Immunoregulatory effects of Huaier (Trametes robiniophila Murr) and relevant clinical applications

Target Article

Reliability Check of the Review (PICO-Based Framework)

Study Design and Sample Size

Detailed Results

[Clinical Efficacy and Safety After Resection of Hepatocellular Carcinoma]

The review cites a large multicentre randomized controlled trial involving 1,044 patients who underwent curative resection for hepatocellular carcinoma. Of these, 696 patients were assigned to receive Huaier granules and 348 were assigned to the control group.

Patients in the Huaier group received Huaier granules at a dose of 20 g three times daily for up to 96 weeks.

The trial reported improved recurrence-free survival in the Huaier group compared with the group receiving no additional postoperative treatment.

The review also discusses the safety findings from this clinical trial. Treatment-related diarrhea occurred in 4.4% of patients in the Huaier group and 1.9% in the control group (P = 0.0505).

Other reported adverse events were generally comparable between the groups, and the adverse events described in the original clinical trial were generally mild and tolerable.

These findings support generally favorable tolerability of the Huaier granule preparation under the conditions of this human clinical trial. However, they should not be interpreted as demonstrating the absence of all potential adverse effects associated with long-term use.

[Selective Cytotoxicity Against Tumor Cells and Safety in Normal Cells]

In vitro experiments reviewed in the article demonstrated that W-NTRP, a purified polysaccharide derived from Huaier, inhibited the proliferation of human cholangiocarcinoma cells, with reported IC50 values ranging from approximately 40-80 μg/mL.

In contrast, W-NTRP did not show detectable inhibition of proliferation in the normal mouse fibroblast cell line L-929 under the experimental conditions.

These findings suggest relatively selective cytotoxic activity against the tumor cells examined in vitro.

However, such selectivity in cultured cells should not be interpreted as demonstrating selective tumor toxicity or clinical safety in vivo.

[Protective Effects Against Cisplatin-Induced Nephrotoxicity]

In a mouse model of cisplatin-induced acute kidney injury, the Huaier-derived polysaccharide HP-1 was administered repeatedly by intraperitoneal injection at a dose of 60 mg/kg. No apparent toxicity attributable to HP-1 itself was reported under the experimental conditions.

HP-1 administration significantly attenuated cisplatin-induced structural damage to renal tissue and reduced the acute body weight loss associated with cisplatin treatment.

These findings suggest a potential renoprotective effect of HP-1 in this experimental model. However, this evidence was obtained in mice and does not establish a protective effect in clinical patients.

[Renoprotective Mechanisms in an Adriamycin-Induced Nephrotic Model]

In a rat model of adriamycin-induced nephropathy, administration of Huaiqihuang (HQH), a compound formulation containing Huaier, inhibited activation of the NF-κB signaling pathway in renal tissue.

More specifically, phosphorylation and nuclear translocation of p65 and IκBα were suppressed.

These molecular changes were associated with attenuation of podocyte injury and a significant reduction in urinary protein excretion.

Because HQH contains Huaier together with other botanical ingredients, these findings should not automatically be attributed to Huaier alone.

[Modulatory Effects on Allergic Airway Inflammation and Immune Balance]

In ovalbumin-induced mouse models of asthma, HQH treatment reduced the infiltration of eosinophils, lymphocytes, neutrophils, and macrophages into bronchoalveolar lavage fluid.

At the transