Background
Atopic dermatitis (AD) and psoriasis represent two of the most common inflammatory skin diseases in developed countries. A hallmark of both diseases is T‐cell infiltration into the skin. ...However, it is still not clarified to what extent these infiltrating T cells are antigen‐specific skin‐homing T cells or unspecific heterogeneous bystander cells.
Methods
To elucidate this, T cells from lesional skin and from blood of 9 AD and 10 psoriasis patients were compared by receptor (TCR) sequencing. Therefore, peripheral blood mononuclear cells (PBMC) were cell‐sorted according to expression of the cutaneous leukocyte antigen (CLA) into skin‐homing (CLA+) and non‐skin‐homing (CLA−) subfractions. Aeroallergen‐specific T‐cell lines were grown from AD patients’ PBMC in parallel.
Results
Intra‐individual comparison of TCRB CDR3 regions revealed that clonally expanded T cells in skin lesions of both AD and psoriasis patients corresponded to skin‐homing circulating T cells. However, in psoriasis patients, these T‐cell clones were also detectable to a larger extent among CLA− circulating T cells. Up to 28% of infiltrating cells in AD skin were identified as allergen‐specific by overlapping TCR sequences.
Conclusions
Our data show that in line with the systemic nature of psoriasis, T‐cell clones that infiltrate psoriatic skin lesions do not exclusively possess skin‐homing ability and are therefore most probably specific to antigens that are not exclusively expressed or located in the skin. T cells driving AD skin inflammation appear to home nearly exclusively to the skin and are, to a certain extent, specific to aeroallergens.
T cell repertoires of lesional skin of atopic dermatitis (AD) and psoriasis are mirrored predominantly by circulating CLA+ T cells. Highly clonally propagated T cells in AD lesional skin are largely derived from circulating CLA+ T cells, in contrast to psoriasis. Aeroallergen‐specific T cells are part of the AD skin infiltrate.Abbreviations: AD, atopic dermatitis; CLA, cutaneous leukocyte antigen; TCR, T cell receptor
Hybridization of reported weakly active antiproliferative hit 5-amino-4-pyrimidinol derivative with 2-anilino-4-phenoxypyrimidines suggests a series of 2,5-diamino-4-pyrimidinol derivatives as ...potential antiproliferative agents. Few compounds belonging to the proposed series were reported as CSF1R/DAPK1 inhibitors as anti-tauopathies. However, the correlation between CSF1R/DAPK1 signalling pathways and cancer progression provides motives to reprofile them against cancer therapy. The compounds were synthesised, characterized, and evaluated against M-NFS-60 cells and a kinase panel which bolstered predictions of their antiproliferative activity and suggested the involvement of diverse molecular targets. Compound 6e, the most potent in the series, showed prominent broad-spectrum antiproliferative activity inhibiting the growth of hematological, NSCLC, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers by 84.1, 52.79, 72.15, 66.34, 66.48, 51.55, 55.95, 61.85, and 60.87%, respectively. Additionally, it elicited an IC
50
value of 1.97 µM against M-NFS-60 cells and good GIT absorption with P
e
value of 19.0 ± 1.1 × 10
−6
cm/s (PAMPA-GIT). Molecular docking study for 6e with CSF1R and DAPK1 was done to help to understand the binding mode with both kinases. Collectively, compound 6e could be a potential lead compound for further development of anticancer therapies.
Background
Atopic dermatitis (AD) is one of the most common inflammatory skin diseases worldwide and Staphylococcus aureus colonization and secondary infections occur in the majority of AD patients. ...Allergic sensitizations against microbial antigens have been discussed as possible trigger factors of AD. Recently, we reported IgE sensitization against fibronectin‐binding protein 1 (FBP1), an essential virulence component in S. aureus, in a subgroup of patients suffering from AD. To expand these findings by investigating delayed‐type immune reactions, the objective of this study was to detect and phenotypically characterize FBP1‐specific T cells as possible trigger factors in AD.
