How α-Helical Motifs Form Functionally Diverse Lipid-Binding Compartments.

Lipids are produced site-specifically in cells and then distributed nonrandomly among membranes via vesicular and nonvesicular trafficking mechanisms. The latter involves soluble amphitropic proteins extracting specific lipids from source membranes to function as molecular solubilizers that envelope their insoluble cargo before transporting it to destination sites. Lipid-binding and lipid transfer structural motifs range from multi-ß-strand barrels, to ß-sheet cups and baskets covered by α-helical lids, to multi-α-helical bundles and layers. Here, we focus on how α-helical proteins use amphipathic helical layering and bundling to form modular lipid-binding compartments and discuss the functional consequences. Preformed compartments generally rely on intramolecular disulfide bridging to maintain conformation (e.g., albumins, nonspecific lipid transfer proteins, saposins, nematode polyprotein allergens/antigens). Insights into nonpreformed hydrophobic compartments that expand and adapt to accommodate a lipid occupant are few and provided mostly by the three-layer, α-helical ligand-binding domain of nuclear receptors. The simple but elegant and nearly ubiquitous two-layer, α-helical glycolipid transfer protein (GLTP)-fold now further advances understanding.

IL-1ß Induces LDL Transcytosis by a Novel Pathway Involving LDLR and Rab27a.

BACKGROUND: In early atherosclerosis, circulating LDLs (low-density lipoproteins) traverse individual endothelial cells by an active process termed transcytosis. The CANTOS trial treated advanced atherosclerosis using a blocking antibody for IL-1ß (interleukin-1ß); this significantly reduced cardiovascular events. However, whether IL-1ß regulates early disease, particularly LDL transcytosis, remains unknown. METHODS: We used total internal reflection fluorescence microscopy to quantify transcytosis by human coronary artery endothelial cells exposed to IL-1ß. To investigate transcytosis in vivo, we injected wild-type and knockout mice with IL-1ß and LDL to visualize acute LDL deposition in the aortic arch. RESULTS: Exposure to picomolar concentrations of IL-1ß induced transcytosis of LDL but not of albumin by human coronary artery endothelial cells. Surprisingly, expression of the 2 known receptors for LDL transcytosis, ALK-1 (activin receptor-like kinase-1) and SR-BI (scavenger receptor BI), was unchanged or decreased. Instead, IL-1ß increased the expression of the LDLR (LDL receptor); this was unexpected because LDLR is not required for LDL transcytosis. Overexpression of LDLR had no effect on basal LDL transcytosis. However, knockdown of LDLR abrogated the effect of IL-1ß on transcytosis rates while the depletion of Cav-1 (caveolin-1) did not. Since LDLR was necessary but overexpression had no effect, we reasoned that another player must be involved. Using public RNAseq data to curate a list of Rab GTPases affected by IL-1ß, we identified Rab27a. Overexpression of Rab27a alone had no effect on basal transcytosis, but its knockdown prevented induction by IL-1ß. This was phenocopied by depletion of the Rab27a effector JFC1. In vivo, IL-1ß increased LDL transcytosis in the aortic arch of wild-type but not Ldlr-/- or Rab27a-deficient mice. The JFC1 inhibitor nexinhib20 also blocked IL-1ß-induced LDL accumulation in the aorta. CONCLUSIONS: IL-1ß induces LDL transcytosis by a distinct pathway requiring LDLR and Rab27a; this route differs from basal transcytosis. We speculate that induction of transcytosis by IL-1ß may contribute to the acceleration of early disease.

Albumin Levels and Risk of Early Cardiovascular Complications After Ischemic Stroke: A Propensity-Matched Analysis of a Global Federated Health Network.

