More Like this

1. The role of elastin on the mechanical properties of the anterior leaflet in porcine tricuspid valves

   https://doi.org/10.1371/journal.pone.0267131  

   Salinas, Samuel D.; Farra, Yasmeen M.; Amini Khoiy, Keyvan; Houston, James; Lee, Chung-Hao; Bellini, Chiara; Amini, Rouzbeh (May 2022, PLOS ONE)

   Jiang, Yi (Ed.)

   Elastin is present in the extracellular matrix (ECM) of connective tissues, and its mechanical properties are well documented. In Marfan syndrome, however, the inability to properly code for the protein fibrillin-1 prematurely leads to the degradation and loss of elastin fiber integrity in the ECM. In this study, the role of elastin in the ECM of the anterior leaflet of the tricuspid valve was investigated by examining the biomechanical behavior of porcine leaflets before and after the application of the enzyme elastase. Five loading protocols were applied to the leaflet specimens in two groups (elastase-treated and control samples). The mechanical response following elastase application yielded a significantly stiffer material in both the radial and circumferential directions. At a physiological level of stress (85 kPa), the elastase group had an average strain of 26.21% and 6.32% in the radial and circumferential directions, respectively, at baseline prior to elastase application. Following elastase treatment, the average strain was 5.28% and 0.97% in the radial and circumferential directions, respectively. No statistically significant change was found in the control group following sham treatment with phosphate-buffered saline (PBS). Two-photon microscopy images confirmed that after the removal of elastin, the collagen fibers displayed a loss of undulation. With a significant reduction in radial compliance, the ability to withstand physiological loads may be compromised. As such, an extracellular matrix that is structurally deficient in elastin may hinder normal tricuspid valve function. 

   more » « less
2. Collagen Fibril Abnormalities in Human and Mice Abdominal Aortic Aneurysm

   Jones, B.; Tonniges, J. R.; Debsk, A.i; Albert, B.; Yeung, D. A.; Gadde, N.; Mahajan, A.; Sharma, N.; Calomeni, E. P.; Go, M.; et al (August 2020, Biomedical Engineering Society 2020 Annual Meeting)

   null (Ed.)

   Introduction: Vascular diseases like abdominal aortic aneurysms (AAA) are characterized by a drastic remodeling of the vessel wall, accompanied with changes in the elastin and collagen content. At the macromolecular level, the elastin fibers in AAA have been reported to undergo significant structural alterations. While the undulations (waviness) of the collagen fibers is also reduced in AAA, very little is understood about changes in the collagen fibril at the sub-fiber level in AAA as well as in other vascular pathologies. Materials and Methods: In this study we investigated structural changes in collagen fibrils in human AAA tissue extracted at the time of vascular surgery and in aorta extracted from angiotensin II (AngII) infused ApoE−/− mouse model of AAA. Collagen fibril structure was examined using transmission electron microscopy and atomic force microscopy. Images were analyzed to ascertain length and depth of D-periodicity, fibril diameter and fibril curvature. Tissues were also stained using collagen hybridizing peptide (CHP) and analyzed using fluorescent microscopy and second harmonic generation (SHG) microscopy to locate regions of healthy and degraded collagen. Results: Abnormal collagen fibrils with compromised D-periodic banding were observed in the excised human tissue and in remodeled regions of AAA in AngII infused mice (Figure 1). These abnormal fibrils were characterized by statistically significant reduction in depths of D-periods and an increased curvature of collagen fibrils. These features were more pronounced in human AAA as compared to murine samples. Additionally, regions of abnormal collagen were located within the remodeled areas of AAA tissue and were distinct from healthy collagen regions as ascertained using CHP staining and SHG (Figure 1). Thoracic aorta from Ang II-infused mice, abdominal aorta from saline-infused mice, and abdominal aorta from non-AAA human controls did not contain abnormal collagen fibrils. Conclusions: The structural alterations in abnormal collagen fibrils appear similar to those reported for collagen fibrils subjected to mechanical overload or chronic inflammation in other tissues. Detection of abnormal collagen could be utilized to better understand the functional properties of the underlying extracellular matrix in vascular as well as other pathologies. 

   more » « less
3. Solvent and Crystallization Effects on the Dermal Absorption of Hydrophilic and Lipophilic Compounds

   https://doi.org/10.1016/j.xphs.2023.09.025  

   Xu, Lijing; Kasting, Gerald B (April 2024, Journal of Pharmaceutical Sciences)

