Emerging and innovative approaches for wound healing and skin regeneration: Current status and advances

With all the advances in tissue engineering for construction of fully functional skin tissue, complete regeneration of chronic wounds is still challenging. Since immune reaction to the tissue damage is critical in regulating both the quality and duration of chronic wound healing cascade, strategies to modulate the immune system are of importance. Generally, in response to an injury, macrophages switch from pro-inflammatory to an anti-inflammatory phenotype. Therefore, controlling macrophages' polarization has become an appealing approach in regenerative medicine. Recently, hydrogels-based constructs, incorporated with various cellular and molecular signals, have been developed and utilized to adjust immune cell functions in various stages of wound healing. Here, the current state of knowledge on immune cell functions during skin tissue regeneration is first discussed. Recent advanced technologies used to design immunomodulatory hydrogels for controlling macrophages' polarization are then summarized. Rational design of hydrogels for providing controlled immune stimulation via hydrogel chemistry and surface modification, as well as incorporation of cell and molecules, are also dicussed. In addition, the effects of hydrogels' properties on immunogenic features and the wound healing process are summarized. Finally, future directions and upcoming research strategies to control immune responses during chronic wound healing are highlighted.

Rational Design of Immunomodulatory Hydrogels for Chronic Wound Healing.

Aging has been linked to several degenerative processes that, through the accumulation of molecular and cellular damage, can progressively lead to cell dysfunction and organ failure. Human aging is linked with a higher risk for individuals to develop cancer, neurodegenerative, cardiovascular, and metabolic disorders. The understanding of the molecular basis of aging and associated diseases has been one major challenge of scientific research over the last decades. Mitochondria, the center of oxidative metabolism and principal site of reactive oxygen species (ROS) production, are crucial both in health and in pathogenesis of many diseases. Redox signaling is important for the modulation of cell functions and several studies indicate a dual role for ROS in cell physiology. In fact, high concentrations of ROS are pathogenic and can cause severe damage to cell and organelle membranes, DNA, and proteins. On the other hand, moderate amounts of ROS are essential for the maintenance of several biological processes, including gene expression. In this review, we provide an update regarding the key roles of ROS-mitochondria cross talk in different fundamental physiological or pathological situations accompanying aging and highlighting that mitochondrial ROS may be a decisive target in clinical practice.

Mitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases.

https://estudogeral.sib.uc.pt/bitstream/10316/84850/1/34_Bajzikova2018_CellMetabolism.pdf

Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells.

The silent information regulation factor 1 (sirtuin Type 1, SIRT1), as a kind of NAD+ dependent class III histone deacetylation enzyme, has been found to be involved in tumor proliferation, invasion, and metastasis. The roles of SIRTl in breast cancer is multifaceted depending on its substrate from upstream or downstream signaling pathway. In this study, we sought to make clear the regulating effects of SIRT1 in breast cancer cells, and to explore the underlying mechanisms through which SIRT1 regulates breast cancer. First, our results showed that SIRT1 was significantly up-regulated in breast cancer tissues and cells, which correlated with histological grade, tumor size, as well as lymph node metastasis. Then we established SIRT1-overexpressed and SIRT1- knockdown breast cancer cell lines to investigate the functions of SIRT1 in regulating colony formation, cell proliferation, cell cycle, cell apoptosis and migration. We found that overexpression of SIRT1 significantly promoted breast cancer growth both in vitro and in vivo, whereas knockdown of SIRT1 inhibited these phenotypes. Furthermore, SIRT1 was found to interact with Akt directly, consequently promoting the activity of Akt in breast cancer cells in vitro and positively correlating with expression of Akt, P-Akt, in breast cancer tissues in vivo. Down regulation the activity of Akt partially weakened the proliferative effect mediated by SIRT1. Taken together, our results demonstrated SIRT1's tumor promotion function and potential mechanisms in breast cancer, thus providing valuable therapeutic targets for breast cancer.

/pdf/sirt1-promotes-formation-of-breast-cancer-through-modulating-32cqvm2cfj.pdf

SIRT1 promotes formation of breast cancer through modulating Akt activity.