BACKGROUND: No studies have investigated the association between albumin levels and the risk of early cardiovascular complications in patients with ischemic stroke. METHODS: Retrospective analysis with a federated research network (TriNetX) based on electronic medical records (International Classification of Diseases-Tenth Revision-Clinical Modification and logical observation identifiers names and codes) mainly reported between 2000 and 2023, from 80 health care organizations in the United States. Based on albumin levels measured at admission to the hospital, patients with ischemic stroke were categorized into 2 groups: (1) reduced (≤3.4 g/dL) and (2) normal (≥3.5 g/dL) albumin levels. The primary outcome was a composite of all-cause death, heart failure, atrial fibrillation, ventricular arrhythmias, myocardial infarction, and Takotsubo cardiomyopathy 30 days from the stroke. Secondary outcomes were the risk for each component of the primary outcome. Cox regression analyses were used to calculate hazard ratios (HRs) and 95% CIs following propensity score matching. RESULTS: Overall, 320 111 patients with stroke had normal albumin levels (70.9±14.7 years; 48.9% females) and 183 729 (57.4%) had reduced albumin levels (72.9±14.3 years; 50.3% females). After propensity score matching, the primary outcomes occurred in 36.0% of patients with reduced and 26.1% with normal albumin levels (HR, 1.48 [95% CI, 1.46-1.50]). The higher risk in patients with reduced albumin levels was consistent also for all-cause death (HR, 2.77 [95% CI, 2.70-2.84]), heart failure (HR, 1.31 [95% CI, 1.29-1.34]), atrial fibrillation (HR, 1.11 [95% CI, 1.09-1.13]), ventricular arrhythmias (HR, 1.38 [95% CI, 1.30-1.46]), myocardial infarction (HR, 1.60 [95% CI, 1.54-1.65]), and Takotsubo cardiomyopathy (HR, 1.51 [95% CI, 1.26-1.82]). The association between albumin levels and the risk of cardiovascular events was independent of advanced age, sex, multimorbidity, and other causes of hypoalbuminemia. A progressively increased risk of adverse events was found in patients with mild and severe reduced compared to normal albumin levels. CONCLUSIONS: Albumin levels are associated with the risk of early cardiovascular events and death in patients with ischemic stroke. The potential pathophysiological or therapeutic roles of albumin in patients with stroke warrant further investigation.

Human amniotic epithelial cells (HAECS); a potential cell type for the hepatic disorders.

OBJECTIVE: To isolate a homogenous population of human amniotic epithelial cells (hAECs) from the amniotic membrane of the human placenta and differentiate them into hepatic-like cells with the help of small molecules. METHODS: hAECs were isolated by using the enzymatic digestion method and characterized for the presence of specific stem cell markers. In-vitro, hepatic differentiation of hAECs was carried out by using a combination of small molecules. Differentiated cells were observed under a live cell imaging microscope for morphological changes followed by gene and protein expression analysis by qPCR and immunocytochemistry respectively. RESULTS: The isolated hAECs attained characteristic cuboid epithelial shape and express stem cells marker. The hepatic differentiation method was optimized based on soluble chemical compounds supplied in the culture medium. The differentiated hAECs phenotypically acquire hepatic-like cell features and expressed hepatic markers as well as hepatic protein albumin at immature levels. CONCLUSIONS: The isolated population of hAECs is highly proliferative. Moreover, hepatic markers expression in the isolated hAECs makes them an exclusive source for the treatment of chronic liver diseases.

Angiogenesis outcomes of metformin utilization in diabetes mellitus: a systematic review and meta-analysis.

OBJECTIVE: To review relevant literature regarding the role of metformin in angiogenesis among diabetic patients. METHODS: The systematic review and meta-analysis conducted from May to September 2022, and comprised search on Medline, ScienceDirect, ProQuest, Web of Science, EBSCOhost and Cochrane Library databases. The studies included were published in the English language and were human studies having angiogenesis endothelial markers as the outcomes of interest among patients of type 2 diabetes mellitus undergoing metformin therapy. Endothelial markers, including vascular endothelial growth factor, von-Willebrand-factor, plasminogen activator inhibitor-1, soluble vascular adhesion molecule- 1, intercellular adhesion molecule-1, soluble endothelialselectin, tissue plasminogen activator, urinary albumin excretion, platelet endothelial cell adhesion molecule-1 and thrombin-activatable fibrinolysis inhibitor, were assessed as angiogenesis outcomes. Data was statistically analysed using Review Manager 5.4. RESULTS: Of the 413 studies identified, 8(1.9%) were included; 5(62.5%) randomised control trials, 2(25.0%) cross-sectional, and 1(12.5%) cohort studies, with overall 1199 patients. Among the outcomes, von-Willebrandfactor (p=0.01), soluble vascular adhesion molecule-1 (p<0.00001), intercellular adhesion molecule-1 (p=0.0003), soluble endothelial-selectin (p=0.007), and tissue plasminogen activator (p<0.00001) showed significantly lower levels after metformin treatment using the random effect methods. CONCLUSIONS: Metformin was found to have an additional effect of endothelial function improvement.

