Meta-analysis of nine randomized controlled trials with a total of 1,421 patients was performed, and analysis of the nine papers included in the study yielded that the clinical effective rate of LHDD combined with conventional western medicines was significantly higher than that of the western medicines-only treatment group. Summarizing the clinical efficacy rate, recurrence rate, pain duration, CD3+ level, CD4+ level, and CD8+ level of the existing studies, it was also concluded that the recurrence rate, pain duration, CD3+ level, CD4+ level, and CD8+ level of the LHDD combined with conventional Western medicine treatment group were better than those of the Western medicine-only treatment group (P<0.05). Based on the evaluation of the above efficacy indexes, it was inferred that LHDD combined with conventional western drug treatment could improve oral ulcers complicated by chemotherapy for malignant tumors and bring clinical benefits to patients.
From the perspective of Chinese medicine, OU belong to the category of "mouth sores" in Chinese medicine. The basic theory of traditional Chinese medicine that the spleen and the mouth should be communicated, the heart and the tongue should be communicated, the kidney meridian through the tongue, cheeks, gums are attributed to the stomach meridian, large intestine meridian. Although OU are born in the mouth, they are closely related to the five viscera and six bowels.[15] The disease of OU is born in the mouth, but it is closely related to the five organs and six viscera. After chemotherapy for malignant tumors, patients may be accompanied by heart-spleen heat, spleen-heat-dampness, middle-anxiety deficiency and cold, yin-deficiency and fire, cold and heat mixed symptoms.[16] The following are some of the symptoms that may be associated with chemotherapy for malignant tumors. Glycyrrhiza glabra LHDD is one of the "five diarrhea heart soups" discussed in Zhang Zhongjing's "Treatise on Miscellaneous Diseases of Typhoid Fever", which consists of seven Chinese medicines, including ginseng, jujube, Huanglian, glycyrrhiza glabra, scutellaria baicalensis, dry ginger, and raw half-summer.[17] It strengthens the spleen and harmonizes the stomach, which is conducive to the production of qi and blood and the recovery of mucous membranes. Scutellaria baicalensis and Rhizoma Coptidis can protect the spleen and stomach from the damage of dampness-heat and prevent the transmission of dampness-heat; jujube and ginseng can tonify the middle qi, and combined with licorice, it can half-heartedly promote the restoration of positive qi.
Modern pharmacological studies of LHDD show that the main extracts of LHDD include quercetin, β-sitosterol, baicalein, kaempferol, stigmasterol, wisteria alkaloids, apigenin, naringenin, and safranin. Quercetin is a kind of flavonoid compound with various biological activities, possessing antioxidant activity, scavenging free radicals, analgesic, anti-inflammatory, antimicrobial, strengthening immunity, etc., in which the anti-inflammatory effect is mainly exerted through the inhibition of inflammatory diseases such as Monocyte Chemo-atractant Protein-1 (MCP-1), Interferon γ -10 inducible protein and other inflammatory mediators. Si Lijun et al.[18] intervened RAW264.7 cells with different concentrations of quercetin and demonstrated that quercetin, as a selective COX-2 inhibitor, possesses good anti-inflammatory activity, can play a promotional role in splenic lymphocyte proliferation and can inhibit T cell and B cell proliferation. Ying Yang[19] Quercetin was found to be able to play important pharmacological roles in antioxidant, antitumor, anti-inflammatory, antimicrobial, and cardiovascular protection by inhibiting oxidative stress, interfering with the renin-angiotensin-aldosterone system, and down-regulating the reactive oxygen species-mediated downstream signaling pathway, which is important for the treatment of oral ulcers after chemotherapy. Sterol is a phytosterol that has several beneficial effects on the body. β-sitosterol can inhibit the production of CAS1 and the activation of MAPK signaling pathway, thus reducing the production of TNF-α, IL-1β, IL-6, IL-8, and playing an anti-inflammatory role to promote the recovery of oral ulcers. β-sitosterol anti-inflammatory mechanism, in addition to inhibiting the cellular inflammatory signaling pathway, has an inhibitory effect on the activity of pro-inflammatory mediator synthase 5-lipoxygenase and cyclooxygenase-2, and also has an inhibitory effect on the activity of 5-lipoxygenase, 5-lipoxygenase, and cyclooxygenase-2. In addition to inhibiting cellular inflammatory signaling pathways, β-sitosterol has an important anti-inflammatory effect on the pro-inflammatory mediator synthases 5-lipoxygenase and cyclooxygenase-2[20]β-Sitosterol also has a certain ability to scavenge reactive oxygen radicals because of its triterpene structure. In the reaction system of lipid mediators, hydrogen transfer reaction is the key to scavenge moderately reactive oxygen radicals by β-sitosterol, and the formation of radical adducts is the mechanism to scavenge strongly reactive oxygen radicals by β-sitosterol. Studies have shown that baicalein has strong anti-inflammatory and antibacterial properties, not only inhibiting staphylococci and pneumococci[21–22], inhibit various pathogenic fungi of the skin, and inhibit the proliferation of oral bacteria. Baicalein, as the main extracted ingredient of LHDD, can maintain oral health and promote the healing of ulcerated surfaces by regulating the microenvironment of oral flora and inflammatory mediators. Kaempferol is an antioxidant that eliminates reactive oxygen species and exerts antioxidant effects, which is important for the treatment of potential diseases of the oral mucosa. Shen Yunzhang et al.