ERK signaling expands mammalian cortical radial glial cells and extends the neurogenic period.

The molecular basis for cortical expansion during evolution remains largely unknown. Here, we report that fibroblast growth factor (FGF)-extracellular signal-regulated kinase (ERK) signaling promotes the self-renewal and expansion of cortical radial glial (RG) cells. Furthermore, FGF-ERK signaling induces bone morphogenic protein 7 (Bmp7) expression in cortical RG cells, which increases the length of the neurogenic period. We demonstrate that ERK signaling and Sonic Hedgehog (SHH) signaling mutually inhibit each other in cortical RG cells. We provide evidence that ERK signaling is elevated in cortical RG cells during development and evolution. We propose that the expansion of the mammalian cortex, notably in human, is driven by the ERK-BMP7-GLI3R signaling pathway in cortical RG cells, which participates in a positive feedback loop through antagonizing SHH signaling. We also propose that the relatively short cortical neurogenic period in mice is partly due to mouse cortical RG cells receiving higher SHH signaling that antagonizes ERK signaling.

Genetic algorithm-based semisupervised convolutional neural network for real-time monitoring of Escherichia coli fermentation of recombinant protein production using a Raman sensor.

As a non-destructive sensing technique, Raman spectroscopy is often combined with regression models for real-time detection of key components in microbial cultivation processes. However, achieving accurate model predictions often requires a large amount of offline measurement data for training, which is both time-consuming and labor-intensive. In order to overcome the limitations of traditional models that rely on large datasets and complex spectral preprocessing, in addition to the difficulty of training models with limited samples, we have explored a genetic algorithm-based semi-supervised convolutional neural network (GA-SCNN). GA-SCNN integrates unsupervised process spectral labeling, feature extraction, regression prediction, and transfer learning. Using only an extremely small number of offline samples of the target protein, this framework can accurately predict protein concentration, which represents a significant challenge for other models. The effectiveness of the framework has been validated in a system of Escherichia coli expressing recombinant ProA5M protein. By utilizing the labeling technique of this framework, the available dataset for glucose, lactate, ammonium ions, and optical density at 600 nm (OD600) has been expanded from 52 samples to 1302 samples. Furthermore, by introducing a small component of offline detection data for recombinant proteins into the OD600 model through transfer learning, a model for target protein detection has been retrained, providing a new direction for the development of associated models. Comparative analysis with traditional algorithms demonstrates that the GA-SCNN framework exhibits good adaptability when there is no complex spectral preprocessing. Cross-validation results confirm the robustness and high accuracy of the framework, with the predicted values of the model highly consistent with the offline measurement results.

Distinct species turnover patterns shaped the richness of antibiotic resistance genes on eight different microplastic polymers.

Elucidating the formation mechanism of plastisphere antibiotic resistance genes (ARGs) on different polymers is necessary to understand the ecological risks of plastisphere ARGs. Here, we explored the turnover and assembly mechanism of plastisphere ARGs on 8 different microplastic polymers (4 biodegradable (bMPs) and 4 non-biodegradable microplastics (nMPs)) by metagenomic sequencing. Our study revealed the presence of 479 ARGs with abundance ranging from 41.37 to 58.17 copies/16S rRNA gene in all plastispheres. These ARGs were predominantly multidrug resistance genes. The richness of plastisphere ARGs on different polymers had a significant correlation with the contribution of species turnover to plastisphere ARGs ß diversity. Furthermore, polymer type was the most critical factor affecting the composition of plastisphere ARGs. More opportunistic pathogens carrying diverse ARGs on BMPs (PBAT, PBS, and PHA) with higher horizontal gene transfer potential may further magnify the ecological risks and human health threats. For example, the opportunistic pathogens Riemerella anatipestifer, Vibrio campbellii, and Vibrio cholerae are closely related to human production and life, which were the important potential hosts of many plastisphere ARGs and mobile genetic elements on BMPs. Thus, we emphasize the urgency of developing the formation mechanism of plastisphere ARGs and the necessity of controlling BMPs and ARG pollution, especially BMPs, with ever-increasing usage in daily life.

Assessment of the Hypoglycemic and Hypolipidemic Activity of Flavonoid-Rich Extract from Angelica keiskei.

