Circadian disruption: from mouse models to molecular mechanisms and cancer therapeutic targets.

The circadian clock is a timekeeping system for numerous biological rhythms that contribute to the regulation of numerous homeostatic processes in humans. Disruption of circadian rhythms influences physiology and behavior and is associated with adverse health outcomes, especially cancer. However, the underlying molecular mechanisms of circadian disruption-associated cancer initiation and development remain unclear. It is essential to construct good circadian disruption models to uncover and validate the detailed molecular clock framework of circadian disruption in cancer development and progression. Mouse models are the most widely used in circadian studies due to their relatively small size, fast reproduction cycle, easy genome manipulation, and economic practicality. Here, we reviewed the current mouse models of circadian disruption, including suprachiasmatic nuclei destruction, genetic engineering, light disruption, sleep deprivation, and other lifestyle factors in our understanding of the crosstalk between circadian rhythms and oncogenic signaling, as well as the molecular mechanisms of circadian disruption that promotes cancer growth. We focused on the discoveries made with the nocturnal mouse, diurnal human being, and cell culture and provided several circadian rhythm-based cancer therapeutic strategies.

Targeting delivery of miR-146a via IMTP modified milk exosomes exerted cardioprotective effects by inhibiting NF-κB signaling pathway after myocardial ischemia-reperfusion injury.

Reperfusion therapy is critical for saving heart muscle after myocardial infarction, but the process of restoring blood flow can itself exacerbate injury to the myocardium. This phenomenon is known as myocardial ischemia-reperfusion injury (MIRI), which includes oxidative stress, inflammation, and further cell death. microRNA-146a (miR-146a) is known to play a significant role in regulating the immune response and inflammation, and has been studied for its potential impact on the improvement of heart function after myocardial injury. However, the delivery of miR-146a to the heart in a specific and efficient manner remains a challenge as extracellular RNAs are unstable and rapidly degraded. Milk exosomes (MEs) have been proposed as ideal delivery platform for miRNA-based therapy as they can protect miRNAs from RNase degradation. In this study, the effects of miR-146a containing MEs (MEs-miR-146a) on improvement of cardiac function were examined in a rat model of MIRI. To enhance the targeting delivery of MEs-miR-146a to the site of myocardial injury, the ischemic myocardium-targeted peptide IMTP was modified onto the surfaces, and whether the modified MEs-miR-146a could exert a better therapeutic role was examined by echocardiography, myocardial injury indicators and the levels of inflammatory factors. Furthermore, the expressions of miR-146a mediated NF-κB signaling pathway-related proteins were detected by western blotting and qRT-PCR to further elucidate its mechanisms. MiR-146 mimics were successfully loaded into the MEs by electroporation at a square wave 1000 V voltage and 0.1 ms pulse duration. MEs-miR-146a can be up-taken by cardiomyocytes and protected the cells from oxygen glucose deprivation/reperfusion induced damage in vitro. Oral administration of MEs-miR-146a decreased myocardial tissue apoptosis and the expression of inflammatory factors and improved cardiac function after MIRI. The miR-146a level in myocardium tissues was significantly increased after the administration IMTP modified MEs-miR-146a, which was higher than that of the MEs-miR-146a group. In addition, intravenous injection of IMTP modified MEs-miR-146a enhanced the targeting to heart, improved cardiac function, reduced myocardial tissue apoptosis and suppressed inflammation after MIRI, which was more effective than the MEs-miR-146a treatment. Moreover, IMTP modified MEs-miR-146a reduced the protein levels of IRAK1, TRAF6 and p-p65. Therefore, IMTP modified MEs-miR-146a exerted their anti-inflammatory effect by inhibiting the IRAK1/TRAF6/NF-κB signaling pathway. Taken together, our findings suggested miR-146a containing MEs may be a promising strategy for the treatment of MIRI with better outcome after modification with ischemic myocardium-targeted peptide, which was expected to be applied in clinical practice in future.

