Stretch-Induced Ordering of Prochiral Dimethyl Sulfoxide in Anisotropic Hydrogels Analysed by H and H Nuclear Magnetic Resonance.

Nuclear spins in small molecules dissolved in stretched hydrogels typically have population-averaged residual interactions. The nuclear magnetic resonance (NMR) spectra of these systems often show additional peaks and splittings compared with free solutions. Residual dipolar couplings (RDCs) and quadrupolar couplings (RQCs) are observed for guest H and H nuclear spins, respectively.

Elevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart.

Elevated intracellular sodium Na adversely affects mitochondrial metabolism and is a common feature of heart failure. The reversibility of acute Na induced metabolic changes is evaluated in Langendorff perfused rat hearts using the Na/K ATPase inhibitor ouabain and the myosin-uncoupler para-aminoblebbistatin to maintain constant energetic demand. Elevated Na decreases Gibb's free energy of ATP hydrolysis, increases the TCA cycle intermediates succinate and fumarate, decreases ETC activity at Complexes I, II and III, and causes a redox shift of CoQ to CoQH, which are all reversed on lowering Na to baseline levels.

Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles.

The naked mole-rat Heterocephalus glaber is a eusocial mammal exhibiting extreme longevity (37-year lifespan), extraordinary resistance to hypoxia and absence of cardiovascular disease. To identify the mechanisms behind these exceptional traits, metabolomics and RNAseq of cardiac tissue from naked mole-rats was compared to other African mole-rat genera (Cape, Cape dune, Common, Natal, Mahali, Highveld and Damaraland mole-rats) and evolutionarily divergent mammals (Hottentot golden mole and C57/BL6 mouse). We identify metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia.

Characterization and Validation of Radiotracer Kinetics Using the Langendorff Isolated Perfused Heart.

The Langendorff isolated perfused heart is a physiologically relevant and controllable ex vivo model well suited to characterizing and validating novel radiotracers for a wide range of molecular imaging applications. It allows the monitoring of first pass tracer uptake kinetics either as a bolus injection or as a continuous infusion in beating myocardial tissue with a high degree of experimental control in terms of cardiac workload, perfusion, energy substrate delivery and composition, and drug co-administration. The radiotracer pharmacokinetic data that it provides is not contaminated by confounding factors such as off-target tracer metabolism, and as a non-imaging technique, time activity curves can be acquired with very high temporal resolution.

Empagliflozin improves cardiac energetics during ischaemia/reperfusion by directly increasing cardiac ketone utilization.

Aims: Empagliflozin (EMPA), a potent inhibitor of the renal sodium-glucose cotransporter 2 and an effective treatment for Type 2 diabetes, has been shown to have cardioprotective effects, independent of improved glycaemic control. Several non-canonical mechanisms have been proposed to explain these cardiac effects, including increasing circulating ketone supply to the heart. This study aims to test whether EMPA directly alters cardiac ketone metabolism independent of supply.

Redox double-switch cancer theranostics through Pt(IV) functionalised manganese dioxide nanostructures.

Manganese dioxide (MnO)-based nanostructures have emerged as promising tumour microenvironment (TME) responsive platforms. Herein, we used a one-pot reaction to prepare MnO nanostructures with Pt(IV) prodrugs as redox- (and thus TME-) responsive theranostics for cancer therapy, in which the Pt(IV) complexes act as prodrugs of cisplatin (Pt(II)), a clinical chemotherapeutic drug. The cytotoxicity of these MnO-Pt(IV) probes was evaluated in two and three dimensional (2D and 3D) A549 cell models and found to be as effective as active drug cisplatin in 3D models.

Characterization of hepatic fatty acids using magnetic resonance spectroscopy for the assessment of treatment response to metformin in an eNOS mouse model of metabolic nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide. Liver biopsy remains the gold standard for diagnosis and staging of disease. There is a clinical need for noninvasive diagnostic tools for risk stratification, follow-up, and monitoring treatment response that are currently lacking, as well as preclinical models that recapitulate the etiology of the human condition.

NOS2 and -nitrosothiol signaling induces DNA hypomethylation and LINE-1 retrotransposon expression.

