Translational research : the journal of laboratory and clinical medicine
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CD36 is a transmembrane glycoprotein receptor for oxidized low density lipoprotein (LDL) and other endogenous danger signals and promotes athero-thrombotic processes. CD36 has been shown to associate physically with other transmembrane proteins, including integrins, tetraspanins, and toll-like receptors, which modulate CD36-mediated cell signaling. The CD36 N-terminal transmembrane domain (nTMD) contains a GXXXG sequence motif that mediates protein-protein interactions in many membrane proteins. ⋯ Prior to performing these assays, cells were incubated with a synthetic 29 amino acid peptide containing the 22 amino acid of CD36 nTMD or a control peptide in which the glycine residues in GXXXG motif were replaced by valines. In functional experiments, macrophages were preincubated with peptides and then treated with oxLDL to assess LDL uptake, foam cell formation, ROS formation and cell migration. CD36 nTMD peptide treated cells compared to untreated or control peptide treated cells showed decreased CD36 surface associations with tetraspanin CD9 and ameliorated pathologically important CD36 mediated responses to oxLDL, including uptake of DiI-labeled oxLDL, foam cell formation, ROS generation, and inhibition of migration.
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Diabetic foot ulcer (DFU) is among the most frequent complications of diabetes and is associated with significant morbidity and mortality. Excessive neutrophil extracellular traps (NETs) delay wound healing in diabetic patients. Therefore, interventions targeting NET release need to be developed to effectively prevent NET-based wound healing impairment. ⋯ Furthermore, inhibition of GSDMD with disulfiram or genic deletion of Gsdmd abrogated NET formation, thereby accelerating diabetic wound healing. Disulfiram could inhibit NETs-mediated diabetic foot ulcer healing impairment by suppressing the NLRP3/Caspase-1/GSDMD pathway. In summary, our findings uncover a novel therapeutic role of disulfiram in inhibiting NET formation, which is of considerable value in accelerating wound healing in patients with DFU.
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A deeper pathophysiologic understanding of available mouse models of sickle cell disease (SCD), such as the Townes model, will help improve preclinical studies. We evaluated groups of Townes mice expressing either normal adult human hemoglobin (HbA), sickle cell trait (HbAS), or SCD (HbS), comparing younger versus older adults, and females versus males. We obtained hematologic parameters in steady-state and hypoxic conditions and evaluated metabolic markers and cytokines from serum. ⋯ Plethysmography suggested obstructive lung disease and inflammatory changes in HbS mice. Histopathological studies showed vascular congestion, increased iron deposition, and disruption of normal tissue architecture in HbS mice. These data correlate with clinical manifestations in SCD patients and highlight analyses and groups to be included in preclinical therapeutic studies.
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Hypertension (HTN) is a common endpoint for numerous cardiovascular diseases, the prevalence of which has been quickly increasing due to a wide range of reasons. Previous research has found that following stress, ELISA and 16S rDNA sequencing indicated substantial changes in plasma cytokines or hormones, as well as alterations in gut microbiota in juvenile hypertensive rats. However, it remains still unclear how such interaction modifications affect microbial populations and organismal function. ⋯ Significant improvements in bacteria linked with short-chain fatty acid synthesis, such as Prevotella and Ruminococcus, were discovered by metagenomic analysis. Adult hypertensive rats are more susceptible to gut microbiota disruption and fibrosis as a result of mild restraint stress. This might contribute to some innovative ideas for HTN both treatment and prevention.
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Multicenter Study
Expression and function of α4β7 integrin predict the success of vedolizumab treatment in inflammatory bowel disease.
Inflammatory bowel diseases are medically intractable and require constant therapy in many cases. While a growing number of biologicals and small molecules is available for treatment, a substantial portion of patients experiences primary non-response to these compounds and head-to-head evidence for therapy selection is scarce. Thus, approaches to predict treatment success in individual patients are a huge unmet need. ⋯ Moreover, high dynamic adhesion of CD4+ T cells to MAdCAM-1 and high reduction of adhesion by vedolizumab in vitro at baseline were associated with clinical remission. These data substantiate the potential of α4β7 integrin function and expression to forecast outcomes of vedolizumab therapy. Further translational efforts are necessary to improve the performance of the assays and to implement the concept in clinical practice.