Fu-Huang ointment ameliorates impaired wound healing associated with diabetes through PI3K-AKT signalling pathway activation.

A diabetic ulcer (DU) is a dreaded and resistant complication of diabetes mellitus with high morbidity. Fu-Huang ointment (FH ointment) is a proven recipe for treating chronic refractory wounds; however, its molecular mechanisms of action are unclear. In this study, we identified 154 bioactive ingredients and their 1127 target genes in FH ointment through the public database. The intersection of these target genes with 151 disease-related targets in DUs resulted in 64 overlapping genes. Overlapping genes were identified in the PPI network and enrichment analyses. The PPI network identified 12 core target genes, whereas Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that upregulation of the PI3K/Akt signalling pathway was involved in the role of FH ointment in treating diabetic wounds. Molecular docking showed that 22 active compounds in FH ointment could enter the active pocket of PIK3CA. Molecular dynamics was used to prove the binding stability of the active ingredients and protein targets. We found that PIK3CA/Isobutyryl shikonin and PIK3CA/Isovaleryl shikonin combinations had strong binding energies. An in vivo experiment was conducted on PIK3CA, which was the most significant gene.This study comprehensively elucidated the active compounds, potential targets, and molecular mechanism of FH ointment application in treating DUs, and believed that PIK3CA is a promising target for accelerated healing.

[Expert consensus on Tongsaimai Tablets/Capsules in treatment of peripheral vascular diseases in clinical practice].

Tongsaimai Tablets/Capsules are composed of Lonicerae Japonicae Flos, Angelicae Sinensis Radix, Achyranthis Bidentatae Radix, Codonopsis Radix, Dendrobii Caulis, Astragali Radix, Scrophulariae Radix, and Glycyrrhizae Radix et Rhizoma, and are effective in promoting blood circulation, removing blood stasis, supplementing Qi, and nourishing Yin. It is widely used in the treatment of peripheral vascular diseases. With 40 years of clinical application, it has accumulated substantial research data and application experience. Its good clinical efficacy and pharmacoeconomic benefits in improving the clinical symptoms of peripheral vascular diseases have been confirmed by relevant research. Meanwhile, this drug has also been recommended by many expert consensus, guidelines, and teaching materials, serving as one of the most commonly used Chinese patent medicines in clinical practice. To further improve the understanding of the drug among clinicians and properly guide its clinical medication, the China Association of Chinese Medicine took the lead and organized experts to jointly formulate this expert consensus. Based on the questionnaire survey of clinicians and the systematic review of research literature on Tongsaimai Tablets/Capsules with clinical problems in the PICO framework, the consensus, combined with expert experience, concludes recommendations or consensus suggestions by GRADE system with the optimal evidence available through the nominal group technique. This consensus defines the indications, usage, dosage, course of treatment, medication time, combined medication, and precautions of Tongsaimai Tablets/Capsules in the treatment of peripheral vascular diseases, and explains the safety of its clinical application. It is recommended for clinicians and pharmacists in the peripheral vascular department(vascular surgery), traditional Chinese medicine surgery(general surgery), and endocrinology department of hospitals at all levels in China.

KangFuXin Liquid in the Treatment of Diabetic Foot Ulcer: A Systematic Review and Meta-Analysis.

BACKGROUND: Diabetic foot ulcer (DFU) is one of the most common complications of diabetes mellitus, with the wound not healing as expected and healing slowly. Poor control can develop into gangrene and even amputation. Currently, the existing treatments are not satisfactory enough. In China, KangFuXin liquid (KFXL) has been clinically used to treat DFU and has shown good clinical efficacy. In order to provide more reference to clinicians and experts, evidence of efficacy for it needs to be further rigorously evaluated. METHODS: Eight electronic databases were searched to identify eligible randomized clinical trials (RCTs) published from construction of the library to April 2019. There is no language or data restriction; 11 trials involving 889 participants met the inclusion criteria. These RCTs compared the total effective rate, cure rate, cure time, and adverse events associated with KFXL. The Cochrane Handbook guidelines were used to assess the risk of bias and to evaluate the methodological quality of eligible studies. The methodological quality of included studies was generally low. Dichotomous and continuous data were presented using risk ratios (RRs) and mean differences (MDs), respectively. RESULTS: Compared with the basic treatment, meta-analyses showed that KFXL combined with basic treatment can improve the total effective rate (RR = 1.38; 95% CI = 1.23-1.54; P < 0.00001; fixed effect model: I 2 = 32%) and cure rate (RR = 1.67; 95% CI = 1.17-2.38; P=0.005; random effect model: I 2 = 65%), and shorten the healing time (MD = -5.73; 95% CI = -6.95 to -4.52; P < 0.00001; random effect model). Moreover, under the same basic treatment, KFXL had a better effect than external use of pharmaceutical medications (RR = 1.95; 95% CI = 1.30-2.93; P=0.001), but the cure rate was not significantly different. Also, KFXL had nothing to do with adverse reactions. CONCLUSION: The evidence confirms that KFXL is an effective treatment for DFU. However, further large-scale, rigorously designed trials and high-quality studies are needed to confirm the role of KFXL in the treatment of DFU.

