Search

Multicenter international clinical trials demonstrated the clinical safety and efficacy by using stem cell educator therapy to treat type 1 diabetes (T1D) and other autoimmune diseases. Previous studies characterized the peripheral blood insulin-producing cells (PB-IPC) from healthy donors with high potential to give rise to insulin-producing cells. PB-IPC displayed the molecular marker glucose transporter 2 (GLUT2), contributing to the glucose transport and sensing. To improve the clinical efficacy of stem cell educator therapy in the restoration of islet β-cell function, we explored the GLUT2 expression on PB-IPC in recent onset and longstanding T1D patients. In the Food and Drug Administration (FDA)-approved phase 2 clinical studies, patients received one treatment with the stem cell educator therapy. Peripheral blood mononuclear cells (PBMC) were isolated for flow cytometry analysis of PB-IPC and other immune markers before and after the treatment with stem cell educator therapy. Flow cytometry revealed that both recent onset and longstanding T1D patients displayed very low levels of GLUT2 on PB-IPC. After the treatment with stem cell educator therapy, the percentages of GLUT2+CD45RO+ PB-IPC were markedly increased in these T1D subjects. Notably, we found that T1D patients shared common clinical features with patients with other autoimmune and inflammation-associated diseases, such as displaying low or no expression of GLUT2 on PB-IPC at baseline and exhibiting a high profile of the inflammatory cytokine interleukin (IL)-1β. Flow cytometry demonstrated that their GLUT2 expressions on PB-IPC were also markedly upregulated, and the levels of IL-1β-positive cells were significantly downregulated after the treatment with stem cell educator therapy. Stem cell educator therapy could upregulate the GLUT2 expression on PB-IPC and restore their function in T1D patients, leading to the improvement of clinical outcomes. The clinical data advances current understanding about the molecular mechanisms underlying the stem cell educator therapy, which can be expanded to treat patients with other autoimmune and inflammation-associated diseases. [ABSTRACT FROM AUTHOR]

As an important cornerstone of the fourth industrial revolution, the industrial Internet transforms isolated industrial systems into connected networks and is an important expansion direction for digital industrialization. Anomaly detection in the industrial Internet of things environment is of great significance for automated decision-making. To address the problem that most existing methods fail to effectively consider the complex unknown topological relationships between sensors and the multi-scale patterns inherent in the industrial IoT temporal data, an unsupervised anomaly detection method MSTSAD with multi-scale spatiotemporal feature fusion for industrial IoT temporal data is proposed, which firstly constructs a novel bi-directional spatiotemporal feature extraction module to sequentially captures the correlation and bidirec- tional dependency between multiple time series. Secondly, a multi- scale gated temporal convolutional neural network is designed to adaptively extract multi-scale temporal features of time series, and a dual affine projection is introduced to realize the cross- fusion of multi-scale temporal features and spatiotemporal features to enhance the feature extraction of the model on the original data. Finally, a variational self-encoder combined with adversarial training is proposed to amplify the reconstruction error of anomalies and enhance the anti-interference ability of the model to train data noise, which enhances the ability of model to discriminate anomalous data. Experiments are conducted on four publicly available datasets, GPW, ECG5000, Occupancy and SWaT, in comparison with five state-of-the-art methods, and the experimental results show that F1 scores of MSTSAD are enhanced by 0.015-0.047. [ABSTRACT FROM AUTHOR]

Thus far, glossing studies have remained at the level of individual words rather than including their lexical environment. To fill this gap, the present study explored if different glossing conditions would have a distinct impact on L2 reading comprehension and incidental lexical and collocational learning. Sixty-three first language (L1) Cantonese speakers read two English stories that contained 12 adjective-pseudonoun collocations. The participants were placed in one of the three conditions, i.e., unglossed, single-word glossed, and collocation glossed. Participants' reading comprehension was measured with twelve true-or-false statements for each story, and their lexical and collocational learning was assessed using unannounced recognition and recall tests. The results revealed that collocational glossing promoted reading comprehension significantly compared to the other two reading conditions. In addition, while both glossing conditions promoted lexical and collocational knowledge in the immediate posttest, collocational glossing demonstrated a more durable facilitative impact in the delayed posttest. [ABSTRACT FROM AUTHOR]

