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ObjectiveTo prepare a rat model of heart failure after myocardial infarction by ligation of the anterior descending branch of the left coronary artery， and to observe the effect of Shenfu Yixin granules on the mitochondrial dynamics of rats with heart failure. MethodFifty SD male rats were randomly taken ten as the sham operation group and the rest as modeling group. The rat model of heart failure after myocardial infarction was prepared by ligation of anterior descending branch of left coronary artery. According to the left ventricular ejection fraction（LVEF） on the 28th day after operation， the model rats were randomly divided into the model group， Shenfu Yixin granule low-dose and high-dose groups（3.011， 15.055 g·kg-1） and sacubitril valsartan sodium group（20.83 mg·kg-1）. Each administration group was gavaged daily with the corresponding dose of drug solution， while the sham operation group and model group were given the same amount of normal saline once a day for 28 days， with 6 rats in each group. Ultrasound was used to detect the cardiac function parameters， rat heart mass and body mass were weighed to calculate the cardiac mass index， enzyme linked immunosorbent assay（ELISA） was used to detect serum brain natriuretic peptide（BNP） and soluble growth stimulation expressed gene 2 protein（sST2） levels. Hematoxylin-eosin（HE） staining was used to observe the pathological morphology of the myocardium. Real-time fluorescence quantitative polymerase chain reaction（Real-time PCR） and Western blot were used to detect the mRNA and protein expression of mitochondrial fusion protein 1/2（Mfn1/2）， optic atrophy protein 1（Opa1）， dynamin-related protein 1（Drp1） and fission protein 1（Fis1）. ResultCompared with the sham operation group， the mRNA and protein expression of LVEF， Mfn1， Mfn2， Opal in the model group decreased（P<0.05）， while BNP， sST2， cardiac mass index， Drp1， Fis1 mRNA and protein levels increased（P<0.05）. Compared with the model group， the expression of LVEF， Mfn1， Mfn2， Opal mRNA and protein increased in Shenfu Yixin granule high-dose and sacubitril valsartan sodium groups（P<0.05）， while BNP， sST2， cardiac mass index， Drp1， Fis1 mRNA and protein levels decreased（P<0.05）. Pathological observation showed that compared with the sham operation group， the model group had disordered arrangement of myocardial cells， inflammatory cell infiltration and myocardial fibrosis. Compared with the model group， the degree of inflammatory cell infiltration， myocardial or interstitial fibrosis was improved and alleviated in all administered groups. ConclusionShenfu Yixin granules can resist heart failure， reduce cardiac mass index， decrease BNP and sST2 contents， and improve cardiac function. Its mechanism may be related to the adjustment of mitochondrial dynamics.

