Involvement of P2X7R-mediated microglia polarization and neuroinflammation in the response to electroacupuncture on post-stroke memory impairment.

PURPOSE: Post-stroke cognitive impairment (PSCI) is a common complication of ischemic stroke episodes. Memory impairment is an important component of the poststroke cognitive syndrome. Microglial activation plays a critical role in stroke-induced neuroinflammation. Previous studies have reported that electroacupuncture (EA) provides neuroprotective effects by reducing the expression levels of the Purinergic receptor P2X ligand-gated ion channel 7 (P2X7) and inhibiting neuroinflammation in rat model of ischemic stroke. Further understanding of the role and connections between P2X7R and microglial activation in EA-induced anti-inflammatory can reveal novel targets for post-stroke memory impairment treatment. METHODS: A Middle cerebral artery occlusion and reperfusion (MCAO/R) model was established. We used 2'(3')-O-(4-benzoyl) benzoyl ATP (BzATP) as a P2X7R agonist. Following MCAO/R injury, the rats underwent EA therapy at the Baihui (DU20) and Shenting (DU24) acupoints for seven consecutive days. The Barnes maze test was used to evaluate memory function. Following intervention, a T2 weighted images (T2WI) scan was performed to identify changes in cerebral infarction volume in MCAO/R rats. The levels of Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6) and Interleukin-4 (IL-4), Interleukin-10 (IL-10) in the peri-infarct hippocampal were examined by ELISA. Immunofluorescence was employed to evaluate Iba-1+ / P2X7R+, Iba-1+/ iNOS+ and Iba-1+/ Arg-1+ cell populations in the peri-infarct hippocampal DG area. The protein expression of P2X7R, Nuclear factor E2-related factor 2 (Nrf2), Recombinant nlr family, pyrin domain containing protein 3 (NLRP3), Inducible nitric oxide synthase (iNOS) and Arginase-1 (Arg-1) in the peri-infarct hippocampal were investigated using western blot assays. Besides, we also measured the levels of reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA). RESULTS: We found EA treatment reduced inflammation and oxidative stress, which is consistent with a decrease in P2X7R expression and improved learning and memory functions. In contrast, we found BzATP enhanced inflammation and oxidative stress. Moreover, our results showed EA treatment up-regulated Nrf2, down-regulated NLRP3, and promoted microglia M2 polarization. Finally, EA-mediated positive effects were reversed by intracerebroventricular injection of BzATP, which is consistent with an increase in P2X7R expression. CONCLUSION: EA ameliorates memory impairment in a rat model of ischemic stroke by reducing inflammation and ROS through the inhibition of P2X7R expression. In turn, this mechanism regulates Nrf2 and NLRP3 expression, suggesting EA is beneficial for ischemic stroke treatment using P2X7R as target.

[Prediction of Lymph Node Metastasis of Mixed Ground-glass Nodules 
Based on Clinical Imaging Information].

BACKGROUND: Previous studies have shown that lymph node metastasis only occurs in some mixed ground-glass nodules (mGGNs) which the pathological results were invasive adenocarcinoma (IAC). However, the presence of lymph node metastasis leads to the upgrading of tumor-node-metastasis (TNM) stage and worse prognosis of the patients, so it is important to perform the necessary evaluation before surgery to guide the operation method of lymph node. The aim of this study was to find suitable clinical and radiological indicators to distinguish whether mGGNs with pathology as IAC is accompanied by lymph node metastasis, and to construct a prediction model for lymph node metastasis. METHODS: From January 2014 to October 2019, the patients with resected IAC appearing as mGGNs in computed tomography (CT) scan were reviewed. All the lesions were divided into two groups (with lymph node metastasis or not) according to their lymph node status. Lasso regression model analysis by applying R software was used to evaluate the relationship between clinical and radiological parameters and lymph node metastasis of mGGNs. RESULTS: A total of 883 mGGNs patients were enroled in this study, among which, 12 (1.36%) showed lymph node metastasis. Lasso regression model analysis of clinical imaging information in mGGNs with lymph node metastasis showed that previous history of malignancy, mean density, mean density of solid components, burr sign and percentage of solid components were informative. Prediction model for lymph node metastasis in mGGNs was developed based on the results of Lasso regression model with area under curve=0.899. CONCLUSIONS: Clinical information combined with CT imaging information can predict lymph node metastasis in mGGNs.

