA replication. In this scenario, new therapeutic tools might be developed by exploiting the action of ONC-elicited RNA derivatives
Gadd 45beta is induced through a CAR-dependent, TNF-independent pathway in murine liver hyperplasia
No full textHepatology. 2005 Nov;42(5):1118-26.
Gadd45beta is induced through a CAR-dependent, TNF-independent pathway in murine liver hyperplasia.
Columbano A, Ledda-Columbano GM, Pibiri M, Cossu C, Menegazzi M, Moore DD, Huang W, Tian J, Locker J.
SourceDepartment of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Italy. [email protected]
Abstract
We previously observed that Gadd45/MyD118, a member of the Gadd45 family of inducible factors, showed the strongest immediate-early induction common to two distinctive proliferation responses of the liver: (1) regeneration induced by surgical partial hepatectomy and (2) hyperplasia induced by the primary mitogen TCPOBOP, a ligand of the constitutive androstane receptor (CAR). Gadd45 is known to be stimulated by nuclear factor (NF) B, which is activated by tumor necrosis factor alpha (TNF) in the early response to partial hepatectomy. We therefore investigated whether TNF and NFB also stimulated Gadd45 as part of the response to CAR ligands, or whether activation occurred by an alternative pathway. TCPOBOP effects were characterized in three mouse genotypes: wild-type, TNFR1-/-, and TNFR1-/-TNFR2-/-. The results showed that TCPOBOP did not activate NFB in any of the mice, but a strong induction of Gadd45 messenger RNA was observed in all three genotypes, where TCPOBOP also induced CyP2b10, a classical target gene of activated CAR, and cyclin D1, a proliferation linked gene. Thus, the absence of TNFR signaling and induction of NFB did not impair CAR-mediated gene induction. Moreover, hepatocyte proliferation was strongly induced, and at significantly higher levels than wild type, in both TNFR1-/- and TNFR1-/-TNFR2-/- mice. Further studies evaluated TCPOBOP-induced gene expression in CAR-/- mice, by microarray expression profiling and Northern blot. The induced changes in gene expression, including the stimulation of Gadd45, were almost completely abolished--hence all were mediated via CAR activation. In conclusion, in the liver, Gadd45 can be induced by a distinctive pathway that requires CAR and is independent of TNF-NFB. The greater induction of proliferation in TNFR-null mice suggests negative cross-talk between the CAR and TNF-NFB controls that regulate proliferation
Antiinflammatory action of EGCG, the main component of green tea, through STAT-1 inhibition
No full textWe examined the effects of many of the polyphenols present in green tea in different cell lines: MDAmb231, MDAmb468, MCF7 (mammary carcinoma cell lines), HeLa (a cervical carcinoma cell line), and HepG2 (an hepatocarcinoma cell line). Among the main polyphenols present in green tea—epigallocatechin, epicatechingallate, gallic acid, epigallocatechin-3-gallate (EGCG) and epicatechin—only EGCG inhibited the expression of genes typically involved in inflammatory processes as inducible nitric oxide synthase (iNOS or NOS II) and the interferon regulating factor-1 (IRF-1). Incubation of cells with EGCG leads to a decrease of the phosphorylation of transcription factor STAT-1α, whose activation is needed for the transcription of these genes, while other involved transcription factors such as NFκB, SP-1, AP-1 are not modulated.
In conclusion, our study revealed that EGCG, by inhibiting STAT-1 activation, may play an important role in modulating the entire process of inflammation. It may be a promising candidate as a drug to modulate STAT-1α signal transduction
Protective role of st. John’s wort and its components hyperforin and hypericin against diabetes through inhibition of inflammatory signaling: Evidence from in vitro and in vivo studies
No full textDiabetes mellitus is a very common chronic disease with progressively increasing prevalence. Besides the well-known autoimmune and inflammatory pathogenesis of type 1 diabetes, in many people, metabolic changes and inappropriate lifestyle favor a subtle chronic inflammatory state that contributes to development of insulin resistance and progressive loss of β-cell function and mass, eventually resulting in metabolic syndrome or overt type 2 diabetes. In this paper, we review the anti-inflammatory effects of the extract of Hypericum perforatum L. (St. John’s wort, SJW) and its main active ingredients firstly in representative pathological situations on inflammatory basis and then in pancreatic β cells and in obese or diabetic animal models. The simultaneous and long-lasting inhibition of signal transducer and activator of transcription (STAT)-1, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinases (MAPKs)/c-jun N-terminal kinase (JNK) signaling pathways involved in pro-inflammatory cytokine-induced β-cell dysfunction/death and insulin resistance make SJW particularly suitable for both preventive and therapeutic use in metabolic diseases. Hindrance of inflammatory cytokine signaling is likely dependent on the hyperforin content of SJW extract, but recent data reveal that hypericin can also exert relevant protective effects, mediated by activation of the cyclic adenosine monophosphate (cAMP)/protein kinase cAMP-dependent (PKA)/adenosine monophosphate activated protein kinase (AMPK) pathway, against high-fat-diet-induced metabolic abnormalities. Actually, the mechanisms of action of the two main components of SJW appear complementary, strengthening the efficacy of the plant extract. Careful quantitative analysis of SJW components and suitable dosage, with monitoring of possible drug–drug interaction in a context of remarkable tolerability, are easily achievable pre-requisites for forthcoming clinical applications
Un museo universitario contemporaneo: il Museo di Scienze Archeologiche ed Arte dell’Università di Padova
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Constitutive nitric oxide synthase (cNOS): a possible key point in pathogenesis of secondary lesion after spinal cord injury.
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