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Objective:To explore the effects of Xintongtai （XTT） on traditional Chinese medicine （TCM） syndrome score and collagen fibers in vascular smooth muscle cells（VSMCs） of rabbits with atherosclerosis in the regulation of p38 mitogen-activated protein kinase （p38 MAPK）/activator protien-1 （AP-1）signaling pathway. Method:A total of 120 rabbits of SPF grade were randomly divided into the sham operation group， combined phlegm and blood stasis model group， rosuvastatin group， and low-， middle-， and high-dose XTT groups. The rabbit model of atherosclerosis due to combined phlegm and blood stasis was established by exposing them to high-fat diet and balloon injury. Following modeling， the corresponding drugs were administered by gavage for eight weeks （2.3， 4.6， 9.2 g·kg^-1 for low-， middle-， and high-dose XTT groups and 0.55 mg·kg^-1for rosuvastatin group）. At the end of medication， the abdominal aorta was isolated and stained with htoxylin-eosin （HE） for observing the vulnerable plaque. Matrix metalloproteinase-9 （MMP-9） and tissue inhibitor of metalloproteinase-1 （TIMP-1） were detected by immunohistochemistry （IHC）. The collagen fiber decomposition in VSMCs was observed after Masson staining. The protein expression levels of p38 MAPK and AP-1 in aorta was assayed by Western blotting. The combined phlegm and blood stasis syndrome was scored based on TCM syndrome scoring scale. Result:Compared with the model group， XTT at each dose and rosuvastatin significantly decreased MMP-9 content， increased TIMP-1， down-regulated p38 MAPK protein expression， and weakened the nuclear translocation of AP-1 （<italic>P</italic><0.01）. Compared with the low-dose XTT group， the middle- and high-dose XTT groups and rosuvastatin group exhibited obviously lowered MMP-9，elevated TIMP-1， down-regulated p38 MAPK protein expression， and diminished AP-1 nuclear translocation （<italic>P</italic><0.05，<italic>P</italic><0.01）. The TCM syndrome scores of the middle- and high-dose XTT groups and rosuvastatin group were significantly improved as compared with that in the model group （<italic>P</italic><0.05，<italic>P</italic><0.01）. The comparison with the low-dose XTT group revealed a remarkable improvement in TCM syndrome score of the middle- and high-dose XTT groups and rosuvastatin group （<italic>P</italic><0.01）. As demonstrated by Masson staining， the smooth muscle fibers in the model group were arranged in disorder， accompanied by enhanced collagen decomposition， thinned fibrous cap， and increased plaque vulnerability. Compared with the model group， the VSMCs in each XTT group and rosuvastatin group were orderly arranged， manifested as decreased collagen fiber decomposition and increased plaque stability. Conclusion:XTT down-regulates the expression of p38 MAPK and MMP-9， increases the level of TIMP-1， reduces the nuclear translocation of AP-1， diminishes the decomposition of collagen fibers in VSMCs， and improves the score of combined phlegm and blood stasis syndrome. XTT alleviates arteriosclerosis due to combined phlegm and blood stasis by regulating p38 MAPK/AP-1 signaling pathway and downstream cytokines and stabilizing vulnerable plaques.

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Engineering biocompatible hydrogels using functional nanoparticles has attracted considerable attention because of their uniquely appealing cooperative effects that can enable multimodality imaging and treatment with improved efficacy against serious diseases. However, the effects of high-content nanoparticle dopants on the rheological properties of hydrogels frequently lead to an unsatisfactory therapeutic result, which is particularly notable in the design of magnetic hydrogel formulations for cancer therapy. Herein is reported a novel magnetic hydrogel functionalized by ferromagnetic vortex-domain iron oxide (FVIOs) with optimally adaptive functions for prevention of breast cancer recurrence. The FVIOs can perfectly incorporate into the dynamic hydrogel networks with an extremely low concentration (0.6 mg mL-1 ), 17 times lower than that of conventional superparamagnetic iron oxide nanoparticles with sufficient heating capacity. Such magnetic hydrogels exhibit high inductive heating and remarkable rheological properties simultaneously. Moreover, the self-healing, self-conformal ability, controlled release of loaded doxorubicin, biodegradation, and pH-responsiveness of the magnetic hydrogel project their efficient sustainable therapeutic ability. In vivo postoperative treatment has further demonstrated the high efficacy of FVIO-based magnetic hydrogels, as evidenced by the significant suppression of the local tumor recurrences compared to chemotherapy or hyperthermia alone. This unique magnetic hydrogel formulation with optimally adaptive functions shows strong potential in preventing relapses of various cancers.