Apoptosis is a physiological process that occurs in all cell types of the human body, and it profoundly changes the fate of hair by affecting hair follicle cells. This review outlines the cellular changes, intrinsic biochemical characteristics, and mechanisms underlying apoptosis and summarizes the hair follicle life cycle, including development, cycle stages, and corresponding cellular changes. Finally, the relationship between apoptosis and the hair cycle is discussed and the significance of apoptosis in hair loss conditions and drug treatments is highlighted. Apoptosis induces cellular changes and exhibits distinctive properties through intricate signaling pathways. Hair follicles undergo cyclic periods of growth, regression, and dormancy. Apoptosis is closely correlated with the regression phase by triggering hair follicle cell death and shedding. Regulation of apoptosis in hair follicles plays an essential role in hair loss due to maladies and drug treatments. Mitigating apoptosis can enhance hair growth and minimize hair loss. A comprehensive understanding of the correlation between apoptosis and the hair cycle can facilitate the development of novel treatments to prevent hair loss and stimulate hair regeneration. [ABSTRACT FROM AUTHOR]

Anisakidae nematode larvae is one of the most common parasites in wild anadromous Coilia nasus. This study aims to explore the mechanism of the C. nasus immune response to the parasitism of Anisakid nematode larvae. Results found that Anisakid nematode larvae parasitism caused liver injury as evidenced by histomorphology results as well as high levels of aminotransferase and aspertate aminotransferase. Furthermore, Anisakid nematode larvae parasitism induced an immune response in the host, which was characterized by the elevated populations of macrophages and neutrophils in the liver and head‐kidney in the Anisakidae‐infected group compared to the noninfected group. The expression of immunoglobulin IgM and IgD in the liver and head‐kidney was also increased in the Anisakidae‐infected group. The Anisakidae‐infected group showed higher activity of antioxidant enzymes catalase and superoxide dismutase, which indicates severe oxidative stress, and increased production of pro‐inflammatory cytokines, TNF‐α, IL‐6 as well as MCP‐1 in the liver compared with the noninfected group. As a result of inflammation, livers of hosts in the Anisakidae‐infected group showed fibrosis, and elevated expression of associated proteins including α‐smooth muscle actin, fibronectin, collagen type I and type III compared with the noninfected group. We demonstrated that Anisakid nematode larvae parasitism results in injury and fibrosis in the liver, and triggers immune cell infiltration and inflammation in the liver and head‐kidney of C. nasus. Altogether, the results provide a foundation for building an interaction between parasite and host, and will contribute to C. nasus population and fishery resource protection. [ABSTRACT FROM AUTHOR]

As one of the most intractable tumours, pancreatic ductal adenocarcinoma (PDA) has a dense extracellular matrix (ECM) which could increase solid stress within tumours to compress tumour vessels, reduce tumour perfusion and compromise nanomedicine delivery for PDA. Thus, alleviating solid stress represents a potential therapeutic target for PDA treatment. In this study, cyclopamine, a special inhibitor of the hedgehog signalling pathway which contributes a lot to ECM formation of PDA, was exploited to alleviate solid stress and improve nanomedicine delivery to PDA. Results demonstrated that cyclopamine successfully disrupted ECM and lowered solid stress within PDA, which increased functional tumour vessels and resulted in enhanced tumour perfusion as well as improved tumour nanomedicine delivery in PDA-bearing animal models. Therefore, solid stress within PDA represents a new therapeutic target for PDA treatment. [ABSTRACT FROM AUTHOR]

A hydrologically contained field study, to assess biochar (produced from mixed crop straws) influence upon soil hydraulic properties and dissolved organic carbon (DOC) leaching, was conducted on a loamy soil (entisol). The soil, noted for its low plant-available water and low soil organic matter, is the most important arable soil type in the upper reaches of the Yangtze River catchment, China. Pore size distribution characterization (by N adsorption, mercury intrusion, and water retention) showed that the biochar had a tri-modal pore size distribution. This included pores with diameters in the range of 0.1-10 μm that can retain plant-available water. Comparison of soil water retention curves between the control (0) and the biochar plots (16 t ha on dry weight basis) demonstrated biochar amendment to increase soil water holding capacity. However, significant increases in DOC concentration of soil pore water in both the plough layer and the undisturbed subsoil layer were observed in the biochar-amended plots. An increased loss of DOC relative to the control was observed upon rainfall events. Measurements of excitation-emission matrix (EEM) fluorescence indicated the DOC increment originated primarily from the organic carbon pool in the soil that became more soluble following biochar incorporation. [ABSTRACT FROM AUTHOR]

