The Experts below are selected from a list of 297 Experts worldwide ranked by ideXlab platform
Zhigang Xiong - One of the best experts on this subject based on the ideXlab platform.
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local anesthetic lidocaine inhibits trpm7 current and trpm7 mediated Zinc Toxicity
CNS Neuroscience & Therapeutics, 2015Co-Authors: Tiandong Leng, Jun Lin, Huawei Sun, Zhao Zeng, Zaven Obryant, Koichi Inoue, Zhigang XiongAbstract:Summary Background Previous study demonstrated that overstimulation of TRPM7 substantially contributes to Zinc-mediated neuronal Toxicity. Inhibition of TRPM7 activity and TRPM7-mediated intracellular Zn2+ accumulation may represent a promising strategy in the treatment of stroke. Aims To investigate whether local anesthetics lidocaine could inhibit TRPM7 channel and TRPM7-mediated Zinc Toxicity. Methods Whole-cell patch-clamp technique was used to investigate the effect of local anesthetics on TRPM7 currents in cultured mouse cortical neurons and TRPM7-overexpressed HEK293 cells. Fluorescent Zn2+ imaging technique was used to study the effect of lidocaine on TRPM7-mediated intracellular Zn2+ accumulation. TRPM7-mediated Zinc Toxicity in neurons was used to evaluate the neuroprotective effect of lidocaine. Results (1) Lidocaine dose dependently inhibits TRPM7-like currents, with an IC50 of 11.55 and 11.06 mM in cultured mouse cortical neurons and TRPM7-overexpressed HEK293 cells, respectively; (2) Lidocaine inhibits TRPM7 currents in a use/frequency-dependent manner; (3) Lidocaine inhibits TRPM7-mediated intracellular Zn2+ accumulation in both cortical neurons and TRPM7-overexpressed HEK293 cells; (4) TRPM7-mediated Zn2+ Toxicity is ameliorated by lidocaine in cortical neurons; (5) QX-314 has a similar inhibitory effect as lidocaine on TRPM7 currents when applied extracellularly; (6) Procaine also shows potent inhibitory effect on the TRPM7 currents in cortical neurons. Conclusion Our data provide the first evidence that local anesthetic lidocaine inhibits TRPM7 channel and TRPM7-mediated Zinc Toxicity.
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Local Anesthetic Lidocaine Inhibits TRPM7 Current and TRPM7‐Mediated Zinc Toxicity
CNS neuroscience & therapeutics, 2014Co-Authors: Tiandong Leng, Jun Lin, Huawei Sun, Zhao Zeng, Koichi Inoue, Zaven O’bryant, Zhigang XiongAbstract:Summary Background Previous study demonstrated that overstimulation of TRPM7 substantially contributes to Zinc-mediated neuronal Toxicity. Inhibition of TRPM7 activity and TRPM7-mediated intracellular Zn2+ accumulation may represent a promising strategy in the treatment of stroke. Aims To investigate whether local anesthetics lidocaine could inhibit TRPM7 channel and TRPM7-mediated Zinc Toxicity. Methods Whole-cell patch-clamp technique was used to investigate the effect of local anesthetics on TRPM7 currents in cultured mouse cortical neurons and TRPM7-overexpressed HEK293 cells. Fluorescent Zn2+ imaging technique was used to study the effect of lidocaine on TRPM7-mediated intracellular Zn2+ accumulation. TRPM7-mediated Zinc Toxicity in neurons was used to evaluate the neuroprotective effect of lidocaine. Results (1) Lidocaine dose dependently inhibits TRPM7-like currents, with an IC50 of 11.55 and 11.06 mM in cultured mouse cortical neurons and TRPM7-overexpressed HEK293 cells, respectively; (2) Lidocaine inhibits TRPM7 currents in a use/frequency-dependent manner; (3) Lidocaine inhibits TRPM7-mediated intracellular Zn2+ accumulation in both cortical neurons and TRPM7-overexpressed HEK293 cells; (4) TRPM7-mediated Zn2+ Toxicity is ameliorated by lidocaine in cortical neurons; (5) QX-314 has a similar inhibitory effect as lidocaine on TRPM7 currents when applied extracellularly; (6) Procaine also shows potent inhibitory effect on the TRPM7 currents in cortical neurons. Conclusion Our data provide the first evidence that local anesthetic lidocaine inhibits TRPM7 channel and TRPM7-mediated Zinc Toxicity.
