Targeted Neurostimulation in Mouse Brains with Non-invasive Ultrasound
2020; 32 (7): 108033
Biogenic nanobubbles for effective oxygen delivery and enhanced photodynamic therapy of cancer.
Recently developed brain stimulation techniques have significantly advanced our ability to manipulate the brain's function. However, stimulating specific neurons in a desired region without significant surgical invasion remains a challenge. Here, we demonstrate a neuron-specific and region-targeted neural excitation strategy using non-invasive ultrasound through activation of heterologously expressed mechanosensitive ion channels (MscL-G22S). Low-intensity ultrasound is significantly better at inducing Ca2+ influx and neuron activation in vitro and at evoking electromyogram (EMG) responses in vivo in targeted cells expressing MscL-G22S. Neurons in the cerebral cortex or dorsomedial striatum of mice are made to express MscL-G22S and stimulated ultrasonically. We find significant upregulation of c-Fos in neuron nuclei only in the regions expressing MscL-G22S compared with the non-MscL controls, as well as in various other regions in the same brain. Thus, we detail an effective approach for activating specific regions and cell types in intact mouse brains by sensitizing them to ultrasound using a mechanosensitive ion channel.
View details for DOI 10.1016/j.celrep.2020.108033
View details for Web of Science ID 000561274200006
View details for PubMedID 32814040
The Mechanosensitive Ion Channel Piezo1 Significantly Mediates In Vitro Ultrasonic Stimulation of Neurons
2019; 21: 448-+
Tumor hypoxia is believed to be a factor limiting successful outcomes of oxygen-consuming cancer therapy, thereby reducing patient survival. A key strategy to overcome tumor hypoxia is to increase the prevalence of oxygen at the tumor site. Oxygen-containing microbubbles/nanobubbles have been developed to supply oxygen and enhance the effects of therapies such as radiotherapy and photodynamic therapy. However, the application of these bubbles is constrained by their poor stability, requiring major workarounds to increase their half-lives. In this study, we explore the potential of biogenic gas vesicles (GVs) as a new kind of oxygen carrier to alleviate tumor hypoxia. GVs, which are naturally formed, gas-filled, protein-shelled compartments, were modified on the surface of their protein shells by a layer of liposome. A substantial improvement of oxygen concentration was observed in hypoxic solution, in hypoxic cells, as well as in subcutaneous tumors when lipid-GVs(O2) were added/tail-injected. Significant enhancement of tumor cell apoptosis and necrosis was also observed during photodynamic therapy (PDT) in the presence of lipid-GVs(O2) both in vitro and in vivo. Lipid-GVs(O2) alone induced no obvious change in cell viability in vitro or any apparent pathological abnormalities after mice were tail-injected with them. In all, lipid-GVs exhibited promising performance for intravenous gas delivery, enhanced PDT efficacy and low toxicity, a quality that may be applied to alleviate hypoxia in cancers, as well as hypoxia-related clinical treatments. STATEMENT OF SIGNIFICANCE: The development of stable oxygen-filled micro/nanobubbles capable of delivering oxygen to tumor sites is a major hurdle to enhancing the efficacy of cancer therapy. Currently, micro/nanobubbles are limited by their instability when oxygen is encapsulated, creating a large pressure gradient and surface tension. To improve stability, we modified the surfaces of GVs, a biogenic stable nanoscale hollow structure, as a new class of oxygen carriers. Lipid-coated GVs were found to be stable in solution and effective O2 carriers. This will overcome the limitations of coalescence, short circulation time of synthetic bubbles during application. Our surface-modified GVs demonstrated low toxicity in vitro cell in vivo, while also being able to overcome hypoxia-associated therapy resistance when combined with photodynamic therapy.
View details for DOI 10.1016/j.actbio.2020.03.034
View details for PubMedID 32268236
PINK1/Parkin-Mediated Mitophagy Promotes Resistance to Sonodynamic Therapy.
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
2018; 49 (5): 1825–39
Ultrasound brain stimulation is a promising modality for probing brain function and treating brain disease non-invasively and with high spatiotemporal resolution. However, the mechanism underlying its effects remains unclear. Here, we examine the role that the mouse piezo-type mechanosensitive ion channel component 1 (Piezo1) plays in mediating the in vitro effects of ultrasound in mouse primary cortical neurons and a neuronal cell line. We show that ultrasound alone could activate heterologous and endogenous Piezo1, initiating calcium influx and increased nuclear c-Fos expression in primary neurons but not when pre-treated with a Piezo1 inhibitor. We also found that ultrasound significantly increased the expression of the important proteins phospho-CaMKII, phospho-CREB, and c-Fos in a neuronal cell line, but Piezo1 knockdown significantly reduced this effect. Our findings demonstrate that the activity of mechanosensitive ion channels such as Piezo1 stimulated by ultrasound is an important contributor to its ability to stimulate cells in vitro.
View details for DOI 10.1016/j.isci.2019.10.037
View details for Web of Science ID 000498899800035
View details for PubMedID 31707258
View details for PubMedCentralID PMC6849147
Visualization of Porphyrin-Based Photosensitizer Distribution from Fluorescence Images In Vivo Using an Optimized RGB Camera
JOURNAL OF APPLIED SPECTROSCOPY
2018; 84 (6): 1124–30
Photoacoustic Imaging in Oxygen Detection
2017; 7 (12)
Ultrasonic Characteristics and Cellular Properties of Anabaena Gas Vesicles.
