Effectiveness of Apoptotic Factors Expressed on the Wounds of Patients With Stage III Pressure Ulcers

Cui

et al. 2020

Bioscience Reports

Pressure ulcers (PUs) are a common clinical issue lacking effective treatment and validated pharmacological therapy in hospital settings. Ischemia–reperfusion injury of deep tissue, especially muscle, plays a vital role in the formation and development of the overwhelming majority of PUs. However, muscular protein expression study in PUs has not been reported. Herein, we aimed to investigate the muscular proteins profiles in PUs and to explore the pathological mechanism of PUs. The iTRAQ LC-MS/MS was conducted to detect the protein profiles in clinical muscle samples of PUs. The GO and KEGG pathways analyses were performed for annotation of differentially expressed proteins. Protein–protein interaction (PPI) network was constructed by STRING online database, and hub proteins were validated by the immunoblotting. Based on proteomics results, we found a number of proteins that were differentially expressed in PU muscle samples compared with the normal and identified unique proteins expression patterns between these two groups, suggesting that they might involve in pathological process of the disease. Importantly, cathepsin B and D, as well as other autophagy–lysosome and apoptosis associated proteins were identified. Further experiments characterize the expression of these proteins and their regulation in the process of apoptosis and autophagy. These findings may provide novel insights into the mechanisms of lysosome-associated pathways involved in the initiation of PUs. This is the first study linking proteomics to PUs muscle tissues, which indicated cathepsin B and D might be key drug target for PUs.

Section: Discussionmentioning

confidence: 99%

Quantitative iTRAQ LC-MS/MS reveals muscular proteome profiles of deep pressure ulcers

Cui

et al. 2020

Bioscience Reports

“…have been suggested to be the main factors in the development of HS, whereas the upstream regulators of apoptosis in the wound environment remain unclear (19)(20)(21). Among the numerous key factors of wound healing (22), of all proteins involved in the apoptotic processes (23,24), the differences in their expression and distribution in the wound healing process (25), a number of targets have been suggested to improve healing without keloids or HS (22)(23)(24). However, little is known about the effects of Smac/DIABLO on skin wound healing processes; it is currently accepted that the expression levels of Smac/DIABLO are downregulated in several excessive proliferative diseases or tumors compared with normal tissues (13)(14)(15)(16)(17)(18).…”

Section: Discussionmentioning

confidence: 99%

Smac/DIABLO regulates the apoptosis of hypertrophic scar fibroblasts

Chen

International Journal of Molecular Medicine

et al. 2013

Hypertrophic scar (HS) is a serious skin fibrotic disease characterized by excessive hypercellularity and extracellular matrix (ECM) component deposition. Autophagy is a tightly regulated physiological process essential for cellular maintenance, differentiation, development and homeostasis. However, during the formation of HS, whether and how autophagy is regulated in dermal fibroblasts are still far from elucidated. Here we detected the autophagic capacity in HS and normal skin (NS) counterparts, explored and verified the key regulatory molecules of autophagy in HS-derived fibroblasts (HSFs), and validated the data using rabbit ear scar model. Transmission electron microscopy (TEM) and immunostaining data showed that LC3-positive cells and autophagosomes in HS/HSFs were more intensive relative to those in NS/NSFs groups. Knockdown of LC3 (shLC3) could significantly block the expressionof type I collagen (Col 1, p < 0.01) and type III collagen (Col 3, p < 0.01) and thus inhibit the fibrosis of HSFs. shLC3 resistant to autophagy was shown to be Bcl-xL-, not Bcl-2-dependent, and silencing of Bcl-xL (sibcl-xL) significantly increased apoptosis of HSFs (p < 0.01). Immunofluorescence results showed that instead of inhibiting α-SMA protein expression, shLC3 could change its architecture arrangement in HSFs. sibcl-xL showed that Bcl-xL was a key signaling molecule involved in HSFs autophagy. More importantly, both shLC3 and sibcl-xL obviously improved the appearance and architecture of the rabbit ear scar, and reduced scar formation on the rabbit ear. Therefore, the aberration of LC3 protein processing compromised autophagy in HS might associate with its pathogenesis in wound repair. LC3 regulated HS fibrosis by controlling the expression of Bcl-xL in HSFs. Thus, Bcl-xL might serve as a potential molecular target, providing a novel strategy for HS therapy.

“…An intriguing qualitative finding is that this fibroplastic induration appeared inversely correlated with the local fibroblast population, suggesting an imbalance between a consolidated fibrotic matrix and the matrix-producing cells. The fact that pressure ulcers-cultured fibroblasts exhibit a short replicative life becoming prematurely senescent [16] and that these cells are "homed" into a pro-apoptotogenic environment [5] incite to speculate that these wounds become "stalled" within the fibrogenic phase with no subsequent turnover or remodeling by a deficit of healthy effector cells. Globally speaking, fibroblasts dysfunction and apoptosis appear as pivotal factors toward wound chronification [17].…”

Section: Discussionmentioning

confidence: 99%

“…From the ethiopathogenic perspective, cutaneous ischemia appears to be the proximal trigger of a downstream cascade of molecular events that converge to impose a chronic evolution. These include the overactivation of molecular regulators toward a pro-apoptotic program [5], imbalance in matrix metalloproteinases regulation (MMP2 and MMP9) [6], and adhesion molecules overexpression [7]. At the experimental level, a reduction of the cutaneous cells constitutive expression of endogenous cytoprotective molecules such as hypoxia-inducible factor-1 alpha (HIF-1α), VEGF, HSP 70 and 90 and hemeoxigenase-1 [8] have been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Histological and Transcriptional Expression differences between Diabetic Foot and Pressure Ulcers

Mendoza‐Marí¹,

Valdés-Pérez²,

Rodríguez-Corrales³

et al. 2013

J Diabetes Metab

Decubitus and diabetic foot ulcers remain as important clinical challenges with significant socioeconomic impact. Both are individual forms of chronic wounds with diverse proximal ethiopathogenic triggers. This study aimed to characterize and compare the main histological features as the transcriptional expression profile of a set of wound-healing relevant genes of the ulcers' granulation tissue. Following patients' consent, biopsies were collected from sacrolumbar pressure ulcers (N=5, stage IV) and diabetic foot ulcers (N=9, both of neuropathic and ischemic origin) with clean, non-infected granulation tissue. Biopsies fragments were processed for histological analysis and for RNA extraction and subsequent transcriptional expression characterization via RT-PCR. The group of targeted genes included cell proliferation control, extracellular matrix, glucose metabolism, anabolismsurvival, as anti-hypoxia and anti-oxidant defense. Gene expression was determined, normalized with an internal housekeeping gene, and statistically compared. Each class of chronic ulcer granulation tissue: decubitus, and diabetics' ischemic and neuropathic proved to develop a particular histological pattern thus establishing individual differences. Moreover, diabetes appeared to significantly reduce the expression of numerous genes irrespective to their biological significance. Most importantly, we found that diabetic granulation tissue cells exhibit a sort of "genetic or epigenetic imprinting" for the expression of glucose-metabolism related genes which are deeply involved in type-2 diabetes pathophysiology. Our data indicate that in addition to a protracted inflammation and abnormal angiogenesis, diabetic granulation tissue cells are affected by gene expression failures that may lead to a negative pro-anabolic and energetic balance. J ou rna l o f D ia be tes & M e ta bolism