柚皮素对人角膜上皮细胞毒性的实验研究

doi:10.3877/cma.j.issn.2095-2007.2021.01.007

目的

探讨柚皮素(Nar)对人角膜上皮细胞(HCECs)的毒性。

方法

对购于青旗上海生物技术发展有限公司的HCECs进行细胞毒性实验和划痕实验。应用四氮唑盐比色分析法检测二甲基亚砜(DMSO)溶剂和Nar对HCECs细胞存活率的影响，采用Graphpad Prism8.0软件绘制细胞存活率曲线并计算半抑制浓度(IC₅₀)。应用划痕实验观察不同浓度Nar对HCECs迁移的影响，采用ImageJ软件计算细胞的愈合率。吸光度值、存活率及愈合率数值符合正态分布，均采用均数±标准差表示。不同浓度的DMSO溶剂和Nar溶液对HCECs 24 h、48 h及72 h存活率的比较；不同浓度Nar对HCECs 6 h、12 h及24 h划痕愈合率的比较，均采用独立样本t检验。

结果

体积百分比为0.04%、0.08%及0.16%的DMSO处理HCECs 24 h，其存活率分别为(94.57±0.83)%、(93.59±1.17)%及(91.43±1.47)%。经t检验，各浓度DMSO处理HCECs 24 h，其存活率与DMEM(dulbecco′s modified eagle medium)组比较的差异均有统计学意义(t＝3.436，3.882，4.960；P<0.05)。体积百分比为0.08%和0.16%的DMSO处理HCECs 48 h，其存活率分别为(94.43±0.38)%和(93.16±0.66)%。经t检验，各浓度DMSO处理HCECs 48 h，其与DMEM组比较存活率的差异均有统计学意义(t＝2.953，3.573；P<0.05)。体积百分比为0.02%、0.04%、0.08%及0.16%的DMSO处理HCECs 72 h，其存活率分别为(96.28±0.29)%、(95.30±0.25)%、(94.65±0.82)%及(93.73±1.18)%。经t检验，各浓度DMSO处理HCECs 72 h，其与DMEM组比较存活率的差异均有统计学意义(t＝3.756，4.763，4.929，5.263；P<0.05)。200 μM、400 μM及800 μM Nar溶液处理HCECs 48 h，其存活率分别为(60.17±0.46)%、(47.55±0.91)%及(29.19±1.25)%；72 h的存活率分别为(60.02±6.20)%、(31.20±1.96)%及(22.96±2.69)%。经t检验，各浓度Nar处理HCECs 48 h和72 h，其与24 h比较存活率的差异均有统计学意义(t＝12.903，6.675, 11.215，5.377，12.696，11.972；P<0.05)。25 μM、400 μM及800 μM Nar溶液处理HCECs 72 h，其存活率分别为(89.41±1.38)%、(31.20±1.96)%及(22.96±2.69)%。经t检验，各浓度Nar溶液处理HCECs 72 h，其与48 h比较存活率的差异均有统计学意义(t＝4.442，13.119，3.631；P<0.05)。Nar溶液对HCECs 24 h、48 h及72 h的IC₅₀分别为690.8 μM、343.4 μM及237.7 μM；IC₅₀ 95%可信区间分别为(574.1~845.5)、(259.2~734.3)及(231.1~266.7)。HCECs在0、100 μM、200 μM及400 μM Nar溶液中HCECs 6 h的划痕愈合率分别为(18.04±1.61)%、(16.91±1.56)%、(16.63±2.12)%及(12.20±2.06)%。划痕愈合的时间越长，HCECs的愈合率越高。细胞在100 μM Nar溶液浓度中各时间段的划痕愈合率与DMEM组比较的差异均无统计学意义(t＝0.872，1.074，1.620；P>0.05)；400 μM Nar溶液各时间段的划痕愈合率与DMEM组比较的差异均有统计学意义(t＝3.863，9.869，27.194；P<0.05)；200 μM Nar溶液处理HCECs 12 h和24 h，其划痕愈合率与DMEM组比较的差异均有统计学意义(t＝5.714，9.119；P<0.05)。

结论

Nar可降低HCECs存活率并抑制HCECs迁移愈合率，对HCECs具有毒性。

关键词: 人角膜上皮细胞, 柚皮素, 二甲基亚砜, 毒性

Objective

The aim of this study was to investigate the toxicity of naringenin (Nar) to human corneal epithelial cells (HCECs).

