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Mitochondria are intracellular organelles that regulate cell survival and death, and hyperglycemia modulates mitochondrial function in endothelial cells. In the current study, we have discovered that high glucose (HG) treatment reduces FUNDC1 (FUN14 domain containing 1) expression in endothelial cells. FUNDC1 expression in mitochondria inhibits proteasomal degradation of COX-IV, and regulates mitochondrial complexes I and IV activity and ATP synthesis. FUNDC1 depletion in HG affects mitochondrial complexes I and IV activity and ATP synthesis and promotes mitochondrial damage through loss of mitochondrial membrane potential and ROS (Reactive Oxygen Species) production. BAM15, a mitochondrial uncoupler, improves mitochondrial function and endothelial survival more effectively. Co-treatment of HG with BAM15 increased FUNDC1 protein expression, mitochondrial translocation of FUNDC1 in HG-treated cells. BAM15-induced up regulation of FUNDC1 expressions improve mitochondrial expression of COX-IV, and complex I and IV activity and ATP synthesis. Our findings propose that FUNDC1 expression in endothelial cells under hyperglycemic stress play a significant role in limiting vascular damage and apoptotic cell death.

To identify immunotherapy biomarkers, we examined granzyme B levels in peripheral blood PD-1To evaluate the association of granzyme B with response to immunotherapy, we tested blood samples obtained from 16 patients with stage IIIC to IV NSCLC receiving immune-checkpoint inhibitor treatment. We used flow cytometry to measure the change in the percentage of PD1We found that the sequential change of granzyme B+ T cells after immunotherapy (t1/t0) significantly predicted durable clinical benefit (DCB) compared to no clinical benefit (NCB) (P=0.048), and prolonged PFS (P=0.025). Patients who demonstrated a PD-L1 tumor proportion score (TPS)50% showed NCB if patients had low granzyme B t1/t0 levels (0.805). Additionally, all patients with 1% PD-L1 TPS (or higher) and high granzyme B t1/t0 (≥0.805) showed DCB. Therefore, granzyme B t1/t0 may be an adjunctive marker with available PD-L1 TPS.Our findings revealed that sequential change in granzyme B might be utilized as a predictive biomarker of immune checkpoint inhibitor monotherapy.

Cardiotoxicity caused by doxorubicin (DOX) is an important issue to consider for both patients and doctors who require DOX. DOX-induced cardiotoxicity is closely associated with cardiomyocyte death and dysfunction. To prevent DOX-induced cardiotoxicity, many studies have been conducted on new therapeutic strategies, including the discovery of novel functional modulators such as antioxidant drugs to restore the loss of function of transplanted or residual cardiac cells in the heart. We investigated whether glutathione (GSH), an antioxidant drug, has a protective effect against DOX-induced cardiotoxicity by decreasing ROS and unraveling the underlying molecular mechanisms. GSH clearly increased the viability of damaged human cardiac progenitor cells (hCPCs) treated with DOX. In addition, ROS generation and apoptosis induced by DOX treatment were significantly reduced. We also observed that GSH restored the capacity of hCPCs, as shown by the wound healing assay, transwell migration, and tube formation. We checked that GSH treatment restored the level of pERK, which increased in the DOX-treated group. The ERK inhibitor, U0126, increased the viability of damaged hCPCs. These data suggest that the restoration mechanism of GSH may be via the regulation of pERK signaling. We confirmed the effects of DOX and GSH using an in vivo model. As a result, GSH was confirmed to have a protective effect against DOX-induced cardiotoxicity through body weight, survival rate, histology, and mRNA level. Taken together, GSH prevents DOX-induced cardiotoxicity and regulates pERK signaling. GSH may be an effective therapeutic strategy for DOX-induced cardiotoxicity.