Modulation of entorhinal cortex-hippocampus connectivity and recognition memory following electroacupuncture on 3×Tg-AD model: Evidence from multimodal MRI and electrophysiological recordings.

Memory loss and aberrant neuronal network activity are part of the earliest hallmarks of Alzheimer's disease (AD). Electroacupuncture (EA) has been recognized as a cognitive stimulation for its effects on memory disorder, but whether different brain regions or neural circuits contribute to memory recovery in AD remains unknown. Here, we found that memory deficit was ameliorated in 3×Tg-AD mice with EA-treatment, as shown by the increased number of exploring and time spent in the novel object. In addition, reduced locomotor activity was observed in 3×Tg-AD mice, but no significant alteration was seen in the EA-treated mice. Based on the functional magnetic resonance imaging, the regional spontaneous activity alterations of 3×Tg-AD were mainly concentrated in the accumbens nucleus, auditory cortex, caudate putamen, entorhinal cortex (EC), hippocampus, insular cortex, subiculum, temporal cortex, visual cortex, and so on. While EA-treatment prevented the chaos of brain activity in parts of the above regions, such as the auditory cortex, EC, hippocampus, subiculum, and temporal cortex. And then we used the whole-cell voltage-clamp recording to reveal the neurotransmission in the hippocampus, and found that EA-treatment reversed the synaptic spontaneous release. Since the hippocampus receives most of the projections of the EC, the hippocampus-EC circuit is one of the neural circuits related to memory impairment. We further applied diffusion tensor imaging (DTI) tracking and functional connectivity, and found that hypo-connected between the hippocampus and EC with EA-treatment. These data indicate that the hippocampus-EC connectivity is responsible for the recognition memory deficit in the AD mice with EA-treatment, and provide novel insight into potential therapies for memory loss in AD.

Exosomes and Atherogenesis.

Myocardial infarction and ischemic stroke are the leading causes of mortality worldwide. Atherosclerosis is their common pathological foundation. It is known that atherosclerosis is characterized by endothelial activation/injury, accumulation of inflammatory immune cells and lipid-rich foam cells, followed by the development of atherosclerotic plaque. Either from arterial vessel wall or blood circulation, endothelial cells, smooth muscle cells, macrophages, T-lymphocytes, B-lymphocytes, foam cells, and platelets have been considered to contribute to the pathogenesis of atherosclerosis. Exosomes, as natural nano-carriers and intercellular messengers, play a significant role in modulation of cell-to-cell communication. Under physiological or pathological conditions, exosomes can deliver their cargos including donor cell-specific proteins, lipids, and nucleic acids to target cells, which in turn affect the function of the target cells. In this review, we will describe the pathophysiological significance of various exosomes derived from different cell types associated with atherosclerosis, and the potential applications of exosome in clinical diagnosis and treatment.

[Retracted] Differential miRNAomics of the synovial membrane in knee osteoarthritis induced by bilateral anterior cruciate ligament transection in rats.

Following the publication of the above article, a number of errors were identified in the paper, and after having consulted with the editor of Molecular Medicine Reports, a corrigendum was published last year ("[Corrigendum] Differential miRNAomics of the synovial membrane in knee osteoarthritis induced by bilateral anterior cruciate ligament transection in rats." Zhou J, Zhao Y, Wu G, Lin B, Li Z and Liu X. Mol Med Rep 20: 5363, 2019). However, following publication of the above corrigendum, the paper was re­examined by the authors, and additional errors were identified; therefore, the authors are going to retract this paper from the publication. All the authors agree to this retraction, and apologize to the Editor of Molecular Medicine Reports and to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 18: 4051­4057, 2018; DOI: 10.3892/mmr.2018.9385].

Electroacupuncture ameliorates learning and memory deficits via hippocampal 5-HT1A receptors and the PKA signaling pathway in rats with ischemic stroke.