Methods

HCECs purchased from Qingqi Shanghai Biotechnology Development Co., Ltd. were used for cytotoxicity test and scratch test. The tetrazolium salt colorimetric assay was used to detect the cell survival of Nar and DMSO on HCECs. Graphpad Prism8.0 software was used to map the cells survival curve and calculate the half inhibitory concentration (IC₅₀). The scratch experiment was used to observe the effect of different concentrations of Nar on the migration of HCECs. ImageJ was used to calculate the cell healing rate (HR). OD value, survival rate (SR) and HR were in accordance with normal distribution, and expressed by ±s.The independent sample t-testing method was used to compare SR of HCECs with different concentrations of DMSO solvent and Nar solution for 24 h, 48 h and 72 h; and the wound HR of cells at 6 h, 12 h and 24 h with different concentrations of Nar.

Results

The SR of HCECs in the DMSO 0.04%, 0.08% and 0.16% groups for 24 h was (94.57±0.83)%, (93.59±1.17)% and (91.43±1.47)%, respectively. After t testing, compared with the DMEM group, the difference in the SR of HCECs was statistically significant (t=3.436, 3.882, 4.960; P<0.05). The SR of HCECs was (94.43±0.38)% and (93.16±0.66)% in the DMSO group with a volume percentage of 0.08% and 0.16% for 48 h. After t testing, compared with the DMEM group, the difference in the SR of HCECs was statistically significant (t=2.953, 3.573; P<0.05). In the DMSO group with the volume percentage of 0.02%, 0.04%, 0.08% and 0.16% for 72 h, the SRs of HCECs were (96.28±0.29)%, (95.30±0.25)%, (94.65±0.82)% and (93.73±1.18)%. After t testing, the difference in the SR of HCECs between different DMSO volume percentage and the DMEM group was statistically significant (t=3.756, 4.763, 4.929, 5.263; P<0.05). The SRs of HCECs treated with 200 μM, 400 μM and 800 μM Nar solutions for 48 h were (60.17±0.46)%, (47.55±0.91)% and (29.19±1.25)%, respectively; the SRs at 72 h were ( 60.02±6.20)%, (31.20±1.96)% and (22.96±2.69)%. After t testing, the difference in SR of HCECs for 48 h and 72 h compared with that for 24 h, was statistically significant (t=12.903, 6.675, 11.215, 5.377, 12.696, 11.972; P<0.05). The SRs of HCECs treated with 25 μM, 400 μM and 800 μM Nar solutions for 72 h were (89.41±1.38)%, (31.20±1.96)% and (22.96±2.69)%, respectively. After t testing, the SR of HCECs for 72 h compared with that for 48 h was significantly different (t=4.442, 13.119, 3.631; P<0.05). The IC₅₀ of Nar solution for HCECs at 24 h, 48 h and 72 h was 690.8 μM, 343.4 μM and 237.7 μM, respectively, and the 95% confidence intervals of IC₅₀ were (574.1 to 845.5), (259.2 to 734.3) and (231.1 to 266.7). The migration area coverage rate of HCECs for 6 h in 0, 100 μM, 200 μM and 400 μM Nar solutions were (18.04±1.61)%, (16.91±1.56)%, (16.63±2.12)% and (12.20±2.06) %, respectively. The migration area coverage rate of HCECs gradually increased with time. Compared with the DMEM group, there was no significant difference in the migration area coverage rate of cells added with 100 μM Nar solution in per time period (t=0.872, 1.074, 1.620; P>0.05); the difference in that of cells added with 400 μM Nar was statistically significant (t=3.863, 9.869, 27.194; P<0.05); the difference in the scar HR of HCECs added with 200 μM Nar after scratching for 12 h and 24 h was significantly different (t=5.714, 9.119; P<0.05).

Conclusions

Nar could reduce the SR of HCECs and inhibit the migration and HR of HCECs, which is toxic to HCECs.