Cardiovascular disease (CVD) and its complications are the leading cause of morbidity and mortality in the world. Because of the side effects and incomplete recovery from current therapy, stem cell therapy emerges as a potential therapy for CVD treatment, and endothelial progenitor cell (EPC) is one of the key stem cells used for therapeutic applications. The effect of this therapy required the expansion of EPC function. To enhance the EPC activation, proliferation, and angiogenesis using dronedarone hydrochloride (DH) is the purpose of this study. DH received approval for atrial fibrillation treatment and its cardiovascular protective effects were already reported. In this study, DH significantly increased EPC proliferation, tube formation, migration, and maintained EPCs surface marker expression. In addition, DH treatment up-regulated the phosphorylation of AKT and reduced the reactive oxygen species production. In summary, the cell priming by DH considerably improved the functional activity of EPCs, and the use of which might be a novel strategy for CVD treatment.

Critical limb ischemia is a condition in which tissue necrosis occurs due to arterial occlusion, resulting in limb amputation in severe cases. Both endothelial cells (ECs) and vascular smooth muscle cells (SMCs) are needed for the regeneration of peripheral arteries in ischemic tissues. However, it is difficult to isolate and cultivate primary EC and SMC from patients for therapeutic angiogenesis. Induced pluripotent stem cells (iPSCs) are regarded as useful stem cells due to their pluripotent differentiation potential. In this study, we explored the therapeutic efficacy of human iPSC‐derived EC and iPSC‐derived SMC in peripheral artery disease model. After the induction of mesodermal differentiation of iPSC, CD34+ progenitor cells were isolated by magnetic‐activated cell sorting. Cultivation of the CD34+ progenitor cells in endothelial culture medium induced the expression of endothelial markers and phenotypes. Moreover, the CD34+ cells could be differentiated into SMC by cultivation in SMC culture medium. In a murine hindlimb ischemia model, cotransplantation of EC with SMC improved blood perfusion and increased the limb salvage rate in ischemic limbs compared to transplantation of either EC or SMC alone. Moreover, cotransplantation of EC and SMC stimulated angiogenesis and led to the formation of capillaries and arteries/arterioles in vivo. Conditioned medium derived from SMC stimulated the migration, proliferation, and tubulation of EC in vitro, and these effects were recapitulated by exosomes isolated from the SMC‐conditioned medium. Together, these results suggest that iPSC‐derived SMC enhance the therapeutic efficacy of iPSC‐derived EC in peripheral artery disease via an exosome‐mediated paracrine mechanism., Co‐transplantation of the induced pluripotent stem cell (iPSC)‐derived endothelial cells and smooth muscle cells enhanced the therapeutic efficacies of endothelial cells and smooth muscle cells in a murine hindlimb ischemia model. Smooth muscle cells promoted angiogenesis and therapy of peripheral artery disease through exosome‐mediated paracrin mechanism.

BACKGROUND: Despite promising advances in stem cell-based therapy, the treatment of ischemic cardiovascular diseases remains a big challenge due to both the insufficient in vivo viability of transplanted cells and poor angiogenic potential of stem cells. The goal of this study was to develop therapeutic human cardiac progenitor cells (hCPCs) for ischemic cardiovascular diseases with a novel M13 peptide carrier. METHOD: In this study, an engineered M13 peptide carrier was successfully generated using a QuikChange Kit. The cellular function of M13 peptide carrier-treated hCPCs was assessed using a tube formation assay and scratch wound healing assay. The in vivo engraftment and cell survival bioactivities of transplanted cells were demonstrated by immunohistochemistry after hCPC transplantation into a myocardial infarction animal model. RESULTS: The engineered M13(RGD+SDKP) peptide carrier, which expressed RGD peptide on PIII site and SDKP peptide on PVIII site, did not affect morphologic change and proliferation ability in hCPCs. In contrast, hCPCs treated with M13(RGD+SDKP) showed enhanced angiogenic capacity, including tube formation and migration capacity. Moreover, transplanted hCPCs with M13(RGD+SDKP) were engrafted into the ischemic region and promoted in vivo cell survival. CONCLUSION: Our present data provides a promising protocol for CPC-based cell therapy via short-term cell priming of hCPCs with engineered M13(RGD+SDKP) before cell transplantation for treatment of cardiovascular disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13770-020-00244-w) contains supplementary material, which is available to authorized users.