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Recently bismuth-based nanoparticles have drawn extensive attention as radiosensitizer in radiotherapy due to high atomic number, low toxicity, and low cost. This study aims to introduce the applicability of bismuth ferrite nanoparticles (BFO, BiFeO3) as a new multifunctional theranostic agent for radiotherapy, magnetic resonance imaging (MRI), and computed tomography (CT) as well as magnetic hyperthermia mediator. After evaluation of BFO nanoparticles biocompatibility which were synthesized by conventional sol-gel method, we investigated dose enhancement property of BFO nanoparticles with gel dosimetry, clonogenic, and cck8 assay. According to clonogenic assay, sensitizer enhancement ratios (SERs) were obtained as 1.35 and 1.76 for nanoparticle concentrations of 0.05 mg/ml and 0.1 mg/ml, respectively. For high concentration (0.5 mg/ml), dose enhancement effect of BFO nanoparticles was demonstrated by gel dosimetry. To prove the contrast enhancement of BFO nanoparticles in MR and CT imaging, the relaxation time rate (R2) and Hounsfield unit (HU) were measured, respectively. It was found that the R2 and Hu have linear relationship with the nanoparticle concentrations. Moreover, whereas BFO nanoparticles have magnetic properties, we measured inductive heating property of the nanoparticles in external alternative magnetic field to evaluate their applicability as magnetic hyperthermia mediator. A rapid temperature increment was detected under alternative magnetic field (12.2 kAm-1 and 17.2 kAm-1, frequency 480 kHz) owing to the high concentration of BFO nanoparticles. Collectively, our experimental investigation results proved that the multifunctional BFO nanoparticles could be employed as a multimodal imaging and radio-thermotherapeutic agent to enhance theranostic efficacy.

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Depression is a debilitating psychiatric disorder with a huge socioeconomic burden, and its treatment relies on antidepressants including selective serotonin reuptake inhibitors (SSRIs). Recently, the melatonergic system that is closely associated with the serotonergic system has been implicated in the pathophysiology and treatment of depression. However, it remains unknown whether combined treatment with SSRI and melatonin has synergistic antidepressant effects. In this study, we applied a sub-chronic restraint stress paradigm, and evaluated the potential antidepressant effects of combined fluoxetine and melatonin in adult male mice. Sub-chronic restraint stress (6 h/day for 10 days) induced depression-like behavior as shown by deteriorated fur state, increased latency to groom in the splash test, and increased immobility time in the forced-swim test. Repeated administration of either fluoxetine or melatonin at 10 mg/kg during stress exposure failed to prevent depression-like phenotypes. However, combined treatment with fluoxetine and melatonin at the selected dose attenuated stress-induced behavioral abnormalities. Moreover, we found that the antidepressant effects of combined treatment were associated with the normalization of brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling in the hippocampus, but not in the prefrontal cortex. Our findings suggest that combined fluoxetine and melatonin treatment exerts synergistic antidepressant effects possibly by restoring hippocampal BDNF-TrkB signaling.

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Objective This study was designed to determine the effect of transient receptor potential vanilloid type 4(TRPV4)on angiotensin Ⅱ(Ang Ⅱ)-induced renal injury in TRPV4-null mutant(TRPV4 -/-)mice. Methods The mice were divided into sham group and Ang Ⅱ-treated group. Ang Ⅱ was infused systemically into wild type(WT)and TRPV4 -/- mice via a miniosmotic pump for 4 weeks, and the sham mice were given with normal saline. Systolic blood pressure,urinary excretion of albumin and 8-isoprostane, serum creatinine, and the pathological changes in the kidney tissues were assayed after the 4-week treatment. Results Compared with corresponding sham mice,Ang Ⅱ infusion led to enhanced systolic blood pressure,increased urinary excretion of albumin and 8-isoprostane,increased serum creatinine(P< 0.05),and enhanced glomerulosclerosis degree and renal tubulointerstitial injury index(P< 0.05)in the WT and TRPV4 -/- mice. The result were associated with enhanced collagen levels in the kidney(P< 0.05). All of them were attenuated by the deletion of TRPV4 in the absence of alteration in blood pressure(P< 0.05). Conclusions Deletion of TRPV4 could alleviate renal injury during Ang Ⅱ-induced hypertension, suggesting that TRPV4 may contribute to the pathophysiology of angiotensin Ⅱ-induced renal injury.

