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1.
Hepatol Commun ; 7(5)2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-37058100

RESUMO

BACKGROUND: HCC is one of the most common causes of cancer-related deaths. Transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable cation channel, was reported to be involved in carcinogenesis and tumor growth recently. However, whether TRPM2 is involved in the pathogenesis and progression of HCC remains unclear. Herein, we systematically elucidated the functional role of TRPM2 in HCC cell cycle regulation and proliferation. APPROACH AND RESULTS: We determine TRPM2 expression to be strongly upregulated in the tumor tissues of HCC patients and associated with a negative prognosis. TRPM2 is highly expressed in HCC cell lines Huh-7 and HepG2 cells, rather than in normal hepatocytes. Inhibition or silencing of TRPM2, or inhibition of the downstream Ca2+-CaM-CaMKII signaling pathway, significantly suppressed the proliferation of Huh-7 and HepG2 cells by arresting the cell cycle at the G1/S phase, accompanied with reduced expression of G1/S checkpoint proteins. Importantly, inhibition or depletion of TRPM2 remarkably slowed down the growth of patient-derived xenografts and Huh-7 xenografts in mice. CONCLUSION: Our results indicate that TRPM2 promotes HCC cell proliferation via activating the Ca2+-CaM-CaMKII signaling pathway to induce the expression of the key G1/S regulatory proteins and accelerate the cell cycle. This study provides compelling evidence of TRPM2 involvement in a previously unrecognized mechanism that drives HCC progression and demonstrates that TRPM2 is a potential target for HCC treatment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Canais de Cátion TRPM , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/patologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cálcio/metabolismo , Neoplasias Hepáticas/patologia , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/metabolismo , Ciclo Celular/genética , Transdução de Sinais
2.
Int J Pharm ; 570: 118648, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31465833

RESUMO

Skin is the first protection of human body. It is always challenged by a range of external factors, resulting in the wounds of skin. Hydrogel, as a dressing with multiple advantages, causes increasing interests or the applications in wound treatment. However, the function and importance of micro-environment of wound region are frequently neglected. In this study, we successfully developed a chemokine loaded biomimetic hydrogel as a functional reservoir to stimulate the rapid in situ recruitment of BMSCs for fast wound repair and regeneration. The biomimetic hydrogel was fabricated by using the Polyvinyl alcohol (PVA) combined with chitosan (CS) as the hybrid materials. The fabricated hydrogel possesses many features such as the porous structure, high swelling rate and moisture retention property. More importantly, the incorporated chemokine could be released with a sustained manner from the hydrogel and recruited the bone marrow mesenchymal stem cells (BMSCs) significantly both in vitro & in vivo. Moreover, the hydrogel was demonstrated to be highly biocompatible to the skin tissue without any side effect or irritation observed. Topical delivery of chemokine by the biomimetic PVA/CS hybrid material based hydrogel is demonstrated as a promising carrier to accelerate wound repair and regeneration without inducing scar formation and any other negative complications. The PVA/CS/SDF-1 hydrogel was shown a novel therapeutic system for wound therapy.


Assuntos
Materiais Biomiméticos/administração & dosagem , Materiais Biomiméticos/química , Quimiocinas/metabolismo , Regeneração/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Animais , Bandagens , Biomimética/métodos , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Quitosana/química , Sistemas de Liberação de Medicamentos/métodos , Humanos , Hidrogéis/química , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Álcool de Polivinil/química , Ratos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/metabolismo
3.
Cell Rep ; 27(12): 3684-3695.e4, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216484

RESUMO

cADPR is a well-recognized signaling molecule by modulating the RyRs, but considerable debate exists regarding whether cADPR can bind to and gate the TRPM2 channel, which mediates oxidative stress signaling in diverse physiological and pathological processes. Here, we show that purified cADPR evoked TRPM2 channel currents in both whole-cell and cell-free single-channel recordings and specific binding of cADPR to the purified NUDT9-H domain of TRPM2 by surface plasmon resonance. Furthermore, by combining computational modeling with electrophysiological recordings, we show that the TRPM2 channels carrying point mutations at H1346, T1347, L1379, S1391, E1409, and L1484 possess distinct sensitivity profiles for ADPR and cADPR. These results clearly indicate cADPR is a bona fide activator at the TRPM2 channel and clearly delineate the structural basis for cADPR binding, which not only lead to a better understanding in the gating mechanism of TRPM2 channel but also shed light on a cADPR-induced RyRs-independent Ca2+ signaling mechanism.


Assuntos
ADP-Ribosil Ciclase/metabolismo , Adenosina Difosfato Ribose/metabolismo , Cálcio/metabolismo , Pirofosfatases/metabolismo , Canais de Cátion TRPM/metabolismo , ADP-Ribosil Ciclase/química , ADP-Ribosil Ciclase/genética , Sítios de Ligação , Células HEK293 , Humanos , Mutação Puntual , Conformação Proteica , Pirofosfatases/química , Pirofosfatases/genética , Canais de Cátion TRPM/química , Canais de Cátion TRPM/genética
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