Gut Microbiota Metabolites Sensed by Host GPR41/43 Protect Against Hypertension.

Background: Fermentation of dietary fiber by the gut microbiota leads to the production of metabolites called short-chain fatty acids, which lower blood pressure and exert cardioprotective effects. Short-chain fatty acids activate host signaling responses via the functionally redundant receptors GPR41 and GPR43, which are highly expressed by immune cells. Whether and how these receptors protect against hypertension or mediate the cardioprotective effects of dietary fiber remains unknown.

Tregs delivered post-myocardial infarction adopt an injury-specific phenotype promoting cardiac repair via macrophages in mice.

Regulatory T cells (Tregs) are key immune regulators that have shown promise in enhancing cardiac repair post-MI, although the mechanisms remain elusive. Here, we show that rapidly increasing Treg number in the circulation post-MI via systemic administration of exogenous Tregs improves cardiac function in male mice, by limiting cardiomyocyte death and reducing fibrosis. Mechanistically, exogenous Tregs quickly home to the infarcted heart and adopt an injury-specific transcriptome that mediates repair by modulating monocytes/macrophages.

Novel formylpeptide receptor 1/2 agonist limits hypertension-induced cardiovascular damage.

Aims: Formylpeptide receptors (FPRs) play a critical role in the regulation of inflammation, an important driver of hypertension-induced end-organ damage. We have previously reported that the biased FPR small-molecule agonist, compound17b (Cmpd17b), is cardioprotective against acute, severe inflammatory insults. Here, we reveal the first compelling evidence of the therapeutic potential of this novel FPR agonist against a longer-term, sustained inflammatory insult, i.

The pro-resolving mediator, annexin A1 regulates blood pressure, and age-associated changes in cardiovascular function and remodeling.

Aging is associated with chronic, low-level inflammation which may contribute to cardiovascular pathologies such as hypertension and atherosclerosis. This chronic inflammation may be opposed by endogenous mechanisms to limit inflammation, for example, by the actions of annexin A1 (ANXA1), an endogenous glucocorticoid-regulated protein that has anti-inflammatory and pro-resolving activity. We hypothesized the pro-resolving mediator ANXA1 protects against age-induced changes in blood pressure (BP), cardiovascular structure and function, and cardiac senescence.

Effect of Fusidic Acid and Some Nitrogen-Containing Derivatives on Liposomal and Mitochondrial Membranes.

The paper assesses the membranotropic action of the natural antibiotic fusidic acid (FA) and its derivatives. It was found that a FA analogue with ethylenediamine moiety (derivative 2), in contrast to native FA and 3,11-dioxime analogue (derivative 1), is able to increase the mobility of the lipid bilayer in the zone of lipid headgroups, as well as to induce permeabilization of lecithin liposome membranes. A similar effect of derivative 2 is also observed in the case of rat liver mitochondrial membranes.

Technetium Nitrido Complexes of Tetradentate Thiosemicarbazones: Kit-Based Radiolabeling, Characterization, and Evaluation.

Bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators have demonstrated utility in nuclear medicine. In particular, the Cu complexes have been extensively developed for hypoxia imaging and molecular imaging of peptide and protein markers of disease. However, the chemistry and application of bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators in combination with Tc, the most widely used radionuclide in nuclear medicine, is underexplored.

A superior extracellular matrix binding motif to enhance the regenerative activity and safety of therapeutic proteins.

Among therapeutic proteins, cytokines and growth factors have great potential for regenerative medicine applications. However, these molecules have encountered limited clinical success due to low effectiveness and major safety concerns, highlighting the need to develop better approaches that increase efficacy and safety. Promising approaches leverage how the extracellular matrix (ECM) controls the activity of these molecules during tissue healing.

3-Amino-Substituted Analogues of Fusidic Acid as Membrane-Active Antibacterial Compounds.

Fusidic acid (FA) is an antibiotic with high activity against ; it has been used in clinical practice since the 1960s. However, the narrow antimicrobial spectrum of FA limits its application in the treatment of bacterial infections. In this regard, this work aims both at the study of the antimicrobial effect of a number of FA amines and at the identification of their potential biological targets.

