Chemical Factory-Guaranteed Enhanced Chemodynamic Therapy for Orthotopic Liver Cancer.

In the field of nanomedicine, there is a tendency of matching designed nanomaterials with a suitable type of orthotopic cancer model, not just a casual subcutaneous one. Under this condition, knowing the specific features of the chosen cancer model is the priority, then introducing a proper therapy strategy using designed nanomaterials. Here, the Fenton chemistry is combined with zinc peroxide nanoparticles in the treatment of orthotopic liver cancer which has a "chemical factory" including that liver is the main place for iron storage, metabolism, and also the main metabolic sites for the majority of ingested substances, guaranteeing customized and enhanced chemodynamic therapy and normal liver cells protection as well. The good results in vitro and in vivo can set an inspiring example for exploring and utilizing suitable nanomaterials in corresponding cancer models, ensuring well-fitness of nanomaterials for disease and satisfactory therapeutic effect.

Intensity-Varied Closed-Loop Noise Stimulation for Oscillation Suppression in the Parkinsonian State.

This work explores the effectiveness of the intensity-varied closed-loop noise stimulation on the oscillation suppression in the Parkinsonian state. Deep brain stimulation (DBS) is the standard therapy for Parkinson's disease (PD), but its effects need to be improved. The noise stimulation has compelling results in alleviating the PD state. However, in the open-loop control scheme, the noise stimulation parameters cannot be self-adjusted to adapt to the amplitude of the synchronized neuronal activities in real time. Thus, based on the delayed-feedback control algorithm, an intensity-varied closed-loop noise stimulation strategy is proposed. Based on a computational model of the basal ganglia (BG) that can present the intrinsic properties of the BG neurons and their interactions with the thalamic neurons, the proposed stimulation strategy is tested. Simulation results show that the noise stimulation suppresses the pathological beta (12-35 Hz) oscillations without any new rhythms in other bands compared with traditional high-frequency DBS. The intensity-varied closed-loop noise stimulation has a more profound role in removing the pathological beta oscillations and improving the thalamic reliability than open-loop noise stimulation, especially for different PD states. And the closed-loop noise stimulation enlarges the parameter space of the delayed-feedback control algorithm due to the randomness of noise signals. We also provide a theoretical analysis of the effective parameter domain of the delayed-feedback control algorithm by simplifying the BG model to an oscillator model. This exploration may guide a new approach to treating PD by optimizing the noise-induced improvement of the BG dysfunction.

Thermo-responsive polymer encapsulated gold nanorods for single continuous wave laser-induced photodynamic/photothermal tumour therapy.

Owing to strong and tunable surface plasmon resonance (SPR) effect and good biocompatibility, gold nanoparticles have been suggested to be a versatile platform for a broad range of biomedical applications. In this study, a new nanoplatform of thermo-responsive polymer encapsulated gold nanorods incorporating indocyanine green (ICG) was designed to couple the photothermal properties of gold nanorods (AuNRs) and the photodynamic properties of ICG to enhance the photodynamic/photothermal combination therapy (PDT/PTT). In addition to the significantly increased payload and enhancing photostability of ICG, the polymer shell in the nanoplatform also has thermo-responsive characteristics that can control the release of drugs at tumour sites upon the laser irradiation. On the basis of these improvements, the nanoplatform strongly increased drug aggregation at the tumour site and improved the photothermal/photodynamic therapeutic efficacy. These results suggest that this nanoplatform would be a great potential system for tumour imaging and antitumour therapy.

Impact of Electroacupuncture Stimulation on Postoperative Constipation for Patients Undergoing Brain Tumor Surgery.

