The Discovery of Novel ACA Derivatives as Specific TRPM2 Inhibitors that Reduce Ischemic Injury Both In Vitro and In Vivo

Zhang, Han; Yu, Peilin; Lin, Hongwei; Jin, Zefang; Zhao, Shaodong; Zhang, Yi; Xu, Qing-Xia; Jin, Hongwei; Liu, Zhenming; Yang, Wei; Zhang, Liangren

doi:10.1021/acs.jmedchem.0c02129

Cited by 23 publications

(24 citation statements)

References 54 publications

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“…Thus, TRPM2 has emerged as a new therapeutic target for ischemic stroke. TRPM2 inhibitors have been in preclinical development to prevent pathological Ca 2+ overload [23][24][25]; however, successful development of specific inhibitors with…”

Section: Discussionmentioning

confidence: 99%

Umbilical cord-derived mesenchymal stem cell conditioned medium reverses neuronal oxidative injury by inhibition of TRPM2 activation and the JNK signaling pathway

Wang

Liu

et al. 2022

Mol Biol Rep

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Background The mechanism by which MSC-CM protects neuronal cells against ischemic injury remains to be elucidated. In this study, we aimed to clarify the protective effect of umbilical cord-derived mesenchymal stem cell conditioned medium (UC-MSC-CM) on neuronal oxidative injury and its potential mechanism. Methods and Results Neuronal oxidative damage was mimicked by H2O2 treatment of the HT22 cell line. The numbers of cleaved-Caspase-3-positive cells and protein expression of Caspase-9 induced by H2O2 treatment were decreased by UC-MSC-CM treatment. Furthermore, SOD protein expression was increased in the MSC-CM group compared with that in the H2O2 group. The H2O2-induced TRPM2-like currents in HT22 cells were attenuated by MSC-CM treatment. In addition, H2O2 treatment downregulated the expression of p-JNK protein in HT22 cells, and this the downward trend was reversed by incubation with MSC-CM. Conclusions UC-MSC-CM protects neurons against oxidative injury, possibly by inhibiting activation of TRPM2 and the JNK signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Umbilical cord-derived mesenchymal stem cell conditioned medium reverses neuronal oxidative injury by inhibition of TRPM2 activation and the JNK signaling pathway

Wang

Liu

et al. 2022

Mol Biol Rep

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“…Overall, this study shows that TRPM2 could be an interesting target for AML treatment. However, the main issue is the current absence of specific inhibitors for TRPM2, although a recent publication proposed the A23 compound as a promising new lead for the development of future clinically relevant TRPM2 inhibitors [155].…”

Section: Chemotherapies Calcium and Mitochondriamentioning

confidence: 99%

Put in a “Ca2+ll” to Acute Myeloid Leukemia

Lewuillon

Laguillaumie

Quesnel

et al. 2022

Cells

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Acute myeloid leukemia (AML) is a clonal disorder characterized by genetic aberrations in myeloid primitive cells (blasts) which lead to their defective maturation/function and their proliferation in the bone marrow (BM) and blood of affected individuals. Current intensive chemotherapy protocols result in complete remission in 50% to 80% of AML patients depending on their age and the AML type involved. While alterations in calcium signaling have been extensively studied in solid tumors, little is known about the role of calcium in most hematologic malignancies, including AML. Our purpose with this review is to raise awareness about this issue and to present (i) the role of calcium signaling in AML cell proliferation and differentiation and in the quiescence of hematopoietic stem cells; (ii) the interplay between mitochondria, metabolism, and oxidative stress; (iii) the effect of the BM microenvironment on AML cell fate; and finally (iv) the mechanism by which chemotherapeutic treatments modify calcium homeostasis in AML cells.

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“…The examples are N-(p-Amylcinnamoyl) anthranilic acid, widely used in research, which additionally affects TRPM8, TRPC6, TPPV1, TRPC3, or flufenamic acid inhibiting TRPC3, TRPC7, TRPM2–5, TRPM7/8, TRPV1, TRPV3/4 [ 47 ]. However, some efforts are made to enhance the specificity of ACA by using its derivatives [ 7 ]. Moreover, some of the substances are characterized by low inhibitory effects or poor membrane permeabilization properties [ 48 ].…”

Section: Trpm2 Inhibitors In Clinical Application and Further Perspectivesmentioning

confidence: 99%

“…TRPM2 channel activity was so far connected with such events as a cellular response to ischemia-reperfusion injury, regulation of endothelial permeability, inflammation, development of cancer and degenerative diseases, or induction of cell death, including apoptosis and autophagy [2,[7][8][9][10][11]. In the context of the endothelial layer, the impact of TRPM2 activation on barrier function, apoptosis, cell migration, angiogenesis, and transendothelial migration of the leukocytes seems to be particularly interesting.…”

Section: Introductionmentioning

confidence: 99%

The Role of TRPM2 in Endothelial Function and Dysfunction

Zielińska

Zabrzyński

Gagat

et al. 2021

IJMS

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The transient receptor potential (TRP) melastatin-like subfamily member 2 (TRPM2) is a non-selective calcium-permeable cation channel. It is expressed by many mammalian tissues, including bone marrow, spleen, lungs, heart, liver, neutrophils, and endothelial cells. The best-known mechanism of TRPM2 activation is related to the binding of ADP-ribose to the nudix-box sequence motif (NUDT9-H) in the C-terminal domain of the channel. In cells, the production of ADP-ribose is a result of increased oxidative stress. In the context of endothelial function, TRPM2-dependent calcium influx seems to be particularly interesting as it participates in the regulation of barrier function, cell death, cell migration, and angiogenesis. Any impairments of these functions may result in endothelial dysfunction observed in such conditions as atherosclerosis or hypertension. Thus, TRPM2 seems to be an attractive therapeutic target for the conditions connected with the increased production of reactive oxygen species. However, before the application of TRPM2 inhibitors will be possible, some issues need to be resolved. The main issues are the lack of specificity, poor membrane permeabilization, and low stability in in vivo conditions. The article aims to summarize the latest findings on a role of TRPM2 in endothelial cells. We also show some future perspectives for the application of TRPM2 inhibitors in cardiovascular system diseases.

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The Discovery of Novel ACA Derivatives as Specific TRPM2 Inhibitors that Reduce Ischemic Injury Both In Vitro and In Vivo

Cited by 23 publications

References 54 publications

Umbilical cord-derived mesenchymal stem cell conditioned medium reverses neuronal oxidative injury by inhibition of TRPM2 activation and the JNK signaling pathway

Umbilical cord-derived mesenchymal stem cell conditioned medium reverses neuronal oxidative injury by inhibition of TRPM2 activation and the JNK signaling pathway

Put in a “Ca2+ll” to Acute Myeloid Leukemia

The Role of TRPM2 in Endothelial Function and Dysfunction

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