Key words: Human corneal epithelial cells, Naringenin, Dimethyl sulfoxide, Toxicity

表1 不同浓度二甲基亚砜中24 h、48 h及72 h细胞存活率的比较(±s)

项目	0	0.0025%DMSO	0.005%DMSO	0.01%DMSO	0.02%DMSO	0.04%DMSO	0.08%DMSO	0.16%DMSO
24 h OD值	0.415±0.011	0.412±0.108	0.409±0.011	0.406±0.012	0.403±0.012	0.398±0.013	0.395±0.014	0.389±0.012
存活率(%)	100.00±2.61	98.92±0.48	98.05±0.55	97.18±0.53	95.98±0.61	94.57±0.83^*	93.59±1.17^*	91.43±1.47^*
t值		0.704	1.266	1.836	2.598	3.436	3.882	4.960
P值		>0.05	>0.05	>0.05	>0.05	<0.05	<0.05	<0.05
48 h OD值	0.477±0.016	0.474±0.015	0.470±0.016	0.467±0.015	0.464±0.015	0.461±0.014	0.456±0.014	0.452±0.013
存活率(%)	100.00±3.25	99.10±0.12	98.11±0.07	97.30±0.20	96.50±0.45	95.60±0.54	94.43±0.38^*	93.16±0.66^*
t值		0.479	1.009	1.436	1.851	2.315	2.953	3.573
P值		>0.05	>0.05	>0.05	>0.05	>0.05	<0.05	<0.05
72 h OD值	0.615±0.010	0.610±0.010	0.605±0.010	0.601±0.015	0.596±0.010	0.591±0.009	0.588±0.010	0.583±0.012
存活率(%)	100.00±1.69	98.96±0.08	98.04±0.06	97.19±0.19	96.28±0.29^*	95.30±0.25^*	94.65±0.82^*	93.73±1.18^*
t值		1.068	2.010	2.860	3.756	4.763	4.929	5.263
P值		>0.05	>0.05	>0.05	<0.05	<0.05	<0.05	<0.05

表1 不同浓度二甲基亚砜中24 h、48 h及72 h细胞存活率的比较(±s)

项目	0	0.0025%DMSO	0.005%DMSO	0.01%DMSO	0.02%DMSO	0.04%DMSO	0.08%DMSO	0.16%DMSO
24 h OD值	0.415±0.011	0.412±0.108	0.409±0.011	0.406±0.012	0.403±0.012	0.398±0.013	0.395±0.014	0.389±0.012
存活率(%)	100.00±2.61	98.92±0.48	98.05±0.55	97.18±0.53	95.98±0.61	94.57±0.83^*	93.59±1.17^*	91.43±1.47^*
t值		0.704	1.266	1.836	2.598	3.436	3.882	4.960
P值		>0.05	>0.05	>0.05	>0.05	<0.05	<0.05	<0.05
48 h OD值	0.477±0.016	0.474±0.015	0.470±0.016	0.467±0.015	0.464±0.015	0.461±0.014	0.456±0.014	0.452±0.013
存活率(%)	100.00±3.25	99.10±0.12	98.11±0.07	97.30±0.20	96.50±0.45	95.60±0.54	94.43±0.38^*	93.16±0.66^*
t值		0.479	1.009	1.436	1.851	2.315	2.953	3.573
P值		>0.05	>0.05	>0.05	>0.05	>0.05	<0.05	<0.05
72 h OD值	0.615±0.010	0.610±0.010	0.605±0.010	0.601±0.015	0.596±0.010	0.591±0.009	0.588±0.010	0.583±0.012
存活率(%)	100.00±1.69	98.96±0.08	98.04±0.06	97.19±0.19	96.28±0.29^*	95.30±0.25^*	94.65±0.82^*	93.73±1.18^*
t值		1.068	2.010	2.860	3.756	4.763	4.929	5.263
P值		>0.05	>0.05	>0.05	<0.05	<0.05	<0.05	<0.05

图4 倒置光学显微镜下人角膜上皮细胞在不同浓度柚皮素各时间段内划痕愈合后的形态(100×)　4A~4D分别示实验初始时人角膜上皮细胞在柚皮素0、100 μM、200 μM及400 μM浓度下的形态；4E~4K分别示划痕6 h后人角膜上皮细胞在柚皮素0、100 μM、200 μM及400 μM浓度下的愈合后形态；4L~4O分别示划痕12 h后人角膜上皮细胞在柚皮素0、100 μM、200 μM及400 μM浓度下的愈合后形态；4P~4S分别示划痕24 h后人角膜上皮细胞在柚皮素0、100 μM、200 μM及400 μM浓度下的愈合后形态

