Cellular Components of the Blood-Brain Barrier and Their Involvement in Aging-Associated Cognitive Impairment.

Human life expectancy has been significantly extended, which poses major challenges to our healthcare and social systems. Aging-associated cognitive impairment is attributed to endothelial dysfunction in the cardiovascular system and neurological dysfunction in the central nervous system. The central nervous system is considered an immune-privileged tissue due to the exquisite protection provided by the blood-brain barrier.

Co-delivery of PD-L1- and EGFR-targeting siRNAs by synthetic PEG-KL4 peptide to the lungs as potential strategy against non-small cell lung cancer.

Background: Small interfering RNA (siRNA) holds great promise for treating various lung diseases, but the lack of safe and efficient pulmonary siRNA delivery systems has hindered its advance into the clinics. The epidermal growth factor receptor (EGFR) which promotes cell proliferation, and the programmed cell death ligand 1 (PD-L1) which plays a crucial role in suppressing cytotoxic T cells activity, are two important targets for treating non-small cell lung cancer (NSCLC). Here, we explored the potential of PEG-KL4, a synthetic peptide, to deliver siRNA to various NSCLC cells and to lung tissues in mice.

Glycolytic enzyme PFKFB3 regulates sphingosine 1-phosphate receptor 1 in proangiogenic glomerular endothelial cells under diabetic condition.

Glomerular angiogenesis is a characteristic feature of diabetic nephropathy (DN). Enhanced glycolysis plays a crucial role in angiogenesis. The present study was designed to investigate the role of glycolysis in glomerular endothelial cells (GECs) in a mouse model of DN.

Enhanced powder dispersion of dual-excipient spray-dried powder formulations of a monoclonal antibody and its fragment for local treatment of severe asthma.

The advent of biologics has brought renewed hope for patients with severe asthma, a condition notorious for being hampered by poor response to conventional therapies and adverse drug reactions owing to corticosteroid dependence. However, biologics are administered as injections, thereby precluding the benefits inhalation therapy could offer such as increased bioavailability at the site of action, minimal systemic side effects, non-invasiveness, and self-administration. Here, 2-hydroxypropyl-beta-cyclodextrin and ʟ-leucine were co-spray-dried, as protein stabiliser and dispersion enhancer, respectively, at various weight ratios to produce a series of formulation platforms.

Neutralisation of SARS-CoV-2 by monoclonal antibody through dual targeting powder formulation.

Neutralising monoclonal antibody (mAb) is an important weapon in our arsenal for combating respiratory viral infections. However, the effectiveness of neutralising mAb has been impeded by the rapid emergence of mutant variants. Early administration of broad-spectrum mAb with improved delivery efficiency can potentially enhance efficacy and patient outcomes.

Spray-Dried and Spray-Freeze-Dried Powder Formulations of an Anti-Interleukin-4Rα Antibody for Pulmonary Delivery.

Objective: The therapeutic options for severe asthma are limited, and the biological therapies are all parenterally administered. The purpose of this study was to formulate a monoclonal antibody that targets the receptor for IL-4, an interleukin implicated in the pathogenesis of severe asthma, into a dry powder intended for delivery via inhalation.

Methods: Dehydration was achieved using either spray drying or spray freeze drying, which exposes the thermolabile biomacromolecules to stresses such as shear and adverse temperatures.

Exploration of natural flavones' bioactivity and bioavailability in chronic inflammation induced-type-2 diabetes mellitus.

Diabetes, being the most widespread illness, poses a serious threat to global public health. It seems that inflammation plays a critical role in the pathophysiology of diabetes. This review aims to demonstrate a probable link between type 2 diabetes mellitus (T2DM) and chronic inflammation during its development.

Dual targeting powder formulation of antiviral agent for customizable nasal and lung deposition profile through single intranasal administration.

Unpredictable outbreaks due to respiratory viral infections emphasize the need for new drug delivery strategies to the entire respiratory tract. As viral attack is not limited to a specific anatomic region, antiviral therapy that targets both the upper and lower respiratory tract would be most effective. This study aimed to formulate tamibarotene, a retinoid derivative previously reported to display broad-spectrum antiviral activity against influenza and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), as a novel dual particle size powder formulation that targets both the nasal cavity and the lung by a single route of intranasal administration.

