Light-Driven Self-Cascade Peroxidase-like Nanozymes without Exogenous H2O2.

The peroxidase (POD)-like nanozyme typically requires the addition of exogenous H2O2. To address the limitation, previous work mainly adopted a cascade strategy for H2O2 production. Herein, we propose a new light-driven self-cascade strategy to construct POD-like nanozymes without exogenous H2O2. The model nanozyme resorcinol-formaldehyde resin-Fe3+ (RF-Fe3+) is synthesized with the hydroxyl-rich photocatalytic material RF as the carrier to in situ chelate metal oxides, which can simultaneously achieve the functions of in situ H2O2 generation under irradiation and substrate oxidation via POD-like behavior. Notably, RF-Fe3+ exhibits high affinity to H2O2, attributed to the excellent adsorption ability and hydroxyl-rich feature of RF. Furthermore, the dual photoelectrode-assisted photofuel cell was further constructed with a high-power density of 120 ± 5 µW cm-2 based on the RF-Fe3+ photocathode. This work not only demonstrates the new self-cascade strategy of in situ generation of catalysis substrates but also provides an opportunity to extend the catalytical field.

Photo-Assisted Robust Anti-Interference Self-Powered Biosensing of MicroRNA Based on Pt-S Bonds and the Inorganic-Organic Hybridization Strategy.

Photo-assisted biofuel cell-based self-powered biosensors (PBFC-SPBs) possess the advantages of no need for external power supply, ease of sensing design, and simple instruments. In this work, a robust anti-interference PBFC-SPB for microRNA detection was constructed based on the Pt-S bond and the inorganic-organic hybridization strategy. The organic semiconductor [6,6]-phenyl-C61-butyric acid methylester@anthraquinone (PCBM@anthraquinone) served as an efficient light-harvesting material, and gold nanoparticle@Pt (AuNP@Pt) nanomaterials were immobilized on the surface via electrostatic adsorption for the binding of DNA. Notably, compared to Au-S bonds for DNA immobilization, the Pt-S bond exhibited better anti-interference ability. Ingeniously, cadmium sulfide quantum dots (CdS QDs) were close to the PCBM@anthraquinone substrate electrode to form sensitization structures, which was beneficial to enhance the photocurrent signal. Combining with the laccase-mimicking activity Cu2+/carbon nanotubes (Cu2+/CNTs) cathode, the PBFC-SPB for microRNA detection was achieved. Once the target existed, the identical sequence complementary microRNA would make DNA2/CdS dissociate and break away from the electrode, leading to a low signal. The linear detection range was 10 fM-100 pM, with the limit of determination of 2.4 fM (3S/N). The as-proposed strategy not only paves a new way for the design of photoelectrochemical biosensing but also opens a door for the construction of robust anti-interference bioassay for microRNA detection.

MicroRNA-3613-3p functions as a tumor suppressor and represents a novel therapeutic target in breast cancer.

BACKGROUND: MicroRNAs have been reported to participate in tumorigenesis, treatment resistance, and tumor metastasis. Novel microRNAs need to be identified and investigated to guide the clinical prognosis or therapy for breast cancer. METHOD: The copy number variations (CNVs) of MIR3613 from Cancer Genome Atlas (TCGA) or Cancer Cell Line Encyclopedia (CCLE) were analyzed, and its correlation with breast cancer subtypes or prognosis was investigated. The expression level of miR-3613-3p in tumor tissues or serum of breast cancer patients was detected using in situ hybridization and qPCR. Gain-of-function studies were performed to determine the regulatory role of miR-3613-3p on proliferation, apoptosis, and tumor sphere formation of human breast cancer cells MDA-MB-231 or MCF-7. The effects of miR-3613-3p on tumor growth or metastasis in an immunocompromised mouse model of MDA-MB-231-luciferase were explored by intratumor injection of miR-3613-3p analogue. The target genes, interactive lncRNAs, and related signaling pathways of miR-3613-3p were identified by bioinformatic prediction and 3'-UTR assays. RESULTS: We found that MIR3613 was frequently deleted in breast cancer genome and its deletion was correlated with the molecular typing, and an unfavorable prognosis in estrogen receptor-positive patients. MiR-3613-3p level was also dramatically lower in tumor tissues or serum of breast cancer patients. Gain-of-function studies revealed that miR-3613-3p could suppress proliferation and sphere formation and promote apoptosis in vitro and impeded tumor growth and metastasis in vivo. Additionally, miR-3613-3p might regulate cell cycle by targeting SMS, PAFAH1B2, or PDK3 to restrain tumor progression. CONCLUSION: Our findings indicate a suppressive role of miR-3613-3p in breast cancer progression, which may provide an innovative marker or treatment for breast cancer patients.