Synthesis of fusidane triterpenoid Mannich bases as potential antibacterial and antitumor agents.

Mannich bases (8 examples) were synthesized aminomethylation of fusidane propargyl esters. antimicrobial screening against key ESKAPE pathogens showed that the fusidic acid based Mannich products exhibit a high antimicrobial effect against Gram-positive bacteria and the fungus . Moreover, the cytotoxic effect of fusidic acid and its analogs, which showed high antibacterial activity, was determined by MTT assay on cancer HepG2, HCT-116, SH-SY5Y, MCF-7, A549 and conditionally normal cells HEK293.

Simultaneous late-gadolinium enhancement and T1 mapping of fibrosis and a novel cell-based combination therapy in hypertensive mice.

Fibrosis is a hallmark of chronic hypertension and disrupts the viability of human bone marrow-derived mesenchymal stromal cells (BM-MSCs) post-transplantation. This study thus, determined whether the anti-fibrotic drug, serelaxin (RLX), could enhance the therapeutic effects of BM-MSCs or BM-MSC-derived exosomes (BM-MSC-EXO) in hypertensive mice. Left ventricular (LV) fibrosis in particular was assessed using conventional histological staining and non-invasive cardiac magnetic resonance imaging (CMRI).

Hexadentate technetium-99m bis(thiosemicarbazonato) complexes: synthesis, characterisation and biodistribution.

The syntheses of non-oxido/non-nitrido bis(thiosemicarbazonato)technetium(V) complexes featuring a series of alkyl and ether substituents is presented. The bis(thiosemicarbazones) were radiolabelled with technetium-99m using an optimised one-pot synthesis from [Tc][TcO]. Mass spectrometry and computational chemistry data suggested a distorted trigonal prismatic coordination environment for the bis(thiosemicarbazonato)technetium(V) complexes by way of a bis(thiosemicarbazone)technetium(V)-oxido intermediate complex.

Enhanced photoacoustic imaging in tissue-mimicking phantoms using polydopamine-shelled perfluorocarbon emulsion droplets.

The current work features process parameters for the ultrasound (25 kHz)-assisted fabrication of polydopamine-shelled perfluorocarbon (PDA/PFC) emulsion droplets with bimodal (modes at 100-600 nm and 1-6 µm) and unimodal (200-600 nm) size distributions. Initial screening of these materials revealed that only PDA/PFC emulsion droplets with bimodal distributions showed photoacoustic signal enhancement due to large size of their optically absorbing PDA shells. Performance of this particular type of emulsion droplets as photoacoustic agents were evaluated in Intralipid®-India ink media, mimicking the optical scattering and absorbanceof various tissuetypes.

Translation of focused ultrasound for blood-brain barrier opening in glioma.

Survival outcomes for patients with glioblastoma multiforme (GBM) have remained poor for the past 15 years, reflecting a clear challenge in the development of more effective treatment strategies. The efficacy of systemic therapies for GBM is greatly limited by the presence of the blood-brain barrier (BBB), which prevents drug penetration and accumulation in regions of infiltrative tumour, as represented in a consistent portion of GBM lesions. Focused ultrasound (FUS) - a technique that uses low-frequency ultrasound waves to induce targeted temporary disruption of the BBB - promises to improve survival outcomes by enhancing drug delivery and accumulation to infiltrating tumour regions.

Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance.

Reactive oxygen species (ROS) generated during exercise are considered integral for the health-promoting effects of exercise. However, the precise mechanisms by which exercise and ROS promote metabolic health remain unclear. Here, we demonstrate that skeletal muscle NADPH oxidase 4 (NOX4), which is induced after exercise, facilitates ROS-mediated adaptive responses that promote muscle function, maintain redox balance, and prevent the development of insulin resistance.

Synthesis, modification, and biological activity of propargylated methyl dihydroquinopimarates.