Angelica keiskei contains a variety of bioactive compounds including chalcone, coumarin, and phytochemicals, endowing it with pharmacological effects such as lipid-lowering activity, antitumor activity, liver protection, and nerve protection. This study aims to study the hypoglycemic and hypolipidemic effects of the flavonoid-rich extract from Angelica keiskei (FEAK) in an effort to exploit new applications of FEAK and increase its commercial value. In this paper, flavonoid compounds in Angelica keiskei were extracted using 50% ethanol, and the contents of the flavonoid compounds were analyzed by UPLC-MS/MS. Then, the hypoglycemic and hypolipidemic activities of the FEAK were investigated through in vitro enzyme activity and cell experiments as well as establishing in vivo zebrafish and Caenorhabditis elegans (C. elegans) models. The UPLC-MS/MS results show that the major flavonoid compounds in the FEAK were aureusidin, xanthoangelol, kaempferol, luteolin, and quercetin. The inhibitory rates of the FEAK on the activity of α-amylase and cholesterol esterase were 57.13% and 72.11%, respectively. In cell lipid-lowering experiments, the FEAK significantly reduced the total cholesterol (TC) and total triglyceride (TG) levels in a dose-dependent manner, with 150 µg/mL of FEAK decreasing the intracellular levels of TC and TG by 33.86% and 27.89%, respectively. The fluorescence intensity of the FEAK group was 68.12% higher than that of the control group, indicating that the FEAK exhibited hypoglycemic effects. When the concentration of the FEAK reached 500 µg/mL, the hypoglycemic effect on zebrafish reached up to 57.7%, and the average fluorescence intensity of C. elegans in the FEAK group was 17% lower than that of the control group. The results indicate that the FEAK had hypoglycemic and hypolipidemic activities. The findings of this study provide theoretical references for the high-value utilization of Angelica keiskei and the development of natural functional food with hypoglycemic and hypolipidemic activities.

Composition change and adsorption performance of EPS from Bacillus vallismortis sp. induced by Na2S.

Sodium sulfide (Na2S) was used as an inducer to regulate the components of Bacillus vallismortis sp. EPS (Extracellular Polymeric Substances). The main objective of this study was to improve the content of sulfhydryl protein and the adsorption property of EPS to Zn (Ⅱ) that as an typical heavy metal. The results showed that the maximum EPS production of 105.58 mg/g VSS coupling with doubled increase in protein in which the contant of -SH increased by 48.2% from 104.15 to 154.36 µmol/L were recorded in the presence of 20 mg/L Na2S. Under this condition, the adsorption capacity of S-EPS (EPS with added exogenous Na2S) for Zn (Ⅱ) was highest. The kinetics of the adsorption process of Zn (Ⅱ) by the S-EPS can be well fitted by the Langmuir isotherm model and the theoretical maximum adsorption amount of 979.09 mg/g EPS could be obtained. The results of 3D-EEM and FTIR analyses, illustrated that -SH, CO, and N-H/C-N played major roles in the removal of Zn (Ⅱ) by S-EPS. The results obtained in this study demonstrated that the addition of sulfur source could increase the content of sulfhydryl protein, and effectively regulate the content of chemical composition, expecially for the sulfhydryl of EPS, and thereby greatly improving the removal efficiency of heavy metals, which showed a great application prospect in the prevention and control of heavy metal pollution.

BMP7 expression in mammalian cortical radial glial cells increases the length of the neurogenic period.

The seat of human intelligence is the human cerebral cortex, which is responsible for our exceptional cognitive abilities. Identifying principles that lead to the development of the large-sized human cerebral cortex will shed light on what makes the human brain and species so special. The remarkable increase in the number of human cortical pyramidal neurons and the size of the human cerebral cortex is mainly because human cortical radial glial cells, primary neural stem cells in the cortex, generate cortical pyramidal neurons for more than 130 days, whereas the same process takes only about 7 days in mice. The molecular mechanisms underlying this difference are largely unknown. Here, we found that bone morphogenic protein 7 (BMP7) is expressed by increasing the number of cortical radial glial cells during mammalian evolution (mouse, ferret, monkey, and human). BMP7 expression in cortical radial glial cells promotes neurogenesis, inhibits gliogenesis, and thereby increases the length of the neurogenic period, whereas Sonic Hedgehog (SHH) signaling promotes cortical gliogenesis. We demonstrate that BMP7 signaling and SHH signaling mutually inhibit each other through regulation of GLI3 repressor formation. We propose that BMP7 drives the evolutionary expansion of the mammalian cortex by increasing the length of the neurogenic period.