[Role of Sertoli cells in regulating spermatogenesis: An update].

Spermatogenesis is a complex process in which Sertoli cells play a pivotal role. Sertoli cells are closely related to testicular development and male fertility by providing nutrition for the proliferation of germ cells and maintaining the balance of microenvironment in seminiferous tubules. This article focuses on the roles of Sertoli cells in normal and abnormal spermatogenesis, outlines the association of spermatogenesis with the number and morphology of and protein expressions and secretions in Sertoli cells, and provides some reference for the studies of the gene therapy for male infertility and male contraception.

Photofuel cell-based self-powered biosensor for HER2 detection by integration of plasmonic-metal/conjugated molecule hybrids and electrochemical sandwich structure.

Human epidermal growth factor receptor 2 (HER2) has been regarded as the considerable biomarker of breast and gastric cancer. Thus, precise detection of HER2 is of significance for the early diagnosis and treatment. Here, a photofuel cell-based self-powered biosensor (PFC-SPB) was constructed for the ultrasensitive HER2 detection, which was composed of a plasmonic gold nanoparticles (Au NPs)/organic semiconductor hybrid photoanode and a cathode with biosensing strategy of electrochemical sandwich structure. The localized surface plasmon resonance effect of Au NPs can obviously enhance the separation efficiency of photo-generated electron/hole pair, which was beneficial to the sensitivity and stability of PFC-SPB. Meanwhile, the cathodic sandwich structure not only was used for the target recognition, but also can guarantee the enrichment of electroactive molecules (molybdophosphate). Consequently, with the open circuit voltage (EOCV) as the output signal, the PFC-SPB can achieve the HER2 detection in the range of 0.1-500 pg mL-1 with a low detection limit of 0.02 pg mL-1. Moreover, the as-proposed bioassay can be applied in cell lysate sample without any pretreatment, providing a promising and powerful tool early clinical diagnosis of cancer.

Dual-mode colorimetric and homogeneous electrochemical detection of intracellular/extracellular H2O2 based on FeSx/SiO2 nanoparticles with high peroxidase-like activity.

Abnormal expression of hydrogen peroxide (H2O2) elucidates cell dysfunctions and might induce the occurrence and deterioration of various diseases. However, limited by its ultralow level under pathophysiological conditions, intracellular and extracellular H2O2 was difficult to be detected accurately. Herein, a colorimetric and homogeneous electrochemical dual-mode biosensing platform was constructed for intracellular/extracellular H2O2 detection based on FeSx/SiO2 nanoparticles (FeSx/SiO2 NPs) with high peroxidase-like activity. In this design, FeSx/SiO2 NPs were synthesized with excellent catalytic activity and stability compared to natural enzymes, which improved the sensitivity and stability of sensing strategy. 3,3',5,5'-Tetramethylbenzidine (TMB), as a multifunctional indicator, was oxidized in the presence of H2O2, generated color changes and realized visual analysis. In this process, the characteristic peak current of TMB decreased, which could realize the ultrasensitive detection of H2O2 by homogeneous electrochemistry. Accordingly, by integrating visual analysis ability of colorimetry and the high sensitivity of homogeneous electrochemistry, the dual-mode biosensing platform exhibited high accuracy, sensitivity and reliability. The detection limits of H2O2 were 0.2 µM (S/N = 3) for the colorimetric method and 2.5 nM (S/N = 3) for the homogeneous electrochemistry assay. Therefore, the dual-mode biosensing platform provided a new opportunity for highly accurate and sensitive detection of intracellular/extracellular H2O2.

Evolution of brain network dynamics in early Parkinson's disease with mild cognitive impairment.