Lymphangiogenesis, a potential treatment target for myocardial injury.

The lymphatic vascular system is crucial for the regulation of tissue fluid homeostasis, lipid metabolism, and immune function. Cardiac injury quickly leads to myocardial edema, cardiac lymphatic dysfunction, which ultimately results in myocardial fluid imbalance and cardiac dysfunction. Therefore, lymphangiogenesis-targeted therapy may improve the recovery of myocardial function post cardiac ischemia as observed in myocardial infarction (MI). Indeed, a promising strategy for the clinical treatment of MI relies on vascular endothelial growth factor-C (VEGF-C)-targeted therapy, which promotes lymphangiogenesis. However, much effort is needed to identify the mechanisms of lymphatic transport in response to heart disease. This article reviews regulatory factors of lymphangiogenesis, and discusses the effects of lymphangiogenesis on cardiac function after cardiac injury and its regulatory mechanisms. The involvement of stem cells on lymphangiogenesis was also discussed as stem cells could differentiate into lymphatic endothelial cells (LECs) and stimulate phenotype of LECs.

Mesenchymal Stem Cells and Their Exocytotic Vesicles.

Mesenchymal stem cells (MSCs), as a kind of pluripotent stem cells, have attracted much attention in orthopedic diseases, geriatric diseases, metabolic diseases, and sports functions due to their osteogenic potential, chondrogenic differentiation ability, and adipocyte differentiation. Anti-inflammation, anti-fibrosis, angiogenesis promotion, neurogenesis, immune regulation, and secreted growth factors, proteases, hormones, cytokines, and chemokines of MSCs have been widely studied in liver and kidney diseases, cardiovascular and cerebrovascular diseases. In recent years, many studies have shown that the extracellular vesicles of MSCs have similar functions to MSCs transplantation in all the above aspects. Here we review the research progress of MSCs and their exocrine vesicles in recent years.

Small Extracellular Vesicles Derived from Induced Pluripotent Stem Cells in the Treatment of Myocardial Injury.

Induced pluripotent stem cell (iPSC) therapy brings great hope to the treatment of myocardial injuries, while extracellular vesicles may be one of the main mechanisms of its action. iPSC-derived small extracellular vesicles (iPSCs-sEVs) can carry genetic and proteinaceous substances and mediate the interaction between iPSCs and target cells. In recent years, more and more studies have focused on the therapeutic effect of iPSCs-sEVs in myocardial injury. IPSCs-sEVs may be a new cell-free-based treatment for myocardial injury, including myocardial infarction, myocardial ischemia-reperfusion injury, coronary heart disease, and heart failure. In the current research on myocardial injury, the extraction of sEVs from mesenchymal stem cells induced by iPSCs was widely used. Isolation methods of iPSCs-sEVs for the treatment of myocardial injury include ultracentrifugation, isodensity gradient centrifugation, and size exclusion chromatography. Tail vein injection and intraductal administration are the most widely used routes of iPSCs-sEV administration. The characteristics of sEVs derived from iPSCs which were induced from different species and organs, including fibroblasts and bone marrow, were further compared. In addition, the beneficial genes of iPSC can be regulated through CRISPR/Cas9 to change the composition of sEVs and improve the abundance and expression diversity of them. This review focused on the strategies and mechanisms of iPSCs-sEVs in the treatment of myocardial injury, which provides a reference for future research and the application of iPSCs-sEVs.

Modified mRNA as a Treatment for Myocardial Infarction.

