Abstract:Nanosecond pulsed electric fields (nsPEFs) have a variety of applications in the biomedical and biotechnology industries. Cancer treatment has been at the forefront of investigations thus far as nsPEFs permeabilize cellular and intracellular membranes leading to apoptosis and necrosis. nsPEFs may also influence ion channel gating and have the potential to modulate cell physiology without poration of the membrane. This phenomenon was explored using live cell imaging and a sensitive fluorescent probe of transmem… Show more
“…It localizes on the cell surface membrane and endoplasmic reticulum (ER). It is expressed in the male urogenital apparatus, such as the prostate gland, testis, and urinary bladder, as well as the liver and nervous system among normal organs, and is found in some malignant tumors, including androgen-dependent prostate cancer, pancreatic cancer, breast cancer, and melanoma ( 13 , 14 , 21 – 26 ). TRPM8 regulates the proliferation and apoptosis of prostatic epithelial cells, and cell death is induced by an inflow of Ca 2+ into cells via TRPM8 ( 13 , 14 ).…”
Section: Discussionmentioning
confidence: 99%
“…TRPM8 is up-regulated in androgen-dependent prostate cancer, and affects the growth inhibition and dedifferentiation of neoplastic cells ( 13 , 14 , 21 – 26 ). TRPM8 was defined as an effective diagnostic and prognostic marker in prostate cancer ( 13 , 14 , 21 ).…”
Section: Discussionmentioning
confidence: 99%
“…TRPM8 has been found in approximately 10 types of malignant tumors including carcinomas derived from the prostate gland, mammary gland, oral cavity, colon, lung, skin, pancreas, and urinary bladder ( 12 – 14 , 21 – 26 ). Furthermore, murine lymphocytes express several subtypes of the TRP superfamily ( 27 – 29 ); however, it currently remains unclear whether TRPM8 localizes in human reactive lymphoid tissues and malignant lymphomas.…”
Transient receptor potential melastatin 8 (TRPM8) is a member of the transient receptor potential superfamily of Ca2+ channels. The aim of the present study was to clarify TRPM8 expression in reactive lymphoid tissues and mature B-cell neoplasms. Reactive and neoplastic lymphoid tissues were used to evaluate TRPM8 expression by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). TRPM8+ cells were frequently detected in the follicular light zone and marginal zone of reactive lymphoid tissues. Double immunostaining revealed that TRPM8+ cells co-expressed cluster of differentiation (CD) 38, CD79a, CD138, interferon regulatory factor 4/melanoma associated antigen (mutated) 1, B cell CLL/lymphoma 6 and transmembrane activator and CAML interactor. TRPM8+ neoplastic cells were frequently detected in plasma cell myeloma. The positive band of TRPM8 mRNA was confirmed by RT-PCR in cases of myeloma. The present study is, to the best of our knowledge, the first to demonstrate the expression of TRPM8 in reactive lymphoid tissues and mature B-cell neoplasms, revealing that TRPM8 is frequently expressed in pre-plasmablasts, plasmablasts, plasma cells and mature B-cell lymphomas that are likely to differentiate into plasma cells.
“…It localizes on the cell surface membrane and endoplasmic reticulum (ER). It is expressed in the male urogenital apparatus, such as the prostate gland, testis, and urinary bladder, as well as the liver and nervous system among normal organs, and is found in some malignant tumors, including androgen-dependent prostate cancer, pancreatic cancer, breast cancer, and melanoma ( 13 , 14 , 21 – 26 ). TRPM8 regulates the proliferation and apoptosis of prostatic epithelial cells, and cell death is induced by an inflow of Ca 2+ into cells via TRPM8 ( 13 , 14 ).…”
Section: Discussionmentioning
confidence: 99%
“…TRPM8 is up-regulated in androgen-dependent prostate cancer, and affects the growth inhibition and dedifferentiation of neoplastic cells ( 13 , 14 , 21 – 26 ). TRPM8 was defined as an effective diagnostic and prognostic marker in prostate cancer ( 13 , 14 , 21 ).…”
Section: Discussionmentioning
confidence: 99%
“…TRPM8 has been found in approximately 10 types of malignant tumors including carcinomas derived from the prostate gland, mammary gland, oral cavity, colon, lung, skin, pancreas, and urinary bladder ( 12 – 14 , 21 – 26 ). Furthermore, murine lymphocytes express several subtypes of the TRP superfamily ( 27 – 29 ); however, it currently remains unclear whether TRPM8 localizes in human reactive lymphoid tissues and malignant lymphomas.…”
Transient receptor potential melastatin 8 (TRPM8) is a member of the transient receptor potential superfamily of Ca2+ channels. The aim of the present study was to clarify TRPM8 expression in reactive lymphoid tissues and mature B-cell neoplasms. Reactive and neoplastic lymphoid tissues were used to evaluate TRPM8 expression by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). TRPM8+ cells were frequently detected in the follicular light zone and marginal zone of reactive lymphoid tissues. Double immunostaining revealed that TRPM8+ cells co-expressed cluster of differentiation (CD) 38, CD79a, CD138, interferon regulatory factor 4/melanoma associated antigen (mutated) 1, B cell CLL/lymphoma 6 and transmembrane activator and CAML interactor. TRPM8+ neoplastic cells were frequently detected in plasma cell myeloma. The positive band of TRPM8 mRNA was confirmed by RT-PCR in cases of myeloma. The present study is, to the best of our knowledge, the first to demonstrate the expression of TRPM8 in reactive lymphoid tissues and mature B-cell neoplasms, revealing that TRPM8 is frequently expressed in pre-plasmablasts, plasmablasts, plasma cells and mature B-cell lymphomas that are likely to differentiate into plasma cells.