Hippocampal 5-HT1A receptors and the PKA signaling pathway have been implicated in learning and memory. This study aimed to investigate whether PKA signaling mediated by 5-HT1A receptors was involved in the electroacupuncture (EA)-mediated learning and memory in a rat model of middle cerebral artery occlusion-induced cognitive deficit (MICD). Compared to no treatment or non-acupoint EA treatment, EA at DU20 and DU24 acupoints improved the neurological deficit of scores, shortened escape latency and increased the frequency of crossing the platform in the Morris water maze test. T2-weighted imaging demonstrated that the MICD rat brain lesions were mainly located in the cortex and hippocampus, and injured volumes were reduced after EA. Furthermore, we found that these behavioral changes were concomitant with the deficit of the 5HT1A and PKA signaling pathways in the hippocampus, as the activation of the 5-HT1A receptor, the reduction of PKA kinase activity, and AMPA and NMDA receptor phosphorylation occurred in the injured hippocampus at Day 14 after MICD. Additionally, EA dramatically elevated the activation of PKA. Moreover, EA significantly increased intracellular calcium concentrations regulated by the activation of NMDA receptors. Therefore, PKA kinase and NMDA receptors mediated by 5-HT1A receptors in the hippocampus might contribute to improving learning and memory during the recovery process following ischemic stroke with an EA intervention.

Automated label-free detection of injured neuron with deep learning by two-photon microscopy.

Stroke is a significant cause of morbidity and long-term disability globally. Detection of injured neuron is a prerequisite for defining the degree of focal ischemic brain injury, which can be used to guide further therapy. Here, we demonstrate the capability of two-photon microscopy (TPM) to label-freely identify injured neurons on unstained thin section and fresh tissue of rat cerebral ischemia-reperfusion model, revealing definite diagnostic features compared with conventional staining images. Moreover, a deep learning model based on convolutional neural network is developed to automatically detect the location of injured neurons on TPM images. We then apply deep learning-assisted TPM to evaluate the ischemic regions based on tissue edema, two-photon excited fluorescence signal intensity, as well as neuronal injury, presenting a novel manner for identifying the infarct core, peri-infarct area, and remote area. These results propose an automated and label-free method that could provide supplementary information to augment the diagnostic accuracy, as well as hold the potential to be used as an intravital diagnostic tool for evaluating the effectiveness of drug interventions and predicting potential therapeutics.

Label-free multiphoton imaging of ß-amyloid plaques in Alzheimer's disease mouse models.

ß -Amyloid ( A ß ) plaque, representing the progressive accumulation of the protein that mainly consists of A ß , is one of the prominent pathological hallmarks of Alzheimer's disease (AD). Label-free imaging of A ß plaques holds the potential to be a histological examination tool for diagnosing AD. We applied label-free multiphoton microscopy to identify extracellular A ß plaque as well as intracellular A ß accumulation for the first time from AD mouse models. We showed that a two-photon-excited fluorescence signal is a sensitive optical marker for revealing the spatial-temporal progression and the surrounding morphological changes of A ß deposition, which demonstrated that both extracellular and intracellular A ß accumulations play an important role in the progression of AD. Moreover, combined with a custom-developed image-processing program, we established a rapid method to visualize different degrees of A ß deposition by color coding. These results provide an approach for investigating pathophysiology of AD that can complement traditional biomedical procedures.

[Corrigendum] Differential miRNAomics of the synovial membrane in knee osteoarthritis induced by bilateral anterior cruciate ligament transection in rats.

