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Aortic stiffening is an inevitable manifestation of chronological aging, yet the mechano-molecular programs that orchestrate region- and layer-specific adaptations along the length and through the wall of the aorta are incompletely defined. Here, we show that the decline in passive cyclic distensibility is more pronounced in the ascending thoracic aorta (ATA) compared to distal segments of the aorta and that collagen content increases in both the medial and adventitial compartments of the ATA during aging. The single-cell RNA sequencing of aged ATA tissues reveals altered cellular senescence, remodeling, and inflammatory responses accompanied by enrichment of T-lymphocytes and rarefaction of vascular smooth muscle cells, compared to young samples. T lymphocyte clusters accumulate in the adventitia, while the activation of mechanosensitive Piezo-1 enhances vasoconstriction and contributes to the overall functional decline of ATA tissues. These results portray the immuno-mechanical aging of the ATA as a process that culminates in a stiffer conduit permissive to the accrual of multi-gerogenic signals priming to disease development., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Objectives: Obesity is characterized by local and systemic low-grade inflammatory responses. Adipose tissue macrophages (ATM) play decisive roles in inflammation, insulin signaling, and various metabolic dysfunctions. Diets enriched with ω-3 polyunsaturated fatty acids (PUFAs) have been shown to improve health and mitigate pathologic conditions. However, the effects of ω-3 PUFA on adipose tissue inflammation, ATM number, and phenotype are poorly defined in human obesity. The aim of this study was to examine differences in expression of metabolic-inflammatory markers in omental, mesenteric, and subcutaneous fat depots of obese women supplemented with ω-3 PUFAs for 4 wk compared with a low-calorie diet before bariatric surgery., Methods: In a randomized controlled trial, inflammatory markers in the abdominal adipose tissue and the systemic response in obese women were studied. Patients were treated with a 2-wk low-calorie diet (LCD) or a 4-wk ω-3 PUFA-enriched diet (920 mg eicosapentaenoic acid, 760 mg docosahexaenoic acid daily) before laparoscopic bypass surgery. Omental, mesenteric, and subcutaneous adipose tissue biopsies were collected during surgery and analyzed for quantity and phenotype of ATMs, and profiled for adipokines, cytokines, and signal transduction molecules., Results: The chronic inflammatory state characterized by ATM markers was mostly improved by ω-3 PUFAs in visceral adipose tissue. We observed a decreased expression of CD45, CCL2, and CD68, indicating a lower inflammatory state. In patients with type 2 diabetes, ω-3 PUFAs lowered the expression of Netrin-1., Conclusions: Compared with an LCD, a diet enriched with ω-3 PUFAs influences the inflammatory state in different adipose tissue depots, by affecting markers of adipose tissue inflammation, macrophage phenotype, and retention. However, this was not reflected in clinical parameters such as insulin resistance and inflammatory cytokines. Subcutaneous adipose tissue and visceral adipose tissue have different responses to an LCD or a ω-3 PUFA-enriched diet. The presence of diabetes modifies the expression of inflammatory markers., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Cumulative evidence has shown that mechanical and frictional forces exert distinct effects in the multi-cellular aortic layers and play a significant role in the development of abdominal aortic aneurysms (AAA). These mechanical cues collectively trigger signaling cascades relying on mechanosensory cellular hubs that regulate vascular remodeling programs leading to the exaggerated degradation of the extracellular matrix (ECM), culminating in lethal aortic rupture. In this review, we provide an update and summarize the current understanding of the mechanotransduction networks in different cell types during AAA development. We focus on different mechanosensors and stressors that accumulate in the AAA sac and the mechanotransduction cascades that contribute to inflammation, oxidative stress, remodeling, and ECM degradation. We provide perspectives on manipulating this mechano-machinery as a new direction for future research in AAA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lowis, Ramara Winaya, Kumari, Rivera, Vlahos, Hermantara, Pratama and Ramkhelawon.)

