Cardiotropic ligand-guided liposomes for myocardial delivery of atorvastatin in a mouse model of myocardial infarction.

The next major advancement in managing myocardial infarction (MI) patients is to protect myocardium against ischemia-reperfusion injury. Although several cardioprotective agents are being developed, their myocardial delivery is still a challenge. In this study, we designed a novel liposome-based nanocarrier for active targeting of damaged myocardium and demonstrated delivery of atorvastatin (ATV) as a model drug.

Chronic β3 adrenergic agonist treatment improves neurovascular coupling responses, attenuates blood-brain barrier leakage and neuroinflammation, and enhances cognition in aged mice.

Microvascular endothelial dysfunction, characterized by impaired neurovascular coupling, reduced glucose uptake, blood-brain barrier disruption, and microvascular rarefaction, plays a critical role in the pathogenesis of age-related vascular cognitive impairment (VCI). Emerging evidence points to non-cell autonomous mechanisms mediated by adverse circulating milieu (an increased ratio of pro-geronic to anti-geronic circulating factors) in the pathogenesis of endothelial dysfunction leading to impaired cerebral blood flow and cognitive decline in the aging population. In particular, age-related adipose dysfunction contributes, at least in part, to an unfavorable systemic milieu characterized by chronic hyperglycemia, hyperinsulinemia, dyslipidemia, and altered adipokine profile, which together contribute to microvascular endothelial dysfunction.

Interrogation of the tumor microenvironment by nanoparticles.

The tumor microenvironment (TME) plays a pivotal role in cancer progression by fostering intricate multicellular crosstalk among cancer cells, stromal cells, and immune cells. This review explores the emerging paradigm of utilizing nanoparticles to disrupt this crosstalk within the TME as a therapeutic strategy. Nanoparticles are engineered with precise physicochemical properties to target specific cell types and deliver therapeutic payloads, thereby inhibiting critical signaling pathways involved in tumor growth, invasion, and metastasis.

Chronic β3 adrenergic agonist treatment improves brain microvascular endothelial function and cognition in aged mice.

Microvascular endothelial dysfunction, characterized by impaired neurovascular coupling, reduced glucose uptake, blood-brain barrier disruption, and microvascular rarefaction, plays a critical role in the pathogenesis of age-related vascular cognitive impairment (VCI). Emerging evidence points to non-cell autonomous mechanisms mediated by adverse circulating milieu (an increased ratio of pro-geronic to anti-geronic circulating factors) in the pathogenesis of endothelial dysfunction leading to impaired cerebral blood flow and cognitive decline in the aging population. In particular, age-related adipose dysfunction contributes, at least in part, to an unfavorable systemic milieu characterized by chronic hyperglycemia, hyperinsulinemia, dyslipidemia, and altered adipokine profile, which together contribute to microvascular endothelial dysfunction.

Role of Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Signaling in Liver and Metabolic Diseases.

MAP4K4 is a serine/threonine protein kinase belonging to the germinal center kinase subgroup of sterile 20 protein family of kinases. MAP4K4 has been involved in regulating multiple biologic processes and a plethora of pathologies, including systemic inflammation, cardiovascular diseases, cancers, and metabolic and hepatic diseases. Recently, multiple reports have indicated the upregulation of MAP4K4 expression and signaling in hyperglycemia and liver diseases.

Advancements in metabolic-associated steatotic liver disease research: Diagnostics, small molecule developments, and future directions.

Metabolic (dysfunction)-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease, is a growing global health concern with no approved pharmacological treatments. At the same time, there are no standard methods to definitively screen for the presence of MASLD because of its progressive nature and symptomatic commonality with other disorders. Recent advances in molecular understanding of MASLD pathophysiology have intensified research on development of new drug molecules, repurposing of existing drugs approved for other indications, and an educated use of dietary supplements for its treatment and prophylaxis.

Evaluation of anti-inflammatory diphenyldihaloketone EF24 in transient ischemic stroke model.