Methods
Immunodominant T‐cell epitopes were mapped by proliferation testing of patient‐derived FBP1‐specific T‐cell lines after stimulation with single 15mer peptides, which were derived from different functional domains of the FBP1 sequence. Major histocompatibility complex class II tetramers carrying immunodominant epitopes successfully stained T helper cells in 8 out of 8 HLA‐matched, IgE‐sensitized AD patients.
Results
Cytokine profiling of multimer‐sorted cells revealed that predominantly the type 2 cytokines IL‐13 and IL‐4 were secreted by these cells. In contrast, IL‐17, the marker cytokine for response to extracellular pathogens, was scarcely detectable.
Conclusions
We demonstrate that FBP1 contains immunodominant peptides that induce a specific pro‐inflammatory T helper cell response with increased Th2 levels that can drive an allergic inflammation in sensitized AD patients.
By means of MHC multimer staining, we describe quantity and quality of FBP1‐specific T cells in patients suffering from atopic dermatitis. We demonstrate that FBP1‐specific T cells drive an allergic type 2 response in atopic dermatitis patients. Our study highlights the role of FBP1 as a microbial allergen and its potential to aggravate atopic dermatitis.
Abbreviations: FACS, fluorescence‐activated cell sorting; FBP1, fibronectin‐binding protein 1; HLA‐DRB1, major histocompatibility complex, class II, DR beta 1; MHC, major histocompatibility complex, Th, T helper cell; S. aureus, Staphylococcus aureus.
This study aimed to explain the influence of zein nanosphere (ZN NS) formulation on the pharmacotherapeutic profile of PTS in MCF7 cells.
Liquid-liquid phase separation was used to formulate PTS-ZN ...NSs. The formulations developed were evaluated for particle-size analysis, encapsulation efficiency, and in vitro diffusion. Also, assays of cytotoxicity, uptake, cell-cycle progression, annexin V, apoptotic gene mRNA expression and biochemical assays were carried out.
The PTS-ZN NS formulation selected showed 104.5±6.2 nm, 33.4±1.8 mV, 95.1%±3.6%, and 89.1%±2.65% average particle size, zeta-potential, encapsulation efficiency and in vitro diffusion, respectively. With MCF7 cells, IC
was reduced approximately 15-fold, with increased cellular uptake, accumulation in the G
/M phase, increased percentage of cells in the pre-G
phase, amelioration of early and late apoptosis, raised mRNA expression of CASP3 and CASP7, lower expression of cyclin-CDK1, and enhanced oxidant potential through decreased glutathione reductase (GR) activity, and enhanced reactive oxygen-species generation and lipid-peroxidation products.
PTS-ZN NSs indicated enhanced antiproliferative, proapoptotic, and oxidant potential toward MCF7 cells compared to free PTS. Ameliorated results of nanosized carriers, cellular uptake, and sustained diffusion may contribute to these outcomes.
This study explored the ability of formic acid (FA) to replace antibiotics in broiler chicken diets. It examined how FA affected the chickens' growth, carcass characteristics, blood chemistry, and ...gut bacteria. The experiment randomly assigned 300 one-day-old (Ross 308) broiler chicks to 5 groups, each divided into 6 replicates with 10 unsexed chicks. The following were the treatments: 1st group, negative control (NC): only received a basal diet; 2nd group, positive control (PC): received a basal diet supplemented with 0.5 grams of Colistin antibiotic per kilogram of diet; 3rd, 4th, and 5th groups (FA2, FA4, and FA6) these groups received a basal diet along with formic acid added at increasing levels: 2, 4, and 6 Cm3 per kilogram of diet, respectively. Results found no significant differences in live body weight (LBW) or body weight gain (BWG) between treatment groups, except for LBW at one week and BWG at 0 to 1 and 4 to 5 wk of age. No significant variations were found in feed intake (FI) and feed conversion ratio (FCR) among the treatment groups, excluding FI and FCR at 1 to 2 wk of age. The treatments significantly impacted carcass traits, dressing percentage, breast meat, thigh meat, spleen, giblets, blood levels of urea, creatinine, total protein, globulin, and albumin, as well as the activity of enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in chicks fed different diets compared to control groups. The addition of FA to the diet significantly impacted antioxidant levels. Also, the FA2 group had the highest total bacterial count (TBC). However, the FA6 group was the opposite; it had the lowest levels of harmful bacteria, such as E. coli and Coliform. Supplementing broiler diets with formic acid improves blood parameters, antioxidant activity, and gut bacteria counts, with 4.0 cm³ formic acid/kg diet supplementation promoting optimal broiler health and product quality.