The development of bufadienolides as anti-tumor agents is limited due to poor pharmacokinetic properties regarding drug half-lives and toxicity in vivo. These serious factors might be improved by increasing the drug/albumin-binding ratio. This study therefore investigated the relationship between the structural properties of nine bufadienolides and their affinities for human serum albumin (HSA) by a fluorescence spectroscopy-based analysis and molecular docking. Fluorescence quenching data showed that the interaction of each bufadienolide with HSA formed a non-fluorescent complex, while thermodynamic parameters revealed negative ΔS and ΔH values, corresponding to changes in enthalpy and entropy, respectively. The structural differences between the various bufadienolides markedly influenced their binding affinity for HSA. With the exception of a C = O bond at the C12 position that decreased the binding affinity for HSA, other polar groups tended to increase the affinity, especially a hydroxyl (OH) group at assorted bufadienolide sites. The rank order of binding affinities for drugs with tri-hydroxyl groups was as follows: 11-OH > 5-OH > 16-OH; in addition, 16-acetoxy (OAc), 10-aldehyde and 14-epoxy constituents notably enhanced the binding affinity. Among these groups, 11-OH and 16-acetyl were especially important for a seamless interaction between the bufadienolides and HSA. Furthermore, molecular docking analysis revealed that either an 11-OH or a 16-OAc group spatially close to a five-membered lactone ring significantly facilitated the anchoring of these compounds within site I of the HSA pocket via hydrogen bonding (H-bonding) with Tyr150 or Lys199, respectively. In summary, bufadienolide structure strongly affects binding with HSA, and 11-OH or 16-OAc groups improve the drug association with key amino acid residues. This information is valuable for the prospective development of bufadienolides with improved pharmacological profiles as novel anti-tumor drugs. [ABSTRACT FROM AUTHOR]

Biochar is a kind of solid residual produced by thermal decomposition of orgnic material under limited or absent supply of oxygen, and relatively low temperatures, biochar has the properties of high internal surface area and microporosity, furthmore, non-biological and biological stability. It used as a soil amendment could greatly improve soil physical and chemical properties, reduce the biological effectiveness of soil pollutant and greatly reduce the emission of carbon dioxide and other greenhouse gases and sequestrated soil carbon in recent years. In this study, a one-year field trail of biochar application in the hilly area of central Sichuan Basin, was carried out in sloping farmland plots, which was located at Yanting Agro-ecological Experimental Station of Purple Soil (105°27'E, 31°16'N), Sichuan, Southwest China, to investigate the effects on hydraulic properties of cultivated purple soil (an entisol). Two treatments were set up: control (NPK) and biochar amended (NPK-BC), with each being replicated three times. Comparison between biochar amended and control plots was made by determining soil hydraulic parameters, soil pore size distribution and the contribution of each pore size to flow at two depths (2-7 and >7-12 cm) of the plough layer. Results showed that: 1) due to biochar application, the soil contact angle was increased by 6.7°and 0.5°at the 2-7 and >7-12 cm depth, respectively. This implies that soil water absorption ability was increased and nutrients will be more easily dissolved in the soil.2) After one year of biochar application, the residual water content (θr), which is unavailable to plants and water content in structure pores (θstr), which is easy to be drained out, was decreased, respectively. But the water content in soil matrix pores (θtxt), which is available to plants, increased significantly (P<0.05) from 0.058±0.003 cm3.cm-3 to 0.085±0.002 cm3/cm3. This implies its stronger ability to retain plant-available water after biochar amended, ;3) due to biochar application, The effective porosity of r>125 μm pores increased by 54% and 8% at the 2-7 and >7-12 cm depth, respectively.Particularly, the effective porosity of r>500 μm pores increased most markedly, reaching 110% and 355% for the two depths, respectively. This shows that biochar application reduces the 250< r < 500 μm pores volume in the soil, but increased the volume of smaller pore (125< r <250 μm) and larger pore (r>500 μm); 4) the saturated hydraulic conductivity at the two depths (2-7 and >7-12 cm) increased by 45% and 35%, respectively, after a year of biochar application. Tension infiltration data show that soil macropores (r>125 μm) were the main contributing (accounting for 92-94%) pores to the fast drainage at the 2-7 and >7-12 cm depth, under control and biochar amended r, in spite of their very low percentage (3-4%) of total porosity. 5)Therefore, it can be inferred that, on one hand, the application of biochar could increase the soil's capacity to hold plant-available water and thus enhance resistance to drought; on the other hand, it can also enhance water permeability of soil, which can reduce surface runoff and potential soil erosion. [ABSTRACT FROM AUTHOR]