Myocardial infarction (MI) is a severe disease with high mortality worldwide. However, regenerative approaches remain limited and with poor efficacy. The major difficulty during MI is the substantial loss of cardiomyocytes (CMs) with limited capacity to regenerate. As a result, for decades, researchers have been engaged in developing useful therapies for myocardial regeneration. Gene therapy is an emerging approach for promoting myocardial regeneration. Modified mRNA (modRNA) is a highly potential delivery vector for gene transfer with its properties of efficiency, non-immunogenicity, transiency, and relative safety. Here, we discuss the optimization of modRNA-based therapy, including gene modification and delivery vectors of modRNA. Moreover, the effective of modRNA in animal MI treatment is also discussed. We conclude that modRNA-based therapy with appropriate therapeutical genes can potentially treat MI by directly promoting proliferation and differentiation, inhibiting apoptosis of CMs, as well as enhancing paracrine effects in terms of promoting angiogenesis and inhibiting fibrosis in heart milieu. Finally, we summarize the current challenges of modRNA-based cardiac treatment and look forward to the future direction of such treatment for MI. Further advanced clinical trials incorporating more MI patients should be conducted in order for modRNA therapy to become practical and feasible in real-world treatment.

Optimized Antimicrobial Peptide Jelleine-I Derivative Br-J-I Inhibits Fusobacterium Nucleatum to Suppress Colorectal Cancer Progression.

Colorectal cancer (CRC) is a major health burden worldwide due to its high morbidity, mortality, and complex etiology. Fusobacterium nucleatum (Fn), a Gram-negative anaerobe found in 30% of CRC patients, promotes CRC carcinogenesis, metastasis, and chemoresistance. Effective antimicrobial treatment is an unmet need for the rising CRC burden. Antimicrobial peptides (AMPs) represent a new class of antimicrobial drugs. In our previous study, we did the structure-activity study of Jelleine-I (J-I) and identified several halogenated J-I derivatives Cl-J-I, Br-J-I, and I-J-I. To determine whether those J-I derivatives can be a new therapy for bacterial-associated CRC, here we tested the antibacterial activities of these AMPs against Fn and their effects on CRC development. We found that Br-J-I showed the highest anti-Fn activity and Br-J-I may target membrane-associated FadA for Fn membrane disruption. More importantly, Fn promoted the growth of CRC cells-derived xenograft tumors. Br-J-I suppressed Fn load, colon inflammation, and Fn-induced CRC growth. Of note, Br-J-I induced better anti-CRC effects than common antibiotic metronidazole and Br-J-I sensitized the cancer-killing effect of chemotherapy drug 5-fluorouracil. These results suggest that Br-J-I could be considered as an adjunctive agent for CRC treatment and AMPs-based combination treatment is a new strategy for CRC in the future.

Modified Taohong Siwu decoction improves cardiac function after myocardial ischaemia and reperfusion in rats by promoting endogenous stem cell mobilization and regulating metabolites.

CONTEXT: Taohong Siwu decoction (THSWD) has been shown to promote heart repair in myocardial infarction. OBJECTIVE: To determine the effects of modified THSWD (THSWD plus four ingredients) on myocardial ischaemia and reperfusion (I/R) injury. MATERIALS AND METHODS: Sixty Sprague-Dawley rats were randomly divided into the I/R group and three different modified THSWD dose groups (gavage administration, 1.215, 2.43, and 4.86 g, respectively). 2,3,5-Triphenyltetrazolium chloride and Evans blue staining were used to detect the infarct area at 24 h after treatment. The serum biochemical indexes and cell apoptosis were examined to determine myocardial injury. The number of endogenous stem cells, expression of stromal dell derived factor-1 (SDF-1) and stem cell factor (SCF), and cardiac function were measured at 4 weeks. The serum was collected for metabolomic analysis. RESULTS: The high-dose modified THSWD group presented a reduced infarction area (decreased by 21.3%), decreased levels of lactate dehydrogenase and creatinine kinase, attenuated cell apoptosis, and enhanced superoxide dismutase activity in early stage I/R compared with other groups. The serum SCF and SDF-1 levels were higher in the high-dose group than in the I/R group. At 4 weeks, the infarct size and collagen content were the lowest, and the ejection fraction and fractional shortening values were the highest in the high-dose group. Moreover, high-dose modified THSWD affected the metabolism of phosphonate and phosphonate, taurine, and hypotaurine. CONCLUSIONS: Endogenous stem cell mobilization and metabolic regulation were related to the cardioprotection of modified THSWD. We provided a new strategy and direction for the treatment of cardiovascular diseases with traditional Chinese medicine.

