Mikkelsenpetersen0296

By pushing the LC mold vertically downward, while measuring the change in position of the bending bar with respect to its start position, the adhesion force between the IOLs and LCs was measured. An in vitro system that can measure the adhesion force reproducibly between an IOL and LC with a resolution of ~1 μN was established in this study. During system optimization, the 10% high molecular weight gelatin produced the best LC with the highest IOL LC adhesion force with all test lenses that were fabricated from acrylic foldable, polymethylmethacrylate (PMMA) and silicone materials. Test IOLs exerted different adhesion force with the 3D simulated LCs in the following sequence acrylic foldable IOL > silicone IOL > PMMA IOL. These results are in good agreement with the clinical observations associated with PCO performance of IOLs made of the same materials. This novel in vitro system can provide valuable insight on the IOL LC interplay and its relationship to clinical PCO outcomes.Sacubitril/valsartan (Entresto™; LCZ696) is the first angiotensin receptor-neprilysin inhibitor (ARNI) drug approved by the US and EU for heart failure (HF) and especially recommended for hypertensive HF (HHF). Sacubitril inhibits the enzyme neprilysin (NEP) which produces both beneficial and adverse effects in the human body. While LCZ696 causes beneficial cardiovascular effects, it may induce memory and cognitive dysfunction, or even exacerbate Alzheimer's disease (AD). This article reviewed data reported by experimental and clinical studies that examined NEP inhibitors and their dementia-related side effects. Based on the literature, LCZ696 increases the risk of memory and cognitive dysfunctions, and clinical trials failed to show compelling evidence for LCZ696 safety for the brain. Together, it was concluded that more experimental and clinical studies with particular focus on LCZ696 side effects on β-amyloid (Aβ) degradation are needed to assess LCZ696 safety for the cognitive function, especially in case of long-term administration.Acute promyelocytic leukemia (APL) is associated with PML-RARα oncogene, which is treated using all-trans retinoic acid (ATRA)-based chemotherapy. However, chemoresistance is observed in 20-30% of treated patients and represents a clinical challenge, raising the importance of the development of new therapeutic options. In the present study, the effects of three synthetic cyclopenta[b]indoles on the leukemia phenotype were investigated using NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Among the tested synthetic cyclopenta[b]indoles, compound 2, which contains a heterocyclic nucleus, was the most active, presenting time-dependent cytotoxic activity in the μM range in APL cells, without cytotoxicity for normal leukocytes, and was selected for further characterization. Compound 2 significantly decreased clonogenicity, increased apoptosis, and caused cell cycle arrest at S and G2/M phases in a drug concentration-dependent manner. Morphological analyses indicated aberrant mitosis and diffuse tubulin staining upon compound 2 exposure, which corroborates cell cycle findings. In the molecular scenario, compound 2 reduced STMN1 expression and activity, and induced PARP1 cleavage and H2AX and CHK2 phosphorylation, and modulated CDKN1A, PMAIP1, GADD45A, and XRCC3 expressions, indicating reduction of cell proliferation, apoptosis, and DNA damage. Moreover, in the in vivo tubulin polymerization assay, NB4 and NB4-R2 cells showed a reduction in the levels of polymerized tubulin upon compound 2 exposure, which indicates tubulin as a target of the drug. Molecular docking supports this hypothesis. Taken together, these data indicated that compound 2 exhibits antileukemic effects through disrupting the microtubule dynamics, identifying a possible novel potential antineoplastic agent for the treatment of ATRA-resistant APL.Phosphodiesterase subtype 4 (PDE4) hydrolyzes cyclic AMP (cAMP), a secondary messenger that mediates intracellular signaling, and plays key roles in inflammatory and profibrotic responses. Clinical benefits of pentoxifylline, a non-selective PDE inhibitor, have been reported in patients with kidney disease. Here, we identified compound A as a potent and selective PDE4 inhibitor and evaluated its potential as a novel therapeutic agent for diabetic nephropathy (DN). To determine its in vivo efficacy on DN, uninephrectomized (UNx-) db/db mice and KKAy mice were used as DN mice models. Eight-week repeated dosing with compound A (1-10 mg/kg, QD, p.o.) showed dose-dependent and significant suppressive effects on glycosylated hemoglobin (GHb) and urinary albumin/creatinine ratio (UACR) in UNx-db/db mice. These effects are more potent than irbesartan, a clinically approved angiotensin II receptor blocker of DN. Moreover, compound A suppressed pro-fibrotic and pro-inflammatory marker mRNAs and increased anti-reactive oxygen species marker mRNAs in the kidneys of UNx-db/db mice. The similar effect of compound A on UACR was also demonstrated by 8-week repeated dose in KKAy mice, another model for DN with intact leptin axis. Taken together, these data suggest that the PDE4-selective inhibitor compound A has potential as a new therapeutic agent for DN with multiple mechanisms of action including anti-diabetic, anti-fibrotic, and anti-reactive oxygen species effects.Coronavirus disease (COVID-19) is currently a serious global issue. Epidemiological studies have identified air pollutants, including particulate matter (PM), as a risk factor for COVID-19 infection and severity of illness, in addition to numerous factors such as pre-existing conditions, aging and smoking. However, the mechanisms by which air pollution is involved in the manifestation and/or progression of COVID-19 is still unknown. In this study, we used a mouse model exposed to crude PM, collected by the cyclone method, to evaluate the pulmonary expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine type 2 (TMPRSS2), the two molecules required for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells. Multiplex immunohistochemical analysis revealed that exposure to PM increased the expression of these two molecules at the same site. Rigosertib Furthermore, image cytometry analysis revealed increased expression of these proteins, particularly, in the alveolar type 2 cells and macrophages, which are potential targets for SARS-CoV-2.