Translational research : the journal of laboratory and clinical medicine
-
Patients with sickle cell disease (SCD) have ongoing hemolysis that promotes endothelial injury, complement activation, inflammation, vaso-occlusion, ischemia-reperfusion pathophysiology, and pain. Complement activation markers are increased in SCD in steady-state and further increased during vaso-occlusive crisis (VOC). However, the mechanisms driving complement activation in SCD have not been completely elucidated. ⋯ Importantly, MASP-2 or MASP-3 mAb pretreatment significantly inhibited microvascular stasis (vaso-occlusion) induced by hypoxia-reoxygenation or hemoglobin. These studies suggest that the LP and the AP are both playing a role in promoting inflammation and vaso-occlusion in SCD. Inhibiting complement activation via the LP or the AP might inhibit inflammation and prevent VOC in SCD patients.
-
As an anti-inflammatory strategy, MAPK-activated protein kinase-2 (MK2) inhibition can potentially avoid the clinical failures seen for direct p38 inhibitors, especially tachyphylaxis. CC-99677, a selective targeted covalent MK2 inhibitor, employs a rare chloropyrimidine that bonds to the sulfur of cysteine 140 in the ATP binding site via a nucleophilic aromatic substitutions (SNAr) mechanism. This irreversible mechanism translates biochemical potency to cells shown by potent inhibition of heat shock protein 27 (HSP27) phosphorylation in LPS-activated monocytic THP-1 cells. ⋯ Dosed orally, CC-99677 is efficacious in a rat model of ankylosing spondylitis. Single doses, 3 to 400 mg, in healthy human volunteers show linear pharmacokinetics and apparent sustained tumor necrosis factor-α inhibition, with a favorable safety profile. These results support further development of CC-99677 for autoimmune diseases like ankylosing spondylitis.
-
Gender-sex differences in autoimmune diseases are gaining increasing attention due to their effects on prevalence and clinical features. Data on gender-sex differences in autoimmune atrophic gastritis (AAG), a chronic not-self-limiting inflammatory condition characterized by corpus-oxyntic mucosa atrophy sparing the antrum, are lacking. This study aimed to assess possible gender-sex differences of clinical, serological, histological, and genetic features in AAG patients. ⋯ AAG was preponderant in women who showed stronger autoimmune serological responsiveness and different HLA-DRB1 association. AAG showed differential clinical profiles in female and male patients occurring mainly in normal weight, dyspeptic women with iron-deficiency anemia and autoimmune thyroid disease, but in overweight male smokers with pernicious anemia. Stratification for sex and gender should be considered in future genetic, immunological, and clinical studies on autoimmune atrophic gastritis.
-
Monocyte and macrophage recruitment occur to the injured vessel wall after percutaneous transluminal angioplasty (PTA) of stenotic arteriovenous fistulas (AVF) through increased expression of MCP-1 leading to venous neointimal hyperplasia (VNH) and venous stenosis (VS). We hypothesized that adventitial delivery of Bindarit, an oral selective inhibitor of MCP-1, -2, and -3 encapsulated in poly lactic-co-glycolic acid (PLGA) nanoparticles embedded in a thermosensitive Pluronic F127 hydrogel (BN NP) could prevent VNH/VS formation in a murine model of PTA with AVF. Scanning electron microscope and dynamic light scattering were used to characterize the BN NP and control nanoparticles (NP C). ⋯ BN NP-treated vessels had reduced MCP-1, MCP-2, and MCP-3 gene, and protein levels, reduced macrophage/monocyte abundance, proinflammatory cytokines, and venous fibrosis resulting in positive vascular remodeling and improved patency with reduced VNH/VS. There was increased peak velocity 21 days after PTA in the BN NP group. Adventitial administration of BN NP to the outflow vein after PTA results in decreased VNH/VS.
-
Review
Central and peripheral regulations mediated by short-chain fatty acids on energy homeostasis.
The human gut microbiota influences obesity, insulin resistance, and the subsequent development of type 2 diabetes (T2D). The gut microbiota digests and ferments nutrients resulting in the production of short-chain fatty acids (SCFAs), which generate various beneficial metabolic effects on energy and glucose homeostasis. However, their roles in the central nervous system (CNS)-mediated outputs on the metabolism have only been minimally studied. ⋯ These functions have been linked with AMPK signaling, GPCRs-dependent pathways, and inhibition of histone deacetylases (HDACs). However, the studies focusing on the central effects of SCFAs are still limited. The mechanisms by which central SCFAs regulate appetite, energy expenditure, and blood glucose during different physiological conditions warrant further investigation.