Visual abstract

Introduction

Hwangryunhaedok-tang (HLHDT) is a representative formula in traditional Korean medicine, primarily selected for its anti-inflammatory and detoxifying effects, and used to treat various diseases [1,2]. This formula includes herbs such as Huanglian (Coptis chinensis), and Huangbai (Phellodendron amurense), which together exhibit complex pharmacological actions based on both their individual characteristics and their interactions [3–5] (Table 1). HLHDT has a long history of use in East Asian traditional medicine and has recently attracted interest in medical research using animal models to determine its efficacy [6,7].

Chronic diseases, characterized by their long-term and persistent nature, have emerged as significant health concerns in contemporary society [8]. Chronic diseases, such as cardiovascular disease, diabetes, chronic respiratory diseases, autoimmune disorders, and cancer, are closely linked to inflammation, and it is becoming increasingly clear that chronic inflammation plays a crucial role in their onset and progression [9,10]. In chronic diseases, the inflammatory response often differs from acute diseases. This is characterized by persistent, poorly regulated inflammation, which in turn leads to damage of normal tissues, thus exacerbating disease progression [11].

Inflammation is a critical defensive mechanism of the immune system that occurs in response to external stimuli [12]. However, chronic inflammation arises from prolonged and excessive activation of the immune system. This state of chronic inflammation leads to sustained activation of immune cells and overproduction of inflammatory mediators, which results in tissue damage and functional impairment. For instance, chronic inflammation can promote the development of atherosclerosis, which increases the risk of cardiovascular diseases, and in diabetes, it can increase insulin resistance and disrupt blood glucose regulation [13,14].

The immunological mechanisms of inflammation can be categorized into acute and chronic inflammation. Acute inflammation involves a rapid immune response to remove pathogens and repair damaged tissues; this is primarily mediated by immune cells such as macrophages and neutrophils that migrate to the site of inflammation and secrete inflammatory mediators [15]. In contrast, chronic inflammation occurs when acute inflammatory responses are inadequate or recurrent, leading to prolonged activation of immune cells and continuous secretion of inflammatory mediators [16].

Key immunological mechanisms in chronic inflammation include cytokines production, sustained activation of immune cells, oxidative stress, and immune regulation mechanisms [17]. Cytokines are molecules secreted by immune cells which play a vital role in regulating inflammation through signaling [18]. Cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 can promote inflammation and induce chronic inflammatory states [19]. In addition, sustained activation of immune cells and continuous secretion of inflammatory mediators can exacerbate chronic inflammation, and excessive production of oxidative stress molecules can damage normal tissues [20]. Immune regulation mechanisms also play a role in balancing the inflammatory response between defense, autoimmunity, and maintenance, to preserve immunological homeostasis [21,22]. Therefore, a clear understanding of the relationship between chronic disease and inflammation, and an analysis of the immunological mechanisms of inflammation may provide essential insight into the prevention and treatment of chronic diseases.

Research on the anti-inflammatory effects of HLHDT has increased in recent years, with focus on its mechanisms of action and clinical utility. Therefore, this scoping review aimed to comprehensively and systematically analyze the scientific evidence regarding the anti-inflammatory effects of this decoction in chronic and acute diseases and conditions. This review sought to systematically organize the research findings on the anti-inflammatory effects of HLHDT, identify current research trends, and propose future research directions to contribute to the development of more effective treatment strategies for HLHDT to provide foundational data for future research.

Materials and Methods

This scoping review involved a comprehensive analysis of (cell-based, animal-based, and clinical) studies regarding the anti-inflammatory effects of HLHDT through a systematic literature search and data extraction process.

The search strategy employed used the following keywords to identify relevant research across PubMed, and China National Knowledge Infrastructure (CNKI) databases up to August 20, 2024: “hwanglyeonhaedok-tang,” “HLHDT,” “huanglian jiedu tang,” “huanglian,” “jiedu,” “huanglian decoction,” “huanglian-jie-du-tang,” “huanglian jie du tang,” “huanglian jiedu,” “huang lian jiedu,” “hwangnyeonhaedok-tang,” “hwangryunhaedok-tang.” Three independent reviewers (Sung Jin Kim, Yea Jung Choi, Mei Tong He) assessed the titles, abstracts, and full texts of the studies for eligibility. Discrepancies in literature selection and data extraction were resolved through discussion and consensus.

