Could SGLT2 Inhibitors Improve Exercise Intolerance in Chronic Heart Failure?

Despite the constant improvement of therapeutical options, heart failure (HF) remains associated with high mortality and morbidity. While new developments in guideline-recommended therapies can prolong survival and postpone HF hospitalizations, impaired exercise capacity remains one of the most debilitating symptoms of HF. Exercise intolerance in HF is multifactorial in origin, as the underlying cardiovascular pathology and reactive changes in skeletal muscle composition and metabolism both contribute. Recently, sodium-related glucose transporter 2 (SGLT2) inhibitors were found to improve cardiovascular outcomes significantly. Whilst much effort has been devoted to untangling the mechanisms responsible for these cardiovascular benefits of SGLT2 inhibitors, little is known about the effect of SGLT2 inhibitors on exercise performance in HF. This review provides an overview of the pathophysiological mechanisms that are responsible for exercise intolerance in HF, elaborates on the potential SGLT2-inhibitor-mediated effects on these phenomena, and provides an up-to-date overview of existing studies on the effect of SGLT2 inhibitors on clinical outcome parameters that are relevant to the assessment of exercise capacity. Finally, current gaps in the evidence and potential future perspectives on the effects of SGLT2 inhibitors on exercise intolerance in chronic HF are discussed.     

How Can Malnutrition Affect Autophagy in Chronic Heart Failure? Focus and Perspectives

Chronic heart failure (CHF) is a disease with important clinical and socio-economic ramifications. Malnutrition and severe alteration of the protein components of the body (protein disarrangements), common conditions in CHF patients, are independent correlates of heart dysfunction, disease progression, and mortality. Autophagy, a prominent occurrence in the heart of patients with advanced CHF, is a self-digestive process that prolongs myocardial cell lifespan by the removal of cytosolic components, such as aging organelles and proteins, and recycles the constituent elements for new protein synthesis. However, in specific conditions, excessive activation of autophagy can lead to the destruction of molecules and organelles essential to cell survival, ultimately leading to organ failure and patient death. In this review, we aim to describe the experimental and clinical evidence supporting a pathophysiological role of nutrition and autophagy in the progression of CHF. The understanding of the mechanisms underlying the interplay between nutrition and autophagy may have important clinical implications by providing molecular targets for innovative therapeutic strategies in CHF patients.     

Calcium and Heart Failure: How Did We Get Here and Where Are We Going?

The occurrence and prevalence of heart failure remain high in the United States as well as globally. One person dies every 30 s from heart disease. Recognizing the importance of heart failure, clinicians and scientists have sought better therapeutic strategies and even cures for end-stage heart failure. This exploration has resulted in many failed clinical trials testing novel classes of pharmaceutical drugs and even gene therapy. As a result, along the way, there have been paradigm shifts toward and away from differing therapeutic approaches. The continued prevalence of death from heart failure, however, clearly demonstrates that the heart is not simply a pump and instead forces us to consider the complexity of simplicity in the pathophysiology of heart failure and reinforces the need to discover new therapeutic approaches.     

Is Correction of Iron Deficiency a New Addition to the Treatment of the Heart Failure?

Anemia is present in about 40% of heart failure (HF) patients. Iron deficiency (ID) is present in about 60% of the patients with anemia (about 24% of all HF patients) and in about 40% of patients without anemia (about 24% of all HF patients). Thus ID is present in about half the patients with HF. The ID in HF is associated with reduced iron stores in the bone marrow and the heart. ID is an independent risk factor for severity and worsening of the HF. Correction of ID with intravenous (IV) iron usually corrects both the anemia and the ID. Currently used IV iron preparations are very safe and effective in treating the ID in HF whereas little information is available on the effectiveness of oral iron. In HF IV iron correction of ID is associated with improvement in functional status, exercise capacity, quality of life and, in some studies, improvement in rate of hospitalization for HF, cardiac structure and function, and renal function. Large long-term adequately-controlled intervention studies are needed to clarify the effect of IV iron in HF. Several heart associations suggest that ID should be routinely sought for in all HF patients and corrected if present. In this paper we present our approach to diagnosis and treatment of iron deficiency in heart failure.     