Bioactive compounds: Application of albumin nanocarriers as delivery systems.

Enriched products with bioactive compounds (BCs) show the capacity to produce a wide range of possible health effects. Most BCs are essentially hydrophobic and sensitive to environmental factors; so, encapsulation becomes a strategy to solve these problems. Many globular proteins have the intrinsic ability to bind, protect, encapsulate, and introduce BCs into nutraceutical or pharmaceutical matrices. Among them, albumins as human serum albumin (HSA), bovine serum albumin (BSA), ovalbumin (OVA) and α-lactalbumin (ALA) are widely abundant, available, and applied in many industrial sectors, becoming promissory materials to encapsulate BCs. Therefore, this review focuses on researches about the main groups of natural origin BCs (namely phenolic compounds, lipids, vitamins, and carotenoids), the different types of nanostructures based on albumins to encapsulate them and the main fields of application for BCs-loaded albumin systems. In this context, phenolic compounds (catechins, quercetin, and chrysin) are the most extensively BCs studied and encapsulated in albumin-based nanocarriers. Other extensively studied subgroups are stilbenes and curcuminoids. Regarding lipids and vitamins; terpenes, carotenoids (ß-carotene), and xanthophylls (astaxanthin) are the most considered. The main application areas of BCs are related to their antitumor, anti-inflammatory, and antioxidant properties. Finally, BSA is the most used albumin to produced BCs-loaded nanocarriers.

EAACI Molecular Allergology User's Guide 2.0.

Since the discovery of immunoglobulin E (IgE) as a mediator of allergic diseases in 1967, our knowledge about the immunological mechanisms of IgE-mediated allergies has remarkably increased. In addition to understanding the immune response and clinical symptoms, allergy diagnosis and management depend strongly on the precise identification of the elicitors of the IgE-mediated allergic reaction. In the past four decades, innovations in bioscience and technology have facilitated the identification and production of well-defined, highly pure molecules for component-resolved diagnosis (CRD), allowing a personalized diagnosis and management of the allergic disease for individual patients. The first edition of the "EAACI Molecular Allergology User's Guide" (MAUG) in 2016 rapidly became a key reference for clinicians, scientists, and interested readers with a background in allergology, immunology, biology, and medicine. Nevertheless, the field of molecular allergology is moving fast, and after 6 years, a new EAACI Taskforce was established to provide an updated document. The Molecular Allergology User's Guide 2.0 summarizes state-of-the-art information on allergen molecules, their clinical relevance, and their application in diagnostic algorithms for clinical practice. It is designed for both, clinicians and scientists, guiding health care professionals through the overwhelming list of different allergen molecules available for testing. Further, it provides diagnostic algorithms on the clinical relevance of allergenic molecules and gives an overview of their biology, the basic mechanisms of test formats, and the application of tests to measure allergen exposure.

Baseline Severity and Inflammation Would Influence the Effect of Simvastatin on Clinical Outcomes in Cirrhosis Patients.

BACKGROUND: Simvastatin administration to decompensated cirrhosis patients improved Child-Pugh (CP) at the end of a safety trial (EST). AIM: To evaluate whether simvastatin reduces cirrhosis severity through a secondary analysis of the safety trial. METHODS: Thirty patients CP class (CPc) CPc A (n = 6), CPc B (n = 22), and CPc C (n = 2) received simvastatin for one year. PRIMARY ENDPOINT: cirrhosis severity. Secondary endpoints: health-related quality of life (HRQoL) and hospitalizations for cirrhosis complications. RESULTS: Cirrhosis severity decreased baseline versus EST only across CP score (7.3 ± 1.3 versus 6.7 ± 1.7, P = 0.041), and CPc: 12 patients lessened from CPc B to CPc A, and three patients increased from CPc A to CPc B (P = 0.029). Due to cirrhosis severity changes and differences in clinical outcomes, 15 patients completed the trial as CPc AEST and another 15 as CPc B/C. At baseline, CPc AEST showed greater albumin and high-density lipoprotein cholesterol concentrations than CPc B/C (P = 0.036 and P = 0.028, respectively). Comparing EST versus baseline, only in CPc AEST, there was a reduction in white-cell blood (P = 0.012), neutrophils (P = 0.029), monocytes (P = 0.035), and C-reactive protein (P = 0.046); an increase in albumin (P = 0.011); and a recovery in HRQoL (P < 0.030). Finally, admissions for cirrhosis complications decreased in CPc AEST versus CPc B/C (P = 0.017). CONCLUSIONS: Simvastatin would reduce cirrhosis severity only in CPc B at baseline in a suitable protein and lipid milieu, possibly due to its anti-inflammatory effects. Furthermore, only in CPc AEST would improve HRQoL and reduce admissions by cirrhosis complications. However, as these outcomes were not primary endpoints, they require validation.