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Sucrose non-fermenting 1-related protein kinases (SnRKs) comprise a major family of signaling genes in plants and are associated with metabolic regulation, nutrient utilization and stress responses. This gene family has been proposed to be involved in sucrose signaling. In the present study, we cloned three copies of the TaSnRK2.10 gene from bread wheat on chromosomes 4A, 4B and 4D. The coding sequence (CDS) is 1086 bp in length and encodes a protein of 361 amino acids that exhibits functional domains shared with SnRK2s. Based on the haplotypes of TaSnRK2.10-4A (Hap-4A-H and Hap-4A-L), a cleaved amplified polymorphic sequence (CAPS) marker designated TaSnRK2.10-4A-CAPS was developed and mapped between the markers D-1092101 and D-100014232 using a set of recombinant inbred lines (RILs). The TaSnRK2.10-4B alleles (Hap-4B-G and Hap-4B-A) were transformed into allele-specific PCR (AS-PCR) markers TaSnRK2.10-4B-AS1 and TaSnRK2.10-4B-AS2, which were located between the markers D-1281577 and S-1862758. No diversity was found for TaSnRK2.10-4D. An association analysis using a natural population consisting of 128 winter wheat varieties in multiple environments showed that the thousand grain weight (TGW) and spike length (SL) of Hap-4A-H were significantly higher than those of Hap-4A-L, but pant height (PH) was significantly lower.

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Cancer stem cells (CSCs) are original cancer cells that are of characteristics associated with normal stem cells. CSCs are toughest against various treatments and thus responsible for cancer metastasis and recurrence. Therefore, development of specific and effective treatment of CSCs plays a key role in improving survival and life quality of cancer patients, especially those in the metastatic stage. Nanomedicine strategies, which include prodrugs, micelles, liposomes and nanoparticles of biodegradable polymers, could substantially improve the therapeutic index of conventional therapeutics due to its manner of sustained, controlled and targeted delivery of high transportation efficiency across the cell membrane and low elimination by intracellular autophagy, and thus provide a practical solution to solve the problem encountered in CSCs treatment. This review gives briefly the latest information to summarize the concept, strategies, mechanisms and current status as well as future promises of nanomedicine strategies for treatment of CSCs.

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AIM: The application of cationic liposomes (CLs) as nonviral vectors is hampered by their cellular toxicity. Thus we aim to investigate the mechanisms underlying the cellular toxicity of CLs. MATERIALS & METHODS: The effect of CLs on the autophagic flux, autophagosome-lysosome fusion, lysosome membrane permeabilization and cell necrosis of liver cells was investigated. RESULTS & CONCLUSION: Our results reveal a novel mechanism of CL-induced cell necrosis involving the induction of lysosome membrane permeabilization and late-stage autophagic flux inhibition that resulted in cytoplasmic release of cathepsin B, mitochondrial dysfunction and reactive oxygen species production, which are the key mediators of cell necrosis. Our study is important for revealing the cellular toxicity of CLs and designing safer gene delivery systems.

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Objective To explore the role of MRI(T1ρ)in the early osteoarthritis,curative efficacy monitoring and speculated that the mechanism of curative effect.Methods (1)(early OA model)A total of 28 New Zealand white rabbits were randomly divided into A,B,C three groups.group A(treatment)and B(control)were both for 1 1 rabbits,and 6 rabbits were considered as blank control group(group C).0.5 mL 1.6% papain was injected into the right knee joint cavity both group A and B according to three times (1,4,7 days).The equivalent dilution was injected into the left knee joint cavity simultaneously.3 weeks after the first injection,and T2 WI,3D-FS-SPGR,and T1ρ mapping in sagittal plain were scanned for three groups.Randomly selected two models pathology test in the group A and B,confirm early OA model is established.(2)(treat models)Then give epimedium lavage to group A two month.The equivalent sterile saline lavage to group B.A certain time (T0 = 0,T1 = 1 mon,T2 = 2 mon)after treated do MR scanned for group A and B.Analysis of the image.T1ρvalues and the cartilage thickness in bilateral femoral condyle cartilage were measured by post-processing software.The all femurs were pathological examined.T1ρvalues and the cartilage thickness were statistic analysis. Results (1)Articular cavity injection of papain can successfully establish early osteoarthritis rabbit model which pathology has been confirmed.T1ρvalues of the experimental (group A,B)were significant higher than of the control side(P0.05).(2)T1ρvalues of the Epimedium treat model (right side)were significant lower than of the pre-treatment that of the preintervention (P 0.05).Conclusion (1)T1ρvalues of the early and advanced stage of OA had increased in various degree,and the values related cartilage matrix composition.(2 )Single herb Epimedium has effective to treat early stages osteoarthritis in knee joint.Spec-ulated that the possible mechanism for treatment common channel in the development of OA,which inhibition protease formation and promote proteoglycan secretion.