Self-assembling peptide modified with QHREDGS as a novel delivery system for mesenchymal stem cell transplantation after myocardial infarction.

The lower cell survival and retention in the hostile microenvironment after transplantation has been implicated as a major bottleneck in the advancement of stem cell therapy for myocardial infarction (MI). In this study, we designed a novel self-assembling peptide (SAP) by attaching prosurvival peptide QHREDGS derived from angiopoeitin-1 to the known SAP, RADA16-I. The mesenchymal stem cells (MSCs) were harvested from male rats and cytoprotective effect of this designer SAP (DSAP) on cultured MSCs was detected by Hoechst 33342 staining after being exposed to oxygen and glucose deprivation (OGD). The cytoprotective effect of MSCs seeded in DSAP (DSAP-MSCs) on OGD treated cardiomyocytes was examined by TUNEL staining, phosphorylated (p-) protein kinase B (Akt) level, and ELISA. The therapeutic potential of MSC transplantation carried in DSAP was evaluated in a female rat MI model. PBS, MSCs alone, MSCs seeded in SAP (SAP-MSCs), or DSAP-MSCs were transplanted into the border of the infarcted area, respectively. DSAP not only increased the proliferation of MSCs and decreased apoptosis of MSCs after OGD treatment but also promoted the secretion of IGF-1 and HGF in MSCs. Treatment with culture supernatant of DSAP-MSCs markedly reduced the percentage of apoptotic cardiomyocytes and increased the level of p-Akt. Compared with the MSC group and SAP-MSC group, DSAP-MSC injection improved cardiac function and reduced infarct size, collagen content, and cell apoptosis. The number of Y chromosome-positive cells and microvessels in the DSAP-MSC group was higher than those in the MSC group and SAP-MSC group. Moreover, DSAP-MSC transplantation down-regulated the expression of IL-6 and IL-1ß and up-regulated the level of VEGF and HGF. Interestingly, miR-21 was enriched in DSAP-MSC-derived exosomes (DSAP-MSC-Exos) and the protection against cardiomyocyte apoptosis by DSAP-MSC-Exos was inhibited when miR-21 was knocked down. Furthermore, miR-21 contributed to the improvement of cardiac function after DSAP-MSC-Exo injection in a rat model of MI. Additionally, the combination of DSAP and cardiotrophin-1 (Ctf1) pretreatment further improved the survival of MSCs and the efficiency of MSC transplantation. We proposed QHREDGS-modified SAP as an effective cell delivery system and demonstrated that MSC transplantation in this DSAP promoted angiogenesis and paracrine, thereby reducing scar size and cell apoptosis as well as improving cardiac function probably via exosome-mediated miR-21 after MI. Furthermore, for the first time, we proposed that DSAP, especially working together with Ctf1 pretreatment, could be a valuable way to improve the survival of MSCs and the efficiency of MSC transplantation after MI.-Cai, H., Wu, F.-Y., Wang, Q.-L., Xu, P., Mou, F.-F., Shao, S.-J., Luo, Z.-R., Zhu, J., Xuan, S.-S., Lu, R., Guo, H.-D. Self-assembling peptide modified with QHREDGS as a novel delivery system for mesenchymal stem cell transplantation after myocardial infarction.

Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice.