BACKGROUND: Constipation is frequently encountered in patients undergoing brain tumor resection. Constipation has negative effects on daily living, well-being, and individuals' quality of life. We examined the impact of acupuncture and electroacupuncture (EA) stimulation on postoperative constipation for patients undergoing brain tumor resection. METHODS: Patients undergoing brain tumor resection (n = 150) were randomly divided into a nontreatment group, an acupuncture group, and an EA group. Rome III Diagnostic Criteria, Cleveland Clinic Constipation Score, symptom assessment, Patient Assessment of Constipation Quality of Life questionnaire, Self-Rating Anxiety Scale, and a Self-Rating Depression Scale were collected. RESULTS: Acupuncture and EA were effective in relieving postoperative constipation. Electroacupuncture decreased constipation and improved quality of life scores. CONCLUSION: Acupuncture and EA are novel adjuvant therapies to treat constipation.

MAVS O-GlcNAcylation Is Essential for Host Antiviral Immunity against Lethal RNA Viruses.

It is known that lethal viruses profoundly manipulate host metabolism, but how the metabolism alternation affects the immediate host antiviral immunity remains elusive. Here, we report that the O-GlcNAcylation of mitochondrial antiviral-signaling protein (MAVS), a key mediator of interferon signaling, is a critical regulation to activate the host innate immunity against RNA viruses. We show that O-GlcNAcylation depletion in myeloid cells renders the host more susceptible to virus infection both in vitro and in vivo. Mechanistically, we demonstrate that MAVS O-GlcNAcylation is required for virus-induced MAVS K63-linked ubiquitination, thereby facilitating IRF3 activation and IFNß production. We further demonstrate that D-glucosamine, a commonly used dietary supplement, effectively protects mice against a range of lethal RNA viruses, including human influenza virus. Our study highlights a critical role of O-GlcNAcylation in regulating host antiviral immunity and validates D-glucosamine as a potential therapeutic for virus infections.

Nonlinear predictive control for adaptive adjustments of deep brain stimulation parameters in basal ganglia-thalamic network.

The efficacy of deep brain stimulation (DBS) for Parkinson's disease (PD) depends in part on the post-operative programming of stimulation parameters. Closed-loop stimulation is one method to realize the frequent adjustment of stimulation parameters. This paper introduced the nonlinear predictive control method into the online adjustment of DBS amplitude and frequency. This approach was tested in a computational model of basal ganglia-thalamic network. The autoregressive Volterra model was used to identify the process model based on physiological data. Simulation results illustrated the efficiency of closed-loop stimulation methods (amplitude adjustment and frequency adjustment) in improving the relay reliability of thalamic neurons compared with the PD state. Besides, compared with the 130Hz constant DBS the closed-loop stimulation methods can significantly reduce the energy consumption. Through the analysis of inter-spike-intervals (ISIs) distribution of basal ganglia neurons, the evoked network activity by the closed-loop frequency adjustment stimulation was closer to the normal state.

Modulation of Parkinsonian State With Uncertain Disturbance Based on Sliding Mode Control.

Parkinson's disease (PD) is a degenerative disorder of central nervous system that endangers the olds' health seriously. The motor symptoms of PD can be attributed to the distorted relay reliability of thalamus to cortical sensorimotor input that results from the increase of inhibitory input from internal segment of the globus pallidum (GPi). Based on this, we construct the GPi-thalamocortical computational model to generate the normal and pathological firing patterns by varying GPi spike train input. A kind of closed-loop deep brain stimulation (DBS) strategy is proposed here. Our control objective is to make the controlled membrane potential of the thalamic neuron return to the normal firing pattern. The control input that directly acts on the thalamus is the DBS waveform, which is adjusted in real time according to the feedback signal. Aimed at a certain system without the change of object parameters or stochastic disturbance, the input-output feedback linearization method is able to eliminate the error between the system output and the desired output. When uncertain elements taken into consideration in the system, the simulation results indicate that sliding mode control scheme provides better effectiveness and higher robustness.

Efficient implementation of a real-time estimation system for thalamocortical hidden Parkinsonian properties.