Biochar is a kind of solid residual produced by thermal decomposition of orgnic material under limited or absent supply of oxygen, and relatively low temperatures, biochar has the properties of high internal surface area and microporosity, furthmore, non-biological and biological stability. It used as a soil amendment could greatly improve soil physical and chemical properties, reduce the biological effectiveness of soil pollutant and greatly reduce the emission of carbon dioxide and other greenhouse gases and sequestrated soil carbon in recent years. In this study, a one-year field trail of biochar application in the hilly area of central Sichuan Basin, was carried out in sloping farmland plots, which was located at Yanting Agro-ecological Experimental Station of Purple Soil (105°27'E,31°16'N), Sichuan, Southwest China, to investigate the effects on hydraulic properties of cultivated purple soil (an entisol). Two treatments were set up: control (NPK) and biochar amended (NPK-BC), with each being replicated three times. Comparison between biochar amended and control plots was made by determining soil hydraulic parameters, soil pore size distribution and the contribution of each pore size to flow at two depths (2-7 and >7-12 cm) of the plough layer. Results showed that: 1) due to biochar application, the soil contact angle was increased by 6.7°and 0.5°at the 2-7 and >7-12 cm depth, respectively. This implies that soil water absorption ability was increased and nutrients will be more easily dissolved in the soil.2) After one year of biochar application, the residual water content (θr), which is unavailable to plants and water content in structure pores (θstr), which is easy to be drained out,was decreased, respectively. But the water content in soil matrix pores (θtxt), which is available to plants, increased significantly (P<0.05) from 0.058±0.003 cm³.cm-3 to 0.085±0.002 cm³/cm³. This implies its stronger ability to retain plant-available water after biochar amended, ; 3) due to biochar application, The effective porosity of r>125 µm pores increased by 54% and 8% at the 2-7 and >7-12 cm depth, respectively. Particularly, the effective porosity of r>500 µm pores increased most markedly, reaching 110% and 355% for the two depths, respectively. This shows that biochar application reduces the 250< r < 500 µm pores volume in the soil, but increased the volume of smaller pore (125< r <250 µm) and larger pore (r>500 µm); 4) the saturated hydraulic conductivity at the two depths (2-7 and >7-12 cm) increased by 45% and 35%, respectively, after a year of biochar application. Tension infiltration data show that soil macropores (r>125 µm) were the main contributing (accounting for 92-94%) pores to the fast drainage at the 2-7 and >7-12 cm depth, under control and biochar amended r, in spite of their very low percentage (3-4%) of total porosity. 5)Therefore, it can be inferred that, on one hand, the application of biochar could increase the soil's capacity to hold plant-available water and thus enhance resistance to drought; on the other hand, it can also enhance water permeability of soil, which can reduce surface runoff and potential soil erosion. [ABSTRACT FROM AUTHOR]