Administration of exosomes derived from mesenchymal stromal cells (MSCs) could improve some neurologic conditions by transferring functional biomolecules to recipient cells. Furthermore, exosomes from hypoxic progenitor cells exerted better therapeutic effects in organ injury through specific cargoes. However, there are no related reports about whether exosomes derived from MSCs or hypoxia-preconditioned MSCs (PC-MSCs) could prevent memory deficits in Alzheimer disease (AD). In this study, the exosomes derived from MSCs or PC-MSCs were systemically administered to transgenic APP/PS1 mice. The expression of miR-21 in MSCs was significantly increased after hypoxic treatment. Injection of exosomes from normoxic MSCs could rescue cognition and memory impairment according to results of the Morris water maze test, reduced plaque deposition, and Aß levels in the brain; could decrease the activation of astrocytes and microglia; could down-regulate proinflammatory cytokines (TNF-α and IL-1ß); and could up-regulate anti-inflammatory cytokines (IL-4 and -10) in AD mice, as well as reduce the activation of signal transducer and activator of transcription 3 (STAT3) and NF-κB. Compared to the group administered exosomes from normoxic MSCs, in the group administered exosomes from PC-MSCs, learning and memory capabilities were significantly improved; the plaque deposition and Aß levels were lower, and expression of growth-associated protein 43, synapsin 1, and IL-10 was increased; and the levels of glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, TNF-α, IL-1ß, and activation of STAT3 and NF-κB were sharply decreased. More importantly, exosomes from PC-MSCs effectively increased the level of miR-21 in the brain of AD mice. Additionally, replenishment of miR-21 restored the cognitive deficits in APP/PS1 mice and prevented pathologic features. Taken together, these findings suggest that exosomes from PC-MSCs could improve the learning and memory capabilities of APP/PS1 mice, and that the underlying mechanism may lie in the restoration of synaptic dysfunction and regulation of inflammatory responses through regulation of miR-21.-Cui, G.-H., Wu, J., Mou, F.-F., Xie, W.-H., Wang, F.-B., Wang, Q.-L., Fang, J., Xu, Y.-W., Dong, Y.-R., Liu, J.-R., Guo, H.-D. Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice.

RVG-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of Alzheimer's disease.

BACKGROUND: Exosomes are lipid-bilayer enclosed nano-sized vesicles that transfer functional cellular proteins, mRNA and miRNAs. Mesenchymal stem cells (MSCs) derived exosomes have been demonstrated to prevent memory deficits in the animal model of Alzheimer's disease (AD). However, the intravenously injected exosomes could be abundantly tracked in other organs except for the targeted regions in the brain. Here, we proposed the use of central nervous system-specific rabies viral glycoprotein (RVG) peptide to target intravenously-infused exosomes derived from MSCs (MSC-Exo) to the brain of transgenic APP/PS1 mice. MSC-Exo were conjugated with RVG through a DOPE-NHS linker. RESULTS: RVG-tagged MSC-Exo exhibited improved targeting to the cortex and hippocampus after being administered intravenously. Compared with the group administered MSC-Exo, in the group administered RVG-conjugated MSC-Exo (MSC-RVG-Exo) plaque deposition and Aß levels were sharply decreased and activation of astrocytes was obviously reduced. The brain targeted exosomes derived from MSCs was better than unmodified exosomes to improve cognitive function in APP/PS1 mice according to Morris water maze test. Additionally, although MSC-Exo injected intravenously reduced the expression of pro-inflammatory mediators TNF-α, IL-ß, and IL-6, but the changes of anti-inflammatory factors IL-10 and IL-13 were not obvious. However, administration of MSC-RVG-Exo significantly reduced the levels of TNF-α, IL-ß, and IL-6 while significantly raised the levels of IL-10, IL-4 and IL-13. CONCLUSIONS: Taken together, our results demonstrated a novel method for increasing delivery of exosomes for treatment of AD. By targeting exosomes to the cortex and hippocampus of AD mouse, there was a significant improvement in learning and memory capabilities with reduced plaque deposition and Aß levels, and normalized levels of inflammatory cytokines.

Correlation Analysis of Breast Cancer DWI Combined with DCE-MRI Imaging Features with Molecular Subtypes and Prognostic Factors.

