•We prepared three Nb/Al-AlOx/Nb Josephson junctions with base Nb layer thicknesses of 100 nm, 500 nm, and 1000 nm.•We investigated the influence of the thickness of the base Nb layer on magnetic ...flux trapping in a Josephson junction.•We found that the magnetic flux became increasingly difficult to be trapped in the Nb superconducting thin film with increasing thickness of the Nb superconducting film.
We measured the two-dimensional magnetic field dependence of a Josephson current by applying external magnetic fields Hx and Hy parallel to the plane of a Nb/Al-AlOx/Nb Josephson junction from two directions. In addition, we measured the modulation characteristics of the Josephson current by applying a magnetic field Hz in the direction perpendicular to the plane of the junction. When the perpendicular magnetic field Hz was applied to the Josephson junction and removed, the main peak of the Fraunhofer pattern did not return to the origin of the (Hx, Hy) plane completely because the magnetic flux was trapped in the Nb superconducting film around the Josephson junction. In the present study, we investigated the influence of the thickness of the base Nb layer on magnetic flux trapping in a Josephson junction by fabricating Josephson junctions with base Nb layers of different thickness. We found that the magnetic flux became increasingly difficult to be trapped in the Nb superconducting thin film with increasing thickness of the Nb superconducting film.
ABCG2, also known as BCRP, is a high-capacity urate exporter, the dysfunction of which raises gout/hyperuricemia risk. Generally, hyperuricemia has been classified into urate 'overproduction type' ...and/or 'underexcretion type' based solely on renal urate excretion, without considering an extra-renal pathway. Here we show that decreased extra-renal urate excretion caused by ABCG2 dysfunction is a common mechanism of hyperuricemia. Clinical parameters, including urinary urate excretion, are examined in 644 male outpatients with hyperuricemia. Paradoxically, ABCG2 export dysfunction significantly increases urinary urate excretion and risk ratio of urate overproduction. Abcg2-knockout mice show increased serum uric acid levels and renal urate excretion, and decreased intestinal urate excretion. Together with high ABCG2 expression in extra-renal tissues, our data suggest that the 'overproduction type' in the current concept of hyperuricemia be renamed 'renal overload type', which consists of two subtypes-'extra-renal urate underexcretion' and genuine 'urate overproduction'-providing a new concept valuable for the treatment of hyperuricemia and gout.
Abstract
Nod-like receptor family pyrin domain-containing 3 (NLRP3) is a cytosolic innate immune receptor that senses organelle dysfunction induced by various stimuli, such as infectious, ...environmental, metabolic and drug stresses. Upon activation, NLRP3 forms an inflammasome with its adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1, to trigger the release of inflammatory cytokines. The development of effective anti-inflammatory drugs targeting the NLRP3 inflammasome is in high demand as its aberrant activation often causes inflammatory diseases. Here, we found that nanaomycin A (NNM-A), a quinone-based antibiotic isolated from Streptomyces, effectively inhibited NLRP3 inflammasome-mediated inflammatory responses induced by imidazoquinolines, including imiquimod. Interestingly, its epoxy derivative nanaomycin E (NNM-E) showed a comparable inhibitory effect against the NLRP3 inflammasome-induced release of interleukin (IL)-1β and IL-18 from macrophages, with a much lower toxicity than NNM-A. NNM-E inhibited ASC oligomerization and caspase-1 cleavage, both of which are hallmarks of NLRP3 inflammasome activation. NNM-E reduced mitochondrial damage and the production of reactive oxygen species, thereby preventing the activation of the NLRP3 inflammasome. NNM-E treatment markedly alleviated psoriasis-like skin inflammation induced by imiquimod. Collectively, NNM-E inhibits NLRP3 inflammasome activation by preventing mitochondrial dysfunction with little toxicity and showed an anti-inflammatory effect in vivo. Thus, NNM-E could be a potential lead compound for developing effective and safe anti-inflammatory agents for the treatment of NLRP3 inflammasome-mediated inflammatory diseases.
Nanaomycin E inhibits activation of the NLRP3 inflammasome
Graphical Abstract
•We fabricated Nb/Al-AlOx/Nb Josephson junctions with different Al layer thicknesses.•We investigated the influence of the thicknesses of Al layers on the characteristics of the Josephson ...junctions.•The Josephson current decreased as the Al layer thickness of the Josephson junction became thicker.•The subpeak of the Fraunhofer diffraction pattern was hardly observed in the Josephson junction with the Al layer thickness of 200 nm.