Claudia J Stocks - One of the best experts on this subject based on the ideXlab platform.
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frontline science lps inducible slc30a1 drives human macrophage mediated Zinc Toxicity against intracellular escherichia coli
Journal of Leukocyte Biology, 2021Co-Authors: Claudia J Stocks, Minhduy Phan, Kate M Peters, Jessica B Von Pein, James E B Curson, James Rae, Darren Foo, Nilesh J Bokil, Taiho Kambe, Robert G PartonAbstract:TLR-inducible Zinc Toxicity is an antimicrobial mechanism utilized by macrophages, however knowledge of molecular mechanisms mediating this response is limited. Here, we show that E. coli exposed to Zinc stress within primary human macrophages reside in membrane-bound vesicular compartments. Since SLC30A Zinc exporters can deliver Zinc into the lumen of vesicles, we examined LPS-regulated mRNA expression of Slc30a/SLC30A family members in primary mouse and human macrophages. A number of these transporters were dynamically regulated in both cell populations. In human monocyte-derived macrophages, LPS strongly up-regulated SLC30A1 mRNA and protein expression. In contrast, SLC30A1 was not LPS-inducible in macrophage-like PMA-differentiated THP-1 cells. We therefore ectopically expressed SLC30A1 in these cells, finding that this was sufficient to promote Zinc-containing vesicle formation. The response was similar to that observed following LPS stimulation. Ectopically expressed SLC30A1 localized to both the plasma membrane and intracellular Zinc-containing vesicles within LPS-stimulated THP-1 cells. Inducible overexpression of SLC30A1 in THP-1 cells infected with the Escherichia coli K-12 strain MG1655 augmented the Zinc stress response of intracellular bacteria and promoted clearance. Furthermore, in THP-1 cells infected with an MG1655 Zinc stress reporter strain, all bacteria contained within SLC30A1-positive compartments were subjected to Zinc stress. Thus, SLC30A1 marks Zinc-containing compartments associated with TLR-inducible Zinc Toxicity in human macrophages, and its ectopic over-expression is sufficient to initiate this antimicrobial pathway in these cells. Finally, SLC30A1 silencing did not compromise E. coli clearance by primary human macrophages, suggesting that other Zinc exporters may also contribute to the Zinc Toxicity response.
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uropathogenic escherichia coli employs both evasion and resistance to subvert innate immune mediated Zinc Toxicity for dissemination
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Claudia J Stocks, Minhduy Phan, Maud E S Achard, Nguyen Thi Khanh Nhu, Nicholas D Condon, Jayde A Gawthorne, Kate M Peters, Alastair G Mcewan, Ronan Kapetanovic, Mark A SchembriAbstract:Toll-like receptor (TLR)-inducible Zinc Toxicity is a recently described macrophage antimicrobial response used against bacterial pathogens. Here we investigated deployment of this pathway against uropathogenic Escherichia coli (UPEC), the major cause of urinary tract infections. Primary human macrophages subjected EC958, a representative strain of the globally disseminated multidrug-resistant UPEC ST131 clone, to Zinc stress. We therefore used transposon-directed insertion site sequencing to identify the complete set of UPEC genes conferring protection against Zinc Toxicity. Surprisingly, Zinc-susceptible EC958 mutants were not compromised for intramacrophage survival, whereas corresponding mutants in the nonpathogenic E. coli K-12 strain MG1655 displayed significantly reduced intracellular bacterial loads within human macrophages. To investigate whether the intramacrophage Zinc stress response of EC958 reflected the response of only a subpopulation of bacteria, we generated and validated reporter systems as highly specific sensors of Zinc stress. Using these tools we show that, in contrast to MG1655, the majority of intramacrophage EC958 evades the Zinc Toxicity response, enabling survival within these cells. In addition, EC958 has a higher tolerance to Zinc than MG1655, with this likely being important for survival of the minor subset of UPEC cells exposed to innate immune-mediated Zinc stress. Indeed, analysis of Zinc stress reporter strains and Zinc-sensitive mutants in an intraperitoneal challenge model in mice revealed that EC958 employs both evasion and resistance against Zinc Toxicity, enabling its dissemination to the liver and spleen. We thus demonstrate that a pathogen of global significance uses multiple mechanisms to effectively subvert innate immune-mediated Zinc poisoning for systemic spread.