The vascular endothelial growth factor receptor 2 (VEGFR-2) is largely recognized as a potent therapeutic molecular target for the development of angiogenesis-related tumor treatment. Tumor growth, ...metastasis and multidrug resistance highly depends on the angiogenesis and drug discovery of the potential small molecules targeting VEGFR-2, with the potential anti-angiogenic activity being of high interest to anti-cancer research. Multiple small molecule inhibitors of the VEGFR-2 are approved for the treatment of different type of cancers, with one of the most recent, tivozanib, being approved by the FDA for the treatment of relapsed or refractory advanced renal cell carcinoma (RCC). However, the endogenous and acquired resistance of the protein, toxicity of compounds and wide range of side effects still remain critical issues, which lead to the short-term clinical effects and failure of antiangiogenic drugs. We applied a combination of computational methods and approaches for drug design and discovery with the goal of finding novel, potential and small molecule inhibitors of VEGFR2, as alternatives to the known inhibitors’ chemical scaffolds and components. From studying several of these compounds, the derivatives of pyrido1,2-apyrimidin-4-one and isoindoline-1,3-dione in particular were identified.
Previously, we discovered that 1-(3,5-dimethoxyphenyl)-3-(4-(3-methoxyphenoxy)-2-((4-morpholinophenyl)amino)pyrimidin-5-yl)urea (AKF-D52), a synthetic phenoxypyrimidine urea derivative, acts as a ...growth inhibitor of various cancer cell types. In this study, we elucidated the antiproliferative properties of AFK-D52 and underlying mechanisms in non-small cell lung cancer (NSCLC) cells and an A549 xenograft animal model. AKF-D52 was found to induce both caspase-dependent and -independent apoptotic cell death. Furthermore, the mitochondrial component of the AKF-D52-induced apoptosis mechanism involves a reduction in mitochondrial membrane potential and regulation in B cell lymphoma-2 family protein expression. Moreover, AKF-D52 activates the extrinsic pathway through up-regulated expression of death receptor 3 and Fas and then the formation of a death-inducing signaling complex. AKF-D52 also induced autophagy by increasing acidic vesicular organelle formation and microtubule-associated protein 1A/1B-light chain 3-II levels and reducing p62 levels. Notably, pretreatment with autophagy inhibitors enhanced AKF-D52-induced cell death, indicating that the induced autophagy is cytoprotective. AKF-D52 treatment also triggered reactive oxygen species (ROS) production in NSCLC cells, whereas the antioxidant α-tocopherol abolished AKF-D52-induced cell death. In a xenograft lung cancer mouse model, AKF-D52 administration attenuated tumor growth by inducing apoptosis and autophagy in tumor tissues. Collectively, our data indicate that AKF-D52-induced ROS production plays a role in mediating apoptosis and cytoprotective autophagy in NSCLC.
Aim
Comparing placental volume (PV) and vascular indices in pregestational diabetic and nondiabetic pregnant women at 11 and 13 weeks gestation.
Methods
A case–control study conducted at Ain Shams ...University Maternity Hospital in collaboration with Feto‐maternal Unit for Ultrasound Assessment, Ain Shams University Maternity Hospital, Egypt. Ninety‐two pregnant women divided into two groups: Group A included 46 women with pregestational diabetes mellitus and group B included 46 nondiabetic pregnant women as control. All participants had PV, vascularization index (VI), flow index (FI) and vascularization flow index (VFI) calculated using three‐dimensional (3D) ultrasonography and 3D power Doppler at 11 and 13 weeks of pregnancy.