We have fabricated Nb/Al-AlOx/Nb Josephson junctions and have measured their current-voltage characteristics and the two-dimensional magnetic field dependence of the Josephson current. When the external magnetic fields (Hx, Hy) parallel to the junction plane are applied to the Josephson junction from two directions, two Fraunhofer diffraction patterns are observed in the (Hx, Hy) plane. In this study, we have fabricated several Nb/Al-AlOx/Nb Josephson junctions with different thicknesses of Al layer and have investigated the effect of the Al layer thicknesses on the two-dimensional magnetic field dependence of the Josephson current. The thicknesses of the Al layers in the Josephson junctions we fabricated are 5 nm, 25 nm, 50 nm, 100 nm and 200 nm. When the Al layer thickness was 5 nm and 25 nm thick, a subpeak of the Fraunhofer diffraction pattern was clearly observed. However, the subpeak of the Fraunhofer diffraction pattern was not obviously observed as the Al layer got thicker. In particular, when the Al layer was 200 nm thick, the subpeak of the Fraunhofer diffraction pattern was not observed at all.
We measured the two-dimensional magnetic field dependence of a Josephson current through an Nb/Al-AlOx/Nb Josephson tunnel junction by applying external magnetic fields (Hx, Hy) parallel to the ...junction plane from two directions. We obtained much information about current distribution within the Josephson junction from a two-dimensional scan of the external magnetic fields (Hx, Hy). We also measured the perpendicular magnetic field Hz dependence of a Josephson current. When the perpendicular magnetic field Hz was applied to the Josephson junction, the Josephson current was modulated by the parallel component of the applied magnetic field Hz produced by the Meissner effect of the base Nb layer. In this study, some Josephson junctions were fabricated on the base Nb layer in our sample, and we investigated how the position of the Josephson junction on the base Nb layer influenced the modulation characteristics of the Josephson current when the perpendicular magnetic field Hz was applied to the junction. The junction at the center of the base Nb layer was not easily affected by the perpendicular magnetic field Hz because of the Meissner effect of the base Nb layer, whereas the junction on the edge of the base Nb layer was susceptible to the perpendicular magnetic field Hz.
Treatment of asymptomatic hyperuricemia is not commonly implemented. However, it is unclear whether urate deposition that begins during asymptomatic hyperuricemia can induce nephropathy. Dysfunction ...of ATP-binding cassette subfamily G member 2 (ABCG2), a urate efflux transporter, leads to elevated serum uric acid concentration (SUA). We investigated the association between asymptomatic hyperuricemia and decreased estimated glomerular filtration rate (eGFR), and the impact of ABCG2 on this relationship.
Retrospective cohort study.
1,885 Japanese adults undergoing routine health care follow-up between 2007 and 2017 who had eGFR ≥60 mL/min/1.73 m2, of which 311 had asymptomatic hyperuricemia (SUA >7.0 mg/dL). Study participants were classified into 3 categories of estimated ABCG2 function (full, 75%, and ≤50% function).
Baseline SUA and estimated ABCG2 function.
Change in eGFR over time.
Linear mixed-effect models were used to analyze the relationship between asymptomatic hyperuricemia, ABCG2 function, and eGFR decline.
Asymptomatic hyperuricemia was negligibly associated with eGFR decline overall. However, among those with eGFR 60-89 mL/min/1.73 m2 and ≤50% ABCG2 function, eGFR decline was associated with asymptomatic hyperuricemia (P = 0.03). ABCG2 was not associated with eGFR reductions when the SUA was <6.0 mg/dL. Among participants with SUA ≥6.0 mg/dL and eGFR 60-89 mL/min/1.73 m2, ≤50% ABCG2 function was associated with approximately 1.2-fold faster eGFR decline compared with fully functional ABCG2 (P = 0.02). Among the participants with SUA ≥6.0 mg/dL and eGFR 60-89 mL/min/1.73 m2, the adjusted eGFR slopes (given as mean ± standard error of the mean, in mL/min/1.73 m2 per year) were −0.946 ± 0.049, −1.040 ± 0.046, and −1.148 ± 0.069 for full, 75%, and ≤50% ABCG2 function, respectively.
Lack of measurement of urinary urate and uremic toxins that are known to be transported by ABCG2, and no independent validation cohort.