This study aimed to deeply analyze the application of DWI and DCE-MRI imaging in breast cancer, the correlation between the imaging characteristics of DWI and DCE-MRI and the molecular subtypes and prognostic factors of breast cancer was studied. Firstly, DWI and DCE-MRI scans of all patients before interventional therapy were performed, and relevant information of the subjects was introduced in turn. Secondly, molecular subtypes were determined according to immunohistochemical results and gene amplification. Siemens 3.0 T post-processing workstation was used for image post-processing. The time signal curve (TIC), early enhancement rate (EER) and ADC values were measured, morphological characteristics were recorded, and the correlation between each image feature and molecular subtypes, prognostic factors (tumor size, pathological grade, lymph node metastasis, ER, PR, HER2, Ki67) was analyzed. The results showed that parameters such as ADC value, EER, lobulation sign, burr sign, enhancement way and TIC type were correlated with prognostic factors and molecular subtypes. And Bayesian model discriminant analysis showed that the above imaging parameters couldn't well predict the expression of immunohistochemical factors and molecular subtypes. However, the above characteristics had a good effect on the prediction of pathological grade, with a false diagnosis rate of 9.69%.

Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival.

RATIONALE: Yes-associated protein (YAP), the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEA (transcriptional enhancer activator)-domain sequence-specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. OBJECTIVE: To identify direct YAP targets that mediate its mitogenic and antiapoptotic effects in the heart. METHODS AND RESULTS: We identified direct YAP targets by combining differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP-bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110ß, a catalytic subunit of phosphoinositol-3-kinase, as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. YAP and TEA-domain occupied a conserved enhancer within the first intron of Pik3cb, and this enhancer drove YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the phosphoinositol-3-kinase-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened YAP mitogenic activity. Reciprocally, impaired heart function in Yap loss-of-function was significantly rescued by adeno-associated virus-mediated Pik3cb expression. CONCLUSIONS: Pik3cb is a crucial direct target of YAP, through which the YAP activates phosphoinositol-3-kinase-AKT pathway and regulates cardiomyocyte proliferation and survival.

M1/M2 macrophage-targeted nanotechnology and PROTAC for the treatment of atherosclerosis.

Macrophages play key roles in atherosclerosis progression, and an imbalance in M1/M2 macrophages leads to unstable plaques; therefore, M1/M2 macrophage polarization-targeted treatments may serve as a new approach in the treatment of atherosclerosis. At present, there is little research on M1/M2 macrophage polarization-targeted nanotechnology. Proteolysis-targeting chimera (PROTAC) technology, a targeted protein degradation technology, mediates the degradation of target proteins and has been widely promoted in preclinical and clinical applications as a novel therapeutic modality. This review summarizes the recent studies on M1/M2 macrophage polarization-targeted nanotechnology, focusing on the mechanism and advantages of PROTACs in M1/M2 macrophage polarization as a new approach for the treatment of atherosclerosis.

Delivery of Stem Cells and BMP-2 With Functionalized Self-Assembling Peptide Enhances Regeneration of Infarcted Myocardium.

Stem cell transplantation is a promising therapeutic strategy for myocardial infarction (MI). However, engraftment, survival and differentiation of the transplanted stem cells in ischemic and inflammatory microenvironment are poor. We designed a novel self-assembly peptide (SAP) by modifying the peptide RADA16 with cell-adhesive motif and BMP-2 (bone morphogenetic protein-2)-binding motif. Effects of the functionalized SAP on adhesion, survival and differentiation of c-kit+ MSCs (mesenchymal stem cells) were examined. Myocardial regeneration, neovascularization and cardiac function were assessed after transplantation of the SAP loading c-kit+ MSCs and BMP-2 in rat MI models. The SAP could spontaneously assemble into well-ordered nanofibrous scaffolds. The cells adhered to the SAP scaffolds and spread well. The SAP protected the cells in the condition of hypoxia and serum deprivation. Following degradation of the SAP, BMP-2 was released sustainedly and induced c-kit+ MSCs to differentiate into cardiomyocytes. At four weeks after transplantation of the SAP loading c-kit+ MSCs and BMP-2, myocardial regeneration and angiogenesis were enhanced, and cardiac function was improved significantly. The cardiomyocytes differentiated from the engrafted c-kit+ MSCs were increased markedly. The differentiated cells connected with recipient cardiomyocytes to form gap junctions. Collagen volume was decreased dramatically. These results suggest that the functionalized SAP promotes engraftment, survival and differentiation of stem cells effectively. Local sustained release of BMP-2 with SAP is a viable strategy to enhance differentiation of the engrafted stem cells and repair of the infarcted myocardium.