The introduction of the alkynyl moiety to the abietane diterpenic core by modification of the cycle of methyl dihydroquinopimarate is described. The arylpropargyl, aminopropargyl, and 1,2,3-triazole derivatives are synthesized Sonogashira reaction, Mannich reaction and click-chemistry, correspondingly. The antitumor effect towards the NCI-60 cancer cell line panel and antimicrobial activity against key ESKAPE pathogens of the synthesized compounds were studied .

Synthesis of New Dihydroquinopimaric Acid Analogs with Nitrile Groups as Apoptosis-Inducing Anticancer Agents.

Background: Cyan-containing compounds are of great interest as potential anticancer agents. Terpenoids can severe as a natural matrix for the development of promising derivatives with antitumor activity.

Methods: The 2-cyanoethoxy methyl dihydroquinopimarate derivatives (5-9) were synthesized by the reaction of the intermediates (1-4) with acrylonitrile in the presence of alkali (30% KOH solution) using triethylbenzylammonium chloride.

Variable outcomes of human heart attack recapitulated in genetically diverse mice.

Clinical variation in patient responses to myocardial infarction (MI) has been difficult to model in laboratory animals. To assess the genetic basis of variation in outcomes after heart attack, we characterized responses to acute MI in the Collaborative Cross (CC), a multi-parental panel of genetically diverse mouse strains. Striking differences in post-MI functional, morphological, and myocardial scar features were detected across 32 CC founder and recombinant inbred strains.

Heart regeneration in the salamander relies on macrophage-mediated control of fibroblast activation and the extracellular landscape.

In dramatic contrast to the poor repair outcomes for humans and rodent models such as mice, salamanders and some fish species are able to completely regenerate heart tissue following tissue injury, at any life stage. This capacity for complete cardiac repair provides a template for understanding the process of regeneration and for developing strategies to improve human cardiac repair outcomes. Using a cardiac cryo-injury model we show that heart regeneration is dependent on the innate immune system, as macrophage depletion during early time points post-injury results in regeneration failure.

Point mutations in murine phenocopy human congenital heart disease and induce pathogenic Wnt signaling.

Mutations in the gene are a main cause of congenital heart disease. Several studies have addressed the phenotypic consequences of disrupting the gene locus, although animal models to date failed to recapitulate the full spectrum of the human disease. Here, we describe a new point mutation murine model, akin to its human counterpart disease-generating mutation.

Congenital valvular defects associated with deleterious mutations in the gene.

Background: The underlying molecular aetiology of congenital heart defects is largely unknown. The aim of this study was to explore the genetic basis of non-syndromic severe congenital valve malformations in two unrelated families.

Methods: Whole-exome analysis was used to identify the mutations in five patients who suffered from severe valvular malformations involving the pulmonic, tricuspid and mitral valves.

An atypical role for the myeloid receptor Mincle in central nervous system injury.

The C-type lectin Mincle is implicated in innate immune responses to sterile inflammation, but its contribution to associated pathologies is not well understood. Herein, we show that Mincle exacerbates neuronal loss following ischemic but not traumatic spinal cord injury. Loss of Mincle was beneficial in a model of transient middle cerebral artery occlusion but did not alter outcomes following heart or gut ischemia.

Synthesis of 5,19-(2,6-Dimethylpyridin-4-yl)-trisnorlupane and Oleanane.

Acetylation of the 3,4-seco-derivatives of betulin, allobetulin and 28-oxyallobetulone gave the 5,19-(2,6-dimethylpyridin-4-yl)-4,23,24,20,29,30-hexanorlupane, and 5-(2,6-dimethylpyridin-4-yl)-4,23,24-trisnor-derivatives of oleanane and ursane.

Synthesis of a Novel 1,2,4-Oxadiazole Diterpene from the Oxime of the Methyl Ester of 1β,13-Epoxydihydroquinopimaric Acid.

Oximation of the dihydroquinopimaric acid O-cyanoethylderivative (2) via the amidoxime 3, and cyclization with trifluoroacetic anhydride resulted in a new 1,2,4-oxadiazole diterpenoid (4).