Cyanine-Flavonol Hybrids for Near-Infrared Light-Activated Delivery of Carbon Monoxide

Carbon monoxide (CO) is an endogenous signaling molecule that controls a number of physiological processes. To circumvent the inherent toxicity of CO, light-activated CO-releasing molecules (photoCORMs) have emerged as an alternative for its administration. However, their wider application requires photoactivation using biologically benign visible and near-infrared (NIR) light. In this work, a strategy to access such photoCORMs by fusing two CO-releasing flavonol moieties with a NIR-absorbing cyanine dye is presented. These hybrids liberate two molecules of CO in high chemical yields upon activation with NIR light up to 820 nm and exhibit excellent uncaging cross-sections, which surpass the state-of-the-art by two orders of magnitude. Furthermore, the biocompatibility and applicability of the system in vitro and in vivo are demonstrated, and a mechanism of CO release is proposed. It is hoped that this strategy will stimulate the discovery of new classes of photoCORMs and accelerate the translation of CO-based phototherapy into practice

Effects of Substituents on Photophysical and CO-Photoreleasing Properties of 2,6-Substituted meso-Carboxy BODIPY Derivatives

Carbon monoxide (CO) is an endogenously produced signaling molecule involved in the control of a vast array of physiological processes. One of the strategies to administer therapeutic amounts of CO is the precise spatial and temporal control over its release from photoactivatable CO-releasing molecules (photoCORMs). Here we present the synthesis and photophysical and photochemical properties of a small library of meso-carboxy BODIPY derivatives bearing different substituents at positions 2 and 6. We show that the nature of substituents has a major impact on both their photophysics and the efficiency of CO photorelease. CO was found to be efficiently released from pi -extended 2,6-arylethynyl BODIPY derivatives possessing absorption spectra shifted to a more biologically desirable wavelength range. Selected photoCORMs were subjected to in vitro experiments that did not reveal any serious toxic effects, suggesting their potential for further biological research

Cobalt protoporphyrin IX increases endogenous G-CSF and mobilizes HSC and granulocytes to the blood

Granulocyte colony-stimulating factor (G-CSF) is used in clinical practice to mobilize cells from the bone marrow to the blood; however, it is not always effective. We show that cobalt protoporphyrin IX (CoPP) increases plasma concentrations of G-CSF, IL-6, and MCP-1 in mice, triggering the mobilization of granulocytes and hematopoietic stem and progenitor cells (HSPC). Compared with recombinant G-CSF, CoPP mobilizes higher number of HSPC and mature granulocytes. In contrast to G-CSF, CoPP does not increase the number of circulating T cells. Transplantation of CoPP-mobilized peripheral blood mononuclear cells (PBMC) results in higher chimerism and faster hematopoietic reconstitution than transplantation of PBMC mobilized by G-CSF. Although CoPP is used to activate Nrf2/HO-1 axis, the observed effects are Nrf2/HO- 1 independent. Concluding, CoPP increases expression of mobilization- related cytokines and has superior mobilizing efficiency compared with recombinant G-CSF. This observation could lead to the development of new strategies for the treatment of neutropenia and HSPC transplantation

CEACAM1 ve zluci a jeho vliv na nukleaci cholesterolu.

CEACAM1 is a transmembrane glycoprotein, a member of the carcinoembryonic antigen (CEA) family of the immunoglobulin superfamily localized in apical domains of hepatocytes and other polarized cells. CEACAM1 biological functions described in the recent studies are primarily intercellular adhesion, signal transduction and tumour cell growth regulation. Its function in the bile were unknown. A pronase resistant 85 kDa glycoprotein in the Concanavalin A-binding fraction (CABF) of biliary glycoproteins were reported to act as a promotor of cholesterol crystallisation. De Bruijn et al. found this protein in a low density protein-lipid complex with potent cholesterol crystallisation promoting activity. This study identifies the protein as CEACAM1 and focuses on its biological function as a cholesterol crystallisation promotor. The study compares the concentration of CEACAM1 in the bile of patients with cholesterol and pigment gallstones and without gallstone disease. An affinity chromatography of CEACAM1 glycoprotein on cellulose with oriented immobilization of monoclonal anti-CEA F34-187 antibody is described. It demonstrates that CEACAM1 is not stainable with any common method of protein staining and the only non-immunochemical method which could detect the 85 kDa band is a lactin staining.Available from STL Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi

Proton-Coupled Triplet-Triplet Energy Transfer: Carbon Monoxide Photorelease from Porphyrin-Flavonol Hybrids