How mild cognitive impairment (MCI) is instantiated in dynamically interacting and spatially distributed functional brain networks remains an unexplored mystery in early Parkinson's disease (PD). We applied a machine-learning technology based on personalized sliding-window algorithm to track continuously time-varying and overlapping subnetworks under the functional brain networks calculated form resting state electroencephalogram data within a sample of 33 early PD patients (13 early PD patients with MCI and 20 early PD patients without MCI). We decoded a set of subnetworks that captured surprisingly dynamically varying and integrated interactions among certain brain lobes. We observed that the master expressed subnetworks were particularly transient, and flexibly switching between high and low expression during integration into a dynamic brain network. This transience was particularly salient in a subnetwork predominantly linking temporal-parietal-occipital lobes, which decreases in both expression and flexibility in early PD patients with MCI and expresses their degree of cognitive impairment. Moreover, MCI induced a regularly interrupted, slow evolution of subnetworks in functional brain network dynamics in early PD at the individual level, and the dynamic expression characteristics of subnetworks also reflected the degree of cognitive impairment in patients with early PD. Collectively, these results provide novel and deeper insights regarding MCI-induced abnormal dynamical interaction and large-scale changes in functional brain network of early PD.

Temporal and spatial variability of dynamic microstate brain network in early Parkinson's disease.

Changes of brain network dynamics reveal variations in macroscopic neural activity patterns in behavioral and cognitive aspects. Quantification and application of changed dynamics in brain functional connectivity networks may contribute to a better understanding of brain diseases, and ultimately provide better prognostic indicators or auxiliary diagnostic tools. At present, most studies are focused on the properties of brain functional connectivity network constructed by sliding window method. However, few studies have explored evidence-based brain network construction algorithms that reflect disease specificity. In this work, we first proposed a novel approach to characterize the spatiotemporal variability of dynamic functional connectivity networks based on electroencephalography (EEG) microstate, and then developed a classification framework for integrating spatiotemporal variability of brain networks to improve early Parkinson's disease (PD) diagnostic performance. The experimental results indicated that compared with the brain network construction method based on conventional sliding window, the proposed method significantly improved the performance of early PD recognition, demonstrating that the dynamic spatiotemporal variability of microstate-based brain networks can reflect the pathological changes in the early PD brain. Furthermore, we observed that the spatiotemporal variability of early PD brain network has a specific distribution pattern in brain regions, which can be quantified as the degree of motor and cognitive impairment, respectively. Our work offers innovative methodological support for future research on brain network, and provides deeper insights into the spatiotemporal interaction patterns of brain activity and their variabilities in early PD.

Capturing the Abnormal Brain Network Activity in Early Parkinsons Disease with Mild Cognitive Impairment based on Dynamic Functional Connectivity.

The early Parkinson's disease (PD) with mild cognitive impairment (ePD-MCI) is a typical non-motor symptom reflected by the brain dysfunction of PD, which can be well depicted by the dynamic characteristics of brain functional connectivity networks. The aim of this study is to determine the unclear dynamic changes in functional connectivity networks induced by MCI in early PD patients. In this paper, the electroencephalogram (EEG) of each subject was reconstructed into the dynamic functional connectivity networks with five frequency bands based on adaptive sliding window method. By evaluating the fluctuations of dynamic functional connectivity and the transition stability of functional network state in ePD-MCI patients compared with early PD without mild cognitive impairment patients, it was found that in the alpha band, the functional network stability of central region, right frontal, parietal, occipital, and left temporal lobes was abnormally increased, and the dynamic connectivity fluctuations in these regions were significantly decreased in ePD-MCI group. In the gamma band, ePD-MCI patients showed decreased functional network stability in the central, left frontal, and right temporal lobes, and active dynamic connectivity fluctuations in the left frontal, temporal, and parietal lobes. The aberrant duration of network state in ePD-MCI patients was significantly negatively correlated with cognitive function in the alpha band, which might pave the way to identify and predict cognitive impairment in early PD patients.

Study on Medication Rules of Traditional Chinese Medicine in Treating Constipation through Data Mining and Network Pharmacology.