The inclusion criteria comprised studies that mentioned HLHDT or similar names, written in English or Korean, focused on either the solo use or combination use of HLHDT, and original research papers (cell-based studies, animal studies, clinical studies). Exclusion criteria included studies that only performed chemical analysis, non-English non-Korean studies (if a translation was not feasible or the original text was unavailable), and studies unrelated to HLHDT.

Information was systematically extracted from selected literature, including: basic study details (authors, year, study design, disease model), formulation details (components of HLHDT, preparation methods), research methodologies (cell types, animal models, experimental conditions, inflammation induction methods), and outcome measures (key findings, inflammation indicators, efficacy evaluation). In addition, it was confirmed that the HLHDT compositions used in the selected studies were consistent with the original prescription, with no additions or omissions.

The extracted data were systematically summarized and presented in tables with descriptions and visual representations of the key findings and methodologies of each study to facilitate a comprehensive understanding of the anti-inflammatory effects of HLHDT. This process was intended to highlight the current status of research on the anti-inflammatory effects of HLHDT, and show the similarities and differences between studies. In turn, this may indicate the directions for future research.

Results

A total of 2,013 articles were retrieved using a comprehensive search strategy. Literature that fulfilled the inclusion criteria was classified into cell, animal, and clinical studies by assessing the abstract and full text according to the stated conditions. As a result of this process, 48 papers were included in the systematic review (Figure 1). These 48 studies were divided into 7 clinical studies and 41 basic studies. Regarding the efficacy of HLHDT in basic research, 16 in vitro and 25 in vivo studies were identified.

1. Clinical trials investigating the anti-inflammatory effects of HLHDT

A study by Wang et al [23], involved patients who had received X-ray induced radiation (a dose of 200 cGy per radiation session, across 35 sessions) for esophageal cancer and had developed radiation dermatitis (RD) (Table 2 [23–29]). Treatment with HLHDT focused on alleviating symptoms of RD on the irradiated skin. Local skin photographs were taken on the 0^th, 7^th, and 14^th days with patient consent, and additional comparative images of skin lesions were captured at various time points following HLHDT treatment. This provided compelling evidence of HLHDT’s clinical effectiveness in treating RD [23].

Beyond RD, the clinical studies encompassed a variety of inflammatory conditions, including atopic dermatitis (AD) with damp-heat syndrome, ulcerative colitis, diabetic foot severe infection (focusing on inflammatory factors and intestinal barrier function), periodontitis associated with inflammatory markers, oral diseases linked to excessive heat in stomach fire syndrome, and acute viral myocarditis (Table 3 [24,30–44]). Together, these studies highlighted the broad therapeutic potential of HLHDT in addressing diverse inflammatory conditions and diseases [24–29].

2. In vitro studies on HLHDT

Most in vitro research on HLHDT was published in China (Table 3 [24,30–44]). Water-extracted HLHDT was widely used, and it demonstrated significant anti-inflammatory properties across various models. Among these, the study by Jiang et al [30] used lipopolysaccharide (LPS)-induced A549 cells to establish an inflammation model, and to evaluate cell proliferation the cholecystokinin receptor 8 assay was used. Similarly, the study by Wang et al [31] investigated HLHDT’s effects using in vivo and ex vivo models, such as an acute inflammatory air-pouch model in mice and a mouse endotoxemia model, showing that HLHDT significantly inhibited leukocyte infiltration, prostaglandin E2 production, and IL-1 activity while reducing NO production in peritoneal macrophages [31].