Coupling dynamics of respiration, gas exchange, and Pseudomonas fluorescens growth on fresh-cut cucumber (Cucumis sativus L.) in passive modified atmosphere packing.

This study established microbial growth models for fresh-cut cucumber packaged with different O2 transmission rate (OTR) films. Biaxially oriented polyamide/low-density polyethylene (BOPA/LDPE) film (Ⅰ: OTR5, Ⅳ: OTR48) and polyethylene (PE) film (Ⅱ: OTR2058, Ⅲ: OTR3875) were used to construct a passive modified atmosphere packaging (MAP). Mathematic models have been established to account for dynamic variations in the O2/CO2 concentration and their impacts on Pseudomonas fluorescens growth. The coupling models included: 1) respiration models of cucumber and P. fluorescens based on Michaëlis-Menten equation, 2) coupling gas exchange models based on Fick's law that contained models of P. fluorescens growth and respiration, 3) coupling microbial growth models contained respiration and gas exchange models. Coupling model with Baranyi function successfully fitted variations of O2/CO2 concentration and P. fluorescens growth in the two packaging. In addition, quality properties of packed fresh-cut cucumber were determined. The film Ⅳ (OTR48) as a high barrier film showed the highest inhibition of P. fluorescens growth, adequately retained its colour, firmness and total soluble solid (TSS) concentration in contrast to the PE films packaging. The constructed coupling models can be utilized for assessing the shelf life and microbial growth of fresh-cut vegetables with spoilage dominated by pseudomonads.

Identification of brain-to-spinal circuits controlling the laterality and duration of mechanical allodynia in mice.

Mechanical allodynia (MA) represents one prevalent symptom of chronic pain. Previously we and others have identified spinal and brain circuits that transmit or modulate the initial establishment of MA. However, brain-derived descending pathways that control the laterality and duration of MA are still poorly understood. Here we report that the contralateral brain-to-spinal circuits, from Oprm1 neurons in the lateral parabrachial nucleus (lPBNOprm1), via Pdyn neurons in the dorsal medial regions of hypothalamus (dmHPdyn), to the spinal dorsal horn (SDH), act to prevent nerve injury from inducing contralateral MA and reduce the duration of bilateral MA induced by capsaicin. Ablating/silencing dmH-projecting lPBNOprm1 neurons or SDH-projecting dmHPdyn neurons, deleting Dyn peptide from dmH, or blocking spinal κ-opioid receptors all led to long-lasting bilateral MA. Conversely, activation of dmHPdyn neurons or their axonal terminals in SDH can suppress sustained bilateral MA induced by lPBN lesion.

Characteristics of EPS from Pseudomonas aeruginosa and Alcaligenes faecalis under Cd(II) stress: changes in chemical components and adsorption performance.

EPS (extracellular polymeric substance) production is a self-protection mechanism by which microorganisms slow or eliminate adverse effects in unfavorable environments. In this study, Pseudomonas aeruginosa and Alcaligenes faecalis were selected to explore changes in EPS components, especially protein components, under stress caused by different concentrations of Cd(II). The results showed that the protein content in EPS was the highest. The two strains achieved maximum EPS production levels of 109.17 and 214.96 mg/g VSS at Cd(II) stress concentrations of 20 and 50 mg/L, which were increased by 52.07% and 409.69% compared with the levels exhibited before stress, respectively. The protein content correlated very well with data from adsorption experiments. Furthermore, FTIR, 3D-EEM, and XPS results illustrated that after Cd(II) stress, C-N, C=O/-COOH, and R-NO2- moieties were formed in substantial quantities, and the stress effects of Pseudomonas aeruginosa were significantly higher than those of Alcaligenes faecalis. The results of this study showed that addition of Cd(NO3)2 effectively regulated the components of EPS, especially the protein content, and improved the adsorption capacity, which has application prospects for prevention and control of heavy metals.

Heat-induced pea protein isolate gels reinforced by panda bean protein amyloid fibrils: Gelling properties and formation mechanism.