Glomerular Endothelial Cells Are the Coordinator in the Development of Diabetic Nephropathy.

The prevalence of diabetes is consistently rising worldwide. Diabetic nephropathy is a leading cause of chronic renal failure. The present study aimed to explore the crosstalk among the different cell types inside diabetic glomeruli, including glomerular endothelial cells, mesangial cells, podocytes, and immune cells, by analyzing an online single-cell RNA profile (GSE131882) of patients with diabetic nephropathy.

The glycolytic process in endothelial cells and its implications.

Endothelial cells play an obligatory role in regulating local vascular tone and maintaining homeostasis in vascular biology. Cell metabolism, converting food to energy in organisms, is the primary self-sustaining mechanism for cell proliferation and reproduction, structure maintenance, and fight-or-flight responses to stimuli. Four major metabolic processes take place in the energy-producing process, including glycolysis, oxidative phosphorylation, glutamine metabolism, and fatty acid oxidation.

Calcitriol Supplementation Ameliorates Microvascular Endothelial Dysfunction in Vitamin D-Deficient Diabetic Rats by Upregulating the Vascular eNOS Protein Expression and Reducing Oxidative Stress.

Diabetes mellitus contributes to macro- and microvascular complications, leading to adverse cardiovascular events. This study examined the effects of vitamin D deficiency on the vascular function and tissue oxidative status in the microcirculation of diabetic rats and to determine whether these effects can be reversed with calcitriol (active vitamin D metabolite) supplementation. Streptozotocin-induced diabetic rats were fed for 10 weeks with control diet (DC) or vitamin D-deficient diet without (DD) or with oral calcitriol supplementation (0.

MicroRNA-17-3p suppresses NF-κB-mediated endothelial inflammation by targeting NIK and IKKβ binding protein.

Nuclear factor kappa B (NF-κB) activation contributes to many vascular inflammatory diseases. The present study tested the hypothesis that microRNA-17-3p (miR-17-3p) suppresses the pro-inflammatory responses via NF-κB signaling in vascular endothelium. Human umbilical vein endothelial cells (HUVECs), transfected with or without miR-17-3p agomir/antagomir, were exposed to lipopolysaccharide (LPS), and the inflammatory responses were determined.

Particulate matter causes skin barrier dysfunction.

The molecular mechanisms that underlie the detrimental effects of particulate matter (PM) on skin barrier function are poorly understood. In this study, the effects of PM2.5 on filaggrin (FLG) and skin barrier function were investigated in vitro and in vivo.

Major histocompatibility complexes are up-regulated in glomerular endothelial cells via activation of c-Jun N-terminal kinase in 5/6 nephrectomy mice.

Background And Purpose: This study aims to explore the mechanism underlying the up-regulation of major histocompatibility complex (MHC) proteins in glomerular endothelial cells in 5/6 nephrectomy mice.

Experimental Approach: C57/BL6 mice were randomly allocated to sham-operated (2K) and 5/6 nephrectomy (5/6Nx) groups. Mouse splenic lymphocytes, from either syngeneic or allogeneic background, were injected into 5/6Nx mice after total body irradiation.

Long-term nitric oxide synthase inhibition prevents 17β-estradiol-induced suppression of cyclooxygenase-dependent contractions and enhancement of endothelium-dependent hyperpolarization-like relaxation in mesenteric arteries of ovariectomized rats.

Endothelial dysfunction is associated with a reduced bioavailability of nitric oxide (NO). In this study, the effects of 17β-estradiol supplement on endothelial function were examined in ovariectomized (OVX) rats following long-term inhibition of NO synthases with L-NAME. Female Sprague Dawley rats were ovariectomized at 12 weeks old.

Vascular adenosine monophosphate-activated protein kinase: Enhancer, brake or both?