Asymptomatic hyperuricemia was not associated with eGFR decline, except when in the presence of ≤50% ABCG2 function.
The urate transporter ABCG2 is a protein that regulates serum urate concentrations; when dysfunctional, it can lead to elevated serum concentrations of this compound (ie, hyperuricemia). Although persistent hyperuricemia induces gout and kidney injury, the effects on organs during the asymptomatic phase have yet to be established. Therefore, to clarify the relationship between ABCG2, asymptomatic hyperuricemia, and kidney function, we conducted a retrospective cohort study of 1,885 healthy participants, including 311 participants with asymptomatic hyperuricemia. We found that the coexistence of asymptomatic hyperuricemia and severe ABCG2 dysfunction was associated with the age-dependent decline in kidney function. We concluded that asymptomatic hyperuricemia represents a risk factor for chronic kidney disease, at least in individuals with highly dysfunctional ABCG2. This new finding highlights the potential importance of ABCG2 in the pathogenesis of hyperuricemia-induced kidney injury.
Display omitted
Abstract
The human body is exposed to various particulates of industrial, environmental, or endogenous origin. Invading or intrinsic particulates can induce inflammation by aberrantly activating the ...immune system, thereby causing crystallopathies. When immune cells such as macrophages phagocytose the particulates, their phagolysosomal membranes undergo mechanical damage, eventually leading to pyroptotic cell death accompanied by the release of inflammatory cytokines, including interleukin (IL)-1α and IL-1β. The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is responsible for particulate-induced IL-1β release and is therefore regarded as a potential therapeutic target for inflammation-mediated crystallopathies. However, IL-1α is released after particulate stimulation in an NLRP3 inflammasome-independent manner and plays a critical role in disease development. Therefore, drugs that exert potent anti-inflammatory effects by comprehensively suppressing particulate-induced responses, including IL-1β release and IL-1α release, should be developed. Here, we found that oridonin, a diterpenoid isolated from Isodon japonicus HARA, strongly suppressed particulate-induced cell death, accompanied by the release of IL-1α and IL-1β in mouse and human macrophages. Oridonin reduced particulate-induced phagolysosomal membrane damage in macrophages without affecting phagocytosis of particulates. Furthermore, oridonin treatment markedly suppressed the symptoms of silica particle-induced pneumonia, which was attributed to the release of IL-1α independently of NLRP3. Thus, oridonin is a potential lead compound for developing effective therapeutics for crystallopathies attributed to NLRP3-dependent as well as NLRP3-independent inflammation.
Oridonin prevents particulate-induced crystallopathy
Graphical Abstract
Background:
Humans are constantly exposed to various industrial, environmental, and endogenous particulates that result in inflammatory diseases. After being engulfed by immune cells, viz. ...Macrophages, such particulates lead to phagolysosomal dysfunction, eventually inducing pyroptosis, a form of cell death accompanied by the release of inflammatory mediators, including members of the interleukin (IL)-1 family. Phagolysosomal dysfunction results in the activation of the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, an immune complex that induces pyroptosis upon exposure to various external stimuli. However, several particulates induce pyroptosis even if the NLRP3 inflammasome is inhibited; this indicates that such inhibition is not always effective in treating diseases induced by particulates. Therefore, discovery of drugs suppressing particulate-induced NLRP3-independent pyroptosis is warranted.
Methods:
We screened compounds that inhibit silica particle (SP)-induced cell death and release of IL-1α using RAW264.7 cells, which are incapable of NLRP3 inflammasome formation. The candidates were tested for their ability to suppress particulate-induced pyroptosis and phagolysosomal dysfunction using mouse primary macrophages and alleviate SP-induced NLRP3-independent lung inflammation.
Results:
Several Src family kinase inhibitors, including dasatinib, effectively suppressed SP-induced cell death and IL-1α release. Furthermore, dasatinib suppressed pyroptosis induced by other particulates but did not suppress that induced by non-particulates, such as adenosine triphosphate. Dasatinib reduced SP-induced phagolysosomal dysfunction without affecting phagocytosis of SPs. Moreover, dasatinib treatment strongly suppressed the increase in IL-1α levels and neutrophil counts in the lungs after intratracheal SP administration.
Conclusion:
Dasatinib suppresses particulate-induced pyroptosis and can be used to treat relevant inflammatory diseases.
PDF