Spontaneous calcium waves in cardiac myocytes are caused by diastolic sarcoplasmic reticulum release (SR Ca2+ leak) through ryanodine receptors. Beta-adrenergic (β-AR) tone is known to increase this leak through the activation of Ca-calmodulin-dependent protein kinase (CaMKII) and the subsequent phosphorylation of the ryanodine receptor. When β-AR drive is chronic, as observed in heart failure, this CaMKII-dependent effect is exaggerated and becomes potentially arrhythmogenic. Recent evidence has indicated that CaMKII activation can be regulated by cellular oxidizing agents, such as reactive oxygen species. Here, we investigate how the cellular second messenger, nitric oxide, mediates CaMKII activity downstream of the adrenergic signaling cascade and promotes the generation of arrhythmogenic spontaneous Ca2+ waves in intact cardiomyocytes. Both SCaWs and SR Ca2+ leak were measured in intact rabbit and mouse ventricular myocytes loaded with the Ca-dependent fluorescent dye, fluo-4. CaMKII activity in vitro and immunoblotting for phosphorylated residues on CaMKII, nitric oxide synthase, and Akt were measured to confirm activity of these enzymes as part of the adrenergic cascade. We demonstrate that stimulation of the β-AR pathway by isoproterenol increased the CaMKII-dependent SR Ca2+ leak. This increased leak was prevented by inhibition of nitric oxide synthase 1 but not nitric oxide synthase 3. In ventricular myocytes isolated from wild-type mice, isoproterenol stimulation also increased the CaMKII-dependent leak. Critically, in myocytes isolated from nitric oxide synthase 1 knock-out mice this effect is ablated. We show that isoproterenol stimulation leads to an increase in nitric oxide production, and nitric oxide alone is sufficient to activate CaMKII and increase SR Ca2+ leak. Mechanistically, our data links Akt to nitric oxide synthase 1 activation downstream of β-AR stimulation. Collectively, this evidence supports the hypothesis that CaMKII is regulated by nitric oxide as part of the adrenergic cascade leading to arrhythmogenesis. [ABSTRACT FROM AUTHOR]

Aims Recent studies suggest that proarrhythmic effects of cardiac glycosides (CGs) on cardiomyocyte Ca2+ handling involve generation of reactive oxygen species (ROS). However, the specific pathway(s) of ROS production and the subsequent downstream molecular events that mediate CG-dependent arrhythmogenesis remain to be defined. Methods and results We examined the effects of digitoxin (DGT) on Ca2+ handling and ROS production in cardiomyocytes using a combination of pharmacological approaches and genetic mouse models. Myocytes isolated from mice deficient in NADPH oxidase type 2 (NOX2KO) and mice transgenically overexpressing mitochondrial superoxide dismutase displayed markedly increased tolerance to the proarrhythmic action of DGT as manifested by the inhibition of DGT-dependent ROS and spontaneous Ca2+ waves (SCW). Additionally, DGT-induced mitochondrial membrane potential depolarization was abolished in NOX2KO cells. DGT-dependent ROS was suppressed by the inhibition of PI3K, PKC, and the mitochondrial KATP channel, suggesting roles for these proteins, respectively, in activation of NOX2 and in mitochondrial ROS generation. Western blot analysis revealed increased levels of oxidized CaMKII in WT but not in NOX2KO hearts treated with DGT. The DGT-induced increase in SCW frequency was abolished in myocytes isolated from mice in which the Ser 2814 CaMKII phosphorylation site on RyR2 is constitutively inactivated. Conclusion These results suggest that the arrhythmogenic adverse effects of CGs on Ca2+ handling involve PI3K- and PKC-mediated stimulation of NOX2 and subsequent NOX2-dependent ROS release from the mitochondria; mitochondria-derived ROS then activate CaMKII with consequent phosphorylation of RyR2 at Ser 2814. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) and superoxide (O2 -) are important cardiac signaling molecules that regulate myocyte contraction. For appropriate regulation, NO and O2 - must exist at defined levels. Unfortunately, the NO and O2 - levels are altered in many cardiomyopathies (heart failure, ischemia, hypertrophy, etc.) leading to contractile dysfunction and adverse remodeling. Hence, rescuing the nitroso-redox levels is a potential therapeutic strategy. Nitrone spin traps have been shown to scavenge O2 - while releasing NO as a reaction byproduct; and we synthesized a novel, cell permeable nitrone, 2-2-3,4-dihydro-2Hpyrrole 1-oxide (EMEPO). We hypothesized that EMEPO would improve contractile function in myocytes with altered nitroso-redox levels. Ventricular myocytes were isolated from wildtype (C57Bl/6) and NOS1 knockout (NOS1-/-) mice, a known model of NO/O2 - imbalance, and incubated with EMEPO. EMEPO significantly reduced O2 - (lucigenin-enhanced chemiluminescence) and elevated NO (DAF-FM diacetate) levels in NOS1-/- myocytes. Furthermore, EMEPO increased NOS1-/- myocyte basal contraction (Ca2+ transients, Fluo-4AM; shortening, video-edge detection), the force-frequency response and the contractile response to β-adrenergic stimulation. EMEPO had no effect in wildtype myocytes. EMEPO also increased ryanodine receptor activity (sarcoplasmic reticulum Ca2+ leak/load relationship) and phospholamban Serine16 phosphorylation (Western blot). We also repeated our functional experiments in a canine post-myocardial infarction model and observed similar results to those seen in NOS1-/- myocytes. In conclusion, EMEPO improved contractile function in myocytes experiencing an imbalance of their nitroso-redox levels. The concurrent restoration of NO and O2 - levels may have therapeutic potential in the treatment of various cardiomyopathies. [ABSTRACT FROM AUTHOR]

