Uromodulin (UMOD) is produced and secreted by tubular epithelial cells. Secreted UMOD polymerizes (pUMOD) in the tubular lumen, where it regulates salt transport and protects the kidney from bacteria ...and stone formation. Under various pathological conditions, pUMOD accumulates within the tubular lumen and reaches extratubular sites where it may interact with renal interstitial cells. Here, we investigated the potential of extratubular pUMOD to act as a damage associated molecular pattern (DAMP) molecule thereby creating local inflammation. We found that intrascrotal and intraperitoneal injection of pUMOD induced leukocyte recruitment
and led to TNF-α secretion by F4/80 positive macrophages. Additionally, pUMOD directly affected vascular permeability and increased neutrophil extravasation independent of macrophage-released TNF-α. Interestingly, pUMOD displayed no chemotactic properties on neutrophils, did not directly activate β2 integrins and did not upregulate adhesion molecules on endothelial cells. In obstructed neonatal murine kidneys, we observed extratubular UMOD accumulation in the renal interstitium with tubular atrophy and leukocyte infiltrates. Finally, we found extratubular UMOD deposits associated with peritubular leukocyte infiltration in kidneys from patients with inflammatory kidney diseases. Taken together, we identified extratubular pUMOD as a strong inducer of leukocyte recruitment, underlining its critical role in mounting an inflammatory response in various kidneys pathologies.
Neutrophils are key players during host defense and sterile inflammation. Neutrophil dysfunction is a characteristic feature of the acquired immunodeficiency during kidney disease. We speculated that ...the impaired renal clearance of the intrinsic purine metabolite soluble uric acid (sUA) may account for neutrophil dysfunction. Indeed, hyperuricemia (HU, serum UA of 9-12 mg/dL) related or unrelated to kidney dysfunction significantly diminished neutrophil adhesion and extravasation in mice with crystal- and coronavirus-related sterile inflammation using intravital microscopy and an air pouch model. This impaired neutrophil recruitment was partially reversible by depleting UA with rasburicase. We validated these findings in vitro using either neutrophils or serum from patients with kidney dysfunction–related HU with or without UA depletion, which partially normalized the defective migration of neutrophils. Mechanistically, sUA impaired β2 integrin activity and internalization/recycling by regulating intracellular pH and cytoskeletal dynamics, physiological processes that are known to alter the migratory and phagocytic capability of neutrophils. This effect was fully reversible by blocking intracellular uptake of sUA via urate transporters. In contrast, sUA had no effect on neutrophil extracellular trap formation in neutrophils from healthy subjects or patients with kidney dysfunction. Our results identify an unexpected immunoregulatory role of the intrinsic purine metabolite sUA, which contrasts the well-known immunostimulatory effects of crystalline UA. Specifically targeting UA may help to overcome certain forms of immunodeficiency, for example in kidney dysfunction, but may enhance sterile forms of inflammation.
•Hyperuricemia suppresses neutrophil adhesion and extravasation during sterile inflammation.•Uric acid impairs neutrophil migration by suppressing β2 integrin activity/recycling and cytoskeletal dynamics upon urate transporter–mediated uric acid uptake.
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Eosinophil recruitment is a pathological hallmark of many allergic and helminthic diseases. Here, we investigated chemokine receptor CCR3-induced eosinophil recruitment in sialyltransferase
mice. We ...found a marked decrease in eosinophil extravasation into CCL11-stimulated cremaster muscles and into the inflamed peritoneal cavity of
mice. Ex vivo flow chamber assays uncovered reduced adhesion of
compared to wild type eosinophils. Using flow cytometry, we show reduced binding of CCL11 to
eosinophils. Further, we noted reduced binding of CCL11 to its chemokine receptor CCR3 isolated from
eosinophils. This was accompanied by almost absent CCR3 internalization of CCL11-stimulated
eosinophils. Applying an ovalbumin-induced allergic airway disease model, we found a dramatic reduction in eosinophil numbers in bronchoalveolar lavage fluid following intratracheal challenge with ovalbumin in
-deficient mice. Finally, we also investigated tissue-resident eosinophils under homeostatic conditions and found reduced resident eosinophil numbers in the thymus and adipose tissue in the absence of ST3Gal-IV. Taken together, our results demonstrate an important role of ST3Gal-IV in CCR3-induced eosinophil recruitment in vivo rendering this enzyme an attractive target in reducing unwanted eosinophil infiltration in various disorders including allergic diseases.
