Life sciences · 2016
Molecular mechanisms of gallic acid-induced growth inhibition, apoptosis, and necrosis in hypertrophic scar fibroblasts.
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Hsieh Shu-Chung, Wu Chun-Chi, Hsu Shih-Lan, Yen Jung-Hsing
Аннотация
AIMS: To explore the effect and molecular mechanism of gallic acid (GA) on the cytostatic and cytotoxicity of hypertrophic scar fibroblasts (HSFs).
MATERIALS AND METHODS: HSFs were treated with a serial dose of GA for indicated time. The cytostatic and cytotoxicity of GA were evaluated by microscopy, trypan blue exclusion assay and LDH releasing. The mechanisms of GA-induced cytostatic were examined by cell cycle distribution assay and the expression of cell cycle-relative protein. GA-elicited apoptosis were verified by TUNEL assay, mitochondria membrane potential, caspase activity and the expression of apoptosis-relative protein. GA-induced necrosis was confirmed by lysosome rupture using acridine orange stain. Various blockers, including intracellular calcium chelator; BAPTA-AM, IP3R blocker; 2-APB, calpain inhibitor, ALLM and ALLN were used to address the signaling cascade in GA-induced HSF necrosis.
KEY FINDINGS: GA-induced growth inhibition, apoptosis, and necrosis in HSFs depend on increasing dose. HSFs treated with GA at non-cytotoxic concentrations (50 to 75μM) significant increased both the S- and G2/M-phase HSFs population, and this event was accompanied with down-regulation of cyclin A, cyclin B, CDK1 and CDK2. Incubation of HSFs with 100-150μM of GA induced apoptosis through Bcl2/Bax-mitochondrial-dependent pathway. While the concentrations up to 200μM of GA that elicited necrosis via a calcium/calpain I/lysosome rupture signaling axis. Interestingly, GA at 200μM did not harm to keratinocyte.
SIGNIFICANCE: These results revealed that GA might have the potential to be developed as a treatment for patients with hypertrophic scar.
MATERIALS AND METHODS: HSFs were treated with a serial dose of GA for indicated time. The cytostatic and cytotoxicity of GA were evaluated by microscopy, trypan blue exclusion assay and LDH releasing. The mechanisms of GA-induced cytostatic were examined by cell cycle distribution assay and the expression of cell cycle-relative protein. GA-elicited apoptosis were verified by TUNEL assay, mitochondria membrane potential, caspase activity and the expression of apoptosis-relative protein. GA-induced necrosis was confirmed by lysosome rupture using acridine orange stain. Various blockers, including intracellular calcium chelator; BAPTA-AM, IP3R blocker; 2-APB, calpain inhibitor, ALLM and ALLN were used to address the signaling cascade in GA-induced HSF necrosis.
KEY FINDINGS: GA-induced growth inhibition, apoptosis, and necrosis in HSFs depend on increasing dose. HSFs treated with GA at non-cytotoxic concentrations (50 to 75μM) significant increased both the S- and G2/M-phase HSFs population, and this event was accompanied with down-regulation of cyclin A, cyclin B, CDK1 and CDK2. Incubation of HSFs with 100-150μM of GA induced apoptosis through Bcl2/Bax-mitochondrial-dependent pathway. While the concentrations up to 200μM of GA that elicited necrosis via a calcium/calpain I/lysosome rupture signaling axis. Interestingly, GA at 200μM did not harm to keratinocyte.
SIGNIFICANCE: These results revealed that GA might have the potential to be developed as a treatment for patients with hypertrophic scar.