Tiandong Leng - One of the best experts on this subject based on the ideXlab platform.
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local anesthetic lidocaine inhibits trpm7 current and trpm7 mediated Zinc Toxicity
CNS Neuroscience & Therapeutics, 2015Co-Authors: Tiandong Leng, Jun Lin, Huawei Sun, Zhao Zeng, Zaven Obryant, Koichi Inoue, Zhigang XiongAbstract:Summary Background Previous study demonstrated that overstimulation of TRPM7 substantially contributes to Zinc-mediated neuronal Toxicity. Inhibition of TRPM7 activity and TRPM7-mediated intracellular Zn2+ accumulation may represent a promising strategy in the treatment of stroke. Aims To investigate whether local anesthetics lidocaine could inhibit TRPM7 channel and TRPM7-mediated Zinc Toxicity. Methods Whole-cell patch-clamp technique was used to investigate the effect of local anesthetics on TRPM7 currents in cultured mouse cortical neurons and TRPM7-overexpressed HEK293 cells. Fluorescent Zn2+ imaging technique was used to study the effect of lidocaine on TRPM7-mediated intracellular Zn2+ accumulation. TRPM7-mediated Zinc Toxicity in neurons was used to evaluate the neuroprotective effect of lidocaine. Results (1) Lidocaine dose dependently inhibits TRPM7-like currents, with an IC50 of 11.55 and 11.06 mM in cultured mouse cortical neurons and TRPM7-overexpressed HEK293 cells, respectively; (2) Lidocaine inhibits TRPM7 currents in a use/frequency-dependent manner; (3) Lidocaine inhibits TRPM7-mediated intracellular Zn2+ accumulation in both cortical neurons and TRPM7-overexpressed HEK293 cells; (4) TRPM7-mediated Zn2+ Toxicity is ameliorated by lidocaine in cortical neurons; (5) QX-314 has a similar inhibitory effect as lidocaine on TRPM7 currents when applied extracellularly; (6) Procaine also shows potent inhibitory effect on the TRPM7 currents in cortical neurons. Conclusion Our data provide the first evidence that local anesthetic lidocaine inhibits TRPM7 channel and TRPM7-mediated Zinc Toxicity.