Objectives: Revascularization is necessary in patients with ischemic stroke, however it does not address inflammation that contribute to reperfusion injury and the early growth of ischemic core. We investigated EF24, an anti-inflammatory agent, in a stroke model.

Methods: Ischemic stroke was induced in mice by occluding middle cerebral artery for 1 h followed by reperfusion.

Positron Emission Tomography (PET) with F-FGA for Diagnosis of Myocardial Infarction in a Coronary Artery Ligation Model.

Location and extent of necrosis are valuable information in the management of myocardial infarction (MI). . We investigated 2-deoxy-2-F-fluoro glucaric acid (FGA), a novel infarct-avid agent, for positron emission tomography (PET) of MI.

Mechanism of Anti-Inflammatory Activity of TLR4-Interacting SPA4 Peptide.

The TLR4-interacting SPA4 peptide suppresses inflammation. We assessed the structural and physicochemical properties and binding of SPA4 peptide to TLR4-MD2. We also studied the changes at the whole transcriptome level, cell morphology, viability, secreted cytokines and chemokines, and cell influx in cell systems and mouse models challenged with LPS and treated with SPA4 peptide.

Biodegradable Polymeric Nanoparticles for Drug Delivery to Solid Tumors.

Advances in nanotechnology have favored the development of novel colloidal formulations able to modulate the pharmacological and biopharmaceutical properties of drugs. The peculiar physico-chemical and technological properties of nanomaterial-based therapeutics have allowed for several successful applications in the treatment of cancer. The size, shape, charge and patterning of nanoscale therapeutic molecules are parameters that need to be investigated and modulated in order to promote and optimize cell and tissue interaction.

Drug-induced cardiomyopathy: Characterization of a rat model by [F]FDG/PET and [Tc]MIBI/SPECT.

Background: Drug-induced cardiomyopathy is a significant medical problem. Clinical diagnosis of myocardial injury is based on initial electrocardiogram, levels of circulating biomarkers, and perfusion imaging with single photon emission computed tomography (SPECT). Positron emission tomography (PET) is an alternative imaging modality that provides better resolution and sensitivity than SPECT, improves diagnostic accuracy, and allows therapeutic monitoring.

Tubulin inhibitory activity of a novel colchicine-binding compounds based on a dinaphthospiropyranran scaffold.

Spiropyrans have been investigated for their thermo- and photochromic characteristics, but their biotherapeutic properties have not been addressed. We report anti-proliferative properties of a novel dinaphthospiropyran analogue (1). The compound 1 was synthesized by a simple and expedient method using a one-pot acid-catalyzed aldol condensation of 2-hydroxy-1-naphthaldehyde with 4-piperidone followed by an acetalization reaction.

Tumor suppressive activities of solvatochromic 3,3'-azadimethylene dinaphthospiropyran in colon cancer model.

Spiropyrans have been extensively investigated because of their thermo- and photochromic characteristics, but their biotherapeutic properties have not been explored much. We report anti-proliferative properties of a novel 3,3'-azadimethylene dinaphthospiropyran 11. Dibenzospiropyrans and dinaphthospiropyrans were synthesized by a simple and expedient method using acid-catalyzed aldol condensation of salicylaldehyde and 2-hydroxy-1-naphthaldehyde, respectively, with cyclic ketones.

Nanoparticles for Targeting of Prostate Cancer.

Prostate cancer (PCa) is the leading cause of death by cancer in men. Because of the drastic decline in the survival rate of PCa patients with advanced/metastatic disease, early diagnosis of disease and therapy without toxic side effects is crucial. Chemotherapy is widely used to control the progression of PCa at the later stages; however, it is associated with off-target toxicities and severe adverse effects due to the lack of specificity.

Lung and general health effects of Toll-like receptor-4 (TLR4)-interacting SPA4 peptide.