Albumin therapy for hepatic encephalopathy: current evidence and controversies.

Hepatic encephalopathy (HE) is a common complication that occurs in 16-21% of end-stage cirrhosis patients. Emerging evidence suggests that systemic inflammation and oxidative stress may play a role in the development of HE. Recent understanding on the anti-inflammatory properties of human albumin has led to growing interest of using human albumin for the treatment and prevention of HE among decompensated patients. In this review, we aim to discuss the current evidence and controversies of using human albumin for the treatment and prevention of HE in advanced cirrhosis patients.

Effect of an Albumin Infusion Treatment Protocol on Delayed Cerebral Ischemia and Relevant Outcomes in Patients with Subarachnoid Hemorrhage.

BACKGROUND: An institutional management protocol for patients with subarachnoid hemorrhage (SAH) based on initial cardiac assessment, permissiveness of negative fluid balances, and use of a continuous albumin infusion as the main fluid therapy for the first 5 days of the intensive care unit (ICU) stay was implemented at our hospital in 2014. It aimed at achieving and maintaining euvolemia and hemodynamic stability to prevent ischemic events and complications in the ICU by reducing periods of hypovolemia or hemodynamic instability. This study aimed at assessing the effect of the implemented management protocol on the incidence of delayed cerebral ischemia (DCI), mortality, and other relevant outcomes in patients with SAH during ICU stay. METHODS: We conducted a quasi-experimental study with historical controls based on electronic medical records of adults with SAH admitted to the ICU at a tertiary care university hospital in Cali, Colombia. The patients treated between 2011 and 2014 were the control group, and those treated between 2014 and 2018 were the intervention group. We collected baseline clinical characteristics, cointerventions, occurrence of DCI, vital status after 6 months, neurological status after 6 months, hydroelectrolytic imbalances, and other SAH complication. Multivariable and sensitivity analyses that controlled for confounding and considered the presence of competing risks were used to adequately estimate the effects of the management protocol. The study was approved by our institutional ethics review board before study start. RESULTS: One hundred eighty-nine patients were included for analysis. The management protocol was associated with a reduced incidence of DCI (hazard ratio 0.52 [95% confidence interval 0.33-0.83] from multivariable subdistribution hazards model) and hyponatremia (relative risk 0.55 [95% confidence interval 0.37-0.80]). The management protocol was not associated with higher hospital or long-term mortality, nor with a higher occurrence of other unfavorable outcomes (pulmonary edema, rebleeding, hydrocephalus, hypernatremia, pneumonia). The intervention group also had lower daily and cumulative administered fluids compared with historic controls (p < 0.0001). CONCLUSIONS: A management protocol based on hemodynamically oriented fluid therapy in combination with a continuous albumin infusion as the main fluid during the first 5 days of the ICU stay appears beneficial for patients with SAH because it was associated with reduced incidence of DCI and hyponatremia. Proposed mechanisms include improved hemodynamic stability that allows euvolemia and reduces the risk of ischemia, among others.

Iron(III) Complexes with Non-Steroidal Anti-Inflammatory Drugs: Structure, Antioxidant and Anticholinergic Activity, and Interaction with Biomolecules.

One the main research goals of bioinorganic chemists is the synthesis of novel coordination compounds possessing biological potency. Within this context, three novel iron(III) complexes with the non-steroidal anti-inflammatory drugs diflunisal and diclofenac in the presence or absence of the nitrogen donors 1,10-phenanthroline or pyridine were isolated and characterized by diverse techniques. The complexes were evaluated for their ability to scavenge in vitro free radicals such as hydroxyl, 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radicals, revealing their selective potency towards hydroxyl radicals. The in vitro inhibitory activity of the complexes towards the enzymes acetylcholinesterase and butyrylcholinesterase was evaluated, and their potential to achieve neuroprotection appeared promising. The interaction of the complexes with calf-thymus DNA was examined in vitro, revealing their ability to intercalate in-between DNA nucleobases. The affinity of the complexes for serum albumins was evaluated in vitro and revealed their tight and reversible binding.

pH-Sensitive Gold Nanorods for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Delivery and DNA-Binding Studies.

