Zizhu Ointment Accelerates Wound-Healing of Diabetic Ulcers through Promoting M2 Macrophage Polarization via Downregulating the Notch4 Signaling Pathway

Huang, Renyan; Hu, Xiaoming; Li, Wenhui; Wang, Lixiang; Fan, Weijing; Han, Qiang; Guo, Fang; Liu, Guobin

doi:10.1155/2022/5173836

Cited by 4 publications

(8 citation statements)

References 26 publications

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“…The crude ingredients of ZZO were purchased from Shanghai Kangqiao Chinese Medicine Tablet Co., Ltd. and processed by the Wuhan Ma Yinglong workshop, with all ingredients corresponding to quality control standards. The ratios of the main medicines (by weight) of ZS, ZC, XJ, HQ, EJ, and BP were 7: 3: 3: 6: 5: 1, and the ratio of the components of ZZO to the base materials was 1: 8 (Huang et al, 2022). The ZZO preparation was also composed of excipients including poloxamer, propylene, water, glycerol, polyethylene glycol (PEG), PEG 1500, PEG 4000, and ethyl p-hydroxybenzoate, for which the ratios were 34: 24: 70: 2.6: 9:9: 3:0.06.…”

Section: Composition and Preparation Of Zzo And Chemical Component Pr...mentioning

confidence: 99%

“…We have found that Zizhu ointment (ZZO)—which consists of cinnabaris (Zhusha, ZS), Astragalus mongholicus Bunge (Fabaceae; Huangqi, HQ), Arnebia guttata Bunge (Boraginaceae; Zicao, ZC), Asini corii colla (Ejiao, EJ), Borneolum (Bingpian, BP), and Calamus draco Willd. (Arecaceae; Xuejie, XJ)—is helpful in clinical practice ( Huang et al, 2022 ). We recruited 76 DU patients to compare wound healing rates with ZZO treatment and basic fibroblast growth factor (bFGF) spay treatment.…”

Section: Introductionmentioning

confidence: 99%

“…Based on the accepted anti-DU clinical efficacy of ZZO, we aimed to further investigate its mechanisms and active compounds. Our previous study found that ZZO accelerates the wound healing process via inhibiting Notch4 signaling and promoting the M2 polarization of macrophages ( Huang et al, 2022 ). Nevertheless, the anti-DU active ingredients of ZZO have not been clearly elucidated and warrant further exploration.…”

Section: Introductionmentioning

confidence: 99%

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Uncovering the pharmacological mechanisms of Zizhu ointment against diabetic ulcer by integrating network analysis and experimental evaluation in vivo and in vitro

Wang

Huang

et al. 2022

Front. Pharmacol.

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Diabetic ulcer (DU) has been recognized as one of the most prevalent and serious complications of diabetes. However, the clinical efficacy of standard treatments for DU remains poor. Traditional Chinese medicine (TCM) shows a positive therapeutic effect on DU. Specifically, Zizhu ointment (ZZO) has been widely used to treat DU in long-term clinical practice, but the exact mechanism by which it promotes DU wound healing remains unknown. In this study, network analysis and high-performance liquid chromatography–high resolution mass spectrometry (UPLC-HRMS) were conducted to identify the active compounds of ZZO. We detected isovalerylshikonin (ISO), mandenol, daidzein, kaempferol, and formononetin in both network analysis and UPLC-HRMS. Moreover, ZZO could ameliorate DU by regulating the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) and inflammation signaling pathways, according to the results of KEGG analysis. We established a DU mouse model with a high-fat diet and streptozotocin injection in vivo to evaluate the network analysis result. The experimental results showed that ZZO could inhibit inflammation, remodel fibrous tissue, and promote angiogenesis in the DU area, facilitating wound healing in DU mice. Moreover, the PI3K/AKT signaling pathway was indeed activated by ZZO treatment, promoting macrophage M2 polarization. In addition, we used molecular docking technology to evaluate the binding sites between ZZO and the PI3K/AKT pathway. The results showed that ISO has a good binding interaction with AKT. Moreover, ISO promoted M2 polarization in macrophages in a dose-dependent manner in vitro. Our study found that ZZO could promote DU wound healing by inhibiting inflammation, which was achieved by macrophage M2 polarization through activating the PI3K/AKT pathway. Further studies have demonstrated that ISO plays major role in the above process. These findings provide a theoretical basis for further preclinical evaluation and lay a foundation for nano-gel compound treatment with ZZO.

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Section: Composition and Preparation Of Zzo And Chemical Component Pr...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Uncovering the pharmacological mechanisms of Zizhu ointment against diabetic ulcer by integrating network analysis and experimental evaluation in vivo and in vitro

Wang

Huang

et al. 2022

Front. Pharmacol.

