Therapeutic Modulation of Calcium Dynamics Using Ultrasound and Other Energy-Based Techniques

Castellanos, Ivan Suarez; Balteanu, Bogdan; Singh, Tania; Zderic, Vesna

doi:10.1109/rbme.2016.2555760

Cited by 24 publications

(23 citation statements)

References 174 publications

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“…Further studies are required to determine the exact mechanisms involved in ultrasound-enhanced insulin release from pancreatic beta cells. In addition to cavitation, other mechanisms documented in literature could play an important role in this process (Suarez Castellanos et al 2016). …”

Section: Discussionmentioning

confidence: 99%

Ultrasound Stimulation of Insulin Release from Pancreatic Beta Cells as a Potential Novel Treatment for Type 2 Diabetes

Castellanos

Jeremić

Cohen

et al. 2017

Ultrasound in Medicine & Biology

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Type 2 diabetes mellitus is a complex metabolic disease that has reached epidemic proportions in the United States and around the world. This disease is characterized by loss of insulin secretion and eventually destruction of insulin-producing pancreatic beta cells. Controlling type 2 diabetes is often difficult as pharmacological management routinely requires complex therapy with multiple medications, and loses its effectiveness over time. The objective of this study was to explore the effectiveness of a novel, non-pharmacological approach that utilizes the application of ultrasound energy to augment insulin release from rat INS 832/13 beta cells. The cells were exposed to unfocused ultrasound for 5 min at peak intensity of 1 W/cm2 and frequencies of 400 kHz, 600 kHz, 800 kHz and 1 MHz. Insulin release was measured with enzyme-linked immunosorbent assay (ELISA) and cell viability was assessed via trypan blue dye exclusion test. A marked release (approximately 150 ng/106 cells, p < 0.05) of insulin was observed when beta cells were exposed to ultrasound at 400 kHz and 600 kHz as compared to their initial control values, however this release was accompanied with a substantial loss in cell viability. Ultrasound application at frequencies of 800 kHz resulted in 24 ng/106 cells of released insulin (p < 0.05) as compared to its unstimulated base level, while retaining cell viability. Insulin release from beta cells caused by application of 800 kHz ultrasound was comparable to that reported by secretagogue glucose, thus operating within physiological secretory capacity of these cells. Ultrasound has a potential to find an application as a novel and alternative method to current approaches aimed at correcting secretory deficiencies in patients with type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Ultrasound Stimulation of Insulin Release from Pancreatic Beta Cells as a Potential Novel Treatment for Type 2 Diabetes

Castellanos

Jeremić

Cohen

et al. 2017

Ultrasound in Medicine & Biology

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“…We have previously shown that the application of ultrasound to pancreatic beta cells induces up to four fold increases in release of insulin as compared to control, while retaining cell viability [ 24 ]. Further, previous published studies demonstrated that ultrasound application can stimulate calcium transients in cells [ 25 ]. In view of this, we hypothesize that the observed increase in insulin secretion is the result of ultrasound-stimulated calcium influx and the subsequent triggering of insulin vesicle exocytosis [ 26 – 30 ].…”

Section: Introductionmentioning

confidence: 99%

Calcium-dependent ultrasound stimulation of secretory events from pancreatic beta cells

et al. 2017

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BackgroundOur previous studies have indicated that ultrasound can stimulate the release of insulin from pancreatic beta cells, providing a potential novel treatment for type 2 diabetes. The purpose of this study was to explore the temporal dynamics and Ca2+-dependency of ultrasound-stimulated secretory events from dopamine-loaded pancreatic beta cells in an in vitro setup.MethodsCarbon fiber amperometry was used to detect secretion from INS-1832/13 beta cells in real time. The levels of released insulin were also measured in response to ultrasound treatment using insulin-specific ELISA kit. Beta cells were exposed to continuous wave 800 kHz ultrasound at intensities of 0.1 W/cm2, 0.5 W/cm2 and 1 W/cm2 for several seconds. Cell viability tests were done with trypan blue dye exclusion test and MTT analysis.ResultsCarbon fiber amperometry experiments showed that application of 800 kHz ultrasound at intensities of 0.5 and 1 W/cm2 was capable of stimulating secretory events for durations lasting as long as the duration of the stimulus. Furthermore, the amplitude of the detected peaks was reduced by 64% (p < 0.01) when extracellular Ca2+ was chelated with 10 mM EGTA in cells exposed to ultrasound intensity of 0.5 W/cm2. Measurements of released insulin in response to ultrasound stimulation showed complete inhibition of insulin secretion by chelating extracellular Ca2+ with 10 mM EGTA (p < 0.01). Viability studies showed that 800 kHz, 0.5 W/cm2 ultrasound did not cause any significant effects on viability and metabolic activity in cells exposed to ultrasound as compared to sham-treated cells.ConclusionsOur results demonstrated that application of ultrasound was capable of stimulating the release of insulin from pancreatic beta cells in a safe, controlled and Ca2+-dependent manner.