The study by Zeng et al [32] evaluated HLHDT’s anti-inflammatory effects in both in vivo and in vitro models. Using a carrageenan-induced rat air-pouch model and liquid chromatography-tandem mass spectrometry, they reported that HLHDT effectively reduced nitric oxide (NO), leukotriene B4, and eicosanoids derived from lipoxygenases, suggesting its potential in treating inflammatory diseases [32]. A study by Wang et al [33] focused on the therapeutic effects of Huanglian Jiedu plaster (HJP) on X-ray-induced RD, demonstrating its capacity to reduce skin damage and inflammation, and in vitro using the AGS cell line it was determined that the high-mobility group box 1-toll-like receptor (TLR) 4-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway was targeted [33]. Studies by Liu et al [34] and by Park et al [35] reported that HLHDT had significant anti-inflammatory and antibacterial effects against Helicobacter pylori, suggesting its potential as an alternative to antibiotics for treating H. pylori infections. In addition to these specific findings, numerous cell line experiments have supported HLHDT’s broad anti-inflammatory mechanisms [33–44]. These studies explored LPS-induced inflammation in A549 cells, the role of autophagy and inflammation in RAW 264.7 foam cells, and the effects of HLHDT on atherosclerosis and macrophage polarization. Further investigations included its impact on inflammatory factors in HT22 cells, the involvement of adenosine monophosphate-activated protein kinase and intercellular adhesion molecule-1 in inflammatory endothelial cells, and the modulation of cholinergic anti-inflammatory responses, providing a comprehensive understanding of HLHDT’s cellular actions (Table 3 [24,30–44]). Together, these findings underscore HLHDT’s potential as a multifaceted therapeutic agent for managing inflammation across diverse biological contexts [33–44].

3. In vivo studies on HLHDT

A study conducted by Li et al [45] investigated the effects of HLHDT on improving inflammation-related insulin resistance (IR) in metabolic syndrome. The study determined that metabolic syndrome in rats, when treated with HLHDT, showed less obesity, hypertension, and cardiac damage. HLHDT inhibited the activation of NF-κB and reduced the serine phosphorylation of insulin-receptor substrate-1, suggesting it protects the heart from insulin-receptor related injury [45]. An overview of major in vivo studies and their therapeutic implications is summarized in Table 4 [45–69].

The therapeutic effects of HLHDT on collagen-induced arthritis (CIA) in rats using a metabolomics approach were investigated by Li et al [46]. Treatment with HLHDT significantly reduced arthritic scores and serum IL-1β levels while improving joint architecture. Metabolic profiling revealed disturbances in energy and lipid metabolism, oxidative stress, and amino acid metabolism in CIA, with many metabolites returning to normal after HLHDT administration. These results suggest that HLHDT ameliorates CIA by partially regulating disrupted energy metabolism, demonstrating the potential of metabolomics to evaluate traditional Chinese medicine therapies [46].

A study by Dai et al [47] demonstrated that oral administration of HLHDT significantly inhibited inflammatory responses in carrageenan-injected rat air pouches, reducing the production of NO and leukotriene B4 without affecting cyclooxygenase-derived eicosanoids. HLHDT also inhibited eicosanoid production in calcium ionophore A23187-stimulated peritoneal macrophages [47].

A study by Dai et al [48] investigated the anti-inflammatory effects of HLHDT (written as Huang-Lian-Jie-Du-Tang), using a rat model of peripheral inflammation and hyperalgesia. The researchers determined that rats treated with HLHDT, 3 days prior to complete Freund’s adjuvant injections, exhibited significantly reduced paw edema and thermal hyperalgesia compared with the controls. Furthermore, the up-regulation of preprodynorphin messenger ribonucleic acid (mRNA) in dorsal horn neurons was less following HLHDT treatment, and it lowered corticotropin-releasing factor mRNA levels in the hypothalamus. These findings suggest that HLHDT possesses anti-inflammatory properties and can alter mRNA expression in neurons, emphasizing its potential influence on neuronal excitability [48].

A study by Cui et al [48] investigated the effects of HLHDT (written as HLJD) on ulcerative colitis in mice, aiming to identify its effective components and therapeutic targets. In this study, 60 Balb/c mice were divided into several groups, with ulcerative colitis induced by administering a 2.5% dextran sulfate sodium solution. The researchers monitored the disease activity index daily, and using Hematoxylin and Eosin staining, observed pathological changes in the colon. In addition, levels of inflammatory cytokines (IL-1β, IL-6, and TNF-α) were measured using enzyme-linked immunosorbent assay [48].

A study by Wang et al [49] investigated the therapeutic effect of HJP on X-ray-induced RD using mouse models. In the study, mice were subjected to continuous X-ray irradiation (800 cGy) on the right hind limb for 5 days to induce RD. Starting from the onset of modeling, HJP was applied to the irradiated skin for 15 days. The results demonstrated that HJP significantly alleviated skin injury, inhibited inflammation, and reduced the expression of inflammatory cytokines (IL-1β, IL-6, TNF-α) as well as epidermal damage-related factors (integrin β1, chemokine ligand 9, cytokeratin 17) [49].