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“…In animal models, Zizhu ointment resulted in rapid wound healing, and downregulated the expression of the Notch4 gene and its target genes and ligands and promoted the proliferation of M2 macrophages and other anti-inflammatory effects[ 36 ]. Components of Shenghong liquid (SH) have an anti-inflammatory effect and improve local circulation[ 37 ].…”

Section: Traditional Chinese Medicinesmentioning

confidence: 99%

Current scenario of traditional medicines in management of diabetic foot ulcers: A review

Rayate¹,

Nagoba²,

Mumbre³

et al. 2023

World J Diabetes

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Diabetic foot infections and diabetic foot ulcers (DFU) cause significant suffering and are often recurring. DFU have three important pathogenic factors, namely, microangiopathy causing local tissue anoxia, neuropathy making the foot prone to injuries from trivial trauma, and local tissue hyperglycaemia favouring infection and delaying the wound healing. DFU have been the leading cause for non-traumatic amputations of part or whole of the limb. Western medicines focus mainly on euglycaemia, antimicrobials, debridement and wound cover with grafts, and off-loading techniques. Advances in euglycaemic control, foot care and footwear, systemic antimicrobial therapy, and overall health care access and delivery, have resulted in an overall decrease in amputations. However, the process of wound care after adequate debridement remains a major cost burden globally, especially in developing nations. This process revolves around two basic concerns regarding control/eradication of local infection and promotion of faster healing in a chronic DFU without recurrence. Wound modulation with various dressings and techniques are often a costly affair. Some aspects of the topical therapy with modern/Western medicines are frequently not addressed. Cost of and compliance to these therapies are important as both the wounds and their treatment are “chronic.” Naturally occurring agents/medications from traditional medicine systems have been used frequently in different cultures and nations, though without adequate clinical base/relevance. Traditional Chinese medicine involves restoring yin-yang balance, regulating the ‘chi’, and promoting local blood circulation. Traditional medicines from India have been emphasizing on ‘naturally’ available products to control wound infection and promote all the aspects of wound healing. There is one more group of chemicals which are not pharmaceutical agents but can create acidic milieu in the wound to satisfy the above-mentioned basic concerns. Various natural and plant derived products ( e.g ., honey, aloe vera, oils, and calendula) and maggots are also used for wound healing purposes. We believe that patients with a chronic wound are so tired physically, emotionally, and financially that they usually accept native traditional medicine which has the same cultural base, belief, and faith. Many of these products have never been tested in accordance to “evidence-based medicine.” There are usually case reports and experience-based reports about these products. Recently, there have been some trials ( in vitro and in vivo ) to verify the claims of usage of traditional medicines in management of DFU. Such studies show that these natural products enhance the healing process by controlling infection, stimulating granulation tissue, antimicrobial action, promoting fibroblastic activity and collagen deposition, etc. In this review, we attempt to study and analyse the available literature on results of topical tradit...

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“…136 Our research group developed a Zizhu ointment (ZZO), which has good clinical efficacy when applied topically to patients with DFU. 137 In addition, ZZO was found to accelerate wound healing in diabetic mice by inhibiting the activation of the Notch4 signalling pathway, promoting the polarization of M2 macrophages and reducing the inflammatory response. 137…”

Section: Prospects Of Traditional Chinese Medicine (Tcm) Preparations...mentioning

confidence: 99%

Preclinical study of diabetic foot ulcers: From pathogenesis to vivo/vitro models and clinical therapeutic transformation

Wang

Fan

et al. 2023

International Wound Journal

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Diabetic foot ulcer (DFU), a common intractable chronic complication of diabetes mellitus (DM), has a prevalence of up to 25%, with more than 17% of the affected patients at risk of amputation or even death. Vascular risk factors, including vascular stenosis or occlusion, dyslipidemia, impaired neurosensory and motor function, and skin infection caused by trauma, all increase the risk of DFU in patients with diabetes. Therefore, diabetic foot is not a single pathogenesis. Preclinical studies have contributed greatly to the pathogenesis determination and efficacy evaluation of DFU. Many therapeutic tools are currently being investigated using DFU animal models for effective clinical translation. However, preclinical animal models that completely mimic the pathogenesis of DFU remain unexplored. Therefore, in this review, the preparation methods and evaluation criteria of DFU animal models with three major pathological mechanisms: neuropathy, angiopathy and DFU infection were discussed in detail. And the advantages and disadvantages of various DFU animal models for clinical sign simulation. Furthermore, the current status of vitro models of DFU and some preclinical studies have been transformed into clinical treatment programs, such as medical dressings, growth factor therapy, 3D bioprinting and pre‐vascularization, Traditional Chinese Medicine treatment. However, because of the complexity of the pathological mechanism of DFU, the clinical transformation of DFU model still faces many challenges. We need to further optimize the existing preclinical studies of DFU to provide an effective animal platform for the future study of pathophysiology and clinical treatment of DFU.

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Zizhu Ointment Accelerates Wound-Healing of Diabetic Ulcers through Promoting M2 Macrophage Polarization via Downregulating the Notch4 Signaling Pathway

Cited by 4 publications

References 26 publications

Uncovering the pharmacological mechanisms of Zizhu ointment against diabetic ulcer by integrating network analysis and experimental evaluation in vivo and in vitro

Uncovering the pharmacological mechanisms of Zizhu ointment against diabetic ulcer by integrating network analysis and experimental evaluation in vivo and in vitro

Current scenario of traditional medicines in management of diabetic foot ulcers: A review

Preclinical study of diabetic foot ulcers: From pathogenesis to vivo/vitro models and clinical therapeutic transformation

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