Women and men share similar diseases; however, women have unique issues, including gynecologic diseases and diseases related to menstruation, menopause, and post menopause. In recent decades, scientists paid more attention to natural products and their derivatives because of their good tolerability and effectiveness in disease prevention and treatment. Olive oil is an essential component in the Mediterranean diet, a diet well known for its protective impact on human well-being. Investigation of the active components in olive oil, such as oleuropein and hydroxytyrosol, showed positive effects in various diseases. Their effects have been clarified in many suggested mechanisms and have shown promising results in animal and human studies, especially in breast cancer, ovarian cancer, postmenopausal osteoporosis, and other disorders. This review summarizes the current evidence of the role of olives and olive polyphenols in women’s health issues and their potential implications in the treatment and prevention of health problems in women.

Colorectal cancer is one of the leading causes of cancer-related deaths. Due to relapse after current therapy regimens, cancer stem cells (CSCs) are being studied to target this small tumor-initiating population. Anterior gradient 2 (AGR2), a disulfide isomerase protein, is a well-known pro-oncogenic/metastatic oncogene overexpressed in various tumor tissues, including colon cancer. We found that AGR2 was a novel stem cell marker that was regulated by the canonical Wnt/β-catenin pathway in colon CSCs. AGR2 was highly co-expressed with surface stem cell markers in spheroidal culture. Silencing of AGR2 resulted in decreased sphere-forming ability and down-regulated expression of stem cell markers, whereas the opposite effects were seen with AGR2 overexpression. Moreover, patients with high β-catenin and AGR2 expression showed lower overall survival than those with low expression. In conclusion, our study describes a novel role for AGR2 as a stem cell marker that is highly regulated by canonical Wnt/β-catenin signaling in colorectal cancer.

Anterior gradient protein 2 homolog (AGR2) belongs to the disulfide isomerase family of endoplasmic reticulum proteins. Itis overexpressed in several types of solid tumors, including tumors of the prostate, lung, and pancreas. However, the role of AGR2 in breast cancer and the regulatory mechanisms underlying AGR2 protein expressionare not fullyunderstood. We demonstrated that AGR2 levels are increased under hypoxic conditions and in breast cancer tumors. Mechanistically, Twist1 binds to, and activates the AGR2 promoter via an E-box sequence. Under hypoxic conditions, the increased expression of ARG2 is attenuated when Twist1 levels are reduced by shRNA. Conversely, Twist1 overexpression fully reverses decreased AGR2 levels upon HIF-1α knockdown. Notably, AGR2 is required for Twist1-induced proliferation, migration, and invasion of breast cancer cells. Collectively, these findings extend our understanding of AGR2 regulation in breast cancer and may contribute to development of Twist1-AGR2 targeting therapeutics for breast cancer.

Rheumatic diseases constitute a diversified group of diseases distinguished by arthritis and often involve other organs. The affected individual has low quality of life, productivity even life-threatening in some severe conditions. Moreover, they impose significant economic and social burdens. In recent years, the patient outcome has been improved significantly due to clearer comprehension of the pathology of rheumatic diseases and the effectiveness of “treat to target” therapies. However, the high cost and the adverse effects are the concerns and full remissions are not often observed. One of the main processes that contributes to the pathogenesis of rheumatic diseases is angiogenesis. Vascular endothelial growth factor (VEGF), a central mediator that regulates angiogenesis, has different isoforms and functions in various physiological processes. Increasing evidence suggests an association between the VEGF system and rheumatic diseases. Anti-VEGF and VEGF receptor (VEGFR) therapies have been used to treat several cancers and eye diseases. This review summarizes the current understanding of VEGF biology and its role in the context of rheumatic diseases, the contribution of VEGF bioavailability in the pathogenesis of rheumatic diseases, and the potential implications of therapeutic approaches targeting VEGF for these diseases.

