Insulin-Like Growth Factor Binding Protein (IGFBP-6) as a Novel Regulator of Inflammatory Response in Cystic Fibrosis Airway Cells

Cystic Fibrosis (CF) patients are prone to contracting bacterial lung infections with opportunistic pathogens, especially Pseudomonas aeruginosa. Prolonged P. aeruginosa infections have been linked to chronic inflammation in the CF lung, whose hallmarks are increased levels of cytokines (i.e., TNF-alpha, IL-1 beta, IL-6) and neutrophil attraction by chemokines, like IL-8. Recently, insulin-like growth factor binding protein 6 (IGFBP-6) has been shown to play a putative role in the immune system and was found at higher levels in the sera and synovial tissue of rheumatoid arthritis patients. Moreover, it has been demonstrated that IGFBP-6 has chemoattractant properties towards cells of the innate (neutrophils, monocytes) and adaptive (T cells) immunity. However, it is not known whether IGFBP-6 expression is dysregulated in airway epithelial cells under infection/inflammatory conditions. Therefore, we first measured the basal IGFBP-6 mRNA and protein levels in bronchial epithelial cells lines (Wt and F508del-CFTR CFBE), finding they both are upregulated in F508del-CFTR CFBE cells. Interestingly, LPS and IL-1 beta+TNF alpha treatments increased the IGFBP-6 mRNA level, that was reduced after treatment with an anti-inflammatory (Dimethyl Fumarate) in CFBE cell line and in patient-derived nasal epithelial cultures. Lastly, we demonstrated that IGFBP-6 reduced the level of pro-inflammatory cytokines in both CFBE and primary nasal epithelial cells, without affecting rescued CFTR expression and function. The addition of a neutralizing antibody to IGFBP-6 increased pro-inflammatory cytokines expression under challenge with LPS. Together, these data suggest that IGFBP-6 may play a direct role in the CF-associated inflammation

ALKALINE HYDROTHERMAL STABILIZATION OF Cr(VI) IN A SANDY SOIL

Chromium (Cr) pollution of soil is a serious environmental problem, especially in industrialized areas. Risks for human and environmental health are strictly connected to Cr oxidation state, which is usually trivalent or hexavalent in soil. While Cr(III) is stable, scarcely mobile and weakly toxic, Cr(VI) is highly soluble, mobile and carcinogenic. Among the different remediation strategies, stabilization/solidification (S/S) is used as rapid and cost-effective technique for heavy metal polluted soils. It consists of the addition of appropriate materials to the polluted soil, mostly under alkaline conditions, in order to chemically and/or physically transform the contaminant in a stable and less toxic form. Waste materials like coal fly ash or other cheap sources of Si and Al can be used to stabilize heavy metals in soil (Terzano et al., 2005). This study aims at evaluating a new S/S process for the reduction of Cr(VI) to Cr(III) in polluted soils and the incorporation of Cr(III) in newly formed minerals by using a reactive mixture of glass and aluminum (recovered from solid municipal wastes) and an alkaline hydrothermal treatment

Mesenchymal Stem Cell-Derived Extracellular Vesicles and Their Therapeutic Use in Central Nervous System Demyelinating Disorders

Autoimmune demyelinating diseases—including multiple sclerosis, neuromyelitis optica spectrum disorder, anti-myelin oligodendrocyte glycoprotein-associated disease, acute disseminated encephalomyelitis, and glial fibrillary acidic protein (GFAP)-associated meningoencephalomyelitis—are a heterogeneous group of diseases even though their common pathology is characterized by neuroinflammation, loss of myelin, and reactive astrogliosis. The lack of safe pharmacological therapies has purported the notion that cell-based treatments could be introduced to cure these patients. Among stem cells, mesenchymal stem cells (MSCs), obtained from various sources, are considered to be the ones with more interesting features in the context of demyelinating disorders, given that their secretome is fully equipped with an array of anti-inflammatory and neuroprotective molecules, such as mRNAs, miRNAs, lipids, and proteins with multiple functions. In this review, we discuss the potential of cell-free therapeutics utilizing MSC secretome-derived extracellular vesicles—and in particular exosomes—in the treatment of autoimmune demyelinating diseases, and provide an outlook for studies of their future applications