[23] studied the inflammatory response of kaempferol at low, medium and high doses on mice with atopic dermatitis, and proved that kaempferol can make the inflammatory response of mice reduced, and has a protective effect on skin tissues, and in a certain range of dermatitis, the effect of symptomatic improvement of dermatitis is proportional to the dose. Soysterol decreased the expression of NF-κB/P65, inhibited the expression of pro-inflammatory mediators (TNF-α, IL-6, IL-1β, inducible nitric oxide synthase and cyclooxygenase-2) and increased the expression of inflammatory factors. Wu Lichao et al.[24] demonstrated the anti-inflammatory efficacy of soy sterols by demonstrating through network pharmacology and cellular experiments that soy sterols can effectively inhibit the levels of inflammatory factors IL-1β and TNF-α, and elevate the level of anti-inflammatory factor IL-10 in inflammation models. Huang Jianchun et al.[25] Observed the scavenging and inhibitory effects of soy sterol on O2- and OH by using in vitro assay method, and verified that both high and medium concentrations of soy sterol had prominent scavenging effects, and showed concentration dependence. Cavandinine inhibits the activity of inflammatory cells and the release of inflammatory factors, and has significant therapeutic effects on various inflammatory states and diseases associated with the inflammatory response process, mainly involving the NF-κB signaling pathway. Cavandinine may protect the ulcer surface by decreasing the levels of IL-6 and TNF-α, inhibiting the expression of cyclooxygenase 2 and the upregulation of NF-κB pathway[26] .
The pathogenesis of LHDD in the treatment of post-chemotherapy OU is mainly related to the following factors:① Regulation of gastric acid secretion and promotion of wound healing. Xu Xiupeng[27] The experimental results of Xu Xiupeng showed thatLHDD is an effective formula for the treatment of ulcers, which can effectively improve the quality of life of patients, such as reducing the frequency of pain, shortening the duration of pain, and decreasing the degree of pain. Lin Xiaochun et al.[28] By administering licorice flavonoids to feed gastritis model rats, it was demonstrated that LHDD has the effect of inhibiting mucosal damage and protecting and repairing damaged mucosal tissues. Chen Yanfen et al.[29] demonstrated that LHDD could reduce gastric fluid volume, total acid excretion and pepsin activity, confirming that LHDD could inhibit gastric acid secretion.Takase H [30] concluded that Huanglian, as an important component of LHDD, could effectively reduce gastric acid secretion induced by central stimulant (2-deoxyglucose). Chen JQ et al.[31] demonstrated that LHDD could affect gastrointestinal motility in rats with gastric ulcers, causing a decrease in gastric juice secretion and an effect on the proton pump, which caused a decrease in H+ in the gastric lumen and a decrease in gastric acid synthesis. Liu A-Min.[32] Clinical observation of internal administration of LHDD combined with external application of moist burns cream in the treatment of leukodystrophy revealed that the time of disappearance of oral ulcers became shorter in patients of LHDD. Liu Xiaohui[33] Using LHDD to treat 240 patients with recurrent oral ulcers, it was found that LHDD could regulate the level of Epidermal Growth Factor (EGF), promote the proliferation and repair of epithelial cells, accelerate the healing of ulcers, and make the healing of ulcers more complete. ②Anti-inflammatory and immunomodulatory effects.LHDD acts as an inhibitory drug for pro-inflammatory factors, which can reduce pain, promote ulcer healing, and prolong the interstitial period. Some scholars[34–35, 37] found that LHDD has outstanding anti-inflammatory effect, can effectively regulate the level of inflammatory mediators, inflammatory cytokines, related enzymes and nuclear factors, and can effectively improve the imbalance of children's blood T-lymphocyte subpopulation, regulate the microenvironment of oral flora, and promote the healing of OU after chemotherapy. Zhang Jianwei et al.[36][38] The experimental results showed that LHDD could significantly reduce the positive expression of TLR4 and NF-KBp 65, decrease the content of tumor necrosis factor TNF-α and interleukin IL-8 in rat serum, and inhibit the expression of pro-inflammatory factors IL-6 and IL-8, which proved that LHDD had a good protective effect on ulcer surfaces, and it could give full play to its anti-inflammatory, immune-modulating and analgesic effects.
This study has some limitations: ① The original data of this study were all in Chinese literature, and there was no English literature, so it is assumed that there is publication bias; ② The shortest treatment period in this study was 7d, and the longest treatment period was 30d, which is a big difference, and it reduces the credibility of the results of the analysis; ③ There is a difference between the clinical use of LHDD, and the conventional western medicines given to the treatment of the control groups are different, which is assumed to affect the credibility of the results; ④ The pain duration and CD8+ level are small in base and total sample size, and the credibility of results is low. (iv) The study base and total sample size of pain duration and CD8+ level were small, and the credibility of the results was low.
In conclusion,according to the current research evidence,LHDD combined with conventional western drugs can effectively treat OU after chemotherapy for malignant tumors with good safety and low recurrence rate of oral OU.