   This study probes the mechanisms by which volatile solvents (water, ethanol) and a nonionic surfactant (Triton X-100) influence the skin permeation of dissolved solutes following deposition of small doses onto unoccluded human skin. A secondary objective was to sharpen guidelines for the use of these and other simple solvent systems for dermal safety testing of cosmetic ingredients at finite doses. Four solutes were studied – niacinamide, caffeine, testosterone and geraniol – at doses close to that estimated to saturate the upper layers of the stratum corneum. Methods included tensiometry, visualization of spreading on skin, polarized light microscopy and in vitro permeation testing using radiolabeled solutes. Ethanol, aqueous ethanol and dilute aqueous Triton solutions all yielded surface tensions below 36 mN/m, allowing them to spread easily on the skin, unlike water (72.4 mN/m) which did not spread. Deposition onto skin of niacinamide (32 ug·cm^2) or caffeine (3.2 ug·cm^2) from water and ethanol led to crystalline deposits on the skin surface, whereas the same amounts applied from aqueous ethanol and 2% Triton did not. Skin permeation of these compounds was inversely correlated to the extent of crystallization. A separate study with caffeine showed the absence of a dose-related skin permeability increase with Triton. Permeation of testosterone (8.2 ug·cm^2) was modestly increased when dosed from aqueous ethanol versus ethanol. Permeation of geraniol (2.9 ug·cm^2) followed the order aqueous ethanol > water ~ 2% Triton >> ethanol and was inversely correlated with evaporative loss. We conclude that, under the conditions tested, aqueous ethanol and Triton serve primarily as deposition aids and do not substantially disrupt stratum corneum lipids. Implications for the design of in vitro skin permeability tests are discussed. 

   more » « less
4. The Beneficial Regulation of Extracellular Matrix and Heat Shock Proteins, and the Inhibition of Cellular Oxidative Stress Eects and Inflammatory Cytokines by 1-alpha, 25 dihydroxyvitaminD3 in Non-Irradiated and Ultraviolet Radiated Dermal Fibroblasts

   Philips, Neena; Ding, Xinxing; Kandalai, Pranathi; Marte, Ilonka; Krawczyk, Hunter; Richardson, Richard (August 2019, Cosmetics)

   null (Ed.)

   Intrinsic skin aging and photoaging, from exposure to ultraviolet (UV) radiation, are associated with altered regulation of genes associated with the extracellular matrix (ECM) and inflammation, as well as cellular damage from oxidative stress. The regulatory properties of 1-alpha, 25dihydroxyvitamin D3 (vitamin D) include endocrine, ECM regulation, cell differentiation, photoprotection, and anti-inflammation. The goal of this research was to identify the beneficial effects of vitamin D in preventing intrinsic skin aging and photoaging, through its direct effects as well as its effects on the ECM, associated heat shock proteins (HSP-47, and -70), cellular oxidative stress effects, and inflammatory cytokines [interleukin (IL)-1 and IL-8] in non-irradiated, UVA-radiated, UVB-radiated dermal fibroblasts. With regard to the ECM, vitamin D stimulated type I collagen and inhibited cellular elastase activity in non-irradiated fibroblasts; and stimulated type I collagen and HSP-47, and inhibited elastin expression and elastase activity in UVA-radiated dermal fibroblasts. With regard to cellular protection, vitamin D inhibited oxidative damage to DNA, RNA, and lipids in non-irradiated, UVA-radiated and UVB-radiated fibroblasts, and, in addition, increased cell viability of UVB-radiated cells. With regard to anti-inflammation, vitamin D inhibited expression of Il-1 and IL-8 in UVA-radiated fibroblasts, and stimulated HSP-70 in UVA-radiated and UVB-radiated fibroblasts. Overall, vitamin D is predominantly beneficial in preventing UVA-radiation induced photoaging through the differential regulation of the ECM, HSPs, and inflammatory cytokines, and protective effects on the cellular biomolecules. It is also beneficial in preventing UVB-radiation associated photoaging through the stimulation of cell viability and HSP-70, and the inhibition of cellular oxidative damage, and in preventing intrinsic aging through the stimulation of type I collagen and inhibition of cellular oxidative damage. 

   more » « less
5. A human multi-lineage hepatic organoid model for liver fibrosis

   https://doi.org/10.1038/s41467-021-26410-9  

   Guan, Yuan; Enejder, Annika; Wang, Meiyue; Fang, Zhuoqing; Cui, Lu; Chen, Shih-Yu; Wang, Jingxiao; Tan, Yalun; Wu, Manhong; Chen, Xinyu; et al (December 2021, Nature Communications)

   Abstract To investigate the pathogenesis of a congenital form of hepatic fibrosis, human hepatic organoids were engineered to express the most common causative mutation for Autosomal Recessive Polycystic Kidney Disease (ARPKD). Here we show that these hepatic organoids develop the key features of ARPKD liver pathology (abnormal bile ducts and fibrosis) in only 21 days. The ARPKD mutation increases collagen abundance and thick collagen fiber production in hepatic organoids, which mirrors ARPKD liver tissue pathology. Transcriptomic and other analyses indicate that the ARPKD mutation generates cholangiocytes with increased TGFβ pathway activation, which are actively involved stimulating myofibroblasts to form collagen fibers. There is also an expansion of collagen-producing myofibroblasts with markedly increased PDGFRB protein expression and an activated STAT3 signaling pathway. Moreover, the transcriptome of ARPKD organoid myofibroblasts resemble those present in commonly occurring forms of liver fibrosis. PDGFRB pathway involvement was confirmed by the anti-fibrotic effect observed when ARPKD organoids were treated with PDGFRB inhibitors. Besides providing insight into the pathogenesis of congenital (and possibly acquired) forms of liver fibrosis, ARPKD organoids could also be used to test the anti-fibrotic efficacy of potential anti-fibrotic therapies. 

   more » « less