Capillary Endothelial Insulin Transport: The Rate Limiting Step for Insulin-stimulated Glucose Uptake

The rate limiting step for skeletal muscle glucose uptake is transport from microcirculation to muscle interstitium. Capillary endothelium poses a barrier that delays the onset of muscle insulin action. Defining physiological barriers that control insulin access to interstitial space is difficult due to technical challenges that confront study of microscopic events in an integrated physiological system. Two physiological variables determine muscle insulin access. These are the number of perfused capillaries and the permeability of capillary walls to insulin. Disease states associated with capillary rarefaction are closely linked to insulin resistance. Insulin permeability through high resistant capillary walls of muscle poses a significant barrier to insulin access. Insulin may traverse the endothelium through narrow intercellular junctions or vesicular trafficking across the endothelial cell. Insulin is large compared to intercellular junctions making this an unlikely route. Transport by endothelial vesicular trafficking is likely the primary route of transit. Studies in vivo show movement of insulin is not insulin receptor-dependent. This aligns with single cell transcriptomics that show the insulin receptor is not expressed in muscle capillaries. Work in cultured endothelial cell lines suggest that insulin receptor activation is necessary for endothelial insulin transit. Controversies remain in the understanding of trans-endothelial insulin transit to muscle. These controversies closely align with experimental approaches. Control of circulating insulin accessibility to skeletal muscle is an area that remains ripe for discovery. Factors that impede insulin access to muscle may contribute to disease and factors that accelerate access may be of therapeutic value for insulin resistance.

Venous discirculation and cognitive impairment

This article considers the aging impact on the functional and structural integrity of venous cerebral circulation from the standpoint of potential mechanisms involved in the pathogenesis of neurodegeneration and cognitive decline. It was reported about venous collagenosis in the brain with apparent leukoaraiosis that demonstrates the participation of pathological re-structure of the venous wall in impairment of white matter both in natural aging and in Alzheimer’s disease. It is likely that due to an age-related decrease in elasticity, the internal jugular vein loses its compensatory ability to increase transmural pressure and therefore results in venous hypertension in the cerebral venous system. Diosminum increases the tone of venous and lymphatic vessels, decreases venous and lymphatic stasis, strengthens the capillary walls and reduces their permeability, has anti-inflammatory, antiedemic, and analgesic effects, improves microcirculation and tissue trophicity, prevents thrombosis. Hesperidin strengthens the walls of small vessels that reduces their permeability and therefore decreases the edemas.

Calculation of the Gibbs–Donnan factors for multi-ion solutions with non-permeating charge on both sides of a permselective membrane

Separation of two ionic solutions with a permselective membrane that is impermeable to some of the ions leads to an uneven distribution of permeating ions on the two sides of the membrane described by the Gibbs–Donnan (G–D) equilibrium with the G–D factors relating ion concentrations in the two solutions. Here, we present a method of calculating the G–D factors for ideal electroneutral multi-ion solutions with different total charge of non-permeating species on each side of a permselective membrane separating two compartments. We discuss some special cases of G–D equilibrium for which an analytical solution may be found, and we prove the transitivity of G–D factors for multi-ion solutions in several compartments interconnected by permselective membranes. We show a few examples of calculation of the G–D factors for both simple and complex solutions, including the case of human blood plasma and interstitial fluid separated by capillary walls. The article is accompanied by an online tool that enables the calculation of the G–D factors and the equilibrium concentrations for multi-ion solutions with various composition in terms of permeating ions and non-permeating charge, according to the presented method.

No Evidence for the Involvement of Leiomodin-1 Antibodies in the Pathogenesis of Onchocerciasis-Associated Epilepsy