表2 不同浓度柚皮素溶液中24 h、48 h及72 h细胞存活率的比较(±s)

项目	0	25 μM Nar	50 μM Nar	100 μM Nar	200 μM Nar	400 μM Nar	800 μM Nar	1600 μM Nar
24 h OD值	0.416±0.006	0.393±0.011	0.378±0.016	0.358±0.011	0.355±0.013	0.297±0.020	0.276±0.013	0.164±0.016
存活率(%)	100.00±1.47	92.81±2.27^a	88.02±3.22^a	82.03±2.03^a	81.11±2.77^a	62.69±3.82^a	56.03±3.95^a	20.87±1.30^a
t值		4.596	5.86	12.421	10.421	15.775	18.058	69.858
P值		<0.05	<0.05	<0.05	<0.05	<0.05	<0.05	<0.05
48 h OD值	0.461±0.008	0.439±0.005	0.404±0.007	0.401±0.006	0.320±0.007	0.275±0.006	0.210±0.005	0.167±0.005
存活率(%)	100.00±0.49	93.78±1.01^a	83.99±3.31^a	83.14±3.07^a	60.17±0.46^ab	47.55±0.91^ab	29.19±1.25^ab	17.04±2.00^a
t值		9.628	8.28	9.397	102.698	88.208	91.503	69.768
P值		<0.05	<0.05	<0.05	<0.05	<0.05	<0.05	<0.05
72 h OD值	0.638±0.030	0.584±0.029	0.568±0.023	0.540±0.030	0.434±0.006	0.287±0.042	0.245±0.019	0.201±0.012
存活率(%)	100.00±1.90	89.41±1.38^ac	86.35±1.53^a	80.81±0.27^a	60.02±6.20^ab	31.20±1.96^abc	22.96±2.69^abc	14.40±4.02^a
t值		7.813	9.765	17.307	10.673	43.648	40.463	33.348
P值		<0.05	<0.05	<0.05	<0.05	<0.05	<0.05	<0.05

表2 不同浓度柚皮素溶液中24 h、48 h及72 h细胞存活率的比较(±s)

项目	0	25 μM Nar	50 μM Nar	100 μM Nar	200 μM Nar	400 μM Nar	800 μM Nar	1600 μM Nar
24 h OD值	0.416±0.006	0.393±0.011	0.378±0.016	0.358±0.011	0.355±0.013	0.297±0.020	0.276±0.013	0.164±0.016
存活率(%)	100.00±1.47	92.81±2.27^a	88.02±3.22^a	82.03±2.03^a	81.11±2.77^a	62.69±3.82^a	56.03±3.95^a	20.87±1.30^a
t值		4.596	5.86	12.421	10.421	15.775	18.058	69.858
P值		<0.05	<0.05	<0.05	<0.05	<0.05	<0.05	<0.05
48 h OD值	0.461±0.008	0.439±0.005	0.404±0.007	0.401±0.006	0.320±0.007	0.275±0.006	0.210±0.005	0.167±0.005
存活率(%)	100.00±0.49	93.78±1.01^a	83.99±3.31^a	83.14±3.07^a	60.17±0.46^ab	47.55±0.91^ab	29.19±1.25^ab	17.04±2.00^a
t值		9.628	8.28	9.397	102.698	88.208	91.503	69.768
P值		<0.05	<0.05	<0.05	<0.05	<0.05	<0.05	<0.05
72 h OD值	0.638±0.030	0.584±0.029	0.568±0.023	0.540±0.030	0.434±0.006	0.287±0.042	0.245±0.019	0.201±0.012
存活率(%)	100.00±1.90	89.41±1.38^ac	86.35±1.53^a	80.81±0.27^a	60.02±6.20^ab	31.20±1.96^abc	22.96±2.69^abc	14.40±4.02^a
t值		7.813	9.765	17.307	10.673	43.648	40.463	33.348
P值		<0.05	<0.05	<0.05	<0.05	<0.05	<0.05	<0.05

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The toxicity of naringenin to human corneal epithelial cells

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The toxicity of naringenin to human corneal epithelial cells