The latest findings indicate the huge therapeutic potential of stem cells in regenerative medicine, including the healing of chronic wounds. Main stem cell types involved in wound healing process ...are: epidermal and dermal stem cells, mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and hematopoietic stem cells (HSCs).
In the therapy of chronic wounds, they can be administrated either topically or using different matrix like hydrogels, scaffolds, dermal substitutes and extracellular matrix (ECM) derivatives. Stem cells are proven to positively influence wound healing by different direct and indirect mechanisms including residing cells stimulation, biomolecules release, inflammation control and ECM remodelling. MSCs are especially worth mentioning as they can be easily derived from bone-marrow or adipose tissue.
Apart from traditional approach of administering living stem cells to wounds, new trends have emerged in recent years. Good healing results are obtained using stem cell secretome alone, for example exosomes or conditioned media. There are also attempts to improve healing potential of stem cells by their co-culture with other cell types as well as by their genetic modifications or pretreatment using different chemicals or cell media. Moreover, stem cells have been tested for novel therapeutic purposes like for example acute burns and have been used in experiments on large animal models including pigs and sheep.
In this review we discuss the role of stem cells in skin wound healing acceleration. In addition, we analyse possible new strategies of stem cells application in treatment of chronic wounds.
Betulin (B) and Betulinic acid (BA) are natural pentacyclic lupane-structure triterpenoids which possess a wide range of pharmacological activities. Recent evidence indicates that B and BA have ...several properties useful for the treatment of metabolic disorders, infectious diseases, cardiovascular disorders, and neurological disorders. In the current review, we discuss B and BA structures and derivatives and then comprehensively explain their pharmacological effects in relation to various diseases. We also explain antiviral, antibacterial and anti-cancer effects of B and BA. Finally, we discuss the delivery methods, in which these compounds most effectively target different systems.
HMG-CoA reductase, the proximal rate-limiting enzyme in the mevalonate pathway, is inhibited by statins. Beyond their cholesterol lowering impact, statins have pleiotropic effects and their use is ...linked to improved lung health. We have shown that mevalonate cascade inhibition induces apoptosis and autophagy in cultured human airway mesenchymal cells. Here, we show that simvastatin also induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in these cells. We tested whether coordination of ER stress, autophagy and apoptosis determines survival or demise of human lung mesenchymal cells exposed to statin. We observed that simvastatin exposure activates UPR (activated transcription factor 4, activated transcription factor 6 and IRE1α) and caspase-4 in primary human airway fibroblasts and smooth muscle cells. Exogenous mevalonate inhibited apoptosis, autophagy and UPR, but exogenous cholesterol was without impact, indicating that sterol intermediates are involved with mechanisms mediating statin effects. Caspase-4 inhibition decreased simvastatin-induced apoptosis, whereas inhibition of autophagy by ATG7 or ATG3 knockdown significantly increased cell death. In BAX−/−/BAK−/− murine embryonic fibroblasts, simvastatin-triggered apoptotic and UPR events were abrogated, but autophagy flux was increased leading to cell death via necrosis. Our data indicate that mevalonate cascade inhibition, likely associated with depletion of sterol intermediates, can lead to cell death via coordinated apoptosis, autophagy, and ER stress. The interplay between these pathways appears to be principally regulated by autophagy and Bcl-2-family pro-apoptotic proteins. These findings uncover multiple mechanisms of action of statins that could contribute to refining the use of such agent in treatment of lung disease.
•Simvastatin induces apoptosis, autophagy, UPR in human airway mesenchymal cells.•Exogenous mevalonate inhibits simvastatin induced apoptosis, autophagy and UPR.•UPR-dependent caspase inhibition (Caspase-4) decreases simvastatin-induced apoptosis.•Autophagy inhibition significantly increases simvastatin-induced apoptosis.•Simvastatin induces necrosis in BAX−/−/BAK−/− model.
Rapid advances in the cancer stem cell (CSC) field have provided cause for optimism for the development of more reliable cancer therapies in the future. Strategies aimed at efficient targeting of ...CSCs are becoming important for monitoring the progress of cancer therapy and for evaluating new therapeutic approaches. Here, we characterize and compare the specific markers that have been found to be present on stem cells, cancer cells and CSCs in selected tissues (colon, breast, liver, pancreas and prostate). We then discuss future directions of this intriguing new research field in the context of new diagnostic and therapeutic opportunities.
Akt, a protein kinase hyperactivated in many tumors, plays a major role in both cell survival and resistance to tumor therapy. A recent study,1 along with other evidences, shows interestingly, that ...Akt is not a single‐function kinase, but may facilitate rather than inhibit cell death under certain conditions. This hitherto undetected function of Akt is accomplished by its ability to increase reactive oxygen species and to suppress antioxidant enzymes. The ability of Akt to down‐regulate antioxidant defenses uncovers a novel Achilles' heel, which could be exploited by oxidant therapies in order to selectively eradicate tumor cells that express high levels of Akt activity.
