Page 85 - 2022-26-中国全科医学

·3282· http://www.chinagp.net E-mail:zgqkyx@chinagp.net.cn

3.Department of Pharmacy，College of Medicine of Qilu，Shandong University，Jinan 250012，China
*
Corresponding authors：LIU Fei，Researcher；E-mail：lfshwu@163.com
GUO Bin，Professor；E-mail：jyguobin@126.com
【Abstract】 Background Excessive levels of oxidative stress and long-term inflammatory state seriously affect wound
healing in diabetic patients. At present，there are biological agents，traditional Chinese medicines，stem cell therapy etc. used
in treating diabetic cutaneous ulcer（DCU）. Due to lack of sufficient evidence of safety and effectiveness，these methods are not
widely applied in clinical treatment. Thus new drugs need to be discovered urgently. Hyaluronic acid oligosaccharide （o-HA）
is a potential drug for the treatment of DCU because of its antioxidant and anti-inflammatory properties. Objective To observe
the effect of o-HA on DCU wound healing and explore its influence on oxidative stress Nrf2 signaling pathway. Methods This
experiment was conducted from April to December，2021. Ninety SPF male mice of six-week-old from Kunming were selected.
Ten of them were reserved as the normal control group（NC group） and the rest were injected with streptozotocin（STZ） by
abdomen to induce diabetes mouse model. Sixty diabetic mice modeled successfully were divided into 6 groups according to random
number table with ten in each group，namely the diabetic model group（DM group），the recombinant human epidermal growth
factor positive control group（rhEGF group），the blank matrix negative group（matrix group），low-dose o-HA treatment group（0.5%
o-HA group），medium-dose o-HA treatment group（1% o-HA group） and high-dose o-HA treatment group（2% o-HA
group）. The DCU model was established in all mice by way of the full-thickness skin excision ring splint. The wounds in NC and
DM group were not treated. For the other groups，the corresponding medicines were evenly applied to and around the wounds after
daily disinfection. The mice in rhEGF group were administered once a day while the mice in the 0.5%，1% and 2% o-HA group
were medicated twice a day for consecutive 14 days. The wound healing condition of DCU mice was recorded after being treated on
the first，the 7th and the 14th day. The morphological changes of granulation tissue，collagen fiber formation and angiogenesis in
mice wounds were observed by HE staining，Masson staining and CD34 immunohistochemical staining. The serum SOD and MDA
levels of mice were examined by the kits. The Nrf2，HO-1 and NQO1 protein expression in wound tissue of mice were detected by
Western-blotting after the administration of 14 days. Results On the seventh day of administration，the wound healing rate of
rhEGF group and 1% o-HA group was higher than that of DM group and the wound healing rate of 0.5% o-HA group and 2% o-HA
group was lower than that of NC group and higher than that of DM group. On the 14th day of administration，the wound healing
rate of rhEGF group，0.5% o-HA group，1% o-HA group and 2% o-HA group was higher than that of DM group（P<0.05）.
The histomorphology showed that the granulation tissue of the wound，collagen fiber and density of neovascularization were
significantly increased after o-HA ointment intervention. The level of MDA in the rhEGF group，0.5% o-HA group，1% o-HA
group and 2% o-HA group was lower than that of DM group，and the level of SOD in these four groups was higher than that of DM
group；the level of MDA in 0.5% o-HA and 2% o-HA groups was higher than that of NC group（P<0.05）. The levels of Nrf2，
HO-1 and NQO1 protein expression in both rhEGF group and 1% o-HA group were higher than those of NC and DM group；
the levels of Nrf2 and NQO1 protein expression in 0.5% o-HA group were higher than those of DM group，and the level of HO-1
protein expression was higher than that of NC and DM group；the level of HO-1 protein expression in 2% o-HA group was
higher than that of NC and DM group，and the level of NQO1 protein expression was higher than that of DM group（P<0.05）.
Conclusion o-HA has a potential healing effect for DCU wound in mice，and the healing effect of 1% o-HA ointment is the
most remarkable. It can help wound healing by accelerating wound closure and re-epithelization，promoting angiogenesis and
affecting the Nrf2 pathway. With advantages of high safety and good stability，o-HA has great potential in clinical diabetic wound
healing.
【Key words】 Diabetes mellitus；Diabetes complications；Diabetic cutaneous ulcers；Hyaluronic acid
oligosaccharides；Wound healing；NF-E2-related factor 2

糖尿病是世界范围内常见和严重的慢性疾病之一。 原因，影响创面愈合的各个阶段，严重者发生感染，甚
根据《国际糖尿病联合会》第 10 版报告，2021 年全球 至截肢 ［3-5］ 。因此，调节机体氧化还原平衡、促进血管
20~79 岁人群糖尿病患病率为 10.5%（5.366 亿），预计 新生从而加速创面愈合是加快糖尿病创面愈合的潜在治
2045 年将上升至 12.2%（7.832 亿） ［1］ 。糖尿病皮肤溃 疗方法。
疡（diabetic cutaneous ulcer，DCU）是糖尿病严重的慢 透 明 质 酸（hyaluronan，HA） 是 细 胞 外 基 质
性并发症之一，致残率高、治疗费用昂贵 ［2-3］ 。糖尿病 （extracellular matrix，ECM）中的一种高分子糖胺聚糖，
状态下氧化应激水平过高是 DCU 患者创面难愈的重要 由重复的 D- 葡萄糖醛酸和 N- 乙酰葡萄糖胺二糖单元