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Local Anesthetic Lidocaine Inhibits TRPM7 Current and TRPM7‐Mediated Zinc Toxicity
CNS neuroscience & therapeutics, 2014Co-Authors: Tiandong Leng, Jun Lin, Huawei Sun, Zhao Zeng, Koichi Inoue, Zaven O’bryant, Zhigang XiongAbstract:Summary Background Previous study demonstrated that overstimulation of TRPM7 substantially contributes to Zinc-mediated neuronal Toxicity. Inhibition of TRPM7 activity and TRPM7-mediated intracellular Zn2+ accumulation may represent a promising strategy in the treatment of stroke. Aims To investigate whether local anesthetics lidocaine could inhibit TRPM7 channel and TRPM7-mediated Zinc Toxicity. Methods Whole-cell patch-clamp technique was used to investigate the effect of local anesthetics on TRPM7 currents in cultured mouse cortical neurons and TRPM7-overexpressed HEK293 cells. Fluorescent Zn2+ imaging technique was used to study the effect of lidocaine on TRPM7-mediated intracellular Zn2+ accumulation. TRPM7-mediated Zinc Toxicity in neurons was used to evaluate the neuroprotective effect of lidocaine. Results (1) Lidocaine dose dependently inhibits TRPM7-like currents, with an IC50 of 11.55 and 11.06 mM in cultured mouse cortical neurons and TRPM7-overexpressed HEK293 cells, respectively; (2) Lidocaine inhibits TRPM7 currents in a use/frequency-dependent manner; (3) Lidocaine inhibits TRPM7-mediated intracellular Zn2+ accumulation in both cortical neurons and TRPM7-overexpressed HEK293 cells; (4) TRPM7-mediated Zn2+ Toxicity is ameliorated by lidocaine in cortical neurons; (5) QX-314 has a similar inhibitory effect as lidocaine on TRPM7 currents when applied extracellularly; (6) Procaine also shows potent inhibitory effect on the TRPM7 currents in cortical neurons. Conclusion Our data provide the first evidence that local anesthetic lidocaine inhibits TRPM7 channel and TRPM7-mediated Zinc Toxicity.
Mark A Schembri - One of the best experts on this subject based on the ideXlab platform.
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uropathogenic escherichia coli employs both evasion and resistance to subvert innate immune mediated Zinc Toxicity for dissemination
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Claudia J Stocks, Minhduy Phan, Maud E S Achard, Nguyen Thi Khanh Nhu, Nicholas D Condon, Jayde A Gawthorne, Kate M Peters, Alastair G Mcewan, Ronan Kapetanovic, Mark A SchembriAbstract:Toll-like receptor (TLR)-inducible Zinc Toxicity is a recently described macrophage antimicrobial response used against bacterial pathogens. Here we investigated deployment of this pathway against uropathogenic Escherichia coli (UPEC), the major cause of urinary tract infections. Primary human macrophages subjected EC958, a representative strain of the globally disseminated multidrug-resistant UPEC ST131 clone, to Zinc stress. We therefore used transposon-directed insertion site sequencing to identify the complete set of UPEC genes conferring protection against Zinc Toxicity. Surprisingly, Zinc-susceptible EC958 mutants were not compromised for intramacrophage survival, whereas corresponding mutants in the nonpathogenic E. coli K-12 strain MG1655 displayed significantly reduced intracellular bacterial loads within human macrophages. To investigate whether the intramacrophage Zinc stress response of EC958 reflected the response of only a subpopulation of bacteria, we generated and validated reporter systems as highly specific sensors of Zinc stress. Using these tools we show that, in contrast to MG1655, the majority of intramacrophage EC958 evades the Zinc Toxicity response, enabling survival within these cells. In addition, EC958 has a higher tolerance to Zinc than MG1655, with this likely being important for survival of the minor subset of UPEC cells exposed to innate immune-mediated Zinc stress. Indeed, analysis of Zinc stress reporter strains and Zinc-sensitive mutants in an intraperitoneal challenge model in mice revealed that EC958 employs both evasion and resistance against Zinc Toxicity, enabling its dissemination to the liver and spleen. We thus demonstrate that a pathogen of global significance uses multiple mechanisms to effectively subvert innate immune-mediated Zinc poisoning for systemic spread.
Kate M Peters - One of the best experts on this subject based on the ideXlab platform.