A study by Wang et al [50] examined the protective effects of HLHDT (written as Huang Lian Jie Du Decoction) on septic rats and its underlying mechanisms. Their findings revealed that HLHDT improved survival rates and reduced inflammation in sepsis-induced rats. The treatment enhanced autophagy, reversing decreases in key autophagy markers, and alleviating inflammatory factors. In addition, HLHDT promoted autophagy by inhibiting the mammalian target of rapamycin pathway via mitogen-activated protein kinase/PI3K signaling and positively influenced the diversity and function of the gut microbiota, underscoring its potential therapeutic benefits in sepsis [50].

A study by Li et al [51] focused on the antipyretic effect of HLHDT and explored its underlying mechanisms. The researchers established a fever model using LPS and measured anal temperatures hourly. They assessed the levels of TNF-α, IL-6, prostaglandin E2, and cyclic adenosine monophosphate in the serum and hypothalamus tissue using enzyme-linked immunosorbent assays. The results showed that HLHDT effectively reduced fever and lowered the expression of these inflammatory markers. In addition, Western blot analysis indicated that HLHDT significantly inhibited the protein expression of phospho-extracellular-signal-regulated kinase, phosphorylated c-Jun N-terminal kinase, and p38, suggesting that its antipyretic effect may be linked to the inhibition of the mitogen-activated protein kinase signaling pathway [51].

A study by Xu et al [53] investigated the anti-inflammatory and anti-pruritus mechanisms of HLHDT as a treatment for AD. This common chronic skin condition is characterized by T-cell-mediated immune responses, inflammation, and itching [54]. The researchers employed various techniques, including immunohistochemistry and flow cytometry, and determined that HLHDT significantly alleviated clinical symptoms and ear swelling in AD-mice. The decoction inhibited the production of several cytokines, such as interleukins (IL-3, IL-4, IL-5, IL-13, IL-17A, IL-31, and IL-33), and histamine, as well as inflammatory mediators like substance P and transient receptor potential vanilloid-1. In addition, HLHDT appeared to reduce the expression of key markers in lymph nodes and suppressed specific receptors and proteins involved in immune activation. These findings suggest that HLHDT may effectively treat AD by modulating dendritic cell function and T-lymphocyte activation, thereby exerting its anti-inflammatory and anti-pruritus effects [55].

A study by Zhou et al [52] investigated the anti-inflammatory mechanisms of HLHDT in a zebrafish model of LPS-induced inflammation. They determined that HLHDT significantly reduced inflammation by 61% at a concentration of 50 μg/mL, primarily through the TLR4/myeloid differentiation primary response protein 88 signaling pathway [52]. Including AD, neuronal damage and nucleotide-binding domain leucine-rich pyron domain 3 (NLRP3) inflammasome activation, atherosclerosis along with macrophage polarization and inflammation, atherosclerotic inflammation and aortic plaque stability, blood-heat psoriasis in relation to immune cells and inflammatory factors, allergic rhinitis and the TLR4/NF-kB pathway, acute lung injury with a focus on oxidative stress and inflammatory factors, atherosclerosis and NLRP3 inflammasome activation, acute hemorrhoids concerning immune function and inflammatory factors, gingivitis, activity of anti-systemic inflammatory response syndrome, insulin resistance alongside inflammatory factors and oxidative stress, hyperlipidemia related to inflammatory factors, acute liver injury with NLRP3 inflammatory corpuscles, rheumatoid arthritis and its connection to inflammatory immunity, the NLRP3 inflammatory pathway in relation to Alzheimer’s disease, and experimental colitis [57–59].

4. Characteristics of the included studies

A total of 47 full-text articles that met the inclusion criteria were identified (Figure 1). The first study was published in 2000. From 2000 to 2024, the number of studies conducted each year varied from 0 to 5, depending on the study type (clinical, in vitro, or in vivo). Between 2000 and 2015, studies were conducted sporadically, with no publications in some years. A noticeable increase in clinical studies was observed after 2018, with a total of 5 clinical studies published between 2019 and 2024. In vitro and in vivo studies also showed a slight increase after 2018, although their numbers remained low. Overall, research activity across all study types intensified after 2018.