Chinese herbal medicines for treating skin and soft-tissue infections.

BACKGROUND: Skin and soft-tissue infections (SSTIs) are common infections of the epidermis, dermis or subcutaneous tissue. SSTIs range in severity from minor, self-limiting, superficial infections to deep, aggressive, gangrenous, life-threatening infections. Some classifications divide SSTIs into 'complicated' and 'uncomplicated' infections based on clinical severity. Treatments of SSTIs involves antibiotic therapy, surgical debridement or drainage, and resuscitation if required. Sometimes these treatments are limited by high treatment costs, bacterial resistance to antibiotics and side effects, therefore, many people with SSTIs are turning to Chinese herbal medicines to treat this problem.Chinese herbal medicines are natural substances that have been used for centuries in China where they are generally considered to be effective for SSTIs. Some Chinese herbal medicines have been shown to have antibacterial and anti-inflammatory properties, although a few herbal medicines have been reported to have side effects. Therefore there is a need to review the current clinical evidence systematically to inform current practice and guide future studies on Chinese herbal medicines for SSTIs. OBJECTIVES: To evaluate the benefits and harms of Chinese herbal medicines for treating skin and soft-tissue infections (SSTIs). SEARCH METHODS: Searches were not restricted by date, language or publication status. In July 2014 we searched the following electronic databases: the Cochrane Wounds Group Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; Ovid AMED (Allied and Complementary Medicine); and EBSCO CINAHL. SELECTION CRITERIA: All randomised controlled trials (RCTs) in people with SSTIs that compared Chinese herbal medicines with another intervention or control. DATA COLLECTION AND ANALYSIS: Two review authors screened the literature search results independently; there were no disagreements. MAIN RESULTS: We identified no RCTs that met the inclusion criteria. AUTHORS' CONCLUSIONS: There is currently no information available from RCTs to support or refute the use of Chinese herbal medicines in treating people with SSTIs.

[Assessment of external methods of traditional Chinese medicine in patients with chronic ulcer of the lower extremities: study protocol of a multicenter, randomized, parallel-group, prospective trial].

BACKGROUND: Chronic ulcer of the lower extremities amounts for a grave and serious problem for public health. Western medicine focuses on controlling infection, improving blood circulation, surgical debridement, skin grafting, etc, but there are bottlenecks in the treatment. Traditional Chinese medicine (TCM) has a long history and a legacy of sound clinical efficacy in this area. TCM has developed a unique, effective external theory, and a large number of topical prescriptions and external technology. Through this research, a safe and effective treatment protocol of TCM for chronic ulcer of the lower extremities can be formed. To this end, during China's "Eleventh Five-Year" Plan, special research committees and projects on TCM external treatments and external technologies were established. This study on ulcer of the lower extremities constitutes one of the major research topics. METHODS AND DESIGN: Clinical information of patients with chronic ulcer of the lower extremities will be first collected in a large, multicenter, epidemiological survey. Concurrently, a large multicenter, randomized, parallel-group, prospective study will be launched based on evidence-based medical principles to evaluate the efficacy and safety of external methods for removing carrion, dissolving stasis, reinforcing deficiency and promoting tissue regeneration. The evaluated indexes will include the wound healing percentage for primary outcome, wound healing time, wound healing rate, time and rate of removal of necrotic tissue, and TCM syndromes for secondary outcomes and routine blood test, routine urine test, liver and kidney function, blood mercury content and finally urine mercury content for adverse events. DISCUSSION: In this trial, the authors will evaluate the efficacy and safety of external methods for removing carrion, dissolving stasis, reinforcing deficiency and promoting tissue regeneration in cases of chronic ulcer of the lower extremities for standardizing external therapy of TCM for treatment of this condition, and establishing the clinical assessment system for TCM. TRIAL REGISTRATION NUMBER: The research program was registered in the Chinese Clinical Trial Registry in both English and Chinese in June 2011. REGISTRATION NUMBER: ChiCTR-TRC-11001365.