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frontline science lps inducible slc30a1 drives human macrophage mediated Zinc Toxicity against intracellular escherichia coli
Journal of Leukocyte Biology, 2021Co-Authors: Claudia J Stocks, Minhduy Phan, Kate M Peters, Jessica B Von Pein, James E B Curson, James Rae, Darren Foo, Nilesh J Bokil, Taiho Kambe, Robert G PartonAbstract:TLR-inducible Zinc Toxicity is an antimicrobial mechanism utilized by macrophages, however knowledge of molecular mechanisms mediating this response is limited. Here, we show that E. coli exposed to Zinc stress within primary human macrophages reside in membrane-bound vesicular compartments. Since SLC30A Zinc exporters can deliver Zinc into the lumen of vesicles, we examined LPS-regulated mRNA expression of Slc30a/SLC30A family members in primary mouse and human macrophages. A number of these transporters were dynamically regulated in both cell populations. In human monocyte-derived macrophages, LPS strongly up-regulated SLC30A1 mRNA and protein expression. In contrast, SLC30A1 was not LPS-inducible in macrophage-like PMA-differentiated THP-1 cells. We therefore ectopically expressed SLC30A1 in these cells, finding that this was sufficient to promote Zinc-containing vesicle formation. The response was similar to that observed following LPS stimulation. Ectopically expressed SLC30A1 localized to both the plasma membrane and intracellular Zinc-containing vesicles within LPS-stimulated THP-1 cells. Inducible overexpression of SLC30A1 in THP-1 cells infected with the Escherichia coli K-12 strain MG1655 augmented the Zinc stress response of intracellular bacteria and promoted clearance. Furthermore, in THP-1 cells infected with an MG1655 Zinc stress reporter strain, all bacteria contained within SLC30A1-positive compartments were subjected to Zinc stress. Thus, SLC30A1 marks Zinc-containing compartments associated with TLR-inducible Zinc Toxicity in human macrophages, and its ectopic over-expression is sufficient to initiate this antimicrobial pathway in these cells. Finally, SLC30A1 silencing did not compromise E. coli clearance by primary human macrophages, suggesting that other Zinc exporters may also contribute to the Zinc Toxicity response.
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uropathogenic escherichia coli employs both evasion and resistance to subvert innate immune mediated Zinc Toxicity for dissemination
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Claudia J Stocks, Minhduy Phan, Maud E S Achard, Nguyen Thi Khanh Nhu, Nicholas D Condon, Jayde A Gawthorne, Kate M Peters, Alastair G Mcewan, Ronan Kapetanovic, Mark A SchembriAbstract:Toll-like receptor (TLR)-inducible Zinc Toxicity is a recently described macrophage antimicrobial response used against bacterial pathogens. Here we investigated deployment of this pathway against uropathogenic Escherichia coli (UPEC), the major cause of urinary tract infections. Primary human macrophages subjected EC958, a representative strain of the globally disseminated multidrug-resistant UPEC ST131 clone, to Zinc stress. We therefore used transposon-directed insertion site sequencing to identify the complete set of UPEC genes conferring protection against Zinc Toxicity. Surprisingly, Zinc-susceptible EC958 mutants were not compromised for intramacrophage survival, whereas corresponding mutants in the nonpathogenic E. coli K-12 strain MG1655 displayed significantly reduced intracellular bacterial loads within human macrophages. To investigate whether the intramacrophage Zinc stress response of EC958 reflected the response of only a subpopulation of bacteria, we generated and validated reporter systems as highly specific sensors of Zinc stress. Using these tools we show that, in contrast to MG1655, the majority of intramacrophage EC958 evades the Zinc Toxicity response, enabling survival within these cells. In addition, EC958 has a higher tolerance to Zinc than MG1655, with this likely being important for survival of the minor subset of UPEC cells exposed to innate immune-mediated Zinc stress. Indeed, analysis of Zinc stress reporter strains and Zinc-sensitive mutants in an intraperitoneal challenge model in mice revealed that EC958 employs both evasion and resistance against Zinc Toxicity, enabling its dissemination to the liver and spleen. We thus demonstrate that a pathogen of global significance uses multiple mechanisms to effectively subvert innate immune-mediated Zinc poisoning for systemic spread.