The roles of panda bean protein amyloid fibrils (PDPF) in modifying the textural and rheological properties of heat-induced pea protein isolate (PPI) gels were investigated. It was found that the incorporation of PDPF significantly enhanced (p < 0.05) the strength of PPI gel. This effect was PDPF concentration-dependent and was predominantly attributable to the enhanced intermolecular interactions between PDPF and PPI through hydrogen bonds and hydrophobic interactions. Synchronously, the non-network proteins content in PPI-PDPF gels decreased from 23.6 % to 6.6 % when PDPF concentration increased from 0 to 1.50 % (w/w). Cryo-scanning electron microscopy proved that PDPF was filled in the PPI gel network leading to more compact and interconnected gel structure. However, the water holding capacity and secondary structures of PPI gel were not significantly affected. The findings of this study showed that PDPF was effective in improving the PPI gel functional quality, which provided scientific support for PDPF as a promising gel ingredient in food industrial applications.

Effects of different exogenous cadmium compounds on the chemical composition and adsorption properties of two gram-negative bacterial EPS.

Three different Cd(II) compounds were used to regulate Pseudomonas aeruginosa and Alcaligenes faecalis EPS (extracellular polymeric substances). The purpose of this study was to improve the content of EPS protein and the adsorption capacity of Cd(II) by different Cd(II) compounds. The results showed that Cd(NO3)2 had the best stress/induction effect on the two strains. Under the best stress/induction, the protein in EPS of the two strains increased most obviously, and the adsorption capacity of Cd(II) was increased by more than 40%. Under these conditions, the kinetics of the adsorption process of Cd(II) by Cd(NO3)2-EPSA. F (EPS produced by Alcaligenes faecalis under Cd(NO3)2 stress) could be well fitted by the Langmuir isotherm model, and the theoretical maximum adsorption amount of 1111.11 mg/g EPS could be obtained. The results of 3D-EEM, FTIR and XPS indicated that proteins, especially CO, CN and NH in proteins, played a major role in the removal of Cd(II) by Cd(NO3)2-EPSA. F. The results of this study show that the addition of Cd(NO3)2 can effectively regulate the content of chemical components, especially the content of protein, and thus greatly improve the removal efficiency of heavy metals, which shows great application prospects in the prevention and control of heavy metal pollution.

Transcription factor Sp9 is a negative regulator of D1-type MSN development.

The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson's Disease. In the present study, we demonstrated that Sp9-positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSN identity and repressing D1-MSN identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2-like MSNs survived normally in adulthood. Taken together, our findings supported that Sp9 was sufficient to promote D2-MSN identity and repress D1-MSN identity, and Sp9 was a negative regulator of D1-MSN fate.

Response of Bacillus vallismortis sp. EPS to exogenous sulfur stress/ induction and its adsorption performance on Cu(II).

The chemical composition of EPS (Extracellular Polymeric Substances) produced by Bacillus vallismortis sp. and its adsorption performance on typical heavy metal were studied under Na2S stress/induction at different concentrations. Its structure was characterized by three-dimensional fluorescence spectrogram (3D-EEM), infrared spectrum (FTIR) and X-ray photoelectron spectroscopy (XPS). The results showed that, when the Na2S stress/induction intensity was 20 mg/L, the protein concentration was nearly doubled compared with Control-EPS (EPS produced by Bacillus vallismortis sp. without exogenous sulfur stress); furthermore, the 3D-EEM results also demonstrated that there was an increase in the protein content, with the -SH content reaching 154.36 µmol/L, which was 48.2% higher than before stress (104.15 µmol/L). Under this condition, S-EPS (EPS produced by Bacillus vallismortis sp. stressed by exogenous sulfur) exhibited the best adsorption effect on Cu(II), with the theoretical maximum adsorption capacity reaching 1428.57 mg/g EPS. FTIR and XPS analyses revealed that the -SH, CO, N-H played a major role in the adsorption of Cu(II); among those, -SH played a key role. Moreover, the adsorption capacity of Cu(II) by S-EPS was correlated with the content of sulfhydryl protein; indeed, the exogenous sulfur stress/induction can effectively regulate the chemical composition of EPS and improve its adsorption performance, which can be crucial in the prevention and control of heavy metal pollution.

Circulating MicroRNA-19b Identified From Osteoporotic Vertebral Compression Fracture Patients Increases Bone Formation.