A new photochemical mechanism, termed proton-coupled energy transfer (PCEnT), was recently discovered in anthracene-phenol-pyridine triads (Pettersson Rimgard et al., Science 2022, 377, 742). It couples an electronic transition to nuclear motions allowing Förster (dipole-dipole) energy transfer even though there is no overlap of the donor emission and acceptor absorption spectra. Here, we extend this concept to triplet-triplet energy transfer (TEnT) from light-harvesting porphyrin to a covalently bound flavonol group. While direct TEnT to the flavonol acceptor would be highly endergonic, it becomes feasible thanks to the flavonol energy stabilization upon intramolecular proton transfer in the triplet state. We describe the overall mechanism as proton-coupled TEnT (PCTEnT) – a one-photon process that enables the activation of a UV-absorbing chromophore by visible light. Several porphyrin-flavonol hybrids containing 4 flavonol units attached to the porphyrin meso positions were designed as photoactivatable carbon monoxide (CO)-releasing molecules (photoCORMs). The photoreaction mechanism was studied by steady-state and transient absorption spectroscopy techniques and complementary quantum-chemical calculations. While intrinsically toxic, CO is an endogenous signaling molecule with therapeutic potential that regulates various physiological processes, and photoCORMs offer precise spatial and temporal control of CO administration. We evaluated the viability of the human hepatoblastoma HepG2 cells in the presence of the studied hybrids and tested the effects associated with the intracellular release of CO and the production of singlet oxygen. We demonstrate that the PCTEnT process could be used to devise new photoactivatable molecular devices with potential biological applications

Expression of Biliverdin Reductase A in peripheral blood leukocytes is associated with treatment response in HCV-infected patients.

Hepatitis C virus (HCV) infection is associated with systemic oxidative stress. Since the heme catabolic pathway plays an important role in antioxidant protection, we attempted to assess the gene expression of key enzymes of heme catabolism, heme oxygenase 1 (HMOX1), heme oxygenase 2 (HMOX2), and biliverdin reductase A (BLVRA) in the liver and peripheral blood leukocytes (PBL) of patients chronically infected with HCV.Gene expressions (HMOX1, HMOX2, BLVRA) and HCV RNA were analyzed in PBL of HCV treatment naïve patients (n = 58) and controls (n = 55), with a subset of HCV patients having data on hepatic gene expression (n = 35). Based upon the therapeutic outcome, HCV patients were classified as either responders (n = 38) or treatment-failure patients (n = 20). Blood samples in HCV patients were collected at day 0, and week 12, 24, 36, and 48 after the initiation of standard antiviral therapy.Compared to the controls, substantially increased BLVRA expression was detected in PBL (p<0.001) of therapeutically naïve HCV patients. mRNA levels of BLVRA in PBL closely correlated with those in liver tissue (r2 = 0.347,p = 0.03). A marked difference in BLVRA expression in PBL between the sustained responders and patients with treatment failure was detected at week 0 and during the follow-up (p<0.001). Multivariate analysis revealed that BLVRA basal expression in PBL was an independent predictor for sustained virological response (OR 15; 95% CI 1.05-214.2; P = 0.046). HMOX1/2 expression did not have any effect on the treatment outcome.Our results suggest that patients with chronic HCV infection significantly upregulate BLVRA expression in PBL. The lack of BLVRA overexpression is associated with non-responsiveness to standard antiviral therapy; whereas, HMOX1/2 does not seem to have any predictive potential

HYCO-3, a dual CO-releaser/Nrf2 activator, reduces tissue inflammation in mice challenged with lipopolysaccharide

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Carbon monoxide-induced metabolic switch in adipocytes improves insulin resistance in obese mice

International audienceObesity is characterized by accumulation of adipose tissue and is one the most important risk factors in the development of insulin resistance. Carbon monoxide-releasing (CO-releasing) molecules (CO-RMs) have been reported to improve the metabolic profile of obese mice, but the underlying mechanism remains poorly defined. Here, we show that oral administration of CORM-401 to obese mice fed a high-fat diet (HFD) resulted in a significant reduction in body weight gain, accompanied by a marked improvement in glucose homeostasis. We further unmasked an action we believe to be novel, by which CO accumulates in visceral adipose tissue and uncouples mitochondrial respiration in adipocytes, ultimately leading to a concomitant switch toward glycolysis. This was accompanied by enhanced systemic and adipose tissue insulin sensitivity, as indicated by a lower blood glucose and increased Akt phosphorylation. Our findings indicate that the transient uncoupling activity of CO elicited by repetitive administration of CORM-401 is associated with lower weight gain and increased insulin sensitivity during HFD. Thus, prototypic compounds that release CO could be investigated for developing promising insulin-sensitizing agents

The Effect of Mycotoxins and Silymarin on Liver Lipidome of Mice with Non-Alcoholic Fatty Liver Disease

Milk thistle-based dietary supplements have become increasingly popular. The extract from milk thistle (Silybum marianum) is often used for the treatment of liver diseases because of the presence of its active component, silymarin. However, the co-occurrence of toxic mycotoxins in these preparations is quite frequent as well. The objective of this study was to investigate the changes in composition of liver lipidome and other clinical characteristics of experimental mice fed by a high-fat methionine-choline deficient diet inducing non-alcoholic fatty liver disease. The mice were exposed to (i) silymarin, (ii) mycotoxins (trichothecenes, enniatins, beauvericin, and altertoxins) and (iii) both silymarin and mycotoxins, and results were compared to the controls. The liver tissue extracts were analyzed by ultra-high performance liquid chromatography coupled with high-resolution tandem mass spectrometry. Using tools of univariate and multivariate statistical analysis, we were able to identify 48 lipid species from the classes of diacylglycerols, triacylglycerols, free fatty acids, fatty acid esters of hydroxy fatty acids and phospholipids clearly reflecting the dysregulation of lipid metabolism upon exposure to mycotoxin and/or silymarin