The purpose of this review is to discuss the effect of natural antioxidant compounds as modulators of the 20S proteasome, a multi-enzymatic multi-catalytic complex present in the cytoplasm and ...nucleus of eukaryotic cells and involved in several cellular activities such as cell-cycle progression, proliferation and the degradation of oxidized and damaged proteins. From this perspective, proteasome inhibition is a promising approach to anticancer therapy and such natural antioxidant effectors can be considered as potential relevant adjuvants and pharmacological models in the study of new drugs.
Tissues are 3D formations of cells integrated in an extracellular matrix (ECM) with specific sites for cell anchorage offering positional and instructive information regulating cell behavior. A vast ...number of publications in the last decades have proven the reciprocal interaction between the ECM, cytoskeleton and nuclear matrix, showing that these structures exert a physical and chemical influence over gene expression. Thus, to culture authentic cells from which safe and therapeutically relevant cells can be generated or real biological questions can be answered, environmental context is pivotal.
Laminins comprise a family of 16 unique heterotrimeric glycoproteins naturally present in the body. Laminins are tissue specific, supply a natural environment for all cell types, and influence cell adhesion, differentiation, migration, phenotypic stability, and cell functionality. As such, recombinant laminins are biologically relevant ECM protein substrates that can be used to mimic the in vivo cell niche in vitro. The laminin 521 isoform is a critical factor supporting pluripotent stem cells in culture, and given the right context, this isoform also provides support for other differentiated cell types.
Biosilk 521 is a biomaterial made of recombinant silk, which is functionalized with human recombinant laminin 521 protein (Biolaminin™ 521). This material supports integration and proliferation of human pluripotent stem cells in vitro and serves as a viable base for the development of subsequent lineage-specific differentiation in a 3D format. Human PSCs (2 hESC and 2 hiPSC lines) seeded in the Biosilk 521 scaffold integrate, migrate, and form small colonies at day 1 post seeding and retain pluripotency thereafter. Human PSCs in the Biosilk 521 scaffold could be cultured using different types of medium, express pluripotent markers, generate all three tissues germ layers upon spontaneous differentiation, and directly to different neural fates. Furthermore, the Biosilk 521 can be used for organoid culture, without the need of Matrigel. Forebrain, midbrain and glia organoids were started in a controlled manner by using the Biosilk 521 and correct regional specific markers, cell morphology and layers were present.
In sum, Biosilk 521 is a xenofree and defined, biorelevant 3D system that is biodegradable and non-immunogenic, and thus ideal for cell culturing and many other biomedical applications.
In this paper we prove the the local Lipschitz continuity for solutions to a class of obstacle problems of the type
min{ ∫
Ω
F
(
x, Dz
) :
z
∈
ψ
(Ω)}.
Here
ψ
(Ω) is the set of admissible functions
z
...∈
u
0
+
W
1,
p
(Ω) for a given
u
0
∈
W
1,
p
(Ω) such that
z
≥
ψ
a.e. in Ω,
ψ
being the obstacle and Ω being an open bounded set of ℝ
n
,
n
≥ 2. The main novelty here is that we are assuming that the integrand
F
(
x
,
Dz
) satisfies (
p
,
q
)-growth conditions and as a function of the
x
-variable belongs to a suitable Sobolev class. We remark that the Lipschitz continuity result is obtained under a sharp closeness condition between the growth and the ellipticity exponents. Moreover, we impose less restrictive assumptions on the obstacle with respect to the previous regularity results. Furthermore, assuming the obstacle
ψ
is locally bounded, we prove the local boundedness of the solutions to a quite large class of variational inequalities whose principal part satisfies non standard growth conditions.
Three pyrazolone-based hydrazone ligands HL′ (HL′ in general; in detail, HL1 = 2-((5-hydroxo-3-methyl-1-phenyl-1H-pyrazol-4-yl)(phenyl)methylene)-1-(2,4-nitrophenyl)hydrazine, HL2 = ...2-((5-hydroxo-3-methyl-1-phenyl-1H-pyrazol-4-yl) (phenyl)methylene)-1-(4-nitrophenyl)hydrazine, and HL3 = 2-((5-hydroxo-3-methyl-1-phenyl-1H-pyrazol-4-yl)(phenyl)methylene)-1-(pyridin-2-yl)hydrazine) have been prepared starting from 4-benzoyl-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one and fully characterized in the solid state and solution, where the existing tautomeric forms were identified by taking advantage of natural abundance 1H–15N coupling in {1H–15N}-HSQC and {1H–15N}-HMBC NMR spectroscopy. Then, six half-sandwich arene-ruthenium(II) derivatives (arene = hexamethylbenzene and p-cymene) of composition (arene)Ru(L′)Cl have been synthesized and fully characterized by IR, 1H, and 13C NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis, and density functional theory calculations. The crystal structures of three complexes, together with the E configurational isomer (with respect to the CN double bond) of the free proligand HL2 and the zwitterionic proligand HL3 were determined by X-ray analysis. The anionic ligands L1 and L2 were found bonded to ruthenium in the N,O-form, while L3 coordinates the metal in the N,N-form affording five-membered chelating rings. The cytotoxicity of the complexes was evaluated against human breast adenocarcinoma cells (MCF-7 and MCF-7CR), as well as against nontumorigenic human breast (MCF-10A) cells and compared to the free ligand and cisplatin.