Results
At 11 weeks, the mean VI, FI and VFI in diabetic group (17.70 ± 12.62, 40.72 ± 11.03 and 7.77 ± 6.37, respectively) were insignificantly higher than in nondiabetic group (12.14 ± 12.62, 34.59 ± 9.66 and 6.52 ± 14.20, respectively) while mean PV in diabetic group (26.90 ± 14.74) was insignificantly lower than in nondiabetic group (27.53 ± 17.46). Also at 13 weeks, the results were not different as the mean VI, FI and VFI in diabetic group (16.51 ± 9.81, 42.52 ± 7.47 and 8.12 ± 7.55, respectively) were insignificantly higher than in nondiabetic group (16.37 ± 14.17, 40.29 ± 17.52 and 7.08 ± 4.35, respectively), and mean PV in diabetic group (52.04 ± 17.95) was insignificantly lower than in nondiabetic group (54.46 ± 17.85). There was strong positive correlation between HbA1C level and VFI measured at 13 weeks gestation.
Conclusions
Placental indices in early pregnancy do not seem to be useful markers to anticipate placental pathology in pregestational diabetes, however there might be a role for HbA1C level measurement to anticipate such complications.
A novel nanocomposite films of native and modified starch/polyvinyl alcohol (PVA)/sorbitol/cardanol oil with in situ synthesis of silver nanoparticles were prepared. The surface morphology of ...modified starch was found to be more homogenous than native starch with a good distribution of silver nanoparticles. This result indicated to boost in plasticization after starch modification as observed by scanning electron microscope. Transmission electron microscope confirms the formation of silver nanoparticles with diameters ranging from 50 to 80 nm with homogenously distributed. Moreover, modified starch showed lower water vapor permeability compared to unmodified starch at 39%. The addition of cardanol oil at 0.2% showed significant increases in the elongation of modified starch films by 280.9% compared to the unmodified starch films. However, the film elongation was increased by 421.7% with 2 mmol silver nanoparticles and 0.2% cardanol oil, while it decreased by 14.2 in the modified starch film. Also, cardanol oil reduces transmittance in the UV region for native and modified starch films by 56.2% and 56.5%, respectively. The nanocomposite films demonstrated good antimicrobial activity against gram‐positive and gram‐negative bacteria and yeast. These films can be a potential candidate for application such as food packaging materials.
Nondegradable plastic packaging is harmful to the environment and to human health, many scientists have been advocating for drastic reductions in plastic packaging production and an increase in the production of biodegradable films for more sustainable food packaging. In this work, we prepare antimicrobial biofilms from biodegradable materials with high mechanical and thermal properties to be used as food packaging.
Our team has previously reported a series of quinazoline-based lapatinib hybrids as potent kinase-targeting anticancer agents. Among them, AF8c showed a relatively safe profile in colorectal cancer ...(CRC) cells. In this study, we delineate a novel anticancer activity of AF8c in CRC cells. AF8c mediated p53-dependent apoptosis of CRC cells via the generation of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS), as well as activation of nuclear respiratory factor 2 alpha subunit (Nrf2) and death receptor 5 (DR5), among others. The silencing of DR5 attenuated the expression levels of Nrf2 and partially inhibited AF8c-induced apoptosis. Additionally, upregulation of Nrf2 by AF8c evoked apoptosis through a decrease in antioxidant levels. Treatment of a CRC mice model with AF8c also resulted in the upregulation of DR5, Nrf2, and CHOP proteins, subsequently leading to a significant decrease in tumor burden. In comparison with lapatinib, AF8c showed higher cellular antiproliferative activity at the tested concentrations in CRC cells and synergized TRAIL effects in CRC cells. Overall, our results suggest that AF8c-induced apoptosis may be associated with DR5/Nrf2 activation through ER stress and ROS generation in CRC cells. These findings indicate that AF8c represents a promising polypharmacological molecule for the treatment of human CRC.
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