Real-time estimation of dynamical characteristics of thalamocortical cells, such as dynamics of ion channels and membrane potentials, is useful and essential in the study of the thalamus in Parkinsonian state. However, measuring the dynamical properties of ion channels is extremely challenging experimentally and even impossible in clinical applications. This paper presents and evaluates a real-time estimation system for thalamocortical hidden properties. For the sake of efficiency, we use a field programmable gate array for strictly hardware-based computation and algorithm optimization. In the proposed system, the FPGA-based unscented Kalman filter is implemented into a conductance-based TC neuron model. Since the complexity of TC neuron model restrains its hardware implementation in parallel structure, a cost efficient model is proposed to reduce the resource cost while retaining the relevant ionic dynamics. Experimental results demonstrate the real-time capability to estimate thalamocortical hidden properties with high precision under both normal and Parkinsonian states. While it is applied to estimate the hidden properties of the thalamus and explore the mechanism of the Parkinsonian state, the proposed method can be useful in the dynamic clamp technique of the electrophysiological experiments, the neural control engineering and brain-machine interface studies.

Closed-Loop Control of Tremor-Predominant Parkinsonian State Based on Parameter Estimation.

A significant feature of Parkinson's disease (PD) is the inability of the thalamus to respond faithfully to sensorimotor information from the cerebral cortex. This may be the result of abnormal oscillations in the basal ganglia (BG). Deep brain stimulation (DBS) is regarded as an effective method to modulate these pathological brain rhythmic activities. However, the selection of DBS parameters is challenging because the mechanism is not well understood. This work proposes the design of a closed-loop control strategy to automatically adjust the parameters of a DBS waveform based on a computational model. By estimating the synaptic input from BG to the thalamic neuron model as feedback variable, we designed and compared various control algorithms to counteract the effects of pathological oscillatory inputs. We then obtained optimal DBS parameters to modulate the tremor-predominant Parkinsonian state. We showed that even a simple proportional controller provides higher fidelity of thalamic relay of sensorimotor information and lower energy expenditure, as compared with classical open-loop DBS. Integral action further enhances DBS performance. Additionally, a positive bias voltage further improves the relay ability of the thalamus with decreased stimulation energy expenditure. These findings were conducive to the development of a more effective DBS to further improve the treatment of the PD.

MiR-381 inhibits epithelial ovarian cancer malignancy via YY1 suppression.

Epithelial ovarian cancer (EOC) is a common type of gynecologic cancer, which accounts for the majority of deaths among all gynecologic malignant tumors in developed countries. A series of recent studies suggested that miR-381 might play important roles in the development of various cancer types. However, the biological function of miR-381 in EOC remains to be investigated. We examined the levels of miR-381 expression in EOC tissues and cell lines. We identified miR-381 target genes by bioinformatic prediction. We also characterized the phenotype regarding cell proliferation, cell migration, and cell invasion in EOC cells lines with altered expression levels of both miR-381 and its target gene, YY1. The expression levels of miR-381 were downregulated in EOC tissues and cell lines. Overexpression of miR-381 significantly inhibited EOC cell proliferation, migration, and invasion. Restoration of YY1 expression partially reversed the phenotype induced by miR-381 overexpression. Knockdown of miR-381 target gene, YY1, mimicked the phenotype induced by miR-381 overexpression. MiR-381 regulated EOC cell through miR-381/YY1/p53 and miR-381/YY1/Wnt signaling axis. We concluded that miR-381 inhibited EOC cell proliferation, migration, and invasion, at least in part, via suppressing YY1 expression.

Therapeutic angiogenesis in ischemic muscles after local injection of fragmented fibers with loaded traditional Chinese medicine.