Nodding syndrome has been suggested to be triggered by neurotoxic leiomodin-1 auto-antibodies cross-reacting with Onchocerca volvulus. Here, we screened serum and CSF samples of persons with nodding syndrome and other forms of onchocerciasis-associated epilepsy (OAE) and African and European controls for leiomodin-1 antibodies by a cell-based assay (CBA) and Western blot (WB). These samples were also investigated for the presence of auto-antibodies cross-reacting with rat brain tissue by immunohistochemistry (IHC). Additionally, IHC was used to detect the leiomodin-1 protein in post-mortem brain samples of persons with OAE who died. Leiomodin-1 antibodies were detected by CBA in 6/52 (12%) and by WB in 23/54 (43%) persons with OAE compared to in 14/61 (23%) (p = 0.113) and 23/54 (43%) (p = 0.479) of controls without epilepsy. Multivariable exact logistic regression did not show an association between O. volvulus infection or epilepsy status and the presence of leiomodin-1. Leiomodin-1 antibodies were not detected in 12 CSF samples from persons with OAE or in 16 CSF samples from persons with acute-onset neurological conditions, as well as not being detected in serum from European controls. Moreover, the leiomodin-1 protein was only detected in capillary walls in post-mortem brain tissues and not in brain cells. IHC on rat brain slides with serum samples from persons with OAE or controls from persons with or without O. volvulus infection revealed no specific staining pattern. In conclusion, our data do not support OAE to be an autoimmune disorder caused by leiomodin-1 antibodies.

Bilayer capillary coatings based on nanosized ion-exchangers for the capillary electrochromatography analyses of biogenic amines and amino acids

Nanoparticles are widely used in capillary electrophoresis as stationary phases adsorbed on the internal capillary walls for the separation and concentration of analytes in capillary electrochromatography. The fastest and simplest approach for the formation of coatings is a physical adsorption of nanoparticles. Nevertheless, the formed coatings frequently possess low stability. The layer-by-layer approach for the formation of stabile and dense coating of internal capillary walls based on negatively charged nanosized cation-exchanger was proposed. The method included the sequential alteration of appositively charged layers of nanosized ion-exchangers. The proposed “anion-exchanger – cation-exchanger” bilayer coating possesses high stability in wide pH range (2-10) and provides up to 120 analyses without the need of re-coating. The coating was applied for the separation and on-line concentration of catecholamines and amino acids in capillary electrochromatography mode. High efficiencies were achieved (N = 450-720 th. t.p./m and N = 400-520 th. t.p./m for cathecholamies and amino acids, respectively), while the analysis time was significantly decreased. It was established, that high concentration of negatively charged functional groups on the capillary surface led to the increase of stacking efficiency factors due to the interactions between analytes and functional groups of the modifier on the capillary walls. It contributed to the 2-4 times reduced detection limits (LODs) of analytes compared to the mono-layer coatings (LODs of catecholamines = 3-4 ng/mL, LODs of amino acids = 40-100 ng/mL).

Transcapillary transport of water, small solutes and proteins during hemodialysis

The semipermeable capillary walls not only enable the removal of excess body water and solutes during hemodialysis (HD) but also provide an essential mechanism for maintaining cardiovascular homeostasis. Here, we investigated transcapillary transport processes on the whole-body level using the three-pore model of the capillary endothelium with large, small and ultrasmall pores. The transcapillary transport and cardiovascular response to a 4-h hemodialysis (HD) with 2 L ultrafiltration were analyzed by simulations in a virtual patient using the three-pore model of the capillary wall integrated in the whole-body compartmental model of the cardiovascular system with baroreflex mechanisms. The three-pore model revealed substantial changes during HD in the magnitude and direction of transcapillary water flows through small and ultrasmall pores and associated changes in the transcapillary convective transport of proteins and small solutes. The fraction of total capillary hydraulic conductivity attributed to ultrasmall pores was found to play an important role in the transcapillary water transport during HD thus influencing the cardiovascular response to HD. The presented model provides a novel computational framework for a detailed analysis of microvascular exchange during HD and as such may contribute to a better understanding of dialysis-induced changes in blood volume and blood pressure.