In ludo veritas Matteo Di Napoli
Acme (Milano),
07/2016, Volume:
69, Issue:
1
Journal Article
Peer reviewed
Open access
Edward Burnett Tylor (1832-1917) fu uno dei padri fondatori dell’antropologia culturale. Per primo evidenziò il valore sociale della cultura, che definì «quel complesso insieme che comprende ...conoscenze, credenze, arte, valori morali, leggi, costumi, e ogni altra capacità e atteggiamento acquisiti da un uomo in quanto membro di una società». Durante la riunione del 14 marzo 1879 alla Royal Institution of Great Britain, Tylor fece un’insolita relazione del proprio lavoro. Il famoso antropologo era stato colpito dal fatto che il gioco del patolli, praticato dagli aztechi già prima della conquista spagnola, fosse molto simile al pachisi indiano. Ciò gli fece supporre che fossero fondate le teorie che ritenevano che la civilizzazione delle Americhe fosse avvenuta dall’Asia. Per questo, durante l’incontro con i colleghi della Royal Institution, Tylor espose le sue riflessioni sull’importanza del gioco come fattore culturale, sostenendo che la diffusione geografica delle attività ludiche è una testimonianza fondamentale dell’incontro tra civiltà e del processo di civilizzazione dell’ecumene. Aggiunse pure che i giochi resistono spesso nel tempo, anche in seguito a cambiamenti linguistici, religiosi o “dinastici”. Per questo sono rivelatori di interessanti indizi sulla storia dei popoli.
To investigate the safety and efficacy in terms of PSA response of a low-dose oral combination of estramustine phosphate (EMP) and etoposide (VP16) in hormone- refractory prostate cancer (HRPC) ...patients. Well-tolerated outpatient chemotherapy regimens for patients unfit and/or unwilling to be admitted to hospital are needed.
Fifty-six HRPC patients with metastatic disease (median age 75 years) were randomized between arm A (daily oral EMP 10 mg/kg, in 3 doses) and arm B (28-day cycle with low-dose EMP 3 mg/kg once daily plus VP16 25 mg/m(2) once daily on days 1 through 14). Baseline characteristics between the two groups were similar. LHRH therapy was maintained. Anti- androgen was stopped 1 month before entry.
The low-dose combination was better tolerated, with a significant advantage in terms of time to treatment interruption for any reason (p = 0.01) or toxicity (6 vs. 12 months, p = 0.02). A trend in favour of arm B was evident in terms of PSA reduction (41.4 vs. 15%), performance status and pain improvement. Hospital admission due to toxicity was never required for arm B patients and there were no treatment-related deaths.
Low-dose oral combination of EMP and VP16 might represent a treatment option for patients unfit for i.v. chemotherapy. This regimen requires minimal toxicity monitoring when administered at home for prolonged periods.
In this work the effect of the milk bactofugation and natural whey culture on the microbiological and physicochemical quality of Mozzarella cheese was studied. To this aim, the microbiological, ...sensory and physico-chemical parameters of the Mozzarella cheese were monitored during the storage at 8°C. The bactofugation treatment did not significantly affect the growth of typical dairy microorganisms, while a significant decrease of Enterobacteriaceae in milk was found. The Mozzarella manufactured with natural whey culture and bactofugated milk showed a slower increase in the Pseudomonas spp. cell load during storage. Moreover, the absence of natural whey culture in the Mozzarella cheese manufacture caused a faster sensorial quality loss during storage (~4.5 days) respect to the product with natural starter (~6 days). However, the factor limiting the shelf life of Mozzarella cheese was the growth of Pseudomonas spp. In particular, a shelf life value of about 4.0 days was obtained for Mozzarella produced with bactofugated milk and natural whey culture versus 3.5 days for the control, with citric acidification, and samples manufactured with natural whey culture and no bactofugated milk. The compositional characteristics of the cheeses were influenced by the use of the natural starter, especially at the end of the storage period. In fact, the control cheese tended to lose soluble compounds (WSN and NaCl) faster and, increase in moisture content.
In this work, the effects of Potassium Sorbate (PS) in the dough, antimicrobial air filter after the pasteurization and Modified Atmosphere Packaging (MAP) as combined preservation techniques were ...studied on shelf life of fresh pasta. In particular, in the first experimental step the influence of an antimicrobial air filter used to cool down pasta temperature after heat treatment and packaging under MAP (70:30 CO2:N2) were tested. Subsequently, different concentrations of PS (500, 750 and 1000 mg kg-1), combined with the air filter, were added to the pasta dough to control moulds and bacteria proliferation. In the final trial, PS (1000 mg kg-1), air filter and MAP were combined. In each experimental step, both microbiological and sensory quality was monitored. Results demonstrated that the preservation strategies adopted in each step were effective to control microbial and fungi proliferation and, when all of them were combined; the shelf life was about 40 days against about 8 days of the control sample.
In the current work, we discovered and analyzed the epidemiological paradox between coronavirus disease 2019 (COVID-19) and malaria in the initial phase of the ongoing pandemic. From the analysis of ...distribution data, the endemic presence of malaria seems to protect some populations from COVID-19 outbreak, particularly in the least developed countries. In this sense, molecular and genetic variations associated with malaria (e.g., in ACE2) might play a protective role against coronavirus infection. Moreover, the mechanism of action of some antimalarial drugs, e.g., the antiviral function, suggests their potential role in the chemoprophylaxis of coronavirus epidemics, despite possible adverse effects (e.g., retinal toxicity). All these data provide important insights to understand the spreading mechanisms of COVID-19, and to direct scientific research toward the study of some currently available medications.
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