Translational research : the journal of laboratory and clinical medicine
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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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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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With the increasing prevalence of Alzheimer's disease (AD) among aging populations and the limited therapeutic options available to slow or reverse its progression, the need has never been greater for improved diagnostic tools for identifying patients in the preclinical and prodomal phases of AD. Biophysics models of the connectome-based spread of amyloid-beta (Aβ) and microtubule-associated protein tau (τ) have enjoyed recent success as tools for predicting the time course of AD-related pathological changes. ⋯ Here we discuss several areas of active research in AD whose insights can be used to enhance the mathematical modeling of AD pathology as well as recent attempts at developing improved connectome-based biophysics models. These efforts toward a comprehensive yet parsimonious mathematical description of AD hold great promise for improving both the diagnosis of patients at risk for AD and our mechanistic understanding of how AD progresses.
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The present study hypothesizes that the ischemic insults activate epicardial adipose tissue-derived stem cells (EATDS) to secrete extracellular vesicles (EVs) packed with regenerative mediators to alter the gene expression in cardiac fibroblasts (CF). EATDS and CF were isolated from hyperlipidemic microswine and EVs were harvested from control, simulated ischemia (ISC) and ischemia-reperfusion (ISC/R) groups. The in vitro interaction between ISC-EVs and CF resulted in the upregulation of cardiomyocyte-specific transcription factors including GATA4, Nkx2.5, IRX4, and TBX5 in CF and the healing marker αSMA and the downregulation of fibroblast biomarkers such as vimentin, FSP1, and podoplanin and the cardiac biomarkers such as troponin-I and connexin-43. ⋯ The LC-MS/MS analysis of ISC-EVs LGALS1, PRDX2, and CCL2 to be the potent protein mediators which are intimately involved in versatile regenerative processes and connected with a diverse array of regenerative genes. Moreover, the LGALS1+, PRDX2+, and CCL2+ EATDS phenotypes were deciphered at single cell resolution revealing corresponding sub-populations with superior healing potential. Overall, the findings unveiled the healing potential of EATDS-derived EVs and sub-populations of regenerative EATDS promising novel translational opportunities in improved cardiac healing following ischemic injury.
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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.