Circulating microRNAs (miRNAs) play important roles in regulating gene expression and have been reported to be involved in various metabolic diseases, including osteoporosis. Although the transcriptional regulation of osteoblast differentiation has been well characterized, the role of circulating miRNAs in this process is poorly understood. Here we discovered that the level of circulating miR-19b was significantly lower in osteoporotic patients with vertebral compression fractures than that of healthy controls. The expression level of miR-19b was increased during osteoblastic differentiation of human mesenchymal stem cells (hMSCs) and MC3T3-E1 cells, and transfection with synthetic miR-19b could promote osteoblastic differentiation of hMSCs and MC3T3-E1 cells. PTEN (phosphatase and tensin homolog deleted from chromosome 10) was found to be directly repressed by miR-19b, with a concomitant increase in Runx2 expression and increased phosphorylation of AKT (protein kinase B, PKB). The expression level of circulating miR-19b in aged ovariectomized mice was significantly lower than in young mice. Moreover, the osteoporotic bone phenotype in aged ovariectomized mice was alleviated by the injection of chemically modified miR-19b (agomiR-19b). Taken together, our results show that circulating miR-19b plays an important role in enhancing osteoblastogenesis, possibly through regulation of the PTEN/pAKT/Runx2 pathway, and may be a useful therapeutic target in bone loss disorders, such as osteoporosis. © 2019 American Society for Bone and Mineral Research.

Understanding the Hierarchical Relationships in Female Sex Workers' Social Networks Based on Knowledge, Attitude, and Practice.

Female sex workers (FSWs) represent a high-risk population for HIV infection and transmission. In general, their fellow FSWs (peers) also play a role in their level of susceptibility to HIV/AIDS. This paper draws from interview data of 93 FSWs to construct a multi-layer FSW social network model based on their knowledge, attitude, and practice (KAP). Statistical analyses of the correlation among the three dimensions of KAP as well as their social interactions indicated that FSWs had basic knowledge of HIV/AIDS prevention but demonstrated little enthusiasm in acquiring relevant information. Their knowledge, attitude, and practice were highly positively correlated. Their attitude was more likely to be negatively influenced by their companions, while their practice was more likely to be positively affected. Besides, FSWs exhibited high homophily in KAP with their neighbors. Thus, during HIV/AIDS interventions, FSWs should receive individualized education based on their specific KAP. Considering the high level of homophily among FSWs, their propensity to be positive or negative in their KAP are significantly influenced by their companions. Making full use of peer education and social interaction-based interventions may help prevent and control the spread of HIV/AIDS.

Understanding the unbalance of interest in taxi market based on drivers' service profit margins.

Nowadays, ride-hailing services have been established as a part of the urban transportation. Their arrival has remade the profit structure and resulted in the unbalance of interest in taxi market. Here, we establish the service models of taxis, carpooling, and car-hailing under "Internet +" from the perspective of profit margins, to perform a comparative analysis among the different services. RESULTS: First, Profit margins are generally higher for short trips than for long trips, though empty cruise fee to a certain degree make up for the driver's decreased profit margins. Second, the profit margin for carpooling is roughly 1.85 times that of ride-hailing, and 1.75 times that of taxis. This shows that the sharing economy has a certain advantage. Third, Profit margins are higher and fluctuations are lower on non-work days than on work days. At last, Profit margins are roughly 1.3 times higher on non-congested roads than on congested roads. The reduced profitability on congested roads makes it even harder to catch a ride during rush hours and on congested roads. We suggest that the relevant departments make appropriate efforts to make it more attractive for drivers to take on passengers during rush hours and on congested roads, and promote the sharing in the taxi market.

The Regulatory Roles of MicroRNAs in Bone Remodeling and Perspectives as Biomarkers in Osteoporosis.

MicroRNAs are involved in many cellular and molecular activities and played important roles in many biological and pathological processes, such as tissue formation, cancer development, diabetes, neurodegenerative diseases, and cardiovascular diseases. Recently, it has been reported that microRNAs can modulate the differentiation and activities of osteoblasts and osteoclasts, the key cells that are involved in bone remodeling process. Meanwhile, the results from our and other research groups showed that the expression profiles of microRNAs in the serum and bone tissues are significantly different in postmenopausal women with or without fractures compared to the control. Therefore, it can be postulated that microRNAs might play important roles in bone remodeling and that they are very likely to be involved in the pathological process of postmenopausal osteoporosis. In this review, we will present the updated research on the regulatory roles of microRNAs in osteoblasts and osteoclasts and the expression profiles of microRNAs in osteoporosis and osteoporotic fracture patients. The perspective of serum microRNAs as novel biomarkers in bone loss disorders such as osteoporosis has also been discussed.

High Strength Multifunctional Multiwalled Hydrogel Tubes: Ion-Triggered Shape Memory, Antibacterial, and Anti-inflammatory Efficacies.