A facile experimental protocol for the synthesis of poly(ethylene glycol)-modified (PEGylated) gold nanorods (AuNRs@PEG) is presented as well as an effective drug loading procedure using the non-steroidal anti-inflammatory drug (NSAID) naproxen (NAP). The interaction of AuNRs@PEG and drug-loaded AuNRs (AuNRs@PEG@NAP) with calf-thymus DNA was studied at a diverse temperature revealing different interaction modes; AuNRs@PEG may interact via groove-binding and AuNRs@PEG@NAP may intercalate to DNA-bases. The cleavage activity of the gold nanoparticles for supercoiled circular pBR322 plasmid DNA was studied by gel electrophoresis while their affinity for human and bovine serum albumins was also evaluated. Drug-release studies revealed a pH-sensitive behavior with a release up to a maximum of 24% and 33% NAP within the first 180 min at pH = 4.2 and 6.8, respectively. The cytotoxicity of AuNRs@PEG and AuNRs@PEG@NAP was evaluated against MCF-7 and MDA-MB-231 breast cancer cell lines. The development of AuNRs as an efficient non-steroidal anti-inflammatory drugs (NSAIDs) delivery system for chemotherapy is still in its infancy. The present work can shed light and inspire other research groups to work in this direction.

Evaluating the effect of cow's milk fortified with albumin powder on malnutrition and anthropometric indices in primary-school children with mild-to-moderate underweight: A randomized double-blinded clinical trial.

Background: A proper diet plan is one of the necessary conditions for maintaining the children's health. The aim of this study was to evaluate the effect of consumption of pasteurized cow's milk fortified with albumin protein in primary-school children, in Yasuj, Iran. Materials and Methods: In this double-blind randomized clinical trial with 12 weeks of duration, 60 children aged 7-13 years, mild to moderate underweight (-1≥ weight-for-age z-score ≥-3), were randomly assigned to control and albumin groups. The albumin group and the control group received 200 cc of milk with 10 g of albumin powder and 200 cc of milk with 10 g of cornstarch powder, respectively. At the beginning and end of the study, food intake and anthropometric indices were measured. Results: After 12 weeks of intervention, none of the anthropometric indices (weight, weight-for-age z-score, body mass index (BMI), BMI-for-age z-score, and waist circumference) showed significant changes as compared to baseline in the control group, but weight-for-age z-score and BMI-for-age z-score showed significant increase as compared to baseline in the albumin group (before: -2.25 ± 0.40, after: -1.98 ± 0.35, P = 0.001 and before: -3.48 ± 0.86, after: -3.06 ± 0.71, P = 0.009, respectively). The comparison of the mean changes between the two groups showed significant difference regarding weight-for-age z-score (control group: -1.70 ± 0.31 in comparison with albumin group: -1.98 ± 0.35, P = 0.002), BMI (control group: 12.08 ± 1.96 in comparison with albumin group: 12.13 ± 1.49, P = 0.03), and BMI-for-age z-score (control group: -3.11 ± 0.91 in comparison with albumin group: -3.06 ± 0.71, P = 0.02). Conclusion: The consumption of albumin powder with milk can improve weight-for-age z-score and BMI-for-age z-score indices in children with mild-to-moderate underweight. Larger controlled interventional studies with longer duration are recommended.

Prognostic value of ambulation ability with albumin and C-reactive protein to predict 28-day mortality in elderly sepsis patients: a retrospective multicentre registry-based study.