Covid-19 Pandemic and Possible Links with Mthfr Mutations, Homocysteinemia, and Metabolic Disturbances: Short Review

Coronovirus-19 (COVID-19) is an associate degree infection caused by the SARS-CoV-2 virus inflicting a worldwide pandemic and chiefly characterized by respiratory symptoms, many times accompanied by a cytokine storm. It causes migration of the neutrophils, macrophages and inflammatory cytokines resulting in the destruction of the alveolar-capillary walls. Coagulopathy in patients with COVID-19 may be a common complication that jeopardizes the clinical course and is related to poorer outcomes and probable death. The methylenetetrahydrofolate enzyme (MTHFR) is coded by the gene with the image MTHFR on chromosome one location p36.3 in humans, and there are desoxyribonucleic acid sequence variants (genetic polymorphisms) related to this gene. However, the 2 commonest ones are C677T and A1298C. Deficiencies within the production of this accelerator are related to raise risk of cardiac muscle infarctions, stroke, thrombosis, and several conditions. Homocysteine (Hcy) is a chemical in the blood formed when the amino acid methionine, a building block of the proteins, is naturally metabolized to be excreted in the urine; throughout this breakdown method, our body will recycle homocysteine to be reused to make different proteins. For this utilization, we need vitamins B12, B6, and folate. Also, for utilization to be the foremost economical, the accelerator MTHFR is needed. Transmissible mutations within the factor that create the MTHFR accelerator will result in an associate degree accelerator that’s not optimally active and should result in elevated homocysteine levels. Several medical conditions, like vascular disorders, obesity, diabetic disorder, peripheral neuropathy, and thrombophilia’s inside others, are associated with high Hcy levels and MTHFR mutations. Few reports link the high risk and poor prognosis with COVID-19 with MTHFR mutation and metabolic disorders like obesity and Diabetes mellitus. In this this review, we provide recommendations to prevent complications in patients with COVID, MTHFR mutations, Diabetes, and Obesity.

Diagnosis of Collagen Type III Glomerulopathy Using Picrosirius Red and PASH/Masson’s Trichrome Stain

Canine collagen type III glomerulopathy (Col3GP) is a rare juvenile nephropathy in which irregular type III collagen fibrils and fibronectin accumulate in glomerular capillary walls and the mesangium. Necropsy findings were reviewed from 5 puppies diagnosed with Col3GP at 6 to 18 weeks of age. Histologically, with hematoxylin and eosin stain, the glomerular capillary walls and mesangium were diffusely and globally expanded by homogeneous pale eosinophilic material. Ultrastructurally, the subendothelial zone and mesangium were expanded by fibronectin and cross-banded collagen type III fibrils, diagnostic of Col3GP. Two additional stains were employed to identify the material within glomeruli as fibrillar collagen using light microscopy. In all 5 cases, the material was red with picrosirius red and birefringent under polarized light, and was blue with periodic acid-Schiff/hematoxylin/trichrome (PASH/TRI), thereby identifying it as fibrillar collagen. Based on these unique staining characteristics with picrosirius red and PASH/TRI, Col3GP may be reliably diagnosed with light microscopy alone.

High Performance Liquid Chromatographic Analysis of Rutin in Allium Species from Bosnia and Herzegovina

Rutin is quercetin heteroside widely present in plants that exhibit many health-beneficial effects, such as strengthening the capillary walls, reducing the harmful effects of LDL cholesterol, and reducing the risk of cardiovascular diseases. Rutin was determined from three <i>Allium</i> species (<i>A. cepa</i>, <i>A. sativum</i>, and <i>A. ursinum</i>) collected in Bosnia and Herzegovina by the HPLC method associated with electrochemical detection. The analysis was performed from methanol extracts of bulb and leaf of garlic, bulb and leaf of onion, and leaves of wood garlic. Rutin was present in all of the examined samples. The highest rutin content was found in garlic leaves (0.78 ± 0.09 mg g<sup>–1</sup>), and the lowest in onion bulbs (0.04 ± 0.10 mg g<sup>–1</sup>). The contents of rutin were higher in leaf samples, suggesting that leaves of onion and garlic are recommended as a better natural source of this glycoside.

Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes

Cerebral blood flow is reduced early in the onset of Alzheimer’s disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. We used live and rapidly fixed biopsied human tissue to establish disease relevance, and rodent experiments to define mechanism. We found that in humans with cognitive decline, amyloid β (Aβ) constricts brain capillaries at pericyte locations. This was caused by Aβ generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ETA receptors. Capillary, but not arteriole, constriction also occurred in vivo in a mouse model of AD. Thus, inhibiting the capillary constriction caused by Aβ could potentially reduce energy lack and neurodegeneration in AD.