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Tripterygium wilfordii Hook. f. induced-hepatotoxicity was the main limitation for its usage in clinic. Qingluo Tongbi formulation showed obvious attenuation for hepatotoxicity in clinic and fundamental research in vivo. To explore the potential mechanism of the attenuation, we conducted a study on the plasma metabolomic profiles of T. wilfordii and Qingluo Tongbi formulation in rats by a sensitive gas chromatography-mass spectrometry (GC-MS/MS) method. In plasma samples, a total of 72 compounds were analyzed by EI source MS, and were successfully identified by matching NIST database. The semi-quantification results were then calculated by OPLS-DA model with SIMCA-P 13.0 software. The three groups were clearly distinguished in OPLS-DA score plot. In addition, the observation values of Qingluo Tongbi formulation showed the obvious trend towards the control levels, suggesting the detoxicity effect of the formulation. Variation metabolites were further analyzed by VIP and One Way ANOVAs, and the results showed a significant increase in compounds of glycogenic amino acids, such as alanine, proline, serine and glutamine after the administration of T. wilfordii, indicated that the tissue proteins were decomposed and amino acids were leakage into blood. Qingluo Tongbi formulation could reverse the amino acids into normal level. On the contrary, the levels of glucose, lactic acid and hydroxy butyrate decrease, and the formulation can relieve the disorder in the levels of lactic acid, suggesting the regulation of the energy metabolism. Additionally, the level of branched chain amino acid was decreased, suggested the toxicity was induced, but the formulation cannot increase it into the normal levels. Nevertheless, all the above results suggested that the classical Qingluo Tongbi formulation displayed the liver protection effect by adjusting the amino acid levels and regulating the energy metabolism. Qingluo Tongbi formulation was developed based on traditional Chinese medicine theory "detoxicity compatibility", and contained Panax notoginseng (Burk.) F. H. Chen to nourish blood and absorb clots. Modern pharmacology suggested that its liver protection effect was correlated with the promotion of protein synthesis. Another important herb is Rehmannia glutinosa Libosch., which can regulate the energy metabolism. Both were consistent with the metabolomic results in this study, which explained the potential mechanism of "detoxicity compatibility" theory. Therefore, the currently developed metabolomic approach and the obtained results would be highly useful for the comprehensive toxicity studies for other herbal medicines and various complex deoxicity formulations.

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<p><b>OBJECTIVE</b>To investigate the effect of respiratory syncytial virus (RSV)-related pulmonary infection on endogenous metabolites in large intestinal mucosa in BALB/c mice using metabolomics technology based on gas chromatography-mass spectrometry (GC-MS).</p><p><b>METHODS</b>Mice were randomly divided into a control group and a RSV pneumonia model group (n=16 each). The mouse model of RSV pneumonia was established using intranasal RSV infection (100×TCID, 50 μL/mouse, once a day). After 7 days of intranasal RSV infection, the mice were sacrificed and GC-MS was used to identify endogenous metabolites and measure the changes in their relative content in colon tissue. SMCA-P12.0 software was used to perform principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) for endogenous metabolites in colon tissue. The differentially expressed metabolites in colon tissue were imported into the metabolic pathway platform Metaboanalyst to analyze related metabolic pathways.</p><p><b>RESULTS</b>PCA and OPLS-DA showed significant differences between the control and RSV pneumonia model groups. A total of 32 metabolites were identified in the colon tissue of the mice with RSV pneumonia. The RSV pneumonia model group had significant increases in the content of leucine, isoleucine, glycine, alanine, arachidonic acid, and lactic acid, which were related to the valine, leucine, isoleucine, arachidonic acid, and pyruvic acid metabolic pathways.</p><p><b>CONCLUSIONS</b>RSV pneumonia might cause metabolic disorders in the large intestinal tissue in mice.</p>