Following the publication of the above article, an interested reader drew to our attention that, in Fig. 4A, in which the authors had presented a western blot image depicting protein expression of IL­18, IL­1ß, NLRP3 and ß­actin from synovial tissue lysates from osteoarthritic rats, upon close examination of the figure a striking similarity was noted between the bands shown for the IL­18­ and NLRP3­stained Sham group experiments, although the bands appeared in an inverted position relative to each other. Following an enquiry with the authors, they realized that they had included incorrect data for this figure; an amended version of Fig. 4, showing the correct data for NLRP3, is shown opposite. Secondly, the authors have realized that, at various points throughout the paper, two miRNAs were written incorrectly: Specifically, references to an 'miR­352' should have appeared as miR­532, and 'miR­233' should have been written as miR­223. This error affected the presentation of Fig. 2; therefore, a revised version of this figure, with the miRNAs correctly labelled as miR­532 and miR­223 respectively, is also shown opposite. Furthermore, mi­233 should have been written as miR­223 at the following places in the text: p. 4051, right­hand column (RHC), line 10 ("Furthermore, the miR­223­regulated...); p. 4054, Results section, left­hand column (LHC), third subheading ("miR­223 negatively regulates the expression of NLRP3."); and in the concluding paragraph of the Discussion on p. 4056, LHC, miR­233 should have been written as miR­223 in all five instances where this occurred (lines 4, 7, 8, 9, and 10 of this paragraph). Finally, the second sentence featured in the subsection of the Results section entitled "Expression validation of miRs by RT­qPCR" on p. 4054 contained additional errors. This sentence should have appeared as follows (changed text is highlighted in bold): "The expression of miR­223, ­100, ­345, ­130, ­382, ­9a and 183 were upregulated, whereas miR­377, ­532, ­200b were downregulated with a fold change of ≥1.5, similar to the microarray data (Fig. 2). All the authors agree to the contents of this Corrigendum, and apologize to the Editor of Molecular Medicine Reports and to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 18: 4051­4057, 2018; DOI: 10.3892/mmr.2018.9385].

Differential miRNAomics of the synovial membrane in knee osteoarthritis induced by bilateral anterior cruciate ligament transection in rats.

The differential microRNA (miRNA) omics of the synovial membrane were investigated using a rat model of knee osteoarthritis (KOA) induced by bilateral anterior cruciate ligament transection, which produced pathological biomarkers in KOA. Sprague­Dawley rats were randomly divided into two groups; Sham­operated and KOA­operated group. The KOA rats were subjected to bilateral anterior cruciate ligament transection. After 6 weeks, total RNA was extracted from the knee joint synovial membrane of the rats and a microRNA (miR) microarray was performed to identify differentially expressed miRs. Subsequently, the obtained differentially expressed miRs were validated by reverse transcription­quantitative polymerase chain reaction (RT­qPCR) analysis. A total of 24 miRs were identified with alterations ≥1.5­fold in the synovial membrane in the KOA­operated group compared with the sham­operated group, of which 4 miRs (miR­532­5p, ­200b­5p, ­377­3p and ­759­5p) were decreased and 20 miRs (miR­382­3p, ­223­3p, ­100­5p, ­30d­5p, ­183­5p, ­130, ­92b­3p, ­125b­3p, ­151­3p, ­155­3p, 27a­3p, ­146b­3p, ­885­5p, ­352, ­184, ­345­5p, ­30a­5p and ­9a­5p) were increased. Subsequently, RT­qPCR was used to validate the expressions of miR­223, ­100, ­345, ­130, ­382, ­377, ­352, ­200b, ­9a and ­183, which were upregulated by a fold change of ≥1.5 in synovial membranes of KOA rats compared with shams. Furthermore, in vitro miR­223 mimic could suppress the luciferase activity of NACHT, LRR and PYD domains­containing protein 3 (NLRP3) 3' untranslated region by detecting of dual luciferase reporter vector. Additionally, the expression of NLRP3, interleukin (IL)­1ß and IL­18 significantly increased in the synovial membrane of KOA rats. A total of 24 different miRs were determined by comparing the miRNAomics in the synovial membrane of the KOA model rats. Furthermore, the miR­233­regulated NLRP3 inflammasome was implicated in synovial membrane injury, which may be an important mechanism of KOA pathogenesis.

Spatial and temporal identification of cerebral infarctions based on multiphoton microscopic imaging.