Ultrasound in medicine & biology
2017; 43 (12): 2862–70
Sonodynamic therapy (SDT), based on the synergistic effect of low-intensity ultrasound and sonosensitizer, is a potential approach for non-invasive treatment of cancers. In SDT, mitochondria played a crucial role in cell fate determination. However, mitochondrial activities and their response to SDT remain elusive. The purpose of this study was to examine the response of mitochondria to SDT in tumor cells.A human breast adenocarcinoma cell line - MCF-7 cells were subjected to 5-aminolevulinic acid (ALA)-SDT, with an average ultrasonic intensity of 0.25W/cm2. Mitochondrial dynamics and redox balance were examined by confocal immunofluorescence microscopy and western blot. The occurrence of mitophagy was determined by confocal immunofluorescence microscopy.Our results showed that ALA-SDT could induce mitochondrial dysfunction through mitochondrial depolarization and fragmentation and lead to mitophagy. The Parkin-dependent signaling pathway was involved and promoted resistance to ALA-SDT induced cell death. Finally, excessive production of ROS was found to be necessary for the initiation of mitophagy.Taken together, we conclude that ROS produced by 5-ALA-SDT could initiate PINK1/Parkin-mediated mitophagy which may exert a protective effect against 5-ALA-SDT-induced cell death in MCF-7 cells.
View details for DOI 10.1159/000493629
View details for PubMedID 30231241
Determination of Optical and Microvascular Parameters of Port Wine Stains Using Diffuse Reflectance Spectroscopy.
Advances in experimental medicine and biology
2016; 923: 359–65
Ultrasound imaging is a common modality in clinical examination and biomedical research, but has not played a significant role in molecular imaging for lack of an appropriate contrast agent. Recently, biogenic gas vesicles (GVs), naturally formed by cyanobacteria and haloarchaea, have exhibited great potential as an ultrasound molecular imaging probe with a much smaller size (∼100 nm) and improved imaging contrast. However, the basic acoustic and biological properties of GVs remain unclear, which hinders future application. Here, we studied the fundamental acoustic properties of a rod-shaped gas vesicle from Anabaena, a kind of cyanobacterium, including attenuation, oscillation resonance, and scattering, as well as biological behaviors (cellular internalization and cytotoxicity). We found that GVs have two resonance peaks (85 and 120 MHz). We also observed a significant non-linear effect and its pressure dependence as well. Ultrasound B-mode imaging reveals sufficient echogenicity of GVs for ultrasound imaging enhancement at high frequencies. Biological characterization also reveals endocytosis and non-toxicity.
View details for DOI 10.1016/j.ultrasmedbio.2017.08.004
View details for PubMedID 28889941
Deep brain stimulation of pallidal versus subthalamic for patients with Parkinson's disease: a meta-analysis of controlled clinical trials.
Neuropsychiatric disease and treatment
2016; 12: 1435–44
Characterizing port wine stains (PWS) with its optical parameters [i.e. absorption coefficient (μ a) and reduced scattering coefficient (μ s')] and microvascular parameters [i.e. blood volume fraction (BVF), mean vessel diameter (MVD), and oxygen saturation (StO2)] is extremely important for elucidating the mechanisms for its light-based treatments, such as pulsed dye laser and photodynamic therapy. In this study, a customized diffuse reflectance spectroscopy (DRS) probe with an appropriate source-detector distance was used to measure the diffuse reflectance spectra of PWS lesions in clinical practice. The results demonstrate that optical parameters of different types of PWS lesions can be accurately extracted by fitting the DRS with diffusion equation. Since the sampling depth of the probe coincides with the depth distribution of abnormal vasculature in PWS, the obtained microvascular parameters of PWS lesions that changed from pink to purple are in agreement with the corresponding physiological conditions. This study suggests that DRS can be utilized to quantitatively determine the optical and microvascular parameters of PWS lesions, which have the potential for planning the protocol and predicting the efficiency for light-based PWS treatments.
View details for DOI 10.1007/978-3-319-38810-6_47
View details for PubMedID 27526164
Parkinson's disease (PD) is a common neurodegenerative disorder that affects many people every year. Deep brain stimulation (DBS) is an effective nonpharmacological method to treat PD motor symptoms. This meta-analysis was conducted to evaluate the efficacy of subthalamic nucleus (STN)-DBS versus globus pallidus internus (GPi)-DBS in treating advanced PD.Controlled clinical trials that compared STN-DBS to GPi-DBS for short-term treatment of PD in adults were researched up to November 2015. The primary outcomes were the Unified Parkinson's Disease Rating Scale Section (UPDRS) III score and the levodopa-equivalent dosage (LED) after DBS. The secondary outcomes were the UPDRS II score and the Beck Depression Inventory (BDI) score.Totally, 13 studies containing 1,148 PD patients were included in this meta-analysis to compare STN-DBS versus GPi-DBS. During the off-medication state, the pooled weighted mean difference (WMD) of UPDRS III and II scores were -2.18 (95% CI =-5.11 to 0.74) and -1.96 (95% CI =-3.84 to -0.08), respectively. During the on-medication state, the pooled WMD of UPDRS III and II scores were 0.15 (95% CI =-1.14 to 1.44) and 1.01 (95% CI =0.12 to 1.89), respectively. After DBS, the pooled WMD of LED and BDI were -254.48 (95% CI =-341.66) and 2.29 (95% CI =0.83 to 3.75), respectively.These results indicate that during the off-medication state, the STN-DBS might be superior to GPi-DBS in improving the motor function and activities of daily living for PD patients; but during the on-medication state, the opposite result is observed. Meanwhile, the STN-DBS is superior at reducing the LED, whereas the GPi-DBS shows a significantly greater reduction in BDI score after DBS.
View details for DOI 10.2147/NDT.S105513
View details for PubMedID 27382286
View details for PubMedCentralID PMC4922776