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showing 10 items of 3539 documents
In Silico Insights towards the Identification of NLRP3 Druggable Hot Spots
2019
NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) activation has been linked to several chronic pathologies, including atherosclerosis, type-II diabetes, fibrosis, rheumatoid arthritis, and Alzheimer’s disease. Therefore, NLRP3 represents an appealing target for the development of innovative therapeutic approaches. A few companies are currently working on the discovery of selective modulators of NLRP3 inflammasome. Unfortunately, limited structural data are available for this target. To date, MCC950 represents one of the most promising noncovalent NLRP3 inhibitors. Recently, a possible region for the binding of MCC950 to the NLRP3 protein was described but no details were …
Phytochemical inhibitors of the NLRP3 inflammasome for the treatment of inflammatory diseases
2021
The NLRP3 inflammasome holds a crucial role in innate immune responses. Pathogen- and danger-associated molecular patterns may initiate inflammasome activation and following inflammatory cytokine release. The inflammasome formation and its-associated activity are involved in various pathological conditions such as cardiovascular, central nervous system, metabolic, renal, inflammatory and autoimmune diseases. Although the mechanism behind NLRP3-mediated disorders have not been entirely illuminated, many phytochemicals and medicinal plants have been described to prevent inflammatory disorders. In the present review, we mainly introduced phytochemicals inhibiting NLRP3 inflammasome in addition…
Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis.
2019
Background & Aims Increased hepatocyte death contributes to the pathology of acute and chronic liver diseases. However, the role of hepatocyte pyroptosis and extracellular inflammasome release in liver disease is unknown. Methods We used primary mouse and human hepatocytes, hepatocyte-specific leucine 351 to proline Nlrp3KICreA mice, and GsdmdKO mice to investigate pyroptotic cell death in hepatocytes and its impact on liver inflammation and damage. Extracellular NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes were isolated from mutant NLRP3-YFP HEK cells and internalisation was studied in LX2 and primary human hepatic stellate cells. We also examined a cohort of 154…
PI3K inhibition reduces murine and human liver fibrogenesis in precisioncut liver slices
2019
Background: Liver fibrosis results from continuous inflammation and injury. Despite its high prevalence worldwide, no approved antifibrotic therapies exist. Omipalisib is a selective inhibitor of the PI3K/mTOR pathway that controls nutrient metabolism, growth and proliferation. It has shown antifibrotic properties in vitro. While clinical trials for idiopathic pulmonary fibrosis have been initiated, an in-depth preclinical evaluation is lacking. We evaluated omipalisib's effects on fibrogenesis using the ex vivo model of murine and human precision-cut tissue slices (PCTS).Methods: Murine and human liver and jejunum PCTS were incubated with omipalisib up to 10 mu M for 48 h. PI3K pathway act…
Prevalence and severity of nonalcoholic fatty liver disease by transient elastography: Genetic and metabolic risk factors in a general population.
2017
BACKGROUND & AIMS The worldwide spread of obesity is leading to a dramatic increase in the prevalence of nonalcoholic fatty liver disease (NAFLD) and its complications. We aimed to evaluate both prevalence and factors associated with NAFLD in a general population in a Mediterranean area. METHODS We considered 890 consecutive individuals included in the community-based ABCD (Alimentazione, Benessere Cardiovascolare e Diabete) study (ISRCTN15840340). Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) were measured with FibroScan. Participants were genotyped for PNPLA3 rs738409 and TM6SF2 rs58542926 variants. RESULTS The prevalence of NAFLD in the cohort was 48%. NAFL…
AMPK phosphorylation modulates pain by activation of NLRP3 inflammasome
2016
et al.
miR-128 Is Implicated in Stress Responses by Targeting MAFG in Skeletal Muscle Cells.
2017
MAFG (v-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog G) is a bZIP-type transcriptional regulator that belongs to the small MAF (sMAFs) protein family. By interacting with other bZIP transcription factors, sMAFs can form homo- and heterodimers governing either repressive or activating transcriptional functions. As heterodimeric partner of Nrf2, MAFG positively influences the ARE-dependent antioxidant/xenobiotic pathways, at least in condition of a correct MAFG:Nrf2 balance. MicroRNAs (miRs) participate to different regulatory networks being involved as fine-tuning regulators of gene expression. However, the connections between cellular surveillance to stresses mediated by MAFG:…
The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM
2018
The accumulation of neurotoxic amyloid-beta (Aβ) in the brain is a characteristic hallmark of Alzheimer's disease (AD). The blood-brain barrier (BBB) provides a large surface area and has been shown to be an important mediator for removal of brain Aβ. Both, the ABC transporter P-glycoprotein (ABCB1/P-gp) and the receptor low-density lipoprotein receptor-related protein 1 (LRP1) have been implicated to play crucial roles in Aβ efflux from brain. Here, with immunoprecipitation experiments, co-immunostainings and dual inhibition of ABCB1/P-gp and LRP1, we show that both proteins are functionally linked, mediating a concerted transcytosis of Aβ through endothelial cells. Late-onset AD risk fact…
Bone marrow B lymphocytes in multiple myeloma and MGUS: Focus on distribution of naïve cells and memory subsets.
2016
Multiple myeloma (MM) is caused by proliferation of clonal plasma cells (cPCs) in bone marrow (BM), associated with numerical and functional defects in immune subsets. An impairment of B cell compartment is involved in onset/progression of the disease.By flow cytometry, we studied distribution of naïve/transitional (IgD(+)CD27(-)), memory unswitched (IgD(+)CD27(+)), memory switched (IgD(-)CD27(+)) and double negative (DN) (IgD(-)CD27(-)) B lymphocytes in BM of control subjects, and responding and relapsing patients.We observed an increased percentage of IgD(+)CD27(+) B cells in healthy controls vs responding patients (p0.05). Treated non complete responders exhibited an expanded DN compartm…
A multidimensional network approach reveals microRNAs as determinants of the mesenchymal colorectal cancer subtype
2016
Colorectal cancer (CRC) is a heterogeneous disease posing a challenge for accurate classification and treatment of this malignancy. There is no common genetic molecular feature that would allow for the identification of patients at risk for developing recurrences and thus selecting patients who would benefit from more stringent therapies still poses a major clinical challenge. Recently, an international multicenter consortium (CRC Subtyping Consortium) was established aiming at the classification of CRC patients in biologically homogeneous CRC subtypes. Four consensus molecular subtypes (CMSs) were identified, of which the mesenchymal CMS4 presented with worse prognosis signifying the impor…