Circadian regulation of cancer stem cells and the tumor microenvironment during metastasis.

The circadian clock regulates daily rhythms of numerous physiological activities through tightly coordinated modulation of gene expression and biochemical functions. Circadian disruption is associated with enhanced tumor formation and metastasis via dysregulation of key biological processes and modulation of cancer stem cells (CSCs) and their specialized microenvironment. Here, we review how the circadian clock influences CSCs and their local tumor niches in the context of different stages of tumor metastasis. Identifying circadian therapeutic targets could facilitate the development of new treatments that leverage circadian modulation to ablate tumor-resident CSCs, inhibit tumor metastasis and enhance response to current therapies.

Electroacupuncture Promotes Nerve Regeneration and Functional Recovery Through Regulating lncRNA GAS5 Targeting miR-21 After Sciatic Nerve Injury.

Although the benefits of electroacupuncture (EA) for peripheral nerve injury (PNI) are well accepted in clinical practice, the underlying mechanism remains incompletely elucidated. In our study, we observed that EA intervention led to a reduction in the expression of the long non-coding RNA growth-arrest-specific transcript 5 (GAS5) and an increased in miR-21 levels within the injured nerve, effectively promoting functional recovery and nerve regeneration following sciatic nerve injury (SNI). In contrast, administration of adeno-associated virus expressing GAS5 (AAV-GAS5) weakened the therapeutic effect of EA. On the other hand, both silencing GAS5 and introducing a miR-21 mimic prominently enhanced the proliferation activity and migration ability of Schwann cells (SCs), while also inhibiting SCs apoptosis. On the contrary, inhibition of SCs apoptosis was found to be mediated by miR-21. Additionally, overexpression of GAS5 counteracted the effects of the miR-21 mimic on SCs. Moreover, SCs that transfected with the miR-21 mimic promoted neurite growth in hypoxia/reoxygenation-induced neurons, which might be prevented by overexpressing GAS5. Furthermore, GAS5 was found to be widely distributed in the cytoplasm and was negatively regulated by miR-21. Consequently, the targeting of GAS5 by miR-21 represents a potential mechanism through which EA enhances reinnervation and functional restoration following SNI. Mechanistically, the GAS5/miR-21 axis can modulate the proliferation, migration, and apoptosis of SCs while potentially influencing the neurite growth of neurons.

Transplantation of induced pluripotent stem cells-derived cardiomyocytes combined with modified Taohong Siwu decoction improved heart repair after myocardial infarction.