Background: A surfactant protein-A-derived peptide, which we call SPA4 peptide (amino acids: GDFRYSDGTPVNYTNWYRGE), alleviates lung infection and inflammation. This study investigated the effects of intratracheally administered SPA4 peptide on systemic, lung, and health parameters in an outbred mouse strain, and in an intratracheal lipopolysaccharide (LPS) challenge model.

Methods: The outbred CD-1 mice were intratracheally administered with incremental doses of SPA4 peptide (0.

PET Detection of Cerebral Necrosis Using an Infarct-Avid Agent 2-Deoxy-2-[F]Fluoro-D-Glucaric Acid (FGA) in a Mouse Model of the Brain Stroke.

Purpose: Ischemic stroke is a leading cause of disability worldwide. The volume of necrotic core in affected tissue plays a major role in selecting stroke patients for thrombolytic therapy or endovascular thrombectomy. In this study, we investigated a recently reported positron emission tomography (PET) agent 2-deoxy-2-[F]fluoro-D-glucaric acid (FGA) to determine necrotic core in a model of transient middle cerebral artery occlusion (t-MCAO) in mice.

Anti-inflammatory mediators ST2 and SIGIRR are induced by diphenyldifluoroketone EF24 in lipopolysaccharide-stimulated dendritic cells.

The objective of this study was to investigate the effect of EF24, an NF-κB-inhibitor, on the expression of negative regulators in IL-1R pathway, namely ST2 and SIGIRR. Murine JAWS II dendritic cells (DC) were challenged with lipopolysaccharide (LPS, 100 ng/ml) for 4 h, followed by treatment with 10 μM EF24 for 1 h. ST2 and SIGIRR expression was monitored by qRT-PCR and immunoblotting.

Production of [N]ammonia from [C]methanol on a 7.5 MeV cyclotron using C(p, n)N reaction: Detection of myocardial infarction in a mouse model.

[N]Ammonia is commonly produced using O(p, α)N reaction but one of the limiting factor of this reaction is the relatively small nuclear cross-section at proton energies of <10 MeV. An alternative production method using C(p, n)N reaction, which has a higher nuclear cross-section at low proton energies, is more suitable for a preclinical PET imaging facility equipped with a <10 MeV cyclotron. Here, we report a novel method to produce [N]ammonia from [C]methanol for preclinical use on a 7.

Surface Modification of Liposomes by a Lipopolymer Targeting Prostate Specific Membrane Antigen for Theranostic Delivery in Prostate Cancer.

Prostate specific membrane antigen (PSMA) is a marker for diagnosis and targeted delivery of therapeutics to advanced/metastasized prostate cancer. We report a liposome-based system for theranostic delivery to PSMA-expressing (PSMA⁺) LNCaP cells. A lipopolymer (P³) comprising of PSMA ligand (PSMAL), polyethylene glycol (PEG), and palmitate was synthesized and post-inserted into the surface of preformed liposomes.

Ubiquitin Receptor RPN13 Mediates the Inhibitory Interaction of Diphenyldihaloketones CLEFMA and EF24 With the 26S Proteasome.

The proteasome is a validated target in drug discovery for diseases associated with unusual proteasomal activity. Here we report that two diphenyldihaloketones, CLEFMA and EF24, inhibit the peptidase activity of the 26S proteasome. The objective of this study was to investigate interaction of these compounds with the proteasome and identify a putative target within the protein components of the 26S proteasome.

Induction of gut proteasome activity in hemorrhagic shock and its recovery by treatment with diphenyldihaloketones CLEFMA and EF24.

Multiorgan failure in hemorrhagic shock is triggered by gut barrier dysfunction and consequent systemic infiltration of proinflammatory factors. Our previous study has shown that diphenyldihaloketone drugs 4-[3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidinyl]-4-oxo-2-butenoic acid (CLEFMA) and 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone (EF24) restore gut barrier dysfunction and reduce systemic inflammatory response in hemorrhagic shock. We investigated the effect of hemorrhagic shock on proteasome activity of intestinal epithelium and how CLEFMA and EF24 treatments modulate proteasome function in hemorrhagic shock.