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“…Our previous work demonstrated that mechanosensory FUS-stimulation generates a robust Ca 2+ signaling response which can be used to distinguish invasive from non-invasive cancer cells (Hwang et al, 2013;Weitz et al, 2017). Others have also demonstrated mechanosensory Ca 2+ signaling responses using non-focused US-stimulation other contexts (Carina et al, 2018;Pan et al, 2018;Wood and Sehgal, 2015) as well as more general studies to clarify the physiological, cell biological and molecular mechanisms underlying mechanosensory dependent Ca 2+ signaling responses (Castellanos et al, 2016;Liu et al, 2017;Maresca et al, 2018;Tyler et al, 2008). Our Removing or lowering external Ca 2+ from culture medium did not eliminate FUS dependent Ca 2+ signaling (see Figure 1D).…”

Section: Discussionmentioning

confidence: 98%

Focused ultrasound stimulates ER localized mechanosensitive PANNEXIN-1 to mediate intracellular calcium release in invasive cancer cells

Lee

Yoon

Wang

et al. 2020

Preprint

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Focused ultrasound (FUS) is a rapidly developing stimulus technology with the potential to uncover novel mechanosensory dependent cellular processes. Since it is noninvasive, it holds great promise for future therapeutic applications in patients used either alone or as a complement to boost existing treatments. For example, FUS stimulation causes invasive but not noninvasive cancer cell lines to exhibit marked activation of calcium signaling pathways. Here, we identify the membrane channel PANNEXIN1 (PANX1) as a mediator for activation of calcium signaling in invasive cancer cells. Knockdown of PANX1 decreases calcium signaling in invasive cells, while PANX1 overexpression enhances calcium elevations in non-invasive cancer cells. We demonstrate that FUS may directly stimulate mechanosensory PANX1 localized in endoplasmic reticulum to evoke calcium release from internal stores. This process does not depend on mechanosensory stimulus transduction through an intact cytoskeleton and does not depend on plasma membrane localized PANX1. Plasma membrane localized PANX1 however plays a different role in mediating the spread of intercellular calcium waves via ATP release.Additionally, we show that FUS stimulation evokes cytokine/chemokine release from invasive cancer cells, suggesting that FUS could be an important new adjuvant treatment to improve cancer immunotherapy. FIGURE 3. Treatment of PC-3 cells with 10 PX1 (PANX1 inhibitor) abolishes the normal FUSinduced Ca 2+ oscillation response but uncovers single Ca 2+ transients. (A)Left column, the cells exhibited strong Ca 2+ responses at 20 min after 200 M scrambled peptide application as a control. Center column, cells were stimulated at 20 min after 200 M 10 Panx1 peptide ( 10 PX1) application, and the responses were partly reduced. Right column, 20 min after 2 M Xestospongin C (XC) application, the responses were also partly reduced. Two representative cells were shown in each treatment. (B) Quantitative CRI values of the inhibitor treatments. n=3 (XC), or n=6 (SC, 10 PX1). Error bars, s.e.m., ANOVA, Dunnet's correction, exact p values. (C) Fluorescence patterns in cells that first responded to the stimulus after the treatments. Two representative cells are shown by F/F. (D) Fluorescence patterns in several cells that first responded to the stimulus after the treatments; Scrambled (9 cells), 10 PX1 (5 cells) and XC (6 cells).

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Therapeutic Modulation of Calcium Dynamics Using Ultrasound and Other Energy-Based Techniques

Cited by 24 publications

References 174 publications

Ultrasound Stimulation of Insulin Release from Pancreatic Beta Cells as a Potential Novel Treatment for Type 2 Diabetes

Ultrasound Stimulation of Insulin Release from Pancreatic Beta Cells as a Potential Novel Treatment for Type 2 Diabetes

Calcium-dependent ultrasound stimulation of secretory events from pancreatic beta cells

Focused ultrasound stimulates ER localized mechanosensitive PANNEXIN-1 to mediate intracellular calcium release in invasive cancer cells

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