Adenosine monophosphate-activated protein kinase (AMPK), expressed/present ubiquitously in the body, contributes to metabolic regulation. In the vasculature, activation of AMPK is associated with several beneficial biological effects including enhancement of vasodilatation, reduction of oxidative stress and inhibition of inflammatory reactions. The vascular protective effects of certain anti-diabetic (metformin and sitagliptin) or lipid-lowering (simvastatin and fenofibrate) therapeutic agents, of active components of Chinese medicinal herbs (resveratrol and berberine) and of pharmacological agents (AICAR, A769662 and PT1) have been attributed to the activation of AMPK (in endothelial cells, vascular smooth muscle cells and/or perivascular adipocytes), independently of changes in the metabolic profile (eg glucose tolerance and/or plasma lipoprotein levels), leading to improved endothelium-derived nitric oxide-mediated vasodilatation and attenuated endothelium-derived cyclooxygenase-dependent vasoconstriction.

Flavonoids reduces lipopolysaccharide-induced release of inflammatory mediators in human bronchial epithelial cells: Structure-activity relationship.

Flavonoids are polyphenolic compounds that are widely present in food and Chinese medicine. The aim of the present study was to identify the flavonoids with anti-inflammatory effects in the airway; and to determine the role of anti-oxidant and cyclic adenosine monophosphate (cAMP) in the anti-inflammatory effect. Human bronchial epithelial BEAS-2B cells were exposed to bacterial endotoxin lipopolysaccharide (LPS) in the absence or presence of different flavonoids, which are categorized according to their chemical structures in seven subclasses [anthocyanidins, chalcones, flavanes, flavanones, flavones, flavonols, isoflavones].

Hypoxic augmentation: The tale of a strange contraction.

Almost fifty years ago, experiments on isolated veins showed that acute hypoxia augments venoconstrictor responses in vitro and that such facilitation relied on anaerobic glycolysis. Over the years, this phenomenon was extended to a number of arterial preparations of different species and revisited, from a mechanistic point of view, with the successive demonstration that it depends on calcium handling in the vascular smooth muscle cells, is endothelium-dependent and requires the production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) and the activation of soluble guanylyl cyclase (sGC). However, rather than the vasodilator cyclic nucleotide 3',5'-cyclic guanosine monophosphate (cGMP), its canonical product, the latter enzyme produces 3',5'-cyclic inosine monophosphate (cIMP) instead during acute hypoxia; this non-canonical cyclic nucleotide facilitates the contractile process in the vascular smooth muscle cells.

Acute activation of endothelial AMPK surprisingly inhibits endothelium-dependent hyperpolarization-like relaxations in rat mesenteric arteries.

Background And Purpose: Endothelium-dependent hyperpolarizations (EDHs) contribute to the regulation of peripheral resistance. They are initiated through opening of endothelial calcium-activated potassium channels (K ); the potassium ions released then diffuse to the underlying smooth muscle cells, causing hyperpolarization and thus relaxation. The present study aimed to examine whether or not AMPK modulates EDH-like relaxations in rat mesenteric arteries.

Activation of NQO-1 mediates the augmented contractions of isolated arteries due to biased activity of soluble guanylyl cyclase in their smooth muscle.

Earlier studies on isolated arteries demonstrated that the para-quinone thymoquinone, like acute hypoxia, induces augmentation of contractions, depending on biased activity of soluble guanylyl cyclase (sGC), generating inosine-3',5'-cyclic monophosphate (cyclic IMP) rather than guanosine-3',5'-cyclic monophosphate (cyclic GMP). NAD(P)H:quinone oxidoreductase 1 (NQO-1), the enzyme responsible for biotransformation of quinones into hydroquinones, was examined for its involvement in these endothelium-dependent augmentations, establishing a link between the metabolism of quinones by NQO-1 and biased sGC activity. Isolated arteries of Sprague-Dawley rats (aortae and mesenteric arteries) and farm pigs (coronary arteries) were studied for measurement of changes in tension and collected to measure NQO-1 activity or its protein level.

Apolipoprotein E favours the blunting by high-fat diet of prostacyclin receptor activation in the mouse aorta.

Background And Purpose: NO-mediated, endothelium-dependent relaxations of isolated arteries are blunted by ageing and high-fat diets, as well as by apolipoprotein E deletion. The present study was designed to test the hypothesis that apolipoprotein E deletion impairs endothelium-dependent responses to prostacyclin (IP) receptor activation.

Experimental Approach: Five-week-old ApoE and ApoE mice were fed normal chow or high-fat diet for 29 weeks.