Mesenchymal Stem Cell-Derived Extracellular Vesicles and Their Therapeutic Use in Central Nervous System Demyelinating Disorders

Autoimmune demyelinating diseases—including multiple sclerosis, neuromyelitis optica spectrum disorder, anti-myelin oligodendrocyte glycoprotein-associated disease, acute disseminated encephalomyelitis, and glial fibrillary acidic protein (GFAP)-associated meningoencephalomyelitis—are a heterogeneous group of diseases even though their common pathology is characterized by neuroinflammation, loss of myelin, and reactive astrogliosis. The lack of safe pharmacological therapies has purported the notion that cell-based treatments could be introduced to cure these patients. Among stem cells, mesenchymal stem cells (MSCs), obtained from various sources, are considered to be the ones with more interesting features in the context of demyelinating disorders, given that their secretome is fully equipped with an array of anti-inflammatory and neuroprotective molecules, such as mRNAs, miRNAs, lipids, and proteins with multiple functions. In this review, we discuss the potential of cell-free therapeutics utilizing MSC secretome-derived extracellular vesicles—and in particular exosomes—in the treatment of autoimmune demyelinating diseases, and provide an outlook for studies of their future applications

Olive Leaf Extract (OLE) as a Novel Antioxidant That Ameliorates the Inflammatory Response in Cystic Fibrosis

The deletion of phenylalanine at position 508 (F508del) produces a misfolded CFTR protein that is retained in the ER and degraded. The lack of normal CFTR channel activity is associated with chronic infection and inflammation which are the primary causes of declining lung function in Cystic Fibrosis (CF) patients. Moreover, LPS-dependent oxidative stress downregulates CFTR function in airway epithelial cells. Olive leaf extract (OLE) is used in traditional medicine for its effects, including anti-oxidant and anti-inflammatory ones. We found that OLE decreased the intracellular ROS levels in a dose-response manner in CFBE cells. Moreover, OLE attenuates the inflammatory response to LPS or IL-1 beta/TNF alpha stimulation, mimicking the infection and inflammatory status of CF patients, in CFBE and primary nasal epithelial (HNE) cells. Furthermore, we demonstrated that OLE restored the LPS-mediated decrease of Trikfafta (TM)-dependent F508del-CFTR function in CFBE and HNE cultures. These findings provide strong evidence of OLE to prevent redox imbalance and inflammation that can cause chronic lung damage by enhancing the antioxidant activity and attenuating inflammation in CF airway epithelial cells. Additionally, OLE might be used in combination with CFTR modulators therapy to improve their efficacy in CF patients

Alkaline hydrothermal stabilization of Cr(VI) in soil using glass and aluminum from recycled municipal solid wastes

Hexavalent chromium was stabilized in soil by using a mixture of glass and aluminum recovered from municipal solid wastes under alkaline hydrothermal conditions. Cr(VI) concentration was reduced by 94-98% already after 7 days of treatment. After the same period, more than 90% of total Cr was stabilized in highly recalcitrant and scarcely mobile chemical forms, with 50% in the residual fraction (when the samples were treated at 1/10 w/w mixture/soil ratio). Longer treatments increased Cr stabilization. X-ray microanalyses revealed that Cr was stabilized in geopolymeric structures within large aluminosilicate mineral aggregates (containing both amorphous and crystalline phases). 3D microstructural analyses showed a limited compaction of the soil with still a 20% internal porosity in the neoformed aggregates. Increased pH and salinity after the treatment can be restored by simple soil amendments and washing

Impiego di vetro e alluminio da RSU per la stabilizzazione idrotermica alcalina di un suolo inquinato da Cr(VI)