Ischemic stroke is a leading cause of death and permanent disability worldwide. Middle cerebral artery occlusion (MCAO) of variable duration times could be anticipated to result in varying degrees of injury that evolve spatially over time. Therefore, investigations following strokes require information concerning the spatiotemporal dimensions of the ischemic core as well as of perilesional areas. In the present study, multiphoton microscopy (MPM) based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) was applied to image such pathophysiological events. The ischemic time-points for evaluation were set at 6, 24, 48, and 72 hours after MCAO. Our results demonstrated that MPM has the ability to not only identify the normal and ischemic brain regions, but also reveal morphological changes of the cortex and striatum at various times following permanent MCAO. These findings corresponded well with the hematoxylin and eosin (H&E) stained tissue images. With the technologic progression of miniaturized imaging devices, MPM can be developed into an effective diagnostic and monitoring tool for ischemic stroke.

Gender-specific association between Apelin/APJ gene polymorphisms and hypertension risk in Southeast China.

To explore the role of genetic factors in the pathogenesis of hypertension, our study investigated the gender-specific association between four polymorphisms in the Apelin/APJ gene and hypertension risk in southeastern Chinese population. All participants including 645 hypertensive patients and 362 normotensive controls were genotyped for 4 gene polymorphisms associated with hypertension susceptibility including Apelin (rs909656, rs5975126) and APJ (rs10501367, rs11544374). According to genotype analysis, for male subjects, the frequencies of genotypes (P = 0.046 and 0.046, respectively) of rs10501367 and rs11544374 revealed significant differences between the hypertension and control groups. Moreover, for female subjects, there was significant difference on the genotype distribution of rs11544374 between two groups (P = 0.046). The association of rs10501367 with hypertension was significant for males under additive models and recessive models, even after adjusting for age, BMI, fasting glucose and waistline. Besides, significant association was observed for rs11544374 in females under additive models. As for haplotype analysis, haplotype T-A (in order of rs10501367 and rs11544374) in APJ gene was marginally overrepresented in controls (17.9%) compared to patients with hypertension (11.6%) in males (P = 0.003). The mutation of polymorphism rs10501367 in APJ gene decreased risk of hypertension in Chinese males.

Roles of electro-acupuncture in glucose metabolism as assessed by 18F-FDG/PET imaging and AMPKα phosphorylation in rats with ischemic stroke.

Targeted energy metabolism balance contributes to neural survival during ischemic stroke. Herein, we tested the hypothesis that electro­acupuncture (EA) can enhance cerebral glucose metabolism assessed by 18F­fluorodeoxyglucose/positron emission tomography (18F­FDG/PET) imaging to prevent propagation of tissue damage and improve neurological outcome in rats subjected to ischemia and reperfusion injury. Rats underwent middle cerebral artery occlusion (MCAO) and received EA treatment at the LI11 and ST36 acupoints or non­acupoint treatment once a day for 7 days. After EA treatment, a significant reduction in the infarct volume was determined by T2­weighted imaging, accompanied by the functional recovery in CatWalk and Rota-rod performance. Moreover, EA promoted higher glucose metabolism in the caudate putamen (CPu), motor cortex (MCTX), somatosensory cortex (SCTX) regions as assessed by animal 18F­FDG/PET imaging, suggesting that three­brain regional neural activity was enhanced by EA. In addition, the AMP­activated protein kinase α (AMPKα) in the CPu, MCTX and SCTX regions was phosphorylated at threonine 172 (Thr172) after ischemic injury; however, phosphorylation of AMPK was further increased by EA. These results indicate that EA could promote AMPKα phosphorylation of the CPu, MCTX and SCTX regions to enhance neural activity and motor functional recovery after ischemic stroke.

Activation of brain glucose metabolism ameliorating cognitive impairment in APP/PS1 transgenic mice by electroacupuncture.