In this study, ion-responsive hydrogen bonding strengthened hydrogels (termed as PVV) were synthesized by one-pot copolymerization of 2-vinyl-4,6-diamino-1,3,5-triazine (VDT), 1-vinylimidazole (VI), and polyethylene glycol diacrylate. The diaminotriazine-diaminotriazine (DAT-DAT) H-bonding interaction and copolymerization of VI contributed to a notable increase in comprehensive performances including tensile/compressive strength, elasticity, modulus, and fracture energy. In addition, introducing mM levels of zinc ions could further increase the mechanical properties of PVV hydrogels and fix a variety of temporary shapes due to the strong coordination of zinc with imidazole. The release of zinc ions from the hydrogel contributed to an antibacterial effect, without compromising the shape memory effect. Remarkably, a multiwalled hydrogel tube (MWHT) fixed with Zn(2+) demonstrated much higher flexural strengths and a more sustainable release of zinc ions than the solid hydrogel cylinder (SHC). A Zn(2+)-fixed MWHT was implanted subcutaneously in rats, and it was found that the Zn(2+)-fixed MWHT exhibited anti-inflammatory and wound healing efficacies. The reported high strength hydrogel with integrated functions holds potential as a tissue engineering scaffold.

A Combination of Targeted Sunitinib Liposomes and Targeted Vinorelbine Liposomes for Treating Invasive Breast Cancer.

Regular chemotherapy cannot eradicate invasive breast cancer cells and the residual cancer cells will form vasculogenic mimicry (VM) channels under hypoxic conditions to provide nutrients for cancer masses prior to angiogenesis. This phenomenon is a major reason for the recurrence of invasive breast cancer after treatment. In this study, a novel type of targeted liposomes was developed by modifying a mitochondria-tropic material, D-a-tocopheryl polyethylene glycol 1000 succinate- triphenylphosphine conjugate (TPGS1000-TPP), to encapsulate sunitinib and vinorelbine separately and a combination of the two targeted drug liposomes was used to treat invasive breast cancer as well as VM channels. Evaluations were performed in breast cancer MCF-7 cells and highly invasive breast cancer MDA-MB-435S cells in vitro and in mice. The results determined that the functional material (TPGS1000-TPP) and suitable size of the liposomes (90-100 nm) resulted in prolonged blood circulation, an enhanced permeability retention (EPR) effect in cancer tissue, and a mitochondrial targeting effect. Targeted drug liposomes were internalized via cellular uptake and accumulated in the mitochondria of invasive breast cancer cells or VM channel-forming cancer cells to induce acute cytotoxic injury and apoptosis. Activated apoptotic enzymes caspase 9 and caspase 3 as well as down-regulated VM channel-forming indicators (MMP-9, EphA2, VE-Cadherin, FAK and HIF-1α) contributed to significantly enhanced efficacy. Therefore, a combination of targeted sunitinib liposomes and targeted vinorelbine liposomes may provide an effective strategy for treating invasive breast cancer and prevent relapse arising from VM channels.

Targeting Epirubicin Plus Quinacrine Liposomes Modified with DSPE-PEG2000-C(RGDfK) Conjugate for Eliminating Invasive Breast Cancer.

Recurrence of invasive breast cancer could arise from the residual cancer cells after comprehensive treatment. It is possible that residual invasive cancer cells are capable of forming highly patterned vasculogenic mimicry (VM) channels, leading to relapse and metastasis. In the present study, a new type of targeting epirubicin plus quinacrine liposomes was developed by modifying functional DSPE-PEG2000 with C(RGDfK), a cyclic peptide containing Arg-Gly-Asp. These liposomes could potentially eliminate invasive breast cancer and destroy VM channels. Evaluations were made in human invasive breast cancer cells and their xenografts in nude mice. The results showed that the targeting epirubicin plus quinacrine liposomes could enhance the accumulation and uptake of the drugs in cancer tissues, kill cancer cells directly, activate apoptotic enzymes, destroy the VM channels and downregulate the VM channel-forming marker molecules (EphA2, FAK, PI3K, MMP 9, MMP 14, VE-Cad and HIF-α), thereby exhibiting a strong overall anticancer efficacy. The targeting epirubicin plus quinacrine liposomes provided a promising strategy to treat invasive breast cancer and to prevent the relapse arising from VM channels after chemotherapy.