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Cancer initiating cells (CIC) are tumorigenic cancer cells that have properties similar to normal stem cells. CD20 is a phenotype of melanoma CIC that is responsible for melanoma drug resistance. Vincristine (VCR) is commonly used in melanoma therapy; however, it has been found ineffective against CIC. To target CD20+ melanoma CIC, we prepared VCR-containing immunoliposomes that were conjugated to CD20 antibodies (VCR-Lip-CD20). The drug release profile and the antibody-mediated targeting of the immunoliposomes were optimized to target CD20+ melanoma CIC. The immunoliposomes had desirable particle size (163 nm), drug encapsulation efficiency (91.8%), and drug release profile. We demonstrated that these immunoliposomes could successfully target more than 55% of CD20+ Chinese Hamster Ovary cells (CHO-CD20) even when the CHO-CD20 cells accounted for only 0.1% of a mixed population of CHO-CD20 and CHO cells. After treating WM266-4 melanoma mammospheres for 96 h, the ICo values of the drug delivered in VCR-Lip-CD20, VCR-Lip (VCR liposomes), and VCR were found to be 53.42, 98.99, and 99.09 µg/mL, respectively, suggesting that VCR-Lip-CD20 was 1.85 times more effective than VCR-Lip and VCR. VCR-Lip-CD20 could almost completely remove the tumorigenic ability of WM266-4 mammospheres in vivo, and showed the best therapeutic effect in WM266-4 melanoma xenograft mice. Significantly, VCR-Lip-CD20 could selectively kill CD20+ melanoma CIC in populations of WM266-4 cells both in vitro and in vivo. We demonstrated that VCR-Lip-CD20 has the potential to efficiently target and kill CD20+ melanoma CIC.

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We developed a system of biodegradable nanoparticles (NPs) of 5,10,15,20-tetrakis(4-aminophenyl)-21H,23H-porphine (TAPP) centered, 4 arm star-shaped copolymers based on poly(ε-caprolactone) (PCL) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) for combinatory chemophotodynamic therapy by using docetaxel (DTX) as a model anticancer drug and TAPP as photodynamic sensitizer. TPGS component in the copolymer plays an important role in enhancing the drug encapsulation efficiency, drug release kinetics and cellular uptake of the NPs, as well as in overcoming the multidrug resistance due to inhibition of P-glycoproteins (P-gp) of the cancer cells. We demonstrated in vitro by using the MCF7/ADR breast cancer cells of P-gp overexpression and the HeLa cervical cancer cells that the proposed chemophotodynamic therapy by the DTX-loaded TAPP-PCL-b-TPGS NPs could have much higher therapeutic effect than the original drug Taxotere®. IC50 data showed that the DTX-loaded TAPP-PCL-b-TPGS NPs chemophotodynamic therapy could be 9.36 and 56.5-fold efficient after 24 and 48h treatment, respectively in comparison with the Taxotere® chemotherapy. The in vivo investigation by employing a cervical cancer xenograft model further confirmed the advantages of the proposed chemophotodynamic therapy by the DTX-loaded TAPP-PCL-b-TPGS NPs versus the Taxotere® chemotherapy.