Background: MT1-MMP (membrane-type 1 matrix metalloproteinase, MMP-14) is a transmembrane-anchored protein with an extracellular proteinase domain and a cytoplasmic tail devoid of proteolytic functions but capable of mediating intracellular signaling that regulates tissue homeostasis. MT1-MMP extracellular proteolytic activity has been shown to regulate pathological remodeling in aortic aneurysm and atherosclerosis. However, the role of the nonproteolytic intracellular domain of MT1-MMP in vascular remodeling in abdominal aortic aneurysms (AAA) is unknown., Methods: We generated a mutant mouse that harbors a point mutation (Y573D) in the MT1-MMP cytoplasmic domain that abrogates the MT1-MMP signaling function without affecting its proteolytic activity. These mice and their control wild-type littermates were subjected to experimental AAA modeled by angiotensin II infusion combined with PCSK9 (proprotein convertase subtilisin/kexin type 9) overexpression and high-cholesterol feeding., Results: The mutant mice developed more severe AAA than the control mice, with concomitant generation of intraaneurysmal atherosclerotic lesions and dramatically increased macrophage infiltration and elastin degradation. Aortic lesion-associated and bone marrow-derived macrophages from the mutant mice exhibited an enhanced inflammatory state and expressed elevated levels of proinflammatory Netrin-1, a protein previously demonstrated to promote both atherosclerosis and AAA., Conclusions: Our findings show that the cytoplasmic domain of MT1-MMP safeguards from AAA and atherosclerotic plaque development through a proteolysis-independent signaling mechanism associated with Netrin-1 expression. This unexpected function of MT1-MMP unveils a novel mechanism of synchronous onset of AAA and atherogenesis and highlights its importance in the control of vascular wall homeostasis.

Background and Aims: In evaluating small bowel Crohn's disease (CD), small intestine contrast-enhanced ultrasonography (SICUS) is emerging as an alternative to magnetic resonance enterography (MRE). This retrospective study compared the diagnostic accuracy of SICUS and MRE with surgical findings, and their level of agreement., Methods: We identified a cohort of CD patients investigated by either SICUS and/or MRE that subsequently required resective bowel surgery within 6 months. The accuracy and agreement of SICUS and MRE to detect small bowel complications were compared with intraoperative findings using kappa coefficient (κ). Agreement between SICUS and MRE in those undergoing both modalities was also assessed., Results: A total of 67 patients were evaluated; 25 underwent SICUS and 17 underwent MRE prior to surgery. Another 25 patients underwent both SICUS and MRE. When compared with intraoperative findings, the sensitivity of SICUS and MRE was 87.5% and 100%, respectively, in detecting strictures, 87.7% and 66.7% for fistulae, 100% for both in identifying abscesses, 100% and 66.7% for bowel dilatation, and 94.7% and 81.8% in defining bowel wall thickening. When correlating SICUS and MRE with surgery, there was a high level of agreement in localizing strictures (κ = 0.75, 0.88, respectively), fistulae (κ = 0.82, 0.79) and abscesses (κ = 0.87, 0.77). Concordance between SICUS and MRE was substantial or almost complete in identifying stricturing disease (κ = 0.84), their number and location (κ = 0.85), fistulae (κ = 0.65), and mucosal thickening (κ = 0.61)., Conclusion: SICUS accurately identified small bowel complications and correlated well with MRE and intraoperative findings. SICUS offers an alternative in the preoperative assessment of CD., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Combination antimalarial therapy may delay the spread of drug resistance, but clinical data supporting this notion are limited. For 1 year, we studied Ugandan children who were treated for uncomplicated malaria with sulfadoxine-pyrimethamine (SP), SP + amodiaquine (AQ), or SP + artesunate (AS). We compared treatment responses and the prevalence of resistance-conferring mutations of new infections with those of recrudescent infections due to parasites that survived prior treatment. Recrudescent infections were associated with the selection of SP resistance-conferring mutations in all treatment groups, but responses to repeat therapy differed. Compared with initial treatments, treatment of recrudescent infections was associated with a higher rate of treatment failure (hazard ratio [HR], 2.44; P=.01), for the SP group, but with a lower rate of treatment failure (HR, 0.40; P=.08), for the SP + AS group. Treatment failure in the SP + AQ group was uncommon, limiting the analysis of recrudescent parasites. Our results suggest that the use of combination antimalarial therapy in Africa may slow the spread of drug-resistant malaria and prolong the therapeutic life span of available treatment regimens.