Endothelial progenitor cells (EPCs) are specialized cells in circulating blood, well known for their ability to form new vascular structures. Aging and various ailments such as diabetes, atherosclerosis and cardiovascular disease make EPCs vulnerable to decreasing in number, which affects their migration, proliferation and angiogenesis. Myocardial ischemia is also linked to a reduced number of EPCs and their endothelial functional role, which hinders proper blood circulation to the myocardium. The current study shows that an aminopyrimidine derivative compound (CHIR99021) induces the inhibition of GSK-3β in cultured late EPCs. GSK-3β inhibition subsequently inhibits mTOR by blocking the phosphorylation of TSC2 and lysosomal localization of mTOR. Furthermore, suppression of GSK-3β activity considerably increased lysosomal activation and autophagy. The activation of lysosomes and autophagy by GSK-3β inhibition not only prevented replicative senescence of the late EPCs but also directed their migration, proliferation and angiogenesis. To conclude, our results demonstrate that lysosome activation and autophagy play a crucial role in blocking the replicative senescence of EPCs and in increasing their endothelial function. Thus, the findings provide an insight towards the treatment of ischemia-associated cardiovascular diseases based on the role of late EPCs.

Intercellular interaction is the most crucial factor in promoting cell viability and functionality in an engineered tissue system. Of the various shapes available for cell-laden constructs, spheroidal multicellular microarchitectures (SMMs) have been introduced as building blocks and injectable cell carriers with substantial cell-cell and cell-extracellular matrix (ECM) interactions. Here, we developed a precise and expeditious SMM printing method that can create a tissue-specific microenvironment and thus be potentially useful for cell therapy. This printing strategy is designed to manufacture SMMs fabricated with optimal bioink blended with decellularized ECM and alginate to enhance the functional performance of the encapsulated cells. Experimental results showed that the proposed method allowed for size controllability and mass production of SMMs with high cell viability. Moreover, SMMs co-cultured with endothelial cells promoted lineage-specific maturation and increased functionality compared to monocultured SMMs. Overall, it was concluded that SMMs have the potential for use in cell therapy due to their high cell retention and proliferation rate compared to single-cell injection, particularly for efficient tissue regeneration after myocardial infarction. This study suggests that utilizing microextrusion-based 3D bioprinting technology to encapsulate cells in cell-niche-standardized SMMs can expand the range of possible applications.

Stem cell-based therapies with clinical applications require millions of cells. Therefore, repeated subculture is essential for cellular expansion, which is often complicated by replicative senescence. Cellular senescence contributes to reduced stem cell regenerative potential as it inhibits stem cell proliferation and differentiation as well as the activation of the senescence-associated secretory phenotype (SASP). In this study, we employed MHY-1685, a novel mammalian target of rapamycin (mTOR) inhibitor, and examined its long-term priming effect on the activities of senile human cardiac stem cells (hCSCs) and the functional benefits of primed hCSCs after transplantation. In vitro experiments showed that the MHY-1685‒primed hCSCs exhibited higher viability in response to oxidative stress and an enhanced proliferation potential compared to that of the unprimed senile hCSCs. Interestingly, priming MHY-1685 enhanced the expression of stemness-related markers in senile hCSCs and provided the differentiation potential of hCSCs into vascular lineages. In vivo experiment with echocardiography showed that transplantation of MHY-1685‒primed hCSCs improved cardiac function than that of the unprimed senile hCSCs at 4 weeks post-MI. In addition, hearts transplanted with MHY-1685-primed hCSCs exhibited significantly lower cardiac fibrosis and higher capillary density than that of the unprimed senile hCSCs. In confocal fluorescence imaging, MHY-1685‒primed hCSCs survived for longer durations than that of the unprimed senile hCSCs and had a higher potential to differentiate into endothelial cells (ECs) within the infarcted hearts. These findings suggest that MHY-1685 can rejuvenate senile hCSCs by modulating autophagy and that as a senescence inhibitor, MHY-1685 can provide opportunities to improve hCSC-based myocardial regeneration., Heart disease: keeping cardiac stem cells younger Stem cells for repairing damaged hearts could be kept in a younger and more viable state using a drug called MHY-1685 which assists processes that resist cell aging. Using stem cells to repair damaged heart tissue requires millions of cells but culturing a suitable cell type often causes many cells to age and become less viable. Ji Hye Park at Pusan University, Yangsan, South Korea, and colleagues explored the potential of MHY-1685 to rejuvenate human cardiac stem cells (hCSCs). The drug enhances a maintenance process called autophagy, which clears cells of worn-out components. Exposure to MHY-1685 generated stem cell populations that proved more effective than unexposed cells at repairing damaged heart tissue when transplanted into rats. Its potential for producing cells for treating patients should be explored.