Inducible nitric oxide synthase (NOS2) produces high local concentrations of nitric oxide (NO), and its expression is associated with inflammation, cellular stress signals, and cellular transformation. Additionally, NOS2 expression results in aggressive cancer cell phenotypes and is correlated with poor outcomes in patients with breast cancer. DNA hypomethylation, especially of noncoding repeat elements, is an early event in carcinogenesis and is a common feature of cancer cells.

N-Centered Tripodal Phosphine Re(V) and Tc(V) Oxo Complexes: Revisiting a [3 + 2] Mixed-Ligand Approach.

N-Triphos derivatives (NP, R = alkyl, aryl) and asymmetric variants (NPX, R' = alkyl, aryl, X = OH, NR, NRR') are an underexplored class of tuneable, tripodal ligands in relation to the coordination chemistry of Re and Tc for biomedical applications. Mixed-ligand approaches are a flexible synthetic route to obtain Tc complexes of differing core structures and physicochemical properties. Reaction of the NP ligand with the Re(V) oxo precursor [ReOCl(PPh)] generated the bidentate complex [ReOCl(κ-NPOH)], which possesses an unusual AA'BB'XX' spin system with a characteristic second-order NMR lineshape that is sensitive to the bi- or tridentate nature of the coordinating diphosphine unit.

One-step, kit-based radiopharmaceuticals for molecular SPECT imaging: a versatile diphosphine chelator for Tc radiolabelling of peptides.

Radiotracers labelled with technetium-99m (Tc) enable accessible diagnostic imaging of disease, provided that radiotracer preparation is simple. Whilst Tc radiopharmaceuticals for imaging perfusion are routinely prepared from kits, and regularly used in healthcare, there are no Tc-labelled receptor-targeted radiopharmaceuticals in widespread clinical use. This is in part due to the multistep radiosyntheses required for the latter.

Cysteine trisulfide oxidizes protein thiols and induces electrophilic stress in human cells.

The cellular effects of hydrogen sulfide (HS) signaling may be partially mediated by the formation of alkyl persulfides from thiols, such as glutathione and protein cysteine residues. Persulfides are potent nucleophiles and reductants and therefore potentially an important endogenous antioxidant or protein post-translational modification. To directly study the cellular effects of persulfides, cysteine trisulfide (Cys-S) has been proposed as an in situ persulfide donor, as it reacts with cellular thiols to generate cysteine persulfide (Cys-S-S).

Extended Bloch-McConnell equations for mechanistic analysis of hyperpolarized C magnetic resonance experiments on enzyme systems.

We describe an approach to formulating the kinetic master equations of the time evolution of NMR signals in reacting (bio)chemical systems. Special focus is given to studies that employ signal enhancement (hyperpolarization) methods such as dissolution dynamic nuclear polarization (dDNP) and involving nuclear spin-bearing solutes that undergo reactions mediated by enzymes and membrane transport proteins. We extend the work given in a recent presentation on this topic (Kuchel and Shishmarev, 2020) to now include enzymes with two or more substrates and various enzyme reaction mechanisms as classified by Cleland, with particular reference to non-first-order processes.

Assessment of hepatic fatty acids during non-alcoholic steatohepatitis progression using magnetic resonance spectroscopy.

Introduction And Objectives: Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver abnormalities including steatosis, steatohepatitis, fibrosis, and cirrhosis. Liver biopsy remains the gold standard method to determine the disease stage in NAFLD but is an invasive and risky procedure. Studies have previously reported that changes in intrahepatic fatty acids (FA) composition are related to the progression of NAFLD, mainly in its early stages.

Subtle Role for Adenylate Kinase 1 in Maintaining Normal Basal Contractile Function and Metabolism in the Murine Heart.

Aims: Adenylate kinase 1 (AK1) catalyses the reaction 2ADP ↔ ATP + AMP, extracting extra energy under metabolic stress and promoting energetic homeostasis. We hypothesised that increased AK1 activity would have negligible effects at rest, but protect against ischaemia/reperfusion (I/R) injury.