Fluorescent,Recombinant-Protein-Conjugated,Near-Infrared-Emitting Quantum Dots for in Vitro and in Vivo Dual-Color Molecular Imaging

Near-infrared (NIR)-emitting fluorescent probes are widely used for molecular imaging at the whole-body level. However, NIR-emitting fluorescent probes emitting over λ=700 nm are not suitable for molecular imaging at the cellular level, because most of the conventional fluorescence microscopes have very low optical sensitivity in the NIR region. Thus, to achieve fluorescence imaging at the cellular and whole-body levels by using single probes, visible and NIR-emitting dual-color fluorescent probes are desirable. For dual-color fluorescence molecular imaging, we synthesized fluorescent, recombinant-protein-conjugated, NIR-emitting quantum dots (QDs), in which the recombinant protein consists of enhanced green fluorescent protein (EGFP) and the immunoglobulin binding domain (B1) of protein G. This dual-color fluorescent QD probe binds the Fc region of immunoglobulin G (IgG) through its B1 domain at the QD surface and acts as a molecular-imaging probe at both the cellular and whole-body levels. In this paper, we present the synthesis of fluorescent, recombinant protein (HisEGFP-GB1)-conjugated, NIR-emitting QDs and their application to the dual-color molecular imaging of breast cancer cells in vitro and in vivo.     

Design,Synthesis, and in vitro Evaluation of Tubulin-Targeting Dibenzothiazines with Antiproliferative Activity as a Novel Heterocycle Building Block

We prepared a series of free NH and N-substituted dibenzonthiazines with potential anti-tumor activity from N-aryl-benzenesulfonamides. A biological test of synthesized compounds (59 samples) was performed in vitro measuring their antiproliferative activity against a panel of six human solid tumor cell lines and its tubulin inhibitory activity. We identified 6-(phenylsulfonyl)-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide and 6-tosyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide as the best compounds with promising values of activity (overall range of 2–5.4 μM). Herein, we report the dibenzothiazine core as a novel building block with antiproliferative activity, targeting tubulin dynamics.     

Identification of Novel Potential β-N-Acetyl-D-Hexosaminidase Inhibitors by Virtual Screening, Molecular Dynamics Simulation and MM-PBSA Calculations

Chitinolytic β-N-acetyl-d-hexosaminidases, as a class of chitin hydrolysis enzyme in insects, are a potential species-specific target for developing environmentally-friendly pesticides. Until now, pesticides targeting chitinolytic β-N-acetyl-d-hexosaminidase have not been developed. This study demonstrates a combination of different theoretical methods for investigating the key structural features of this enzyme responsible for pesticide inhibition, thus allowing for the discovery of novel small molecule inhibitors. Firstly, based on the currently reported crystal structure of this protein (OfHex1.pdb), we conducted a pre-screening of a drug-like compound database with 8 × 10(6) compounds by using the expanded pesticide-likeness criteria, followed by docking-based screening, obtaining 5 top-ranked compounds with favorable docking conformation into OfHex1. Secondly, molecular docking and molecular dynamics simulations are performed for the five complexes and demonstrate that one main hydrophobic pocket formed by residues Trp424, Trp448 and Trp524, which is significant for stabilization of the ligand-receptor complex, and key residues Asp477 and Trp490, are respectively responsible for forming hydrogen-bonding and π-π stacking interactions with the ligands. Finally, the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis indicates that van der Waals interactions are the main driving force for the inhibitor binding that agrees with the fact that the binding pocket of OfHex1 is mainly composed of hydrophobic residues. These results suggest that screening the ZINC database can maximize the identification of potential OfHex1 inhibitors and the computational protocol will be valuable for screening potential inhibitors of the binding mode, which is useful for the future rational design of novel, potent OfHex1-specific pesticides.     

Synthesis and Aggregation of Novel Sugar-Based Gemini Surfactant with a N,N′-Acetylethylenediamine Spacer in Aqueous Solution