Therapeutic angiogenesis remains the most effective method to re-establish a proper blood flow in ischemic tissues. There is a great clinical need to identify an injectable format to achieve a well accumulation following local administration and a sustained delivery of biological factors at the ischemic sites. In the current study, fragmented nanofibers with loaded traditional Chinese medicines, astragaloside IV (AT), the main active ingredient of astragalus, and ferulic acid (FA), the main ingredient of angelica, were proposed to promote the microvessel formation after intramuscular injection into ischemic hindlimbs. Fragmented fibers with average lengths of 5 (FF-5), 20 (FF-20) and 80 µm (FF-80) were constructed by the cryocutting of aligned electrospun fibers. Their dispersion in sodium alginate solution (0.2%) indicated good injectability. After injection into the quadriceps muscles of the hindlimbs, FF-20 and FF-80 fiber fragments showed higher tissue retentions than FF-5, and around 90% of the injected doses were determined after 7 days. On a hindlimb ischemia model established by ligating the femoral arteries, intramuscular injection of the mixtures of FA-loaded and AT-loaded FF-20 fiber fragments substantially reduced the muscle degeneration with minimal fibrosis formation, significantly enhanced the neovessel formation and hindlimb perfusion in the ischemic tissues, and efficiently promoted the limb salvage with few limb losses. Along with the easy manipulation and lower invasiveness for in vivo administration, fragmented fibers should become potential drug carriers for disease treatment, wound recovery and tissue repair after local injection.

Adaptive control of Parkinson's state based on a nonlinear computational model with unknown parameters.

The objective here is to explore the use of adaptive input-output feedback linearization method to achieve an improved deep brain stimulation (DBS) algorithm for closed-loop control of Parkinson's state. The control law is based on a highly nonlinear computational model of Parkinson's disease (PD) with unknown parameters. The restoration of thalamic relay reliability is formulated as the desired outcome of the adaptive control methodology, and the DBS waveform is the control input. The control input is adjusted in real time according to estimates of unknown parameters as well as the feedback signal. Simulation results show that the proposed adaptive control algorithm succeeds in restoring the relay reliability of the thalamus, and at the same time achieves accurate estimation of unknown parameters. Our findings point to the potential value of adaptive control approach that could be used to regulate DBS waveform in more effective treatment of PD.

Effect of electroacupuncture stimulation at Zusanli acupoint (ST36) on gastric motility: possible through PKC and MAPK signal transduction pathways.

BACKGROUND: Electroacupuncture (EA) stimulation has been shown to have a great therapeutic potential for treating gastrointestinal motility disorders. However, no evidence has clarified the mechanisms contributing to the effects of EA stimulation at the Zusanli acupoint (ST.36). This study was designed to investigate the regulative effect of EA stimulation at the ST.36 on gastric motility and to explore its possible mechanisms. METHODS: Thirty Sprague-Dawley rats were randomly divided into three groups: the ST.36 group, the non-acupoint group, and the control group. EA stimulation was set at 2 Hz, continuous mode, and 1 V for 30 min. The frequency and average peak amplitude of gastric motility were measured by electrogastrography. The protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) signaling pathways were assessed using real-time polymerase chain reactions. Caldesmon (CaD) and calponin (CaP) protein expression in the gastric antrum were detected on Western blots. A Computed Video Processing System was used to evaluate morphological changes in smooth muscle cells (SMCs) from the gastric antrum. RESULTS: EA stimulation at ST.36 had a dual effect on the frequency and average peak amplitude. Additionally, EA stimulation at ST.36 regulated the expression of some genes in the PKC and MAPK signaling pathways, and it regulated the expression of the CaD and CaP proteins. EA serum induced SMC contractility. Promotion of gastric motility may correlate with up-regulation of MAPK6 (ERK3), MAPK13, and Prostaglandin-endoperoxide synthase 2 (PTGS2) gene expression, and the down-regulation of the collagen, type I, alpha 1 (COL1A1) gene and CaD and CaP protein expression. Inhibition of gastric motility may correlate with down-regulation of the Interleukin-1 receptor type 2 (IL1R2) and Matrix metalloproteinase-9 (MMP9) genes, and up-regulation of CaD and CaP protein expression. CONCLUSIONS: EA stimulation at ST.36 regulated gastric motility, and the effects were both promoting and inhibiting in rats. The possible mechanisms may correlate with the PKC and MAPK signal transduction pathways.