Discussion

HLHDT has a strong potential for treating inflammation-related conditions and diseases, particularly those driven by chronic inflammation [3,13]. This low-grade activation of immune cells and overproduction of inflammatory mediators, is a significant contributor to various chronic diseases, including cardiovascular diseases, diabetes, and autoimmune disorders [4,6,9,13,26]. A comprehensive analysis of the literature revealed a strong consensus regarding the significant anti-inflammatory effects of HLHDT. PubMed and CNKI searches yielded a total of 2,013 articles, with specific focus on HLHDT therapeutic potential in treating inflammation-related diseases. In the PubMed search, a total of 329 articles were retrieved. After applying the exclusion criteria, there were 12 studies were included in this systematic review of which there was 1 clinical study. Four studies were in vitro and 6 were in vivo studies.. The CNKI search identified 1,684 articles, from which 36 were selected after rigorous screening, including 12 in vitro studies, 18 in vivo studies, and 6 clinical studies. The recurrent theme was HLHDT efficacy in modulating inflammation across various models. In vitro studies demonstrated the capacity of HLHDT to suppress inflammatory pathways, such as LPS-induced inflammation in A549 cells, and autophagy-related effects in RAW 264.7 foam cells. In vivo studies explored conditions such as AD, atherosclerosis, and acute lung injury, and the focus was on key inflammatory pathways, including TLR4/NF-κB. The studies collectively pointed to HLHDT multifaceted approach to alleviating inflammation at cellular, tissue, and systemic levels. Significant reductions in pro-inflammatory markers, such as NO and leukotriene B4, were observed, reinforcing HLHDT extensive anti-inflammatory effects.

HLHDT has the potential to treat acute and chronic inflammatory conditions associated with metabolic disorders. This was particularly noted in research examining its effects on insulin resistance and metabolic syndrome. Importantly, the bioactive constituents of HLHDT’s component herbs have been identified as critical contributors to its therapeutic effects. For example, berberine, a major alkaloid derived from Coptis chinensis, has been shown to exert significant anti-inflammatory effects by inhibiting NF-κB activation and reducing cytokine production [70]. Baicalin from Scutellaria baicalensis, geniposide from Gardenia jasminoides, and palmatine from Phellodendron amurense are also well-documented for their anti-inflammatory activities through various molecular mechanisms [71–73]. These bioactive compounds likely work synergistically within HLHDT to enhance its overall efficacy.

Although a large number of studies were identified in the initial CNKI database, many studies were published in Chinese and often lacked English abstracts or standardized methodological reporting. This posed challenges in objectively evaluating study quality and integrating findings with internationally indexed literature. Overall, in this review, findings from studies retrieved from PubMed and CNKI reported that HLHDT was a significant therapeutic agent in traditional Chinese medicine, underscoring its effectiveness for a wide range of inflammatory diseases. The consistent results across diverse experimental settings highlight the need for further clinical investigations to validate these findings and explore underlying mechanisms of action.

Conclusion

Significant anti-inflammatory effects of HLHDT were observed across various models of inflammation. The studies consistently demonstrated HLHDT’s capacity to modulate key inflammatory pathways, reduce pro-inflammatory markers, and address both acute and chronic inflammation, including conditions linked to metabolic disorders. These therapeutic mechanisms and applications are schematically summarized in Figure 3. While the predominance of studies from China and the lack of randomized controlled trials poses limitations, HLHDT shows promise as an effective therapeutic agent in traditional Chinese medicine. Further clinical research is needed to validate these findings and explore its mechanisms of action.

Article information

Author Contribution

All authors conceptualized and designed the study, performed the literature review, and were responsible for data analysis and interpretation.

Conflicts of Interest

The authors have no conflicts of interest to declare.

Author Use of AI Tools Statement

The AI tool did not contribute to the scientific content, data analysis, or interpretation. The authors take full responsibility for all content.

Funding

This research was supported by the Ministry of Food and Drug Safety (Grant no.: 24202MFDS239-2).

Ethical Statement

This research did not involve any human or animal experiments.

Data Availability

Figure 1

The flow chart of study selection.

CNKI = China National Knowledge Infrastructure.

Figure 2

Trends in vitro and in vivo clinical studies using Hwangryunhaedok-tang to treat inflammation-related conditions/diseases.

Figure 3

Schematic description of Hwangryunhaedok-tang and its therapeutic application.

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