Background: To explore the rules of TCM medication in the treatment of constipation in network pharmacology. Methods: Collect and screen the clinical intervention literature on TCM for constipation from China's national knowledge infrastructure, Wanfang and VIP databases established a database of TCM for constipation, applied R software (3.3.1) to analyze the pattern of prescriptions for TCM for constipation, and summarized the core prescription. The effective active compounds and action targets in the core prescription were screened by Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Traditional Chinese Medicine Integrated Databases (TCMID), constipation-related targets were derived from the DisGeNET and GeneCards databases, Protein-protein interaction network (PPI) was drawn by STRING database, and enrichment analysis was conducted by the Clusterprofiler package in R software (3.3.1). Finally, molecular docking was used to validate the binding ability of candidate compounds to potential targets. Results: Two hundred sixteen target prescriptions were screened through data mining, involving 226 herbs. Association rule analysis results suggested that the "Angelicae sinensis-Radix-dried rehmanniae-Cistanche deserticola-Atractylodes macrocephala-Astragali Radix" was a strong affinity for medicine. Network pharmacology analysis of the core prescription resulted in the screening of 115 candidate compounds, such as quercetin, kaempferol, mangostin, eugenol A, and beta-sitosterol; 131 potential targets, such as PTGS2, PTGS1, and CHRM3; and 160 signaling pathways, such as lipid and atherosclerosis, proteoglycans in cancer, hepatitis B, Kaposi's sarcoma-associated herpesvirus infection, and PI3K/AKT pathways. Molecular docking showed that PTGS1-formononetin, PTGS2-kaempferol, and CHRM3-kaempferol were all well bound and well matched. Conclusions: This study provides a new method and ideas for clinical applications of integrated Chinese and western medicine in treating constipation.

Altered BDNF levels are associated with cognitive impairment in Parkinson's disease patients with depression.

OBJECTIVE: Depression and cognitive impairment are both common non-motor symptoms of Parkinson's disease (PD). Brain-derived neurotrophic factor (BDNF) may play an important role in both cognitive function and depression. In this study, we examined BDNF levels, cognitive function, and the relationship between BDNF and cognitive function in PD patients with and without depressive symptoms, which has not been reported yet. METHODS: We recruited 96 PD patients with (n = 46) and without depression (n = 50) and 102 controls and examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and BDNF levels in all groups. The Zung Self-Rating Depression Scale (SDS) was used to assess the severity of depression and the Hoehn-Yahr staging test was used to assess motor abilities in PD patients. RESULTS: BDNF levels were lower in patients with depressive symptoms than in patients without depressive symptoms (p<0.01). The RBANS total score and the immediate memory, language and attention scores were lower in patients with depressive than in patients without depressive (all p < 0.05). Multiple regression analysis showed that BDNF was independent contributor to immediate memory, language and RBANS total score in the patients with depressive symptoms. BDNF and SDS were independent contributors to attention, and SDS was an independent contributor to delay memory (all p < 0.001). CONCLUSIONS: BDNF may be involved in the pathophysiology of PD patients with depressive symptoms. Moreover, the association between BDNF and cognitive performance only in patients with depressive symptoms suggest a close relationship in BDNF, cognition and depressive symptoms in PD patients.

A Panel of Plasma Biomarkers for Differential Diagnosis of Parkinsonian Syndromes.

OBJECTIVE: The aim of our study is to explore the most reliable panel of plasma biomarkers for differential diagnosis of parkinsonian syndromes (PDSs). We selected five kinds of neurodegenerative proteins in plasma: neurofilament light chain (NfL), α-synuclein (α-syn), total tau, ß-amyloid 42 (Aß42) and ß-amyloid 40 (Aß40), and investigated the diagnostic value of these biomarkers. METHODS: A total of 99 plasma samples from patients with Parkinson's disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy, and age-matched healthy controls (HCs) were enrolled in our study. Plasma NfL, α-syn, total tau, Aß42, and Aß40 levels were quantified by ultrasensitive single molecule array immunoassay. We used logistic regression analyses to examine diagnostic accuracy of these plasma biomarkers. Disease severity was assessed by the modified Hoehn and Yahr staging scale, Unified Parkinson's Disease Rating Scale part III (UPDRS III), and the Mini-Mental State Examination (MMSE), and subsequently, correlation analysis was performed. RESULTS: A combination of α-syn, Aß42, Aß40, Aß42/40, and NfL could achieve a best diagnostic value in differentiating PDSs from HC and PD from HC, with an AUC of 0.983 and 0.977, respectively. By adding NfL to measurements of α-syn or Aß42 or Aß40 or Aß42/40, the best discriminating panel was formed in differentiating atypical parkinsonian disorder (APD) and HC, and the discriminatory potential could reach a sensitivity of 100% and specificity of 100% (AUC = 1.000). For further distinguishing PD from APD, we found a combination of NfL, Aß42, and total tau was the most reliable panel with equally high diagnostic accuracy. With respect to differentiating the subtypes of APD from one another, our results revealed that measurement of NfL, total tau, Aß42, Aß40, and Aß42/40 was the best discriminating panel. Correlation analysis suggests that plasma Aß42 levels were positively correlated to UPDRS part III scores in MSA. In terms of cognitive function, there was a relationship between plasma Aß42/40 level and MMSE scores in patients with APD. CONCLUSION: In our study, various combinations of plasma biomarkers have great potentialities in identifying PDSs, with important clinical utility in improving diagnostic accuracy. Plasma NfL may have added value to a blood-based biomarker panel for differentiating PDSs.