BACKGROUND There is mounting evidence that deteriorated semen quality may be associated with increased serum concentration of 1,1,1-trichloro-2,2-bis(chlorodiphenyl)ethane (DDT) and its metabolites. ...The problem is exacerbated in situations where DDT is the only resource available to control malaria mosquitoes and DDT metabolite plasma concentration can reach 1000-fold the level found in other populations. There are limited and contradictory epidemiological data on whether DDT/dichlorodiphenyl-dichloroethylene (DDE) can also damage sperm DNA. Therefore, there is a need to investigate the possible adverse effects on human sperm genetic integrity in a sufficiently large study population with adequate exposure contrasts, especially in the high exposure range. METHODS We conducted a cross-sectional study, recruiting 209 young males from three communities in an endemic malaria area where DDT is sprayed annually. Blood plasma p,p′-DDT and its metabolite p,p′-DDE levels were measured and expressed as lipid adjusted p,p′-DDT and p,p′-DDE values. The sperm chromatin structure assay and Aniline Blue test were used to assess sperm DNA/chromatin integrity. RESULTS The lipid adjusted p,p′-DDT mean (±SD) and median concentrations were 109.2 (±106.6) and 83.9 µg/g, respectively; and the lipid adjusted p,p′-DDE mean (±SD) and median concentrations were 246.2 (±218.5) and 177.8 µg/g, respectively. The results point to a weak association between DDT/DDE plasma concentration and the incidence of sperm with chromatin defects. CONCLUSIONS The results suggest that non-occupational environmental DDT exposure may have a negative impact on sperm chromatin integrity in young South African males.
BACKGROUND The sperm chromatin structure assay (SCSA) parameter DNA fragmentation index (DFI) has been shown to predict in vivo and in vitro fertility. So far most SCSA studies have been based on ...SCSA analysis performed on neat semen. The aim of this study is to assess whether SCSA analysis of sperm prepared by density gradient centrifugation (DGC) could add more information in regard to the prediction of treatment outcome. METHODS The study included 510 assisted reproductive technique (ART) cycles. SCSA was performed in neat semen and post DGC. SCSA results were expressed in terms of DFI and high DNA stainability (HDS) cell fractions. The outcome parameter was clinical pregnancy (CP). RESULTS Scatter-plot diagrams demonstrated that for DGC samples, no DFI cut-off values could be set for in vivo or in vitro fertility. In intrauterine insemination, IVF and ICSI groups the mean difference (95% CI) in DFI post DGC between those who achieved CP and those who did not was 0.2% (−1.7 to 2.0%), 0.4% (−1.9 to 2.8%) and 1.3% (−3.1 to 5.9%), respectively, none of these being statistically significant. The corresponding differences for HDS were 0.1% (−1.3 to 1.5%), 0.1% (−0.7 to 0.9%) and 0.6% (−1.6 to 2.7%), respectively (all P-values >0.6). CONCLUSIONS SCSA performed in semen prepared by DGC cannot predict the outcome of ART.
Abstract Background Reduced flow-mediated dilation (FMD) is a known prognostic marker in heart failure (HF), but may be influenced by the brachial artery (BA) diameter. Aiming to adjust for this ...influence, we normalized FMD (nFMD) by the peak shear rate (PSR) and tested its prognostic power in HF patients. Methods and Results BA diameter, FMD, difference in hyperemic versus rest brachial flow velocity (FVD), PSR (FVD/BA), and nFMD (FMD/PSR × 1000) were assessed in 71 HF patients. At follow-up (mean 512 days), 19 HF (27%) reached the combined endpoint (4 heart transplantations HTs, 1 left ventricle assist device implantation LVAD, and 14 cardiac deaths CDs). With multivariate Cox regression analysis, New York Heart Association functional class ≥III (hazard ratio HR 9.36, 95% confidence interval CI 2.11–41.4; P = .003), digoxin use (HR 6.36, 95% CI 2.18–18.6; P = .0010), FMD (HR 0.703, 95% CI 0.547–0.904; P = .006), PSR (HR 1.01, 95% CI 1.005–1.022; P = .001), FVD (HR 1.04, 95% CI 1.00–1.06; P = .02), and nFMD (HR 0.535, 95% CI 0.39–0.74; P = .0001) were predictors of unfavorable outcome. Receiver operating characteristic curve for nFMD showed that patients with nFMD >5 seconds had significantly better event-free survival than patients with nFMD ≤5 seconds (log-rank test: P < .0001). Conclusions nFMD is a strong independent predictor of CD, HT, and LVAD in HF with left ventricular ejection fraction <40%. Patients with nFMD >5 seconds have a better prognosis than those with lower values.