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A major problem in cancer treatment is the multidrug resistance. siRNA inhibitors have great advantages to solve the problem, if the bottleneck of their delivery could be well addressed by the various nanocarriers. Moreover, co-delivery of siRNA together with the various anticancer agents in one nanocarrier may maximize their additive or synergistic effect. This review provides a comprehensive summary on the state-of-the-art of the nanocarriers, which may include prodrugs, micelles, liposomes, dendrimers, nanohydrogels, solid lipid nanoparticles, nanoparticles of biodegradable polymers and nucleic acid nanocarriers for delivery of siRNA and co-delivery of siRNA together with anticancer agents with focus on synthesis of the nanocarrier materials, design and characterization, in vitro and in vivo evaluation, and prospect and challenges of nanocarriers.

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AIM: To develop novel nanoliposomes (Lip-ADR-Cer) codelivering doxorubicin (ADR) and PEGylated C16 ceramide (PEG-ceramide C16) to overcome multidrug resistance. MATERIALS & METHODS: The antitumor activity and mechanism of Lip-ADR-Cer were evaluated. RESULTS & CONCLUSION: The IC50 of Lip-ADR-Cer after 48-h treatment with the MCF-7/ADR and HL-60/ADR cancer cells, both being ADR resistant, was 2.2- and 1.4-fold effective respectively versus the general nanoliposomes with no PEG-ceramide C16 (Lip-ADR). The antitumor assay in mice bearing MCF-7/ADR or HL-60/ADR xenograft tumors confirmed the superior antitumor activity of Lip-ADR-Cer over Lip-ADR. We found that the improved therapeutic effect of Lip-ADR-Cer may be attributed to both of the cytotoxic effect of PEG-ceramide C16 and glucosylceramide synthase overexpression in multidrug resistance cells.

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In this study we examined the efficacy of our micellar system in xenograft models of triple negative breast cancers and explored the effect of the micelles on post-treatment tumours in order to elucidate the mechanism underlying the nanomedicine treatment in oncology. Here, we developed docetaxel-loaded vitamin E D-α-tocopheryl polyethylene glycol succinate (TPGS) micelles, of which the surface modified with cetuximab ligands for targeting epidermal growth factor receptors (EGFR) that are overexpressed in MDA-MB-231 breast cancer cells. The targeting micelles accumulated in the tumours immediately after the intravenous injection and retained for at least 24 h. The successful delivery of docetaxel into the tumours by the targeting micelles was shown by the greater degree of tumour growth inhibition than that for Taxotere(®) after the 15-day treatment. Furthermore, the explanted tumour culture study involving gene analysis and immunohistochemistry staining indicated that the in vivo micelle treatment induced cell cycle arrest and attenuated cell proliferation. In addition, the targeting and non-targeting micellar formulations brought about anti-angiogenesis and anti-migration effects. Overall, both the in vivo and ex vivo data increased the confidence that our micellar formulations effectively targeted and inhibited EGFR-overexpressing MDA-MB-231 tumours.

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Plant hormones modulate plant growth, development, and defense. However, many aspects of the origin and evolution of plant hormone signaling pathways remain obscure. Here, we use a comparative genomic and phylogenetic approach to investigate the origin and evolution of nine major plant hormone (abscisic acid, auxin, brassinosteroid, cytokinin, ethylene, gibberellin, jasmonate, salicylic acid, and strigolactone) signaling pathways. Our multispecies genome-wide analysis reveals that: (1) auxin, cytokinin, and strigolactone signaling pathways originated in charophyte lineages; (2) abscisic acid, jasmonate, and salicylic acid signaling pathways arose in the last common ancestor of land plants; (3) gibberellin signaling evolved after the divergence of bryophytes from land plants; (4) the canonical brassinosteroid signaling originated before the emergence of angiosperms but likely after the split of gymnosperms and angiosperms; and (5) the origin of the canonical ethylene signaling pathway postdates shortly the emergence of angiosperms. Our findings might have important implications in understanding the molecular mechanisms underlying the emergence of land plants.

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