Sirtuins regulate several processes associated with tumor development. Resveratrol was shown to stimulate sirtuin 1 and 3 (SIRT1/3) activities and to result in cytotoxicity for some tumor types. The relationship between modulation of sirtuin activities, cellular metabolic remodeling and resveratrol cytotoxicity mechanism on breast cancer cells is still an open question. Here, we evaluated whether sirtuin 1 and 3 are involved in resveratrol toxicity and whether resveratrol leads to a metabolic remodeling and cell differentiation. Results using the Extracellular Flux Analyzer indicated that resveratrol inhibits mitochondrial respiration in breast cancer cells. We also demonstrated here for the first time that resveratrol cytotoxic effects on breast cancer cells were modulated by SIRT1 and also involved mitochondrial complex I inhibition. Importantly, we also demonstrated that resveratrol reduced the pool of breast cancer cells with stemness markers through a SIRT1-dependent mechanism. Our data highlights the role of SIRT1 in regulating resveratrol induced differentiation and/or toxicity in breast cancer cells.

Sirtuin 1-dependent resveratrol cytotoxicity and pro-differentiation activity on breast cancer cells

The combinatorial delivery of miRNAs holds great promise to modulate cell activity in the context of angiogenesis. Yet, the delivery of multiple miRNAs with spatiotemporal control remains elusive. Here, we report a plasmonic nanocarrier to control the release of two microRNAs. The nanocarrier consists of gold nanorods modified with single-stranded DNA for hybridization with complementary DNA-conjugated microRNAs. DNA strands with distinct melting temperatures enable the independent release of each microRNA with a near-infrared laser using the same wavelength but different powers. Tests in human outgrowth endothelial cells (OECs) indicate that this system can be used to silence different targets sequentially and, by doing so, to modulate cell activity with spatiotemporal resolution. Finally, using an in vivo acute wound healing animal model, it is demonstrated that the order by which each miRNA was released in transplanted OECs significantly impacted the wound healing kinetics.

/pdf/modulation-of-angiogenic-activity-by-light-activatable-mirna-53wxz8enrf.pdf

Modulation of Angiogenic Activity by Light-Activatable miRNA-Loaded Nanocarriers

No effective therapeutic dressings are currently available in the market that can prevent bacterial infection and simultaneously promote skin regeneration in diabetic patients. The lack of re-epithelization, prevalence of inflammation, and high risk of infection are hallmarks of non-healing wounds. Here, we have evaluated the antimicrobial and pro-regenerative effect of a relatively non-leaching LL37 peptide immobilized in polyurethane (PU)-based wound dressings (PU-adhesive-LL37 dressing). The PU-adhesive-LL37 (63 μg LL37NPs/cm2) dressing killed Gram-positive and Gram-negative bacteria in human serum without inducing bacterial resistance after 16 antimicrobial test cycles in contrast to commercially available dressings with the capacity to release antimicrobial Ag ions. Importantly, type II diabetic mice (db/db mice) treated with the PU-adhesive-LL37 dressing for different periods of time (6 or 14 days) showed enhanced wound healing and re-epithelialization (i.e., high keratin 14/5 levels) and lower macrophage infiltration in the wounds compared to animals treated with PU. The wounds treated with PU-adhesive-LL37 dressings showed also low expression of pro-inflammatory cytokines such as TNF-α and IL6 after 6 days of treatment, indicating that they act as an anti-inflammatory dressing. Additionally, PU-adhesive-LL37 dressings do not induce acute inflammatory responses in the peripheral blood mononuclear cells (PBMCs) after 3 days of exposure, in contrast to controls. Taken together, PU-adhesive-LL37NP dressings might prevent the bacterial infections and facilitate wound healing by tissue contact, inducing re-epithelialization and anti-inflammatory processes in diabetic conditions.

Antimicrobial Peptide-Tether Dressing Able to Enhance Wound Healing by Tissue Contact.

Strategies and challenges for non-viral delivery of non-coding RNAs to the heart.

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Sirtuin 1-dependent resveratrol cytotoxicity and pro-differentiation activity on breast cancer cells

Modulation of Angiogenic Activity by Light-Activatable miRNA-Loaded Nanocarriers

Antimicrobial Peptide-Tether Dressing Able to Enhance Wound Healing by Tissue Contact.

Strategies and challenges for non-viral delivery of non-coding RNAs to the heart.