Ventricular myocytes deficient in endothelial nitric oxide synthase (NOS3-/-) exhibit prolonged action potential (AP) duration and enhanced spontaneous activity (early and delayed afterdepolarizations) during β-adrenergic (β-AR) stimulation. Studies have shown that nitric oxide is able to regulate various K+ channels. Our objective was to examine if NOS3-/- myocytes had altered K+ currents. APs, transient outward (Ito), sustained (IKsus), and inward rectifier (IK1) K+ currents were measured in NOS3-/- and wildtype (WT)myocytes. During β-AR stimulation, AP duration (measured as 90% repolarization-APD90) was prolonged in NOS3-/- compared to WT myocytes. Nevertheless, we did not observe differences in Ito, IKsus, or IK1 between WT and NOS3-/- myocytes. Our previous work showed that NOS3-/- myocytes had a greater Ca2+ influx via L-type Ca2+ channels with β-AR stimulation. Thus, we measured β-AR-stimulated SR Ca2+ load and found a greater increase in NOS3-/- versus WT myocytes. Hence, our data suggest that the prolonged AP in NOS3-/- myocytes is not due to changes in Ito, IKsus, or IK1. Furthermore, the increase in spontaneous activity in NOS3-/- myocytes may be due to a greater increase in SR Ca2+ load. This may have important implications for heart failure patients, where arrhythmias are increased and NOS3 expression is decreased. [ABSTRACT FROM AUTHOR]

The sarcoplasmic reticulum (SR) Ca2+ release channel (ryanodine receptor, RyR2) has been proposed to be an end target of neuronal nitric oxide synthase (NOS1) signalling. The purpose of this study is to investigate the mechanism of NOS1 modulation of RyR2 activity and the corresponding effect on myocyte function. Myocytes were isolated from NOS1 knockout (NOS1−/−) and wild-type mice. NOS1−/− myocytes displayed a decreased fractional SR Ca2+ release, NOS1 knockout also led to reduced RyR2 S-nitrosylation levels. RyR2 channels from NOS1−/− hearts had decreased RyR2 open probability. Additionally, knockout of NOS1 led to a decrease in [3H]ryanodine binding, Ca2+ spark frequency (CaSpF) and a rightward shift in the SR Ca2+ leak/load relationship. Similar effects were observed with acute inhibition of NOS1. These data are indicative of decreased RyR2 activity in myocytes with NOS1 knockout or acute inhibition. Interestingly, the NO donor and nitrosylating agent SNAP reversed the depressed RyR2 open probability, the reduced CaSpF, and caused a leftward shift in the leak/load relationship in NOS1−/− myocytes. SNAP also normalized Ca2+ transient and cell shortening amplitudes and SR fractional release in myocytes with NOS1 knockout or acute inhibition. Furthermore, SNAP was able to normalize the RyR2 S-nitrosylation levels. These data suggest that NOS1 signalling increases RyR2 activity via S-nitrosylation, which contributes to the NOS1-induced positive inotropic effect. Thus, RyR2 is an important end target of NOS1. [ABSTRACT FROM AUTHOR]

Aims: Peroxynitrite production increases during the pathogenesis of numerous cardiac disorders (e.g. heart failure). However, limited studies have investigated the mechanism through which peroxynitrite exerts anti-adrenergic effects. Thus, the purpose of this study is to investigate the contribution of phospholamban (PLB), a critical excitation–contraction coupling protein, to the peroxynitrite-induced dysfunction. [ABSTRACT FROM PUBLISHER]