Objective: This study aimed to study whether modified Taohong Siwu decoction (MTHSWD) combined with human induced pluripotent stem cells-derived cardiomyocytes (iPS-CMs) transplantation can promote cardiac function in myocardial infarction (MI) nude mouse model and explore its possible mechanism. Methods: The MI mouse model was established by the ligation of left anterior descending coronary artery. After 4 weeks of gavage of MTHSWD combined with iPS-CMs transplantation, the changes in heart function of mice were examined by echocardiography. The histological changes were observed by Masson's trichrome staining. The survival and differentiation of transplanted cells were detected by double immunofluorescence staining of human nuclear antigen (HNA) and cardiac troponin T (cTnT). The number of c-kit-positive cells in the infarct area were evaluated by immunofluorescent staining. The levels of stromal cell-derived factor 1 (SDF-1), stem cell factor (SCF), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor in infarcted myocardium tissues were detected by ELISA. Results: MTHSWD combined with iPS-CMs transplantation can improve the heart function of MI mice, reduce the infarct size and collagen deposition in infarct area. By immunofluorescence double-label detection of HNA and cTnT, it was found that MTHSWD combined with iPS-CMs transplantation can improve the survival and maturation of iPS-CMs. In addition, MTHSWD combined with iPS-CMs transplantation can activate more endogenous c-kit positive cardiac mesenchymal cells, and significantly increase the content of SDF-1, SCF and VEGF in myocardial tissues. Conclusions: The combination of MTHSWD with iPS-CMs transplantation promoted cardiac function of nude mice with MI by improving the survival and maturation of iPS-CMs in the infarct area, activating the endogenous c-kit positive cardiac mesenchymal cells, and increasing paracrine.

Dihydrotanshinone I reduces H9c2 cell damage by regulating AKT and MAPK signaling pathways.

Cardiovascular disease is the deadliest disease in the world. Previous studies have shown that Dihydrotanshinone I (DHT) can improve cardiac function after myocardial injury. This study aimed to observe the protective effect and mechanism of DHT on H9c2 cells by establishing an oxygen-glucose deprivation/reoxygenation (OGD/R) injury model. By constructing OGD/R injury simulation of H9c2 cells in a myocardial injury model, the proliferation of H9c2 cells treated with DHT concentrations of 0.1 µmol/L were not affected at 24, 48, and 72 h. DHT can significantly reduce the apoptosis of H9c2 cells caused by OGD/R. Compared with the OGD/R group, DHT treatment significantly reduced the level of MDA and increased the level of SOD in cells. DHT treatment of cells can significantly reduce the levels of ROS and Superoxide in mitochondria in H9c2 cells caused by OGD/R and H2O2. DHT significantly reduced the phosphorylation levels of P38MAPK and ERK in H9c2 cells induced by OGD/R, and significantly increased the phosphorylation levels of AKT in H9c2 cells. DHT can significantly reduce the oxidative stress damage of H9c2 cells caused by H2O2 and OGD/R, thereby reducing the apoptosis of H9c2 cells. And this may be related to regulating the phosphorylation levels of AKT, ERK, and P38MAPK.

Astragaloside IV attenuates sunitinib-associated cardiotoxicity by inhibiting COUP-TFII.

Sunitinib (SU) is widely used to treat solid tumors but it can be cardiotoxic and often leads to drug withdrawn or discontinuation. Astragaloside IV (ASIV) is the essential active component of the Chinese herb Astragalus membranaceus which shows potential cardioprotective effects. Herein, we investigated the effect of ASIV on SU-associated cardiotoxicity and its mechanisms. We showed that ASIV significantly ameliorated SU-induced myocardial injury in mice, as evidenced by an improvement in left ventricular ejection fraction (EF) and a decrease in blood pressure and serum concentration of myocardial injury markers. ASIV attenuated SU-induced myocardial inflammatory infiltration and fibrotic lesions. In addition, ASIV suppressed SU-induced myocardial oxidative stress and apoptosis both in vitro and in vivo. Furthermore, SU increased COUP-TFII expression both in mRNA and protein levels in mice myocardial tissue, primary neonatal rat cardiomyocytes (NRCMs) and H9c2 cell lines, and this effect was rescued by ASIV. Knockdown of COUP-TFII reduced the oxidative stress and apoptosis induced by SU in NRCMs and H9c2 cell lines. However, the overexpression of COUP-TFII blocked the protective effects of ASIV on SU-treated cardiomyocytes. Thus, our results demonstrated that ASIV ameliorated SU-indued cardiotoxicity by inhibiting COUP-TFII, suggesting that ASIV might be a potential therapeutic strategy for the prevention of SU-associated cardiotoxicity.