Association of Plasma and Electroencephalography Markers With Motor Subtypes of Parkinson's Disease.

Objective: The aim of this study was to investigate the correlations of plasma neurodegenerative proteins and electroencephalography (EEG) dynamic functional network (DFN) parameters with disease progression in early Parkinson's disease (PD) with different motor subtypes, including tremor-dominant (TD) and postural instability and gait disorder (PIGD). Methods: In our study, 33 patients with PD (21 TD and 12 PIGD) and 33 healthy controls (HCs) were enrolled. Plasma neurofilament light chain (NfL), α-synuclein (α-syn), total-tau (t-tau), ß-amyloid 42 (Aß42), and ß-amyloid 40 (Aß40) levels were measured using an ultrasensitive single-molecule array (Simoa) immunoassay. All the patients with PD underwent EEG quantified by DFN analysis. The motor and non-motor performances were evaluated by a series of clinical assessments. Subsequently, a correlation analysis of plasma biomarkers and EEG measures with clinical scales was conducted. Results: In the TD group, plasma NfL exhibited a significant association with MDS-UPDRS III and Montreal Cognitive Assessment (MoCA). A higher Aß42/40 level was significantly related to a decrease in Hamilton Depression Rating Scale (HAMD) and Hamilton Anxiety Rating Scale (HAMA) in the PIGD group. In terms of the correlation between EEG characteristic parameters and clinical outcomes, trapping time (TT) delta was positively correlated with MDS-UPDRS III and MoCA scores in the TD group, especially in the prefrontal and frontal regions. For other non-motor symptoms, there were significant direct associations of k PLI theta with HAMD and HAMA, especially in the prefrontal region, and k PLI gamma was particularly correlated with Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire (RBDSQ) scores in the prefrontal, frontal, and parietal regions in the TD group. Furthermore, there was a significant positive correlation between plasma t-tau and k PLI , and pairwise correlations were found among plasma NfL, theta TT, and MoCA scores in the TD group. Conclusion: These results provide evidence that plasma neurodegenerative proteins and EEG measures have great potential in predicting the disease progression of PD subtypes, especially for the TD subtype. A combination of these two kinds of markers may have a superposition effect on monitoring and estimating the prognosis of PD subtypes and deserves further research in larger, follow-up PD cohorts.

Highly sensitive and stable self-powered biosensing for exosomes based on dual metal-organic frameworks nanocarriers.

Biofuel cells (BFCs)-based self-powered biosensors suffer from the limited stability of bioenzymes. Meanwhile, the poor performance of self-powered biosensors affects the sensitivity of biosensing, thus, it is significant and challenging to improve their stability and sensitivity. In our work, a BFC-based self-powered biosensor, with simultaneously enhanced stability and sensitivity, was constructed utilizing dual metal-organic frameworks (MOFs) as the carriers of the bioenzyme and the electroactive probe, respectively. Anodic enzyme, glucose dehydrogenase (GDH), was encapsulated in zeolitic imidazolate framework-8 (ZIF-8) to form GDH@ZIF-8 composites, enhancing the catalytic activity and stability of GDH. Meanwhile, another zirconium metal-organic frameworks (UiO-66-NH2) loaded with electroactive molecules (K3[Fe(CN)6]) served as nano-enrichment carriers and improved the capability of the cathode to accept electrons from the anode, further improving the sensitivity of the as-proposed biosensor. Herein, the "signal-on" BFC-based self-powered biosensing of exosomes, the model analyte, with excellent stability and outstanding sensitivity was realized with the assistance of dual MOFs, and the detection limit was down to 300 particles mL-1 (based on 3s/k), which was superior to those previously reported in literatures. Furthermore, the developed protocol was capable of detecting exosomes derived from cancer cells in complex biological samples. Overall, in this work the enhancement of both stability and sensitivity has been achieved by utilizing two types of MOFs, which laid the foundation for expanding the applications of BFC-based self-powered biosensors.

