Organ function is preserved despite reorganization of niche architecture in the hair follicle.

The ability of stem cells to build and replenish tissues depends on support from their niche. Although niche architecture varies across organs, its functional importance is unclear. During hair follicle growth, multipotent epithelial progenitors build hair via crosstalk with their remodeling fibroblast niche, the dermal papilla, providing a powerful model to functionally interrogate niche architecture. Through mouse intravital imaging, we show that dermal papilla fibroblasts remodel individually and collectively to form a morphologically polarized, structurally robust niche. Asymmetric TGF-ß signaling precedes morphological niche polarity, and loss of TGF-ß signaling in dermal papilla fibroblasts leads them to progressively lose their stereotypic architecture, instead surrounding the epithelium. The reorganized niche induces the redistribution of multipotent progenitors but nevertheless supports their proliferation and differentiation. However, the differentiated lineages and hairs produced by progenitors are shorter. Overall, our results reveal that niche architecture optimizes organ efficiency but is not absolutely essential for organ function.

Cell cycle controls long-range calcium signaling in the regenerating epidermis.

Skin homeostasis is maintained by stem cells, which must communicate to balance their regenerative behaviors. Yet, how adult stem cells signal across regenerative tissue remains unknown due to challenges in studying signaling dynamics in live mice. We combined live imaging in the mouse basal stem cell layer with machine learning tools to analyze patterns of Ca2+ signaling. We show that basal cells display dynamic intercellular Ca2+ signaling among local neighborhoods. We find that these Ca2+ signals are coordinated across thousands of cells and that this coordination is an emergent property of the stem cell layer. We demonstrate that G2 cells are required to initiate normal levels of Ca2+ signaling, while connexin43 connects basal cells to orchestrate tissue-wide coordination of Ca2+ signaling. Lastly, we find that Ca2+ signaling drives cell cycle progression, revealing a communication feedback loop. This work provides resolution into how stem cells at different cell cycle stages coordinate tissue-wide signaling during epidermal regeneration.

Roles of exosomal miRNA in vascular aging.

Aging is a major risk factor for human diseases. As global average life expectancy has lengthened, delaying or reducing aging and age-related diseases has become an urgent issue for improving the quality of life. The vascular aging process represents an important link between aging and age-related diseases. Exosomes are small extracellular vesicles (EV) that can be secreted by almost all eukaryotic cells, and they deliver characteristic biological information about donor cells to regulate the cellular microenvironment, mediate signal transmission between neighboring or distant cells, and affect the expression of target genes in recipient cells. Many recent studies have shown that exosomal microribonucleic acids (miRNA) are involved in the regulation of vascular aging by participating in the physiological functions of vascular cells and the destruction and remodeling of the extracellular matrix (ECM). This review summarizes the regulatory functions of exosomal miRNA in vascular aging because they interact with the ECM, and participate in vascular cell senescence, and the regulation of senescence-related functions such as proliferation, migration, apoptosis, inflammation, and differentiation.

Serum exosomal miR-122-5p is a new biomarker for both acute coronary syndrome and underlying coronary artery stenosis.

PURPOSE: Acute coronary syndrome presents as unstable angina (UA) or acute myocardial infarction (AMI). We explored the use of exosomal miR-122-5p as a biomarker for UA and AMI and determined whether its expression level is positively correlated with the severity of coronary stenosis. METHODS: This study enrolled 34 patients with AMI, 31 patients with UA, and 22 control subjects. qPCR was used to detect the expression levels of serum exosomal miR-122-5p. RESULTS: The expression of serum exosomal miR-122-5p in UA and AMI patients was significantly higher than that in the control group, and expression levels differed between UA and AMI patients. Receiver operating characteristic analysis demonstrated that serum exosomal miR-122-5p might be used as a diagnostic biomarker for AMI and UA. In addition, we also found that serum exosomal miR-122-5p was positively correlated with the severity of coronary artery stenosis for UA patients based on the Gensini score. Serum exosomal miR-122-5p was highly expressed in patients with a coronary artery stenosis severity greater than 80% during acute coronary syndrome. CONCLUSION: Serum exosomal miR-122-5p might be useful as a diagnostic biomarker for AMI and UA, and increased serum exosomal miR-122-5p levels could be useful to predict the severity of coronary lesions.