A urine ‘biomarker panel’ comprising alpha-1-acid-glycoprotein, ceruloplasmin, transferrin and lipocalin-like-prostaglandin-D synthase performs to an ‘excellent’ level for lupus nephritis ...identification in children cross-sectionally. The aim of this study was to assess if this biomarker panel predicts lupus nephritis flare/remission longitudinally.
The novel urinary biomarker panel was quantified by enzyme linked immunoabsorbant assay in participants of the United Kingdom Juvenile Systemic Lupus Erythematosus (UK JSLE) Cohort Study, the Einstein Lupus Cohort, and the South African Paediatric Lupus Cohort. Monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1 were also quantified in view of evidence from other longitudinal studies. Serial urine samples were collected during routine care with detailed clinical and demographic data. A Markov Multi-State model of state transitions was fitted, with predictive clinical/biomarker factors assessed by a corrected Akaike Information Criterion (AICc) score (the better the model, the lower the AICc score).
The study included 184 longitudinal observations from 80 patients. The homogeneous multi-state Markov model of lupus nephritis activity AICc score was 147.85. Alpha-1-acid-glycoprotein and ceruloplasmin were identified to be the best predictive factors, reducing the AICc score to 139.81 and 141.40 respectively. Ceruloplasmin was associated with the active-to-inactive transition (hazard ratio 0.60 (95% confidence interval 0.39, 0.93)), and alpha-1-acid-glycoprotein with the inactive-to-active transition (hazard ratio 1.49 (95% confidence interval 1.10, 2.02)). Inputting individual alpha-1-acid-glycoprotein/ceruloplasmin values provides 3, 6 and 12 months probabilities of state transition.
Alpha-1-acid-glycoprotein was predictive of active lupus nephritis flare, whereas ceruloplasmin was predictive of remission. The Markov state-space model warrants testing in a prospective clinical trial of lupus nephritis biomarker led monitoring.
•Urinary biomarkers outperform traditional biomarkers for active LN identification.•‘Urine biomarker panels’ have further improved LN identification.•Markov Multi-State modelling has shown uAGP/CP to predict LN flare/remission.
Uveal melanoma (UM) is fatal in ~50% of patients as a result of disseminated disease. This study aims to externally validate the Liverpool Uveal Melanoma Prognosticator Online V3 (LUMPO3) to ...determine its reliability in predicting survival after treatment for choroidal melanoma when utilizing external data from other ocular oncology centers. Anonymized data of 1836 UM patients from seven international ocular oncology centers were analyzed with LUMPO3 to predict the 10-year survival for each patient in each external dataset. The analysts were masked to the patient outcomes. Model predictions were sent to an independent statistician to evaluate LUMPO3's performance using discrimination and calibration methods. LUMPO3's ability to discriminate between UM patients who died of metastatic UM and those who were still alive was fair-to-good, with C-statistics ranging from 0.64 to 0.85 at year 1. The pooled estimate for all external centers was 0.72 (95% confidence interval: 0.68 to 0.75). Agreement between observed and predicted survival probabilities was generally good given differences in case mix and survival rates between different centers. Despite the differences between the international cohorts of patients with primary UM, LUMPO3 is a valuable tool for predicting all-cause mortality in this disease when using data from external centers.
Pomegranate (
Punica granatum) is an important source of polyphenols with assessed antioxidant properties. The aims of this study were: (i) the characterization of the monomeric phenolic variability ...on each isolated fruit component (endocarp, mesocarp, aril); (ii) the study on the effect of pomegranate fruit components on human thrombin amidolytic activity. Collectively, our data show that pomegranate components contain bioactive metabolites (mainly ellagic acid) and suggest a potential role for the pomegranate extract in the regulation of a number of physio-pathological processes involving thrombin (or thrombin-like proteinase).
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