Comparative iTRAQ Proteomics Reveals Multiple Effects of Selenium Yeast on Dairy Cows in Parturition.

The effects of prepartum dietary supplementation with selenium yeast on low abundant plasma proteins in postpartum dairy cows are not known. In this study, 24 healthy parturient dairy cows were divided into two groups (group C, a control group, and group T, a selenium treatment group). Low abundance proteins were extracted from plasma samples of calving cows, and 542 proteins were identified by isobaric tags for relative and absolute quantitation (iTRAQ) proteomic analysis. Dietary supplementation with selenium yeast caused differential abundance of 48 proteins with a fold change of more than 1.2 or less than 0.83 (p < 0.05); 14 proteins were upregulated and 34 were downregulated. The top five gene ontology (GO) enrichment terms for the differentially expressed proteins were protein homotetramerization (or tetramerization), defense response to bacteria or fungus, acute-phase reactions, nucleotide catabolic process, and positive regulation of lipid metabolic process. All proteins involved in acute-phase reactions were downregulated, indicating that selenium ameliorates systemic inflammation. The vast majority of proteins involved in the defense response to microorganisms were downregulated, thereby affecting innate immunity. The decreased abundance of apolipoprotein A-I and apolipoprotein C-II, critical proteins for positive regulation of lipid metabolism, indicated that selenium may optimize lipid metabolism. The iTRAQ results showed that prenatal supplementation with yeast selenium can relieve systemic inflammation after parturition. Moreover, selenium may reduce the effects of metabolic diseases, which can improve glyconeogenesis and prevent ketosis and fatty liver.

Targeting LIN28B reprograms tumor glucose metabolism and acidic microenvironment to suppress cancer stemness and metastasis.

The altered metabolism and acidic microenvironment plays an important role in promoting tumor malignant characteristics. A small population of cancer stem cells (CSCs) were considered as a therapy target to reserve tumor relapse, resistance, and metastasis. However, the molecular mechanism that regulates CSCs metabolism remains poorly understood. In this study, we demonstrate a fundamental role of stemness gene LIN28B in maintaining CSCs glycolysis metabolism. Using LIN28B-expressing cancer cell lines, we found that the rate of extracellular acidification, glucose uptake, and lactate secretion are all suppressed by LIN28B knockdown in vitro and in vivo. Importantly, metabolic analyses reveal that CSCs have enhanced aerobic glycolysis metabolic characteristics and the glycolytic product lactate further promotes cancer associated stemness properties. LIN28B silencing suppresses MYC expression that further increases miR-34a-5p level. Furthermore, the glycolysis metabolism of human breast cancer cell line MDA-MB-231 is suppressed by either MYC siRNA or miR-34a-5p mimic. Clinically, high MYC and low miR-34a-5p level are correlated with high LIN28B expression and poor prognosis in human breast cancer patients. Notably, blocking LIN28B/MYC/miR-34a-5p signaling pathway by LIN28B-specific inhibitor causes dramatic inhibition of tumor growth and metastasis in immunodeficient orthotopic mouse models of human breast cancer cell MDA-MB-231. Taken together, our findings offer a preclinical investigation of targeting LIN28B to suppress CSCs glycolysis metabolism and tumor progression that may improve the therapeutic benefit for cancer patients.

miR-100 maintains phenotype of tumor-associated macrophages by targeting mTOR to promote tumor metastasis via Stat5a/IL-1ra pathway in mouse breast cancer.

Tumor-associated macrophages (TAMs), the main part of immune cells in tumor microenvironment (TME), play a potent role in promoting tumorigenesis through mechanisms such as stimulating angiogenesis, enhancing tumor migration and suppressing antitumor immunity. MicroRNAs (miRNAs) are considered as crucial regulators in multiple biological processes. The relationship between miRNAs and macrophages function has been extensively reported, but the roles that miRNAs play in regulating TAMs phenotype remain unclear. In this study, we screened highly expressed microRNAs in TAMs, and first identified that miR-100 represented a TAMs-high expression pattern and maintained TAMs phenotype by targeting mTOR signaling pathway. Moreover, miR-100 expression level in TAMs was positively related to IL-1ra secretion, a traditional immune-suppressive cytokine, which was determined to promote tumor cells stemness via stimulating Hedgehog pathway. Mechanism study suggested that mTOR/Stat5a pathway was involved in IL-1ra transcriptional regulation process mediated by miR-100. More importantly, tumor metastasis and invasion capacity were significantly decreased in a 4T1 mouse breast cancer model injected intratumorally with miR-100 antagomir, and combination therapy with cisplatin showed much better benefit. In this study, we confirm that highly expressed miR-100 maintains the phenotype of TAMs and promotes tumor metastasis via enhancing IL-1ra secretion. Interfering miR-100 expression of TAMs in mouse breast cancer model could inhibit TAMs pro-tumor function and reduce tumor metastasis, which suggests that miR-100 could serve as a potential therapy target to remodel tumor microenvironment in breast cancer.