Circular RNAs in the pathogenesis of atherosclerosis.

Atherosclerosis is a common cause of cardiovascular and cerebrovascular diseases. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) have attracted substantial attention for their roles in various physiological and pathological processes. In recent years, research on the roles of circRNAs in atherosclerosis has progressed rapidly, and they have been implicated in the pathophysiological processes underlying the development of atherosclerosis, including changes in the functions of endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and macrophages. In this review article, we summarize currently available data regarding the role of circRNAs in atherosclerosis and how circRNAs influence the development of atherosclerosis by regulating ECs, VSMCs, and macrophages. We also discuss their potential as diagnostic biomarkers for coronary artery disease.

Silk fibroin peptide suppresses proliferation and induces apoptosis and cell cycle arrest in human lung cancer cells.

Silkworm cocoon was recorded to cure carbuncle in the Compendium of Materia Medica. Previous studies have demonstrated that the supplemental silk protein sericin exhibits anticancer activity. In the present study, we investigated the effects of silk fibroin peptide (SFP) extracted from silkworm cocoons against human lung cancer cells in vitro and in vivo and its possible anticancer mechanisms. SFP that we prepared had high content of glycine (~ 30%) and showed a molecular weight of ~ 10 kDa. Intragastric administration of SFP (30 g/kg/d) for 14 days did not affect the weights, vital signs, routine blood indices, and blood biochemical parameters in mice. MTT assay showed that SFP dose-dependently inhibited the growth of human lung cancer A549 and H460 cells in vitro with IC50 values of 9.921 and 9.083 mg/mL, respectively. SFP also dose-dependently suppressed the clonogenic activity of the two cell lines. In lung cancer H460 xenograft mice, intraperitoneal injection of SFP (200 or 500 mg/kg/d) for 40 days significantly suppressed the tumor growth, but did not induce significant changes in the body weight. We further examined the effects of SFP on cell cycle and apoptosis in H460 cells using flow cytometry, which revealed that SFP-induced cell cycle arrest at the S phase, and then promoted cell apoptosis. We demonstrated that SFP (20-50 mg/mL) dose-dependently downregulates Bcl-2 protein expression and upregulates Bax protein in H460 cells during cell apoptosis. The results suggest that SFP should be studied further as a novel therapeutic agent for the treatment of lung cancer.

Glutathione reductase mediates drug resistance in glioblastoma cells by regulating redox homeostasis.

Glutathione (GSH) and GSH-related enzymes constitute the most important defense system that protects cells from free radical, radiotherapy, and chemotherapy attacks. In this study, we aim to explore the potential role and regulatory mechanism of the GSH redox cycle in drug resistance in glioblastoma multiforme (GBM) cells. We found that temozolomide (TMZ)-resistant glioma cells displayed lower levels of endogenous reactive oxygen species and higher levels of total antioxidant capacity and GSH than sensitive cells. Moreover, the expression of glutathione reductase (GSR), the key enzyme of the GSH redox cycle, was higher in TMZ-resistant cells than in sensitive cells. Furthermore, silencing GSR in drug-resistant cells improved the sensitivity of cells to TMZ or cisplatin. Conversely, the over-expression of GSR in sensitive cells resulted in resistance to chemotherapy. In addition, the GSR enzyme partially prevented the oxidative stress caused by pro-oxidant L-buthionine -sulfoximine. The modulation of redox state by GSH or L-buthionine -sulfoximine regulated GSR-mediated drug resistance, suggesting that the action of GSR in drug resistance is associated with the modulation of redox homeostasis. Intriguingly, a trend toward shorter progress-free survival was observed among GBM patients with high GSR expression. These results indicated that GSR is involved in mediating drug resistance and is a potential target for improving GBM treatment.