BACKGROUND: Sepsis is a series of organ failures caused by dysregulated responses to infection. Risk factors for sepsis are multiple comorbidities, a poor nutrition status, and limited mobility. The primary purpose of the study was to determine whether ambulation ability with albumin and C-reactive protein are predictive of 28-day mortality of elderly patients with sepsis. METHODS: This was a retrospective observational study using a multicentre-based registry of elderly patients between November 2016 and February 2017. The inclusion criteria were a patient ≥65 years and a diagnosis of sepsis and exclusion criteria were a patient with covariates of ambulation ability such as central nervous system diseases, or malignancy. The area under the receiver operating characteristic curve of prediction models were calculated and compared. The survival rates according to the ambulation ability were estimated and compared by the log-rank test. RESULTS: 2291 patients ≥65 years visited with infectious diseases. 496 subjects with central nervous system diseases, 710 subjects with malignancy and 817 subjects with a Sequential Organ Failure Assessment score ≤ 1 were excluded. Ultimately, 278 subjects were included in the primary analysis. 133 (47.8%) subjects were male and the median age was 78 years. 228 (82%) subjects could ambulate independently before morbidity and 28 (10.1%) subjects expired in 28 days. In the inability to ambulate and C-reactive protein to albumin ratio model, the area under the curve predicting 28-day mortality was 0.761 with no significant difference from the Sequential Organ Failure Assessment score (0.859, p = 0.097) and the estimated survival rate on 28th day according to the ability to ambulate showed a significant difference (hazard ratio = 1.212, p < 0.001). CONCLUSION: The premorbid ambulation ability with albumin and C-reactive protein can be combined to predict 28-day mortality in elderly patients with sepsis.

The importance of the 2S albumins for allergenicity and cross-reactivity of peanuts, tree nuts, and sesame seeds.

Allergies to peanuts, tree nuts, and sesame seeds are among the most important food-related causes of anaphylaxis. Important clinical questions include: Why is there a variable occurrence of coallergy among these foods and Is this immunologically mediated? The clinical and immunologic data summarized here suggest an immunologic basis for these coallergies that is based on similarities among the 2S albumins. Data from component resolved diagnostics have highlighted the relationship between IgE binding to these allergens and the presence of IgE-mediated food allergy. Furthermore, in vitro and in vivo experiments provide strong evidence that the 2S albumins are the most important allergens in peanuts for inducing an allergic effector response. Although the 2S albumins are diverse, they have a common disulfide-linked core with similar physicochemical properties that make them prime candidates to explain much of the observed coallergy among peanuts, tree nuts, and sesame seeds. The well-established frequency of cashew and pistachio nut coallergy (64%-100%) highlights how the structural similarities among their 2S albumins may account for observed clinical cross-reactivity. A complete understanding of the physicochemical properties of the 2S albumins in peanuts, tree nuts, and sesame seeds will enhance our ability to diagnose, treat, and ultimately prevent these allergies.

Photonics of Trimethine Cyanine Dyes as Probes for Biomolecules.

Cyanine dyes are widely used as fluorescent probes in biophysics and medical biochemistry due to their unique photophysical and photochemical properties (their photonics). This review is focused on a subclass of the most widespread and studied cyanine dyes-trimethine cyanines, which can serve as potential probes for biomolecules. The works devoted to the study of the noncovalent interaction of trimethine cyanine dyes with biomolecules and changing the properties of these dyes upon the interaction are reviewed. In addition to the spectral-fluorescent properties, elementary photochemical properties of trimethine cyanines are considered, including: photoisomerization and back isomerization of the photoisomer, generation and decay of the triplet state, and its quenching by oxygen and other quenchers. The influence of DNA and other nucleic acids, proteins, and other biomolecules on these properties is covered. The interaction of a monomer dye molecule with a biomolecule usually leads to a fluorescence growth, damping of photoisomerization (if any), and an increase in intersystem crossing to the triplet state. Sometimes aggregation of dye molecules on biomolecules is observed. Quenching of the dye triplet state in a complex with biomolecules by molecular oxygen usually occurs with a rate constant much lower than the diffusion limit with allowance for the spin-statistical factor 1/9. The practical application of trimethine cyanines in biophysics and (medical) biochemistry is also considered. In conclusion, the prospects for further studies on the cyanine dye-biomolecule system and the development of new effective dye probes (including probes of a new type) for biomolecules are discussed.

Copper(II) Complexes of 5-Fluoro-Salicylaldehyde: Synthesis, Characterization, Antioxidant Properties, Interaction with DNA and Serum Albumins.

The synthesis, characterization and biological profile (antioxidant capacity, interaction with calf-thymus DNA and serum albumins) of five neutral copper(II) complexes of 5-fluoro-salicylaldehyde in the absence or presence of the N,N'-donor co-ligands 2,2'-bipyridylamine, 2,9-dimethyl-1,10-phenanthroline, 1,10-phenanthroline and 2,2'-bipyridine are presented herein. The compounds were characterized by physicochemical and spectroscopic techniques. The crystal structures of four complexes were determined by single-crystal X-ray crystallography. The ability of the complexes to scavenge 1,1-diphenyl-picrylhydrazyl and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radicals and to reduce H2O2 was investigated in order to evaluate their antioxidant activity. The interaction of the compounds with calf-thymus DNA possibly takes place via intercalation as suggested by UV-vis spectroscopy and DNA-viscosity titration studies and via competitive studies with ethidium bromide. The affinity of the complexes with bovine and human serum albumins was examined by fluorescence emission spectroscopy revealing the tight and reversible binding of the complexes with the albumins.