[Effects of Chinese herbal medicine Yiqi Huayu formula on substance P expression in skin ulcers of rats with diabetes mellitus].

OBJECTIVE: To investigate the effects of Chinese herbs for replenishing qi (Yiqi) and dissolving stasis (Huayu) on substance P expression in granulation tissue of skin ulcers in rats with diabetes mellitus. METHODS: One hundred male Sprague-Dawley rats with back full-thickness skin lesion were randomly divided into five groups: ulcer control group, diabetic ulcer group, Yiqi Huayu herb group, Yiqi herb group, and Huayu herb group. Except ulcer control group, the other rats were also injected streptozotocin to induce diabetes mellitus. Rats in each group were given normal saline or herbal drugs for 15 d and the wound healing rate of the rats was observed on days 8 and 15, respectively. After treatment, the expression of substance P in granulation tissues of the rats was tested with immunohistochemical method and the immunohistochemical index was calculated. RESULTS: On the 8th and 15th days after treatment, the wound healing rate of the ulcer control group was higher than that of the diabetic ulcer group (P<0.01); the wound healing rates of all the treated groups were higher than that of the diabetic ulcer group (P<0.05); the wound healing rate of the Yiqi Huayu herb group was higher than those of the Yiqi herb group and the Huayu herb group (P<0.05). Compared with the diabetic ulcer group, the expression of substance P of the ulcer control group was increased (P<0.05); the expressions of substance P of the Yiqi Huayu herb group and the Huayu herb group were higher than that of the diabetic ulcer group (P<0.05). CONCLUSION: Yiqi Huayu herbs can promote wound healing in rats with diabetes mellitus by up-regulating the expression of substance P.

[Effects and action mechanisms of Buyang Huanwu Decoction in wound healing of chronic skin ulcers of rats].

OBJECTIVE: To explore the effects and action mechanisms of Buyang Huanwu Decoction, a compound traditional Chinese herbal medicine, in wound healing of chronic skin ulcers of rats. METHODS: A total of 54 male SD rats with back full-thickness skin lesion were used in this study. Except for the normal control group, the rats were injected with hydrocortisone for inducing chronic skin ulcers, and were randomly divided into untreated group and Buyang Huanwu Decoction group. The rate and the time of wound healing were observed. Immunohistochemical method and image analytical method were used to test the expression of vascular endothelial growth factor (VEGF) and microvessel count (MVC) in granulation tissue of chronic skin ulcers in the rats. RESULTS: The rate of wound healing was significantly lowered in the untreated group as compared with the normal control group (P<0.01, P<0.05), and the time of wound healing was obviously longer too (P<0.01). In the Buyang Huanwu Decoction group, the rate of wound healing was significantly higher than that in the untreated group (P<0.01), and the time of wound healing was obviously shorter than the latter's (P<0.01). In the untreated group, the expression of VEGF and MVC were significantly lower than those in the normal control group (P<0.01); the expression of VEGF and MVC were obviously increased in the Buyang Huanwu Decoction group as compared with those in the untreated group (P<0.01). CONCLUSION: Buyang Huanwu Decoction has the effect to promote the wound healing for chronic skin ulcers of rats by regulating the expression of VEGF in granulation tissue of chronic skin ulcers.

[Effects of oral and external application of recipes for promoting granulation in rats with chronic skin ulcers].

OBJECTIVE: To investigate the efficacy of oral, external and oral plus external application of recipes for promoting granulation on chronic skin ulcers in rats. METHODS: Sixty SD male rats were randomly divided into normal group, untreated group, oral group, external group and combined group (n=12). Chronic skin ulcer was induced by hydrocortisone injection and back skin incision. After oral administration of Fuzheng Huyu Recipe or (and) external application of Baiyu ointment, the compound traditional Chinese medicines for wound healing, healing time and healing rate of the ulcers were observed. RESULTS: The healing rate was lower and the healing time was longer in the untreated group than in the normal group (P<0.01). The healing rates of the oral group and the combined group were higher than those of the untreated group at all observation points (P<0.05), and the healing rate of the external group was higher on the 3rd and 14th day after model establishment (P<0.05). On the 7th and 10th day after model establishment, the healing rates of the oral group and the combined group were higher than those of the external group (P<0.05), and the healing time of the combined group was shorter than that of the oral group and external group (P<0.05). CONCLUSION: Both orally and externally administered wound healing recipes can promote the restoration of chronic refractory ulcers; the effect of combined administration is superior to single administration. Oral, external and combined application can all improve the wound healing in inflammatory phase. Oral and combined application can obviously improve the wound healing in granulation phase and epithelial phase.