BHX, a novel pyrazoline derivative, inhibits breast cancer cell invasion by reversing the epithelial-mesenchymal transition and down-regulating Wnt/ß-catenin signalling.

The novel pyrazoline derivative, BHX, has recently been shown to exhibit potent anti-tumour activity by blocking the Wnt/ß-catenin signalling pathway. However, its effect on breast cancer growth and invasion are unknown. Our results show that BHX suppresses MDA-MB-231 cell viability and colony formation in a dose-dependent manner, and induces apoptosis and G0/G1 phase arrest. BHX-treated breast cancer cells showed morphological characteristics of cells undergoing apoptosis. Furthermore, BHX inhibited cell migration and invasion, which was associated with increased E-cadherin mRNA and protein expression, and down-regulation of SNAIL and vimentin. In addition, BHX induced the generation of intracellular ROS and decreased ß-catenin protein and mRNA expression. We used a mouse xenograft model to investigate the effects of BHX in vivo, where the growth of MDA-MB-231 xenografted tumours was suppressed in nude mice treated continuously with BHX for 21 days. Finally, the rat plasma concentration of BHX was measured by ultra-performance liquid-chromatography tandem mass spectrometry and the pharmacokinetic parameters of BHX were processed by non-compartmental analysis. In conclusion, BHX merits further study as a novel therapeutic small molecule for the treatment of breast cancer.

BHX Inhibits the Wnt Signaling Pathway by Suppressing ß-catenin Transcription in the Nucleus.

BHX (N-(4-hydroxybenzyl)-1,3,4-triphenyl-4,5-dihydro-1H-pyrazole-5-carboxamide), a Wnt signaling pathway inhibitor, effectively inhibits tumor cell growth, but the underlying mechanism is unclear. Thus, we aim to investigate the effects and associated mechanism of BHX action on A549 and MCF-7 cell lines. In our study, MTT(3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide) and xenograft model assay indicated that cell growth was inhibited by BHX at a range of concentrations in vitro and in vivo. The expression of ß-catenin and Wnt signaling pathway downstream target genes were decreased evidently under BHX treatment. Flow cytometry also revealed that BHX treatment significantly induced G1 arrest. Further analysis showed that BHX lowered the transcriptional level of ß-catenin. In conclusion, BHX inhibited the nuclear synthesis of ß-catenin, thereby suppressing the Wnt signaling pathway and further inhibiting tumor growth and proliferation.

Ursolic acid attenuates temozolomide resistance in glioblastoma cells by downregulating O(6)-methylguanine-DNA methyltransferase (MGMT) expression.

The DNA-alkylating agent temozolomide (TMZ) is an effective chemotherapeutic agent against malignant glioma, including glioblastoma multiforme (GBM). However, the clinical efficacy of TMZ is limited in many patients because of O(6)-methylguanine-DNA methyltransferase (MGMT)-driven resistance. Thus, new strategies to overcome TMZ resistance are urgently needed. Ursolic acid (UA) is a naturally derived pentacyclic triterpene acid that exerts broad anticancer effects, and shows capability to cross the blood-brain barrier. In this study, we evaluated the possible synergistic effect of TMZ and UA in resistant GBM cell lines. The results showed that UA prevented the proliferation of resistant GBM cells in a concentration-dependent manner. Compared with TMZ or UA treatment alone, the combination treatment of TMZ and UA synergistically enhanced cytotoxicity and senescence in TMZ-resistant GBM cells. This effect was correlated with the downregulation of MGMT. Moreover, experimental results with an in vivo mouse xenograft model showed that the combination treatment of UA and TMZ reduced tumor volumes by depleting MGMT. Therefore, UA as both a monotherapy and a resensitizer, might be a candidate agent for patients with refractory malignant gliomas.