A novel sugar-based Gemini surfactant with a N,N′-acetylethylenediamine spacer (N,N′ (N-dodecyl-2-D-glucosaminyl acetyl) ethylenediamine, Glu(12)-(AA)-Glu(12)), was synthesized with D-(+)-Glucono-1,5-lactone as starting material in three steps. The surfactant's structure was confirmed using ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopy and electrospray ionization mass spectrometry (ESI-MS). The aggregation behavior of Glu(12)-(AA)-Glu(12) in aqueous solution at pH 4.0, 7.0, and 10.0 was investigated by surface tension, dynamic light scattering (DLS), and cryogenic transmission electron microscopic (Cryo-TEM) measurements. The surface tension measurement shows that the critical micelle concentration (CMC) of Glu(12)-(AA)-Glu(12) is at the concentration level of 10⁻⁵ mol·L⁻¹ at 25 °C, which is significantly lower than that of corresponding monomeric sugar-based surfactants. Compared with such sugar-based Gemini surfactants with similar hydrophilic spacers, Glu(12)-(AA)-Glu(12) demonstrated similar or slightly lower surface activity. The CMC value of Glu(12)-(AA)-Glu(12) underwent a slight decrease with the increase of pH. DLS and Cryo-TEM measurements reveal that Glu(12)-(AA)-Glu(12) forms micelles at acidic pH (pH 4.0) and the micelles are transformed into vesicles at neutral or high pH (pH 7.0, 10.0). The microstructural transformation of Glu(12)-(AA)-Glu(12) aggregates is related to the protonation state of its two tertiary amines in the head groups versus pH.     

Novel Missense Mutation in the NOD2 Gene in a Patient with Early Onset Ulcerative Colitis: Causal or Chance Association?

Deregulated immune response to gut microflora in genetically predisposed individuals is typical for inflammatory bowel diseases. It is reasonable to assume that genetic association with the disease will be more pronounced in subjects with early onset than adult onset. The nucleotide-binding oligomerization domain containing-2 gene, commonly involved in multifactorial risk of Crohn’s disease, and interleukin 10 receptor genes, associated with rare forms of early onset inflammatory bowel diseases, were sequenced in an early onset patient. We identified a novel variant in the NOD2 gene (c.2857A > G p.K953E) and two already described missense variants in the IL10RA gene (S159G and G351R). The new NOD2 missense variant was examined in silico with two online bioinformatics tools to predict the potentially deleterious effects of the mutation. Although cumulative effect of these variations in the early onset of the disease can be only hypothesized, we demonstrated that family information and in silico studies can be used to predict association with the disease.     

The discrepancies in energy balance in furnace testing,a bug or a feature?

The paper aims to explain the differences found in the heat release rate measurements in a large sample of standard fire tests (EN 1363-1). A total of 379 tests of vertical assemblies was investigated, all performed in furnace SPARK of the ITB Fire Testing Laboratory, in 2015-2018. The assemblies were subdivided into two groups—wall assemblies and fire-rated doors. These assemblies were also compared with the results of the test of a wall built with aerated autoclaved concrete blocks that was considered as the benchmark test. It was observed that walls built with highly insulated sandwich panels require less heat to maintain standard thermal exposure conditions (20%-30% less) than their counterparts built from gypsum plasterboard or aluminium and fire-rated glass. In case of doors, it was observed that combustible samples required significantly less heat than the benchmark case (40%-70% less), which indicates that the combustion of the sample inside of the furnace was an additional, significant source of heat release, that may skew the qualitative assessment of their performance in fire. A more in-depth discussion of the results is provided, with some ideas on the direction of further developments in fire testing.     

Astaxanthin,a Carotenoid,Stimulates Immune Responses by Enhancing IFN-γ and IL-2 Secretion in Primary Cultured Lymphocytes in Vitro and ex Vivo

Astaxanthin, a potent antioxidant carotenoid, plays a major role in modulating the immune response. In this study, we examined the immunomodulatory effects of astaxanthin on cytokine production in primary cultured lymphocytes both in vitro and ex vivo. Direct administration of astaxanthin (70–300 nM) did not produce cytotoxicity in lipopolysaccharide (LPS, 100 µg/ mL)- or concanavalin A (Con A, 10 µg/ mL)-activated lymphocytes, whereas astaxanthin alone at 300 nM induced proliferation of splenic lymphocytes (p < 0.05) in vitro. Although astaxanthin, alone or with Con A, had no apparent effect on interferon (INF-γ) and interleukin (IL-2) production in primary cultured lymphocytes, it enhanced LPS-induced INF-γ production. In an ex vivo experiment, oral administration of astaxanthin (0.28, 1.4 and 7 mg/kg/day) for 14 days did not cause alterations in the body or spleen weights of mice and also was not toxic to lymphocyte cells derived from the mice. Moreover, treatment with astaxanthin significantly increased LPS-induced lymphocyte proliferation ex vivo but not Con A-stimulated lymphocyte proliferation ex vivo. Enzyme linked immunosorbent assay (ELISA) analysis revealed that administration of astaxanthin significantly enhanced INF-γ production in response to both LPS and Con A stimulation, whereas IL-2 production increased only in response to Con A stimulation. Also, astaxanthin treatment alone significantly increased IL-2 production in lymphocytes derived from mice, but did not significantly change production of INF-γ. These findings suggest that astaxanthin modulates lymphocytic immune responses in vitro, and that it partly exerts its ex vivo immunomodulatory effects by increasing INF-γ and IL-2 production without inducing cytotoxicity.     