SURF4, which is located in the Surfeit gene cluster, encodes for a conserved integral membrane protein containing multiple putative transmembrane regions. However, the physiological role of SURF4 has not been determined. We found that SURF4 demonstrated aberrant amplification and increased expression in the tumor tissues of several human cancer patients. Overexpression of SURF4 led to increased cell proliferation, migration, and maintenance of anchorage-independent growth. In addition, NIH3T3 cells overexpressing SURF4 induced tumor growth in the mice. Collectively, our findings demonstrate that SURF4 has the potential for inducing cellular transformation and cell migration in vitro and has oncogenic transformation ability in vivo.

Mesenchymal stem cells (MSCs) are multipotent progenitor cells with self-renewing properties; thus, transplanting functionally enhanced MSCs might be a promising strategy for cell therapy against ischemic diseases. However, extensive oxidative damage in ischemic tissue affects the cell fate of transplanted MSCs, eventually resulting in cell damage and autophagic cell death. Oleuropein (OLP) is a bioactive compound isolated from olives and olive oil that harbors antioxidant properties. This study aimed to investigate the potential cytoprotective effects of OLP against oxidative stress and autophagic cell death in MSCs. We found that short-term priming with OLP attenuated H2O2-induced apoptosis by regulating the pro-apoptotic marker Bax and the anti-apoptotic markers Bcl-2 and Mcl-1. Notably, OLP inhibits H2O2 -induced autophagic cell death by modulating autophagy-related death signals, including mTOR (mammalian target of rapamycin), ULK1 (unc-51 like autophagy activating kinase 1), Beclin-1, AMPK (AMP-activated protein kinase), and LC3 (microtubule-associated protein 1a/1b-light chain 3). Our data suggest that OLP might reduce H2O2-induced autophagy and cell apoptosis in MSCs by regulating both the AMPK-ULK axis and the Bcl-2-Mcl-1 axis. Consequently, short-term cell priming with OLP might enhance the therapeutic effect of MSCs against ischemic vascular diseases, which provides an important potential improvement for emerging therapeutic strategies.

B cell leukemia/lymphoma 3 (Bcl3) plays a pivotal role in immune homeostasis, cellular proliferation, and cell survival, as a co-activator or co-repressor of transcription of the NF-κB family. Recently, it was reported that Bcl3 positively regulates pluripotency genes, including Oct4, in mouse embryonic stem cells (mESCs). However, the role of Bcl3 in the maintenance of pluripotency and self-renewal activity is not fully established. Here, we report the dynamic regulation of the proliferation, pluripotency, and self-renewal of mESCs by Bcl3 via an influence on Nanog transcriptional activity. Bcl3 expression is predominantly observed in immature mESCs, but significantly decreased during cell differentiation by LIF depletion and in mESC-derived EBs. Importantly, the knockdown of Bcl3 resulted in the loss of self-renewal ability and decreased cell proliferation. Similarly, the ectopic expression of Bcl3 also resulted in a significant reduction of proliferation, and the self-renewal of mESCs was demonstrated by alkaline phosphatase staining and clonogenic single cell-derived colony assay. We further examined that Bcl3-mediated regulation of Nanog transcriptional activity in mESCs, which indicated that Bcl3 acts as a transcriptional repressor of Nanog expression in mESCs. In conclusion, we demonstrated that a sufficient concentration of Bcl3 in mESCs plays a critical role in the maintenance of pluripotency and the self-renewal of mESCs via the regulation of Nanog transcriptional activity. [BMB Reports 2018; 51(2): 92-97].