[Effects of retinol on expressions of epidermal growth factor, stem cell factor, colony-stimulating factor 1 and leukemia inhibitory factor in human umbilical cord-derived mesenchymal stem cells].

OBJECTIVE: To investigate effects of retinol on the expressions of epidermal growth factor (EGF), stem cell factor (SCF), colony-stimulating factor 1 (CSF1) and leukemia inhibitory factor (LIF) in cultured human umbilical-derived mesenchymal stem cells (UCMSCs). METHODS: Human UCMSCs were isolated from human umbilical cord and identified for immunophenotypes. The cells were then cultured in DMEM/F12 media supplemented with 12% fetal bovine serum (FBS), 12% FBS+1 µmol/L retinol, 15% knockout serum replacement (KSR) and 15% KSR+ 1 µmol/L retinol. The expressions of the cytokines EGF, SCF, CSF1 and LIF in the cells were detected using RT-PCR and ELISA. RESULTS: The isolated cells exhibited characteristic immunophenotypes of human UCMSCs and expressed EGF, CSF1 and SCF at both mRNA and protein levels but not LIF protein. Retinol (1 µmol/L) significantly promoted the expressions of SCF and CSF1 at both mRNA and protein levels but did not result in changes of EGF and LIF expressions in human UCMSCs. CONCLUSION: Retinol at the concentration of 1 µmol/L can promote expression of SCF and CSF1 in human UCMSCs in vitro.

Bioactive molecules derived from umbilical cord mesenchymal stem cells.

Umbilical cord mesenchymal stem cells (UCMSCs) retain their intrinsic stem cell potential while at the same time displaying high proliferation rates, powerful differentiation capacity, and low immunogenicity. They can also secrete multiple bioactive molecules that exert specific physiological functions. Thus, UCMSCs represent excellent candidates for cell therapy in regenerative medicine and tissue engineering. Abundant preclinical research on different disease models has shown that UCMSCs can accelerate wound or nerve damage recovery and suppress tumor progression. In fact, UCMSCs are thought to possess a higher therapeutic potential than MSCs derived from other tissues. Increasing evidence suggests that the mechanism underlying UCSMCs efficacy depends mostly on cell secretions, in contrast to the early paradigm of cell replacement and differentiation. In this review, we discuss UCMSCs biological characteristics, their secretome-based therapeutic mechanism, and potential applications.

IKKß Enforces a LIN28B/TCF7L2 Positive Feedback Loop That Promotes Cancer Cell Stemness and Metastasis.

Considerable evidence suggests that proinflammatory pathways drive self-renewal of cancer stem-like cells (CSC), but the underlying mechanisms remain mainly undefined. Here we report that the let7 repressor LIN28B and its regulator IKBKB (IKKß) sustain cancer cell stemness by interacting with the Wnt/TCF7L2 (TCF4) signaling pathway to promote cancer progression. We found that LIN28B expression correlated with clinical progression and stemness marker expression in breast cancer patients. Functional studies demonstrated that the stemness properties of LIN28B-expressing human breast and lung cancer cells were enhanced by IKKß, whereas loss of LIN28B abolished stemness properties in these settings. These phenomena were driven through interactions with TCF7L2, which enhanced LIN28B expression by direct binding to intron 1 of the LIN28B gene, which in turn promoted TCF7L2 mRNA translation through a positive feedback loop. Notably, RNAi-mediated silencing of LIN28B or pharmacologic inhibition of IKKß was sufficient to suppress primary and metastatic tumor growth in vivo. Together, our results establish the LIN28B/TCF7L2 interaction loop as a central mediator of cancer stemness driven by proinflammatory processes during progression and metastasis, possibly offering a new therapeutic target for generalized interventions in advanced cancers.