An essential feature of Alzheimer's disease (AD) is implicated in brain energy metabolic impairment that is considered underlying pathogenesis of cognitive impairment. Therefore, therapeutic interventions to allay cognitive deficits that target energy metabolism may be an efficacy strategy in AD. In this study, we found that electroacupuncture (EA) at the DU20 acupoint obviously increased glucose metabolism in specific brain regions such as cortex, hippocampus, cingulate gyrus, basal forebrain septum, brain stem, and cerebellum in APP/PS1 transgenic mice by animal 18F-Fluoro-2-deoxy-D-Glucose (18F-FDG)/positron emission tomography (PET) imaging, accompanied by cognitive improvements in the spatial reference learning and memory and memory flexibility and novel object recognition performances. Further evidence shown energy metabolism occurred in neurons or non-neuronal cells of the cortex and hippocampus in terms of the co-location of GLUT3/NeuN and GLUT1/GFAP. Simultaneously, metabolic homeostatic factors were critical for glucose metabolism, including phosphorylated adenosine monophosphate-activated protein kinase (AMPK) and AKT serine/threonine kinase. Furthermore, EA-induced phosphorylated AMPK and AKT inhibited the phosphorylation level of the mammalian target of rapamycin (mTOR) to decrease the accumulation of amyloid-beta (Aß) in the cortex and hippocampus. These findings are concluded that EA is a potential therapeutic target for delaying memory decline and Aß deposition of AD. The AMPK and AKT are implicated in the EA-induced cortical and hippocampal energy metabolism, which served as a contributor to improving cognitive function and Aß deposition in a transgenic mouse model of AD.

Resting-state Functional Magnetic Resonance Imaging Analysis of Brain Functional Activity in Rats with Ischemic Stroke Treated by Electro-acupuncture.

OBJECTIVE: To evaluate whether electro-acupuncture (EA) treatment at acupoints of Zusanli (ST 36) and Quchi (LI 11) could reduce motor impairments and enhance brain functional recovery in rats with ischemic stroke. MATERIALS AND METHODS: A rat model of middle cerebral artery occlusion (MCAO) was established. EA at ST 36 and LI 11was started at 24 hours (MCAO + EA group) after ischemic stroke. The nontreatment (MCAO) and sham-operated control (SC) groups were included as controls. The neurologic deficits of all groups were assessed by Zea Longa scores and the modified neurologic severity scores on 24 hours and 8 days after MCAO. To further investigate the effect of EA on infract volume and brain function, magnetic resonance imaging was used to estimate the brain lesion and brain neural activities of each group at 8 days after ischemic stroke. RESULTS: Within 1 week after EA treatment, the neurologic deficits were significantly alleviated, and the cerebral infarctions were improved, including visual cortex, motor cortex, striatum, dorsal thalamus, and hippocampus. Furthermore, whole brain neural activities of auditory cortex, lateral nucleus group of dorsal thalamus, hippocampus, motor cortex, orbital cortex, sensory cortex, and striatum were decreased in MCAO group, whereas that of brain neural activities were increased after EA treatment, suggesting these brain regions are in accordance with the brain structure analysis. CONCLUSION: EA at ST 36 and LI 11 could enhance the neural activity of motor function-related brain regions, including motor cortex, dorsal thalamus, and striatum in rats, which is a potential treatment for ischemia stroke.

Reduction of polyethylenimine-coated iron oxide nanoparticles induced autophagy and cytotoxicity by lactosylation.

Superparamagnetic iron oxide (SPIO) nanoparticles are excellent magnetic resonance contrast agents and surface engineering can expand their applications. When covered with amphiphilic alkyl-polyethyleneimine (PEI), the modified SPIO nanoparticles can be used as MRI visible gene/drug delivery carriers and cell tracking probes. However, the positively charged amines of PEI can also cause cytotoxicity and restricts their further applications. In this study, we used lactose to modify amphiphilic low molecular weight polyethylenimine (C12-PEI2K) at different lactosylation degree. It was found that the N-alkyl-PEI-lactobionic acid wrapped SPIO nanocomposites show better cell viability without compromising their labelling efficacy as well as MR imaging capability in RAW 264.7 cells, comparing to the unsubstituted ones. Besides, we found the PEI induced cell autophagy can be reduced via lactose modification, indicating the increased cell viability might rely on down-regulating autophagy. Thus, our findings provide a new approach to overcome the toxicity of PEI wrapped SPIO nanocomposites by lactose modification.

Correct folding of an α-helix and a ß-hairpin using a polarized 2D torsional potential.