“…It is particularly significant that nsPEF, demonstrated in primary cultures of rat hippocampal neurons, depolarizes the cell membrane in a dose-dependent manner and eventually evokes an AP [ 120 ]. A summary of in vitro , in vivo and in silico studies [ 105 , 116 , 120 – 127 ] is provided in figure 4 . Figure 4.…”
Section: Biological Effects Of Millimetre Wavementioning
Since regular radio broadcasts started in the 1920s, the exposure to human-made electromagnetic fields has steadily increased. These days we are not only exposed to radio waves but also other frequencies from a variety of sources, mainly from communication and security devices. Considering that nearly all biological systems interact with electromagnetic fields, understanding the affects is essential for safety and technological progress. This paper systematically reviews the role and effects of static and pulsed radio frequencies (100–109 Hz), millimetre waves (MMWs) or gigahertz (109–1011 Hz), and terahertz (1011–1013 Hz) on various biomolecules, cells and tissues. Electromagnetic fields have been shown to affect the activity in cell membranes (sodium versus potassium ion conductivities) and non-selective channels, transmembrane potentials and even the cell cycle. Particular attention is given to millimetre and terahertz radiation due to their increasing utilization and, hence, increasing human exposure. MMWs are known to alter active transport across cell membranes, and it has been reported that terahertz radiation may interfere with DNA and cause genomic instabilities. These and other phenomena are discussed along with the discrepancies and controversies from published studies.
“…However, it remains unclear whether the electric field during such short pulses is able to directly move the VSDs, or whether the channel activation is indirect due to post-pulse membrane depolarization caused by nonselective ion leakage across the electropermeabilized membrane. Furthermore, this activation of VGICs has been found to participate in post-pulse membrane depolarization (13,14) and intracellular calcium increase (15)(16)(17), both of which are important signals that can initiate cell death, proliferation, or differentiation depending on their spatio-temporal profile (18,19). Understanding the effects of pulsed electric fields on VGICs is thus also interesting for new applications in wound healing and tissue engineering.…”
Pulsed electric fields are increasingly used in medicine to transiently increase the cell membrane permeability via electroporation, in order to deliver therapeutic molecules into the cell. One type of events that contributes to this increase in membrane permeability is the formation of pores in the membrane lipid bilayer. However, electrophysiological measurements suggest that membrane proteins are affected as well, particularly voltagegated ion channels (VGICs). The molecular mechanisms by which the electric field could affects these molecules remain unidentified. In this study we used molecular dynamics (MD) simulations to unravel the molecular events that take place in different VGICs when exposing them to electric fields mimicking electroporation conditions. We show that electric fields induce pores in the voltage-sensor domains (VSDs) of different VGICs, and that these pores form more easily in some channels than in others. We demonstrate that poration is more likely in VSDs that are more hydrated and are electrostatically more favorable for the entry of ions. We further show that pores in VSDs can expand into so-called complex pores, which become stabilized by lipid head-groups. Our results suggest that such complex pores are considerably more stable than conventional lipid pores and their formation can lead to severe unfolding of VSDs from the channel. We anticipate that such VSDs become dysfunctional and unable to respond to changes in transmembrane voltage, which is in agreement with previous electrophyiological measurements showing a decrease in the voltage-dependent transmembrane ionic currents following pulse treatment. Finally, we discuss the possibility of activation of VGICs by submicrosecond-duration pulses. Overall our study reveals a new mechanism of electroporation through membranes containing voltage-gated ion channels.
Statement of SignificancePulsed electric fields are often used for treatment of excitable cells, e.g., for gene delivery into skeletal muscles, ablation of the heart muscle or brain tumors. Voltage-gated ion channels (VGICs) underlie generation and propagation of action potentials in these cells, and consequently are essential for their proper function. Our study reveals the molecular mechanisms by which pulsed electric fields directly affect VGICs and addresses questions that have been previously opened by electrophysiologists. We analyze VGICs' characteristics, which make them prone for electroporation, including hydration and electrostatic properties. This analysis is easily transferable to other membrane proteins thus opening directions for future investigations. Finally, we propose a mechanism for long-lived membrane permeability following pulse treatment, which to date remains poorly understood.
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