A DNA-Encoded Chemical Library Based on Peptide Macrocycles.

The synthesis and characterization of a novel DNA-encoded library of macrocyclic peptide derivatives are described; the macrocycles are based on three sets of proteinogenic and non-proteinogenic amino acid building blocks and featuring the use of copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction for ring closure. The library (termed YO-DEL) which contains 1 254 838 compounds, was encoded with DNA in single-stranded format and was screened against target proteins of interest using affinity capture procedures and photocrosslinking. YO-DEL selections yielded specific binders against serum albumins, carbonic anhydrases and NKp46, a marker of activated Natural Killer cells.

Mono- and bis-pyrazolophthalazines: Design, synthesis, cytotoxic activity, DNA/HSA binding and molecular docking studies.

In an attempt to find new potent cytotoxic compounds, several mono- and bis-pyrazolophthalazines 4a-m and 6a-h were synthesized through an efficient, one-pot, three- and pseudo five-component synthetic approach. All derivatives were evaluated for their in vitro cytotoxic activities against four human cancer cell lines of A549, HepG2, MCF-7, and HT29. Compound 4e showed low toxicity against normal cell lines (MRC-5 and MCF 10A, IC50 > 200 µM) and excellent cytotoxic activity against A549 cell line with IC50 value of 1.25 ± 0.19 µM, which was 1.8 times more potent than doxorubicin (IC50 = 2.31 ± 0.13 µM). In addition, compound 6c exhibited remarkable cytotoxic activity against A549 and MCF-7 cell lines (IC50 = 1.35 ± 0.12 and 0.49 ± 0.01 µM, respectively), more than two-fold higher than that of doxorubicin. The binding properties of the best active mono- and bis-pyrazolophthalazine (4e and 6c) with HSA and DNA were fully evaluated by various techniques including UV-Vis absorption, circular dichroism (CD), Zeta potential and dynamic light scattering analyses indicating interaction of the compounds with the secondary structure of HSA and significant change of DNA conformation, presumably via a groove binding mechanism. Additionally, molecular docking and site-selective binding studies confirmed the fundamental interaction of compounds 4e and 6c with base pairs of DNA. Compounds 4e and 6c showed promising features to be considered as potential lead structures for further studies in cancer therapy.

Prognostic value of the preoperative albumin-globulin ratio in patients with upper urinary tract urothelial carcinoma treated with radical nephroureterectomy: results from a large multicenter international collaboration.

OBJECTIVE: To assess the value of preoperative albumin to globulin ratio for predicting pathologic and oncological outcomes in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy in a large multi-institutional cohort. MATERIALS AND METHODS: Preoperative albumin to globulin ratio was assessed in a multi-institutional cohort of 2492 patients. Logistic regression analyses were performed to assess the association of the albumin to globulin ratio with pathologic features. Cox proportional hazards regression models were performed for survival endpoints. RESULTS: The optimal cut-off value was determined to be 1.4 according to a receiver operating curve analysis. Lower albumin to globulin ratios were observed in 797 patients (33.6%) compared with other patients. In a preoperative model, low preoperative albumin to globulin ratio was independently associated with nonorgan-confined diseases (odds ratio 1.32, P = 0.002). Patients with low albumin to globulin ratios had worse recurrence-free survival (P < 0.001), cancer-specific survival (P = 0.001) and overall survival (P = 0.020) in univariable and multivariable analyses after adjusting for the effect of standard preoperative prognostic factors (recurrence-free survival: hazard ratio (HR) 1.31, P = 0.001; cancer-specific survival: HR 1.31, P = 0.002 and overall survival: HR 1.18, P = 0.024). CONCLUSIONS: Lower preoperative albumin to globulin ratio is associated with locally advanced disease and worse clinical outcomes in patients treated with radical nephroureterectomy for upper tract urothelial carcinoma. As it is difficult to stage disease entity, low preoperative serum albumin to globulin ratio may help identify those most likely to benefit from intensified care, such as perioperative systemic therapy, and the extent and type of surgery.