La definizione di strategie sostenibili per il rimedio dei suoli inquinati da metalli pesanti rappresenta una delle principali sfide ambientali, considerato che i metalli pesanti non sono degradabili e quindi tendono ad accumularsi nel suolo. Tra le diverse metodologie di bonifica, quella della stabilizzazione/solidificazione (S/S) è sicuramente una delle più efficaci ed economicamente vantaggiose. Essa consiste nell’apporto al suolo di materiali e/o reagenti chimici capaci di ridurre la solubilità e la tossicità degli inquinanti e/o di immobilizzarli all’interno di fasi solide di neosintesi. In questo studio, è stato testato un metodo innovativo di S/S per la stabilizzazione del cromo esavalente (Cr(VI)) in un suolo sabbioso mediante l’impiego di materiali di scarto, quali vetro e alluminio provenienti da RSU, in condizioni idrotermiche alcaline. L’obiettivo è stato quello di valutare la capacità della tecnica di S/S di ridurre il Cr(VI) a Cr(III), forma meno tossica e molto stabile nel suolo, e di immobilizzare successivamente il Cr(III) in minerali di neoformazione. Il suoloè stato inquinato artificialmente con una soluzione di K2Cr2O7 fino a 1500 mg kg-1 (Cr totale) e lasciato poi indisturbato per 3 mesi fino a stabilizzarsi ad una concentrazione finale di 580 mg kg-1 di Cr(VI). E' stato quindi addizionato con una miscela di vetro e alluminio polverizzati e KOH (MIX), in rapporto di 1/10 e 1/20 (MIX:suolo, m/m). I campioni di suolo+MIX sono stati trasferiti in barattoli di HDPE, addizionati con acqua (1:2 m/v) e conservati in stufa a 90°C. Due controlli di suolo senza MIX, trattati a 90°C solo con KOH e solo con acqua, sono stati preparati in contemporanea. Dopo 1, 7, 30 e 60 giorni è stata prelevata da ciascun barattolo un’aliquota di suolo per la determinazione del Cr(VI) e le estrazioni sequenziali del Cr . Inoltre, al fine di comprendere i meccanismi di stabilizzazione del Cr, i campioni sono stati sottoposti ad analisi mineralogica mediante diffrazione di raggi X (XRPD), e di micro fluorescenza di raggi X (µ-XRF). Il trattamento S/S ha prodotto una netta e rapida diminuzione della concentrazione di Cr(VI) nel suolo, soprattutto in presenza di MIX. Dopo soli 7 giorni, la concentrazione di Cr(VI) nel suolo+MIX si è ridotta del 94% e 98% rispetto a quella iniziale (per le miscele 1/10 e 1/20, rispettivamente). Nei campioni controllo, la riduzione è stata invece del 71% (controllo con KOH) e 85% (controllo senza KOH). Prolungando il trattamento fino a 60 giorni, le concentrazioni di Cr(VI) si sono ridotte ulteriormente, risultando il trattamento con MIX sempre quello più efficace (sia 1/10 che 1/20). Inoltre, in presenza di MIX, la mobilità del Cr si è significativamente ridotta rispetto ai controlli, come dimostrato dalle estrazioni sequenziali. Infatti, già dopo 7 giorni ben il 95% e 87% del Cr totale è apparso legato al suolo in forme stabili (per le miscele 1/10 e 1/20, rispettivamente), mentre nei controlli solo il 55% e 38% del Cr è risultato stabilizzato nella fase solida (in presenza e assenza di KOH, rispettivamente). Nei successivi rilievi, la stabilità del Cr è aumentata considerevolmente nel tempo, anche nei controlli, senza tuttavia raggiungere i risultati ottenuti in presenza di MIX. L’analisi mineralogica ha rivelato in tutti i campioni una diminuzione di quarzo e illite e, in alcuni casi, la formazione di zeolite (edingtonite). Il trattamento idrotermico alcalino ha modificato profondamente la struttura del suolo, come dimostrato dall’analisi µ-XRF, e favorito l'intrappolamento del Cr in macroaggregati contenenti Si, K, Al, Fe e Mn. Ulteriori indagini microanalitiche sono in corso per studiare i meccanismi di inclusione del Cr in tali aggregati