Prebiotics Progress Shifts in the Intestinal Microbiome That Benefits Patients with Type 2 Diabetes Mellitus.

Hypoglycemic medications that could be co-administered with prebiotics and functional foods can potentially reduce the burden of metabolic diseases such as Type 2 Diabetes Mellitus (T2DM). The efficacy of drugs such as metformin and sulfonylureas can be enhanced by the activity of the intestinal microbiome elaborated metabolites. Functional foods such as prebiotics (e.

The sulfonadyns: a class of aryl sulfonamides inhibiting dynamin I GTPase and clathrin mediated endocytosis are anti-seizure in animal models.

We show that dansylcadaverine (1) a known in-cell inhibitor of clathrin mediated endocytosis (CME), moderately inhibits dynamin I (dynI) GTPase activity (IC 45 μM) and transferrin (Tfn) endocytosis in U2OS cells (IC 205 μM). Synthesis gave a new class of GTP-competitive dynamin inhibitors, the Sulfonadyns™. The introduction of a terminal cinnamyl moiety greatly enhanced dynI inhibition.

Human Dendritic Cells Express the Complement Receptor Immunoglobulin Which Regulates T Cell Responses.

The B7 family-related protein V-set and Ig containing 4 (VSIG4), also known as Z39Ig and Complement Immunoglobulin Receptor (CRIg), is the most recent of the complement receptors to be identified, with substantially distinct properties from the classical complement receptors. The receptor displays both phagocytosis-promoting and anti-inflammatory properties. The receptor has been reported to be exclusively expressed in macrophages.

Cytokines regulate complement receptor immunoglobulin expression and phagocytosis of Candida albicans in human macrophages: A control point in anti-microbial immunity.

Complement Receptor Immunoglobulin (CRIg), selectively expressed by macrophages, plays an important role in innate immunity by promoting phagocytosis of bacteria. Thus modulation of CRIg on macrophages by cytokines can be an important mechanism by which cytokines regulate anti-microbial immunity. The effects of the cytokines, tumor necrosis factor, transforming growth factor-β1, interferon-γ, interleukin (IL)-4, IL-13, IL-10, IL-1β, IL-6, lymphotoxin-α, macrophage-colony stimulating factor (M-CSF) and GM-CSF on CRIg expression were examined in human macrophages.

Protein kinase cα regulates the expression of complement receptor Ig in human monocyte-derived macrophages.

The complement receptor Ig (CRIg) is selectively expressed by macrophages. This receptor not only promotes the rapid phagocytosis of bacteria by macrophages but also has anti-inflammatory and immunosuppressive functions. Previous findings have suggested that protein kinase C (PKC) may be involved in the regulation of CRIg expression in human macrophages.

Role of dynamin in elongated cell migration in a 3D matrix.

The use of 3-dimensional (3D) collagen gels has yielded new insights into the migratory behaviour of cancer cells. While the large GTPase dynamin has emerged as an important regulator of cancer cell migration and invasion under 2D conditions, its role in 3D migration is unclear. We have used a potent dynamin modulator, a bis-tyrphostin derivative, Ryngo® 1-23, to investigate the role of dynamin in 3D migration in 3 different cell lines.

Building a better dynasore: the dyngo compounds potently inhibit dynamin and endocytosis.

Dynamin GTPase activity increases when it oligomerizes either into helices in the presence of lipid templates or into rings in the presence of SH3 domain proteins. Dynasore is a dynamin inhibitor of moderate potency (IC₅₀ ~ 15 μM in vitro). We show that dynasore binds stoichiometrically to detergents used for in vitro drug screening, drastically reducing its potency (IC₅₀ = 479 μM) and research tool utility.

Pyrimidyn compounds: dual-action small molecule pyrimidine-based dynamin inhibitors.

Dynamin is required for clathrin-mediated endocytosis (CME). Its GTPase activity is stimulated by phospholipid binding to its PH domain, which induces helical oligomerization. We have designed a series of novel pyrimidine-based "Pyrimidyn" compounds that inhibit the lipid-stimulated GTPase activity of full length dynamin I and II with similar potency.

Regulation of CRIg expression and phagocytosis in human macrophages by arachidonate, dexamethasone, and cytokines.

Although the importance of the macrophage complement receptor immunoglobulin (CRIg) in the phagocytosis of complement opsonized bacteria and in inflammation has been established, the regulation of CRIg expression remains undefined. Because cellular activation during inflammation leads to the release of arachidonate, a stimulator of leukocyte function, we sought to determine whether arachidonate regulates CRIg expression. Adding arachidonate to maturing human macrophages and to prematured CRIg(+) macrophages caused a significant decrease in the expression of cell-surface CRIg and CRIg mRNA.

The pthaladyns: GTP competitive inhibitors of dynamin I and II GTPase derived from virtual screening.

We report the development of a homology model for the GTP binding domain of human dynamin I based on the corresponding crystal structure of Dictyostelium discoidum dynamin A. Virtual screening identified 2-[(2-biphenyl-2-yl-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonyl)amino]-4-chlorobenzoic acid (1) as a approximately 170 microM potent inhibitor. Homology modeling- and focused library-led synthesis resulted in development of a series of active compounds (the "pthaladyns") with 4-chloro-2-(2-(4-(hydroxymethyl)phenyl)-1,3-dioxoisoindoline-5-carboxamido)benzoic acid (29), a 4.

Iminochromene inhibitors of dynamins I and II GTPase activity and endocytosis.

Herein we report the synthesis of discrete iminochromene ("iminodyn") libraries (14-38) as potential inhibitors of dynamin GTPase. Thirteen iminodyns were active (IC(50) values of 260 nM to 100 microM), with N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (17), N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (22), and N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (23) (IC(50) values of 330 +/- 70, 450 +/- 50, and 260 +/- 80 nM, respectively) being the most potent. Five of the most potent iminodyns all inhibited dynamins I and II approximately equally.

Gene signatures reflect the marked heterogeneity of tissue-resident macrophages.

Tissue-resident macrophages play an important role in defense against pathogens and perform key functions in organ homeostasis, innate and adaptive immunity. Tissue macrophages originate from blood monocytes that infiltrate virtually every organ in the body. Macrophages in different tissues share many characteristics, including their ability to migrate, phagocytose particles, metabolize lipids and present antigens.

Contribution of histidine-rich glycoprotein in clearance of immune complexes and apoptotic cells: implications for ameliorating autoimmune diseases.

The molecular mechanisms that protect against the harmful properties of immune complexes and dying cells are not well understood. This review focuses on newly discovered mechanisms for the disposal of immune complexes and apoptotic cells by histidine-rich glycoprotein (HRG). Since HRG is abundantly synthesized by the liver and released into the blood stream at basal levels, it is readily available to engage in the removal of circulating modified self (e.

CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens.

The complement system serves an important role in clearance of pathogens, immune complexes, and apoptotic cells present in the circulation. Complement fragments deposited on the particle surface serve as targets for complement receptors present on phagocytic cells. Although Kupffer cells, the liver resident macrophages, play a dominant role in clearing particles in circulation, complement receptors involved in this process have yet to be identified.

Histidine-rich glycoprotein binds to DNA and Fc gamma RI and potentiates the ingestion of apoptotic cells by macrophages.

Histidine-rich glycoprotein (HRG) is an abundant serum protein that exhibits many functions in diverse biological systems. In this study, we show that HRG potentiates the ingestion of apoptotic cells by mature human monocyte-derived macrophages (HMDM). HRG bound specifically to apoptotic Jurkat cells and mature HMDM in a saturable and concentration-dependent manner.