The Discovery of Potential MDM2 Inhibitors: A Combination of Pharmacophore Modeling,Virtual Screening,Molecular Docking Studies,and in vitro/in vivo Biological Evaluation

Small-molecule inhibitors of MDM2 that block the MDM2-p53 protein-protein interaction have been considered as potential therapeutic agents for the treatment of cancer. Here, we identify five highly potent inhibitors of MDM2 (termed as WY 1–5) that display significant inhibitory effects on MDM2-p53 interaction by using a combined strategy of pharmacophore modeling, virtual screening, and molecular docking studies. Among them, WY-5 is the most active MDM2 inhibitor with an IC₅₀ value of 14.1±2.8 nM. Moreover, WY-5 significantly up-regulate the protein level of p53 in SK-Hep-1 cells harboring wild-type p53. In vitro anticancer study reveals that WY-5 markedly inhibits the survival of SK-Hep-1 cells. In vivo anticancer study suggests that WY-5 significantly inhibits the growth of SK-Hep-1 cells-derived xenograft in nude mice, with no observable toxicity. Our results demonstrate that WY-5 may be a promising candidate for the treatment of cancer harboring wild-type p53.     

Synthesis and Inhibition Effect of a Novel Tri-cationic Surfactant on Carbon Steel Corrosion in 0.5 M H2SO4 Solution

A novel Tri-cationic surfactant was synthesized, purified and characterized. The critical micelle concentration value of the prepared surfactant was determined by surface tension and conductivity measurements. The surface parameters were calculated by surface tension measurements. The relationship between the surface properties and the corrosion inhibition efficiency of the prepared surfactant was discussed. The inhibition effect of the novel Tri-cationic surfactant on carbon steel corrosion in 0.5 M H₂SO₄ was studied by potentiodynamic polarization, electrochemical impedance spectroscopy and weight loss techniques. Potentiodynamic polarization studies revealed that the inhibitor acted as a mixed-type inhibitor. The high inhibition efficiency was attributed to the blocking of active sites on the steel surface through the adsorption of inhibitor molecules. Inhibitor adsorption on the carbon steel surface was in accordance with the Langmuir adsorption isotherm model. Thermodynamic adsorption and kinetic parameters were obtained from weight losses at different temperatures (20–60 °C).     

Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 2: Subtypes and Divergent Differentiation

Following several attempts to achieve a molecular stratification of bladder cancer (BC) over the last decade, a “consensus” classification has been recently developed to provide a common base for the molecular classification of bladder cancer (BC), encompassing a six-cluster scheme with distinct prognostic and predictive characteristics. In order to implement molecular subtyping (MS) as a risk stratification tool in routine practice, immunohistochemistry (IHC) has been explored as a readily accessible, relatively inexpensive, standardized surrogate method, achieving promising results in different clinical settings. The second part of this review deals with the pathological and clinical features of the molecular clusters, both in conventional and divergent urothelial carcinoma, with a focus on the role of IHC-based subtyping.     