Methods And Results: Cardiac-specific AK1 overexpressing mice (AK1-OE) had 31% higher AK1 activity ( = 0.

Dipeptide inhibitors of the prostate specific membrane antigen (PSMA): A comparison of urea and thiourea derivatives.

Glutamate carboxypeptidase II (GCP(II)), also known as the prostate-specific membrane antigen (PSMA), is a transmembrane zinc(II) metalloenzyme overexpressed in prostate cancer. Inhibitors of this receptor are used to target molecular imaging agents and molecular radiotherapy agents to prostate cancer and if the affinity of inhibitors for GCP(II)/PSMA could be improved, targeting might also improve. Compounds containing the dipeptide OH-Lys-C(O)-Glu-OH (compound 3), incorporating a urea motif, have high affinity for GCP(II)/PSMA.

Off-target effects of sodium-glucose co-transporter 2 blockers: empagliflozin does not inhibit Na+/H+ exchanger-1 or lower [Na+]i in the heart.

Aims: Emipagliflozin (EMPA) is a potent inhibitor of the renal sodium-glucose co-transporter 2 (SGLT2) and an effective treatment for type-2 diabetes. In patients with diabetes and heart failure, EMPA has cardioprotective effects independent of improved glycaemic control, despite SGLT2 not being expressed in the heart. A number of non-canonical mechanisms have been proposed to explain these cardiac effects, most notably an inhibitory action on cardiac Na+/H+ exchanger 1 (NHE1), causing a reduction in intracellular [Na+] ([Na+]i).

Mitochondrial pyruvate carrier abundance mediates pathological cardiac hypertrophy.

Cardiomyocytes rely on metabolic substrates, not only to fuel cardiac output, but also for growth and remodelling during stress. Here we show that mitochondrial pyruvate carrier (MPC) abundance mediates pathological cardiac hypertrophy. MPC abundance was reduced in failing hypertrophic human hearts, as well as in the myocardium of mice induced to fail by angiotensin II or through transverse aortic constriction.

Breast cancer-associated macrophages promote tumorigenesis by suppressing succinate dehydrogenase in tumor cells.

Tumor-associated macrophages (TAMs) can exist in pro- and anti-inflammatory states. Anti-inflammatory TAMs (also referred to as M2-polarized) generally suppress antitumor immune responses and enhance the metastatic progression of cancer. To explore the mechanisms behind this phenomenon, we isolated macrophages from mice and humans, polarized them ex vivo, and examined their functional interaction with breast cancer cells in culture and in mice.

Intracellular sodium elevation reprograms cardiac metabolism.

Intracellular Na elevation in the heart is a hallmark of pathologies where both acute and chronic metabolic remodelling occurs. Here, we assess whether acute (75 μM ouabain 100 nM blebbistatin) or chronic myocardial Na load (PLM mouse) are causally linked to metabolic remodelling and whether the failing heart shares a common Na-mediated metabolic 'fingerprint'. Control (PLM), transgenic (PLM), ouabain-treated and hypertrophied Langendorff-perfused mouse hearts are studied by Na, P, C NMR followed by H-NMR metabolomic profiling.

[Ga]Ga-THP-Pam: A Bisphosphonate PET Tracer with Facile Radiolabeling and Broad Calcium Mineral Affinity.

Calcium minerals such as hydroxyapatite (HAp) can be detected noninvasively using nuclear imaging agents such as [F]NaF (available from cyclotrons), for positron emission tomography (PET) and Tc-radiolabeled bisphosphonates (BP; available from Tc generators for single photon emission computed tomography (SPECT) or scintigraphy). These two types of imaging agents allow detection of bone metastases (based on the presence of HAp) and vascular calcification lesions (that contain HAp and other calcium minerals). With the aim of developing a cyclotron-independent PET radiotracer for these lesions, with broad calcium mineral affinity and simple one-step radiolabeling, we developed [Ga]Ga-THP-Pam.

Investigating the effects of ebselen, a potential new lithium mimetic, on glutamate transmission.

Ebselen, a potential new lithium-like drug, treatment reduced brain glutamate, as measured by PET imaging using the mGluR5 radioligand [ F]FPEB in rats.