A new modification to the AMBER force field that incorporates the coupled two-dimensional main chain torsion energy has been evaluated for the balanced representation of secondary structures. In this modified AMBER force field (AMBER03(2D)), the main chain torsion energy is represented by 2-dimensional Fourier expansions with parameters fitted to the potential energy surface generated by high-level quantum mechanical calculations of small peptides in solution. Molecular dynamics simulations are performed to study the folding of two model peptides adopting either α-helix or ß-hairpin structures. Both peptides are successfully folded into their native structures using an AMBER03(2D) force field with the implementation of a polarization scheme (AMBER03(2D)p). For comparison, simulations using a standard AMBER03 force field with and without polarization, as well as AMBER03(2D) without polarization, fail to fold both peptides successfully. The correction to secondary structure propensity in the AMBER03 force field and the polarization effect are critical to folding Trpzip2; without these factors, a helical structure is obtained. This study strongly suggests that this new force field is capable of providing a more balanced preference for helical and extended conformations. The electrostatic polarization effect is shown to be indispensable to the growth of secondary structures.

Multivalent manganese complex decorated amphiphilic dextran micelles as sensitive MRI probes.

T1 contrast agents based on Mn(II) were conjugated on amphiphilic dextran micelles via click chemistry. The obtained paramagnetic nanomicelle contrast agent has a higher T1 relaxivity (13.3 Mn mmol-1 s-1) and better sensitivity than those of free Mn(II) complexes. Studies carried out in vivo suggest that this contrast agent has a better and long-acting vascular enhancement effect at a lower manganese dosage (0.1 Mn mmol kg-1 BW).

Superparamagnetic iron oxide nanoparticles for MR imaging and therapy: design considerations and clinical applications.

Superparamagnetic iron oxide nanoparticles (SPION) based magnetic resonance imaging (MRI) is a powerful non-invasive tool in biomedical imaging, clinical diagnosis and therapy. In this review, the physicochemical properties of SPION and their in vivo performance were thoroughly discussed, also covering how surface engineering will prolong the circulation time and overcome biological barriers at organ, tissue, and cellular levels. Clinical applications and future potentials of SPION based MR imaging in cancer, cardiovascular, and inflammation diseases were addressed. Targeting mechanisms of SPION in both research and clinical use were summarized for better understanding of their performance. Addition of new targeting mechanisms to clinically approved SPION will bring opportunities to discover early diseases at cellular and molecular levels, and to track MRI-visible drug carriers. Clinical trial information related to SPION on Clinicaltrials.gov was summarized mainly based on their disease categories, therapeutic applications and clinical trial stages. It gives us a brief outlook of their clinical applications in the near future.

Delivery of siRNA by MRI-visible nanovehicles to overcome drug resistance in MCF-7/ADR human breast cancer cells.

Multidrug resistance (MDR) is one of the major barriers in cancer chemotherapy. P-glycoprotein (P-gp), a cell membrane protein in MDR, also a member of ATP-Binding cassette (ABC) transporter, can increase the efflux of various hydrophobic anticancer drugs. In this study, polycation/iron oxide nanocomposites, were chosen as small interfering RNA (siRNA) carriers to overcome MDR through silencing of the target messenger RNA and subsequently reducing the expression of P-gp. Amphiphilic low molecular weight polyethylenimine was designed with different alkylation groups and alkylation degree to form various nanocarriers with clustered iron oxide nanoparticles inside and carrying siRNA through electrostatic interaction. A few optimized formulations can form stable nanocomplexes with siRNA and protect them from degradation during delivery, and lead to effective silencing effect that comparable to a commercial golden standard transfection agent, Lipofectamine 2000. Human breast cancer MCF-7/ADR cells can be vulnerable to doxorubicin treatment after the strong downregulation of P-gp through siRNA tranfection. Once transfected with these nanocomplexes, the cells displayed significant contrast enhancement against non-transfected cells under a 3T clinical MRI scanner. These nanocomposites also demonstrated their downregulation efficacy of P-gp in a MCF-7/ADR orthotopic tumor model in mice.