Flaxseed Oil Supplementation Improve Gene Expression Levels of PPAR-γ, LP(a), IL-1 and TNF-α in Type 2 Diabetic Patients with Coronary Heart Disease

This study was carried out to determine the effects of flaxseed oil administration on gene expression levels related to insulin, lipid and inflammation in overweight diabetic patients with coronary heart disease (CHD). This randomized double‐blind, placebo‐controlled trial was conducted among 60 diabetic patients with CHD. Subjects were randomly allocated into two groups to intake either 1000 mg n‐3 fatty acid from flaxseed oil containing 400 mg α‐Linolenic acid [ALA (18:3n‐3)] (n = 30) or placebo (n = 30) twice a day for 12 weeks. Gene expression related to insulin, lipid and inflammation were quantified in peripheral blood mononuclear cells (PBMC) of diabetic patients with CHD with RT‐PCR method. Results of RT‐PCR demonstrated that after the 12‐week intervention, compared with the placebo, flaxseed oil supplementation could up‐regulate gene expression of peroxisome proliferator‐activated receptor gamma (PPAR‐γ) (P = 0.02) in PBMC of diabetic patients with CHD. In addition, compared with the placebo, taking flaxseed oil supplements down‐regulated gene expression levels of lipoprotein(a) [LP(a)] (P = 0.001), interleukin‐1 (IL‐1) (P = 0.001) and tumor necrosis factor alpha (TNF‐α) (P = 0.02) in PBMC of diabetic patients with CHD. We did not observe any significant effect of flaxseed oil supplementation on gene expression levels of low‐density lipoprotein receptor (LDLR), IL‐8 and transforming growth factor beta (TGF‐β) in PBMC of diabetic patients with CHD. Overall, flaxseed oil supplementation for 12 weeks in diabetic patients with CHD significantly improved gene expression levels of PPAR‐γ, LP(a), IL‐1 and TNF‐α, but did not influence LDLR, IL‐8 and TGF‐β.     

Supramolecular Interaction of Molecular Cage and β-Galactosidase: Application in Enzymatic Inhibition,Drug Delivery and Antimicrobial Activity

Enzyme inhibitors play a crucial role in diagnosis of a wide spectrum of diseases related to bacterial infections. We report here the effect of a water-soluble self-assembled Pd^II₈ molecular cage towards β-galactosidase enzyme activity. The molecular cage is composed of a tetrapyridyl donor ( L ) and cis-[(en)Pd(NO₃)₂] (en=ethane-1,2-diamine) acceptor and it has a hydrophobic internal cavity. We have observed that the acceptor moiety mainly possesses the ability to inactivate the β-galactosidase enzyme activity. Kinetic investigation revealed the mixed mode of inhibition. This inhibition strategy was extended to control the growth of methicillin-resistant Staphylococcus aureus. The internalization of the Pd(II) cage inside the bacteria was confirmed when bacterial solutions were incubated with curcumin loaded cage. The intrinsic green fluorescence of curcumin made the bacteria glow when put under an optical microscope. Furthermore, this curcumin loaded molecular cage shows an enhanced antibacterial activity. Thus, Pd^II₈ molecular cage is quite attractive due to its dual role as enzyme inhibitor and drug carrier.     

Gene Networks of Hyperglycemia,Diabetic Complications,and Human Proteins Targeted by SARS-CoV-2: What Is the Molecular Basis for Comorbidity?

People with diabetes are more likely to have severe COVID-19 compared to the general population. Moreover, diabetes and COVID-19 demonstrate a certain parallelism in the mechanisms and organ damage. In this work, we applied bioinformatics analysis of associative molecular networks to identify key molecules and pathophysiological processes that determine SARS-CoV-2-induced disorders in patients with diabetes. Using text-mining-based approaches and ANDSystem as a bioinformatics tool, we reconstructed and matched networks related to hyperglycemia, diabetic complications, insulin resistance, and beta cell dysfunction with networks of SARS-CoV-2-targeted proteins. The latter included SARS-CoV-2 entry receptors (ACE2 and DPP4), SARS-CoV-2 entry associated proteases (TMPRSS2, CTSB, and CTSL), and 332 human intracellular proteins interacting with SARS-CoV-2. A number of genes/proteins targeted by SARS-CoV-2 (ACE2, BRD2, COMT, CTSB, CTSL, DNMT1, DPP4, ERP44, F2RL1, GDF15, GPX1, HDAC2, HMOX1, HYOU1, IDE, LOX, NUTF2, PCNT, PLAT, RAB10, RHOA, SCARB1, and SELENOS) were found in the networks of vascular diabetic complications and insulin resistance. According to the Gene Ontology enrichment analysis, the defined molecules are involved in the response to hypoxia, reactive oxygen species metabolism, immune and inflammatory response, regulation of angiogenesis, platelet degranulation, and other processes. The results expand the understanding of the molecular basis of diabetes and COVID-19 comorbidity.