The combination of stem cell therapy with a supportive scaffold is a promising approach to improving cardiac tissue engineering. Stem cell therapy can be used to repair nonfunctioning heart tissue ...and achieve myocardial regeneration, and scaffold materials can be utilized in order to successfully deliver and support stem cells in vivo. Current research describes passive scaffold materials; here an electroactive scaffold that provides electrical, mechanical, and topographical cues to induced human pluripotent stem cells (iPS) is presented. The poly(lactic‐co‐glycolic acid) fiber scaffold coated with conductive polymer polypyrrole (PPy) is capable of delivering direct electrical and mechanical stimulation to the iPS. The electroactive scaffolds demonstrate no cytotoxic effects on the iPS as well as an increased expression of cardiac markers for both stimulated and unstimulated protocols. This study demonstrates the first application of PPy as a supportive electroactive material for iPS and the first development of a fiber scaffold capable of dynamic mechanical actuation.
Here a new type of smart cardiac patch material, the electromechanically active fiber scaffold, is presented. The scaffold is capable of delivering electrical and mechanical stimulation to individual cells and demonstrates controlled volume change actuation. The scaffold is noncytotoxic and may enhance the cardiac differentiation of human induced pluripotent stem cells.
The complex formed by two members of the S100 calcium-binding protein family, S100A8/A9, exerts apoptosisinducing activity in various cells of different origins. Here, we present evidence that the ...underlying molecular mechanisms involve both programmed cell death I （PCD I, apoptosis） and PCD II （autophagy）-like death. Treatment of cells with S100A8/A9 caused the increase of Beclin-1 expression as well as Atgl2-Atg5 formation. S100A8/A9-induced cell death was partially inhibited by the specific PI3-kinase class Ⅲ inhibitor, 3-methyladenine （3-MA）, and by the vacuole H＋-ATPase inhibitor, bafilomycin-A1 （Baf-A1）. S100A8/A9 provoked the translocation of BNIP3, a BH3 only pro-apoptotic Bcl2 family member, to mitochondria. Consistent with this finding, ATM-BNIP3 overexpression partially inhibited S100A8/A9-induced cell death, decreased reactive oxygen species （ROS） generation, and partially pro- tected against the decrease in mitochondrial transmembrane potential in S100A8/A9-treated ceils. In addition, either ATM-BNIP3 overexpression or N-acetyl-L-cysteine co-treatment decreased lysosomal activation in cells treated with S100A8/A9. Our data indicate that S100A8/A9-promoted cell death occurs through the cross-talk of mitochondria and lysosomes via ROS and the process involves BNIP3.
The complex formed by two members of the S100 calcium‐binding protein family, S100A8/A9, exerts apoptosis‐inducing activity against various cells, especially tumor cells. Here, we present evidence ...that S100A8/A9 also has cell growth‐promoting activity at low concentrations. Receptor of advanced glycation end product (RAGE) gene silencing and cotreatment with a RAGE‐specific blocking antibody revealed that this activity was mediated via RAGE ligation. To investigate the signaling pathways, MAPK phosphorylation and NF‐κB activation were characterized in S100A8/A9‐treated cells. S100A8/A9 caused a significant increase in p38 MAPK and p44/42 kinase phosphorylation, and the status of stress‐activated protein kinase/JNK phosphorylation remained unchanged. Treatment of cells with S100A8/A9 also enhanced NF‐κB activation. RAGE small interfering RNA pretreatment abrogated the S100A8/A9‐induced NF‐κB activation. Our data indicate that S100A8/A9‐promoted cell growth occurs through RAGE signaling and activation of NF‐κB.
Here, we show that CDK2, an S-phase cyclin-dependent kinase, is a novel target for Akt during cell cycle progression and apoptosis. Akt phosphorylates CDK2 at threonine 39 residue both in vitro and ...in vivo. Although CDK2 threonine 39 phosphorylation mediated by Akt enhances cyclin-A binding, it is dispensable for its basal binding and the kinase activity. In addition, for the first time, we report a transient nucleo-cytoplasmic shuttling of Akt during specific stages of the cell cycle, in particular during the late S and G2 phases. The Akt that is re-localized to the nucleus phosphorylates CDK2 and causes the temporary cytoplasmic localization of the CDK2-cyclin-A complex. The CDK2 cytoplasmic redistribution is required for cell progression from S to G2-M phase, because the CDK2 T39A mutant, which lacks the phosphorylation site and is defective in cytoplasmic localization, severely affects cell cycle progression at the transition from S to G2-M. Interestingly, we also show that the Akt/CDK2 pathway is constitutively activated by some anticancer drugs, such as methotrexate and docetaxel, and under these conditions it promotes, rather than represses, cell death. Thus, the constitutive activation of the Akt/CDK2 pathway and changed subcellular localization promotes apoptosis. By contrast, the transient, physiological Akt/CDK2 activation is necessary for cell cycle progression.
Glioblastoma (GBM) is a devastating type of brain tumor, and current therapeutic treatments, including surgery, chemotherapy, and radiation, are palliative at best. The design of effective and ...targeted chemotherapeutic strategies for the treatment of GBM require a thorough analysis of specific signaling pathways to identify those serving as drivers of GBM progression and invasion. The Wnt/β-catenin and PI3K/Akt/mTOR (PAM) signaling pathways are key regulators of important biological functions that include cell proliferation, epithelial-mesenchymal transition (EMT), metabolism, and angiogenesis. Targeting specific regulatory components of the Wnt/β-catenin and PAM pathways has the potential to disrupt critical brain tumor cell functions to achieve critical advancements in alternative GBM treatment strategies to enhance the survival rate of GBM patients. In this review, we emphasize the importance of the Wnt/β-catenin and PAM pathways for GBM invasion into brain tissue and explore their potential as therapeutic targets.
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