There is a growing interest in electronic nose-based diagnostic systems that are fast and portable. However, existing technologies are suitable only for operation in the laboratory, making them difficult to apply in a rapid, non-face-to-face, and field-suitable manner. Here, we demonstrate a DNA-derived phage nose (D2pNose) as a portable respiratory disease diagnosis system requiring no pretreatment. D2pNose was produced based on phage colour films implanted with DNA sequences from mammalian olfactory receptor cells, and as a result, it possesses the comprehensive reactivity of these cells. The manipulated surface chemistry of the genetically engineered phages was verified through a correlation analysis between the calculated and the experimentally measured reactivity. Breaths from 31 healthy subjects and 31 lung cancer patients were collected and exposed to D2pNose without pretreatment. With the help of deep learning and neural pattern separation, D2pNose has achieved a diagnostic success rate of over 75% and a classification success rate of over 86% for lung cancer based on raw human breath. Based on these results, D2pNose can be expected to be directly applicable to other respiratory diseases.

Dysfunction or loss of blood vessel causes several ischemic diseases. Although endothelial progenitor cells (EPCs) are a promising source for cell-based therapy, ischemia-induced pathophysiological condition limits the recovery rate by causing drastic cell death. To overcome this issue, we attempted to develop a cell-targeted peptide delivery and priming system to enhance EPC-based neovascularization using an engineered M13 bacteriophage harboring nanofibrous tubes displaying ~2700 multiple functional motifs. The M13 nanofiber was modified by displaying RGD, which is an integrin-docking peptide, on the minor coat protein, and by mutilayering SDKP motifs, which are the key active sites for thymosin β4, on the major coat protein. The engineered M13 nanofiber dramatically enhanced ischemic neovascularization by activating intracellular and extracellular processes such as proliferation, migration, and tube formation in the EPCs. Furthermore, transplantation of the primed EPCs with the M13 nanofiber harboring RGD and SDKP facilitated functional recovery and neovascularization in a murine hindlimb ischemia model. Overall, this study demonstrates the effectiveness of the M13 nanofiber-based novel peptide delivery and priming strategy in promoting EPC bioactivity and neovessel regeneration. To our knowledge, this is first report on M13 nanofibers harboring dual functional motifs, the use of which might be a novel strategy for stem and progenitor cell therapy against cardiovascular ischemic diseases.

Transcriptional co-activator with a PDZ-binding motif (TAZ) is an important factor in lysophosphatidic acid (LPA)-induced promotion of migration and proliferation of human mesenchymal stem cells (MSCs). The expression of TAZ significantly increased at 6 h after LPA treatment, and TAZ knockdown inhibited the LPA-induced migration and proliferation of MSCs. In addition, embryonic fibroblasts from TAZ knockout mice exhibited the reduction in LPA-induced migration and proliferation. The LPA1 receptor inhibitor Ki16425 blocked LPA responses in MSCs. Although TAZ knockdown or knockout did not reduce LPA-induced phosphorylation of ERK and AKT, the MEK inhibitor U0126 or the ROCK inhibitor Y27632 blocked LPA-induced TAZ expression along with the reduction in the proliferation and migration of MSCs. Our data suggest that TAZ is an important mediator of LPA signaling in MSCs in the downstream of MEK and ROCK signaling.