Cancer-associated fibroblasts (CAFs) and myeloma cells could mutually drive myeloma progression, indicating that drug delivery to kill both CAFs and myeloma cells simultaneously could achieve better therapeutic benefits than to kill each cell type alone. Here, we designed a dual-targeting drug delivery system by conjugating paclitaxel (PTX)-loaded poly(ethylene glycol)-poly(lactic acid) nanoparticles (NPs) with a cyclic peptide (CNPs-PTX) with a special affinity with platelet-derived growth factor/platelet-derived growth factor receptor (PDGFR-β) overexpressed on both CAFs and myeloma cells. Cellular uptake experiments revealed that the cyclic peptide modification on CNPs could significantly enhance CNPs uptake by both CAFs and myeloma cells compared with unmodified NPs. Cytotoxicity tests showed that CNPs-PTX was more toxic to both CAFs and myeloma cells compared with its counterpart PTX-loaded conventional NPs (NPs-PTX). In vivo imaging and biodistribution experiments showed that CNPs could abundantly accumulate in tumors and were highly co-localized with CAFs and myeloma cells. The in vivo anti-tumor experiments confirmed that the anti-myeloma efficacy of CNPs-PTX was significantly stronger than that of NPs-PTX and free drugs. In summary, it is the first time that a dual-targeting strategy was utilized in the field of myeloma treatment through targeting both CAFs and myeloma cells simultaneously, which harbors a high potential of clinical translation for myeloma treatment. [ABSTRACT FROM AUTHOR]

Background: The management of metastatic cancer remains a major challenge in cancer therapy worldwide. The targeted delivery of chemotherapeutic drugs through rationally designed formulations is one potential therapeutic option. Notably, excipient-free nanodispersions that are entirely composed of pharmaceutically active molecules have been evaluated as promising candidates for the next generation of drug formulations. Formulated from the self-assembly of drug molecules, these nanodispersions enable the safe and effective delivery of therapeutic drugs to local disease lesions. Here, we developed a novel and green approach for preparing nanoparticles via the self-assembly of rhein (RHE) and doxorubicin (DOX) molecules, named RHE/DOX nanoparticles (RD NPs); this assembly was associated with the interaction force and did not involve any organic solvents. Results: According to molecular dynamics (MD) simulations, DOX molecules tend to assemble around RHE molecules through intermolecular forces. This intermolecular retention of DOX was further improved by the nanosizing effect of RD NPs. Compared to free DOX, RD NPs exerted a slightly stronger inhibitory effect on 4T1 cells in the scratch healing assay. As a dual drug-loaded nanoformulation, the efficacy of RD NPs against tumor cells in vitro was synergistically enhanced. Compared to free DOX, the combination of DOX and RHE in nanoparticles exerted a synergistic effect with a combination index (CI) value of 0.51 and showed a stronger ability to induce cell apoptosis. Furthermore, the RD NP treatment not only effectively suppressed primary tumor growth but also significantly inhibited tumor metastasis both in vitro and in vivo, with a better safety profile. Conclusions: The generation of pure nanodrugs via a self-assembly approach might hold promise for the development of more efficient and novel excipient-free nanodispersions, particularly for two small molecular antitumor drugs that potentially exert synergistic antiproliferative effects on metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Mitochondria are usually located in the cytoplasm of cells where they generate adenosine triphosphate (ATP) to empower cellular functions. However, we found circulating mitochondria in human and animal blood. Electron microscopy confirmed the presence of mitochondria in adult human blood plasma. Flow cytometry analyses demonstrated that circulating mitochondria from the plasma of human cord blood and adult peripheral blood displayed the immune tolerance-associated membrane molecules such as CD270 and PD-L1 (programmed cell death-ligand 1). Similar data were obtained from fetal bovine serum (FBS) and horse serum of different vendors. Mitochondria remained detectable even after 56 °C heat inactivation. A real-time PCR array revealed purified mitochondria from animal sera expressed several genes that contribute to human T- and B-cell activation. Transwell experiments confirmed the migration capability of mitochondria through their expression of the chemokine receptor CXCR4 in responses to its ligand stromal-derived factor-1α (SDF-1α). Functional analysis established that human plasma mitochondria stimulated the proliferation of anti-CD3/CD28 bead-activated PBMC, up-regulated the percentage of activated CD4+ T and CD8+ T cells, and reduced the production of inflammatory cytokines. These findings suggested that the existence of circulating mitochondria in blood may function as a novel mediator for cell-cell communications and maintenance of homeostasis. Plasma-related products should be cautiously utilized in cell cultures due to the mitochondrial contamination. [ABSTRACT FROM AUTHOR]