Short time effect of Delta oscillation under microcurrent transcutaneous electrical nerve stimulation at ST36.

This paper was to study the short time effect of Delta brain oscillation under microcurrent transcutaneous electrical nerve stimulation (MTENS) at ST36 (Zusanli). The 64-channal electroencephalograph (EEG) signals from 12 healthy volunteers were recorded including baseline stage, during stimulation and after stimulation. Autoregressive (AR) Burg method was used to estimate the power spectrum. Then power variation rate (PVR) was calculated to quantify the effects compared with the baseline in Delta band. The results showed that MTENS at ST36 on right side led to increased Delta band power in left frontal.

Closed-loop control of the thalamocortical relay neuron's Parkinsonian state based on slow variable.

A novel closed-loop control strategy is proposed to control Parkinsonian state based on a computational model. By modeling thalamocortical relay neurons under external electric field, a slow variable feedback control is applied to restore its relay functionality. Qualitative and quantitative analysis demonstrates the performance of feedback controller based on slow variable is more efficient compared with traditional feedback control based on fast variable. These findings point to the potential value of model-based design of feedback controllers for Parkinson's disease.

Multi-scale order recurrence quantification analysis of EEG signals evoked by manual acupuncture in healthy subjects.

To explore the effects of manual acupuncture (MA) on brain activities, we design an experiment that acupuncture at acupoint ST36 of right leg with four different frequencies to obtain electroencephalograph (EEG) signals. Many studies have demonstrated that the complexity of EEG can reflect the states of brain function, so we propose to adopt order recurrence quantification analysis combined with discrete wavelet transform, to analyze the dynamical characteristics of different EEG rhythms under acupuncture, further to explore the effects of MA on the complexity of brain activities from multi-scale point of view. By analyzing the complexity of five EEG rhythms, it is found that the complexity of delta rhythm during acupuncture is lower than before acupuncture, and for alpha rhythm that is higher, but for beta, theta and gamma rhythms there are no obvious changes. All of those effects are especially obvious during acupuncture with frequency of 200 times/min. Furthermore, the determinism extracted from delta, alpha and gamma rhythms can be regarded as a characteristic parameter to distinguish the state acupuncture at 200 times/min and the state before acupuncture. These results can provide a theoretical support for selecting appropriate acupuncture frequency for patients in clinical, and the proposed methods have the potential of exploring the effects of acupuncture on brain activities.

Upregulated IL-21 and IL-21 receptor expression is involved in experimental autoimmune uveitis (EAU).

PURPOSE: Interleukin (IL)-21 has recently been shown to play a vital role in the development of many autoimmune diseases. Our study is designed to investigate the alteration and possible function of IL-21 in the development of an experimental autoimmune uveitis (EAU) model. METHODS: EAU was induced in B10.RIII mice by subcutaneous injection of interphotoreceptor retinoid-binding protein (IRBP) 161-180 emulsified with complete Freund's adjuvant (CFA) and evaluated by clinical and histopathologic observation. IL-21 and IL-21R mRNA expressions in cells of draining lymph node (DLN) and spleen in EAU and control mice were determined by reverse transcription-PCR. The frequencies of interleukin-21 receptor positive cells were also examined using flow cytometry. IL-17 levels in the supernatant of the cell culture upon IL-21 stimulation were assayed by enzyme-linked immunosorbent assay. RESULTS: Results showed that EAU was successfully induced by IRBP161-180. Expression of IL-21 mRNA was significantly increased in cells of DLN and spleen in EAU compared with recovery phase mice and normal controls. IL-21R was also found upregulated in DLN and spleen cells of EAU mice by reverse transcription-PCR and flow cytometry. Cells in EAU cultured with IL-21 combined with transforming growth factor-beta induced increased production of IL-17. CONCLUSION: The findings revealed that increased IL-21 and IL-21R expression may be involved in the development of EAU, possibly by promoting IL-17 secretion.