In this study, the suitability of gelatin methacryloyl (GelMA) nanogels for transdermal delivery of macromolecules was demonstrated. The synthesis of GelMA nanogels (GNs) and fluorescein isothiocyanate labelled bovine serum albumin (FITC-BSA) loaded GelMA nanogels (FGNs) were implemented when confined in water-in-oil nanoemulsion droplets via the photopolymerization of the methacryloyl substituents to create crosslinked nanogels. Both GNs and FGNs existed as fine particles in aqueous condition (pH 7.4) for 7 days. No distinct aggregation of nanogel particles were observed. In the MTT assay, high percentage of cell viability indicated that GNs did not exhibit any growth inhibitory effect or significant cytotoxicity. The skin penetration study results showed that FGNs permeated across the epidermis and into the dermis of a porcine model when compared to the FITC-BSA dissolved in PBS. Possible penetration routes of FITC-BSA through the stratum corneum (SC) were illustrated by visualizing the SC structure with fluorescent signals of FITC-BSA. The penetration mechanism of FGNs across the SC layer was successfully demonstrated by explaining three penetration routes (intercellular, follicular, and transcellular route). The results suggest that GNs have a potential as a transdermal delivery carrier for hydrophilic macromolecules.

Cardiac progenitor cells (CPCs) are resident stem cells present in a small portion of ischemic hearts and function in repairing the damaged heart tissue. Intense oxidative stress impairs cell metabolism thereby decreasing cell viability. Protecting CPCs from undergoing cellular apoptosis during oxidative stress is crucial in optimizing CPC-based therapy. Histochrome (sodium salt of echinochrome A&mdash, a common sea urchin pigment) is an antioxidant drug that has been clinically used as a pharmacologic agent for ischemia/reperfusion injury in Russia. However, the mechanistic effect of histochrome on CPCs has never been reported. We investigated the protective effect of histochrome pretreatment on human CPCs (hCPCs) against hydrogen peroxide (H2O2)-induced oxidative stress. Annexin V/7-aminoactinomycin D (7-AAD) assay revealed that histochrome-treated CPCs showed significant protective effects against H2O2-induced cell death. The anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and Bcl-xL were significantly upregulated, whereas the pro-apoptotic proteins BCL2-associated X (Bax), H2O2-induced cleaved caspase-3, and the DNA damage marker, phosphorylated histone (&gamma, H2A.X) foci, were significantly downregulated upon histochrome treatment of hCPCs in vitro. Further, prolonged incubation with histochrome alleviated the replicative cellular senescence of hCPCs. In conclusion, we report the protective effect of histochrome against oxidative stress and present the use of a potent and bio-safe cell priming agent as a potential therapeutic strategy in patient-derived hCPCs to treat heart disease.

Cardiovascular diseases (CVDs) are a major cause of death worldwide. Due to the prevalence of many side effects and incomplete recovery from pharmacotherapies, stem cell therapy is being targeted for the treatment of CVDs. Among the different types of stem cells, endothelial progenitor cells (EPCs) have great potential. However, cellular replicative senescence decreases the proliferation, migration, and overall function of EPCs. Sirtuin 1 (SIRT1) has been mainly studied in the mammalian aging process. MHY2233 is a potent synthetic SIRT1 activator and a novel antiaging compound. We found that MHY2233 increased the expression of SIRT1, and its deacetylase activity thereby decreased expression of the cellular senescence biomarkers, p53, p16, and p21. In addition, MHY2233 decreased senescence-associated beta-galactosidase- (SA-β-gal-) positive cells and senescence-associated secretory phenotypes (SASPs), such as the secretion of interleukin- (IL-) 6, IL-8, IL-1α, and IL-1β. MHY2233 treatment protected senescent EPCs from oxidative stress by decreasing cellular reactive oxygen species (ROS) levels, thus enhancing cell survival and function. The angiogenesis, proliferation, and migration of senescent EPCs were enhanced by MHY2233 treatment. Thus, MHY2233 reduces replicative and oxidative stress-induced senescence in EPCs. Therefore, this novel antiaging compound MHY2233 might be considered a potent therapeutic agent for the treatment of age-associated CVDs.

There is a minor spelling error in the last of name of the 9th author in the originally published article.