[Superiority of thread-dragging therapy in treatment of refractory sinus tracts or fistulae].

The thread-dragging therapy, as a new external treatment of traditional Chinese medicine, could eliminate pathogenic factors and restore the vital qi by promoting qi and activating blood circulation to advance tissue repair in treating refractory sinus tracts or fistulae. This article reviewed its origin and development, and introduced its use in treating refractory sinus tracts or fistulae.

[Applying collateral disease theory to treat chronic dermal ulcer].

Collateral disease theory has been applied to investigate the pathogenesis of chronic dermal ulcer in traditional Chinese medicine. It is suggested that deficiency of vital qi is the pathological basis of chronic dermal ulcer with collaterals stagnation as the major pathological factor, and collaterals impairment by toxin evil is the main pathological change. The important principle in treatment of chronic dermal ulcer is established as strengthening the body resistance, dredging collaterals and removing toxins, and this enriched the theory of wound healing in traditional Chinese medicine, and has practical value.

[Therapy mainly for strengthening healthy energy to promote blood circulation in treating 112 diabetic patients with gangrene].

OBJECTIVE: To evaluate the effects of the therapy mainly for strengthening healthy energy to promote blood circulation in treating diabetic patients with gangrene. METHODS: A series of 112 diabetic patients with gangrene were investigated before and after treatment in the changes of wounds, clinical symptoms and quality of life. RESULTS: Fifty-eight cases were cured, 12 cases showed response, 36 cases improved, and 6 cases failure of treatment. The total obvious effect rate was 62.5% (70/112) and the amputation rate was 8.9% (10/112). The 104 diabetic cases of three-stage gangrene were classified into grade I, II and III. The total effect rates of the diabetic cases of grade I, II and III were 83.3% (30/36), 55.6% (35/63) and 20% (1/5), and the amputation rates were 0%, 12.7% (8/63), and 40% (2/5) respectively. After the treatment, the clinical symptoms, gangrene number, gangrene area and gangrene depth were obviously improved (P<0.05), and the quality of life was obviously improved (P<0.01), especially in physical condition, emotional well-being and therapeutic effects on patients (P<0.05). CONCLUSION: Strengthening healthy energy to promote blood circulation is effective in treating diabetic patients with gangrene.

[Effects of reinforcing qi and nourishing blood recipes on vascular endothelial growth factor and microvessel count in granulation tissue in rats with chronic skin ulcers].

OBJECTIVE: To explore the effects of reinforcing qi and nourishing blood recipes on vascular endothelial growth factor (VEGF) and the microvessel count (MVC)in granulation tissue in rats with chronic skin ulcers. METHODS: A total of 90 male SD rats with back full-thickness skin lesion were used in this study. Except for the normal control group, the rats were injected with hydrocortisone for inducing chronic skin ulcers, and were randomly divided into untreated group, Sijunzi Decoction group, Siwu Decoction group and Bazhen Decoction group. The time of wound healing was observed; immunohistochemical method and image analytical method were used to test the expressions of VEGF and MVC in granulation tissue of dermal chronic ulcers in the rats. RESULTS: In the untreated group, the time of wound healing was significantly longer than that in the normal group (P<0.01). The time of wound healing was obviously shortened in the three treated groups as compared with the untreated group (P<0.01, P<0.05). In the Sijunzi Decoction group, the time of wound healing was obviously shorter than those in Siwu Decoction group and Bazhen Decoction group (P<0.05, P<0.01). In the untreated group, the expression of VEGF and MVC were significantly lower than those in the normal control group (P<0.01). The expression of VEGF and MVC were obviously increased in the three treated groups as compared with those in the untreated group (P<0.01, P<0.05). In the Sijunzi Decoction group, the expression of VEGF and MVC were obviously lower than those in Siwu Decoction group and Bazhen Decoction group (P<0.05, P<0.01). CONCLUSION: Reinforcing qi and nourishing blood recipes can promote wound healing in rats through up-regulating the expression of VEGF in granulation tissue of dermal chronic ulcers, and inducing angiogenesis.

Effect of runing II on the growth and metastasis of transplanted tumor in mammary cancer-bearing mice and its mechanism.

OBJECTIVE: To study the effect of Runing II (a Chinese herbal preparation for mammary cancer) on the growth and metastasis of transplanted tumor of mammary cancer MA-891-bearing TA2 mice and its mechanism. METHODS: The model of mammary cancer MA-891 cell strain transplanted tumor of TA2 mice with lung metastasis were developed to observe the effect of Runing II on the growth and metastasis of the transplanted tumor. The immunohistochemical method and image analysis were adopted to detect the levels of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), and micro-vessel count (MVC) and micro-vessel area (MVA). RESULTS: In the Runing II group, the tumor weight inhibition rate and the lung metastasis inhibition rate were 37.3% and 65.4% respectively, the tumor growth and lung metastasis were obviously inhibited; And the levels of VEGF and VEGFR, MVC and MVA were significantly decreased as compared with those in the tumor-bearing control group (P<0.05). CONCLUSION: The Chinese herbal preparation Running II can inhibit the metastasis of tumor through inhibiting the angiogenesis, and the mechanism is possibly related with down-regulation of VEGF and VEGFR expression.

[Effects of Chinese herbs for replenishing qi and resolving stagnation on transforming growth factor-beta1 of skin ulcers in rats with diabetes].

OBJECTIVE: To explore the effects of Yiqi Huayu Recipe, a compound traditional Chinese herbal medicine for replenishing qi and resolving stagnation, on transforming growth factor-beta1(TGF-beta1) of skin ulcers in rats with diabetes. METHODS: Sixty rats were randomly divided into six groups, Yiqi Huayu Recipe-treated group, Yiqi (replenishing qi) Recipe-treated group, Huayu (resolving stagnation) Recipe-treated group, basic fibroblast growth factor (bFGF) treated group, untreated group and normal control group. Diabetes was induced by peritoneal injection of streptozotocin and skin ulcers were made by surgery method in rats except for the normal control group. Then the rats were administered with different drugs respectively, and the expression of TGF-beta1 in granulation tissue of the skin ulcers was detected with the methods of Western blotting, image analysis and immunohistochemistry. RESULTS: The level of TGF-beta1 expression in the untreated group was lower than that in the normal control group (P<0.01); and the level of TGF-beta1 expression in the drug-treated groups was higher than that in the untreated group (P<0.01); and the TGF-beta1 expression in the Yiqi Huayu Recipe-treated group was higher than that in the Yiqi Recipe-treated group, Huayu Recipe-treated group and bFGF-treated group (P<0.05). CONCLUSION: The replenishing qi and resolving stagnation therapy can control the secretion of TGF-beta1 of the wound in the process of wound healing in the levels of gene and molecule.

[Effects of Chinese herbs for replenishing qi and resolving stagnation on hypoxia-inducible factor-1alpha and vascular endothelial growth factor in granulation tissue of skin ulcers in rats with diabetes].

OBJECTIVE: To explore the effects of Chinese herbs for replenishing qi and resolving stagnation on hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in granulation tissue of skin ulcers in rats with syndrome of blood stasis and qi deficiency. METHODS: Diabetic rats with back full-thickness skin lesion and syndrome of blood stasis and qi deficiency were divided in to five groups: untreated group, basic fibroblast growth factor (bFGF)-treated group, Yiqi Huayu Recipe (a recipe for replenishing qi and resolving stagnation)-treated group, Yiqi Recipe (a recipe for replenishing qi)-treated group and Huayu Recipe (a recipe for resolving stagnation)-treated group, and another eight normal rats served as normal control group. Immunohistochemical method and image analysis were used to test the expressions of HIF-1alpha and VEGF in granulation tissue of skin ulcers in rats with diabetes. RESULTS: In the untreated group, the expression of HIF-1alpha was significantly increased and the expression of VEGF was significantly decreased as compared with those in the normal control group (P<0.01). The expression of HIF-1alpha was obviously lower (P<0.01) and the expression of VEGF was significantly higher in the four drug treated groups as compared with those in the untreated group. In the Yiqi Huayu Recipe-treated group, the expression of HIF-1alpha was obviously lower than those in the bFGF-treated, Yiqi Recipe-treated and Huayu Recipe-treated groups (P<0.05 or P<0.01), and the expression of VEGF was significantly higher than that in the bFGF-treated group (P<0.01). CONCLUSION: Chinese herbs for replenishing qi and resolving stagnation can promote the wound healing in rats through reducing the expression of HIF-1alpha, accelerating the expression of VEGF in granulation tissue of skin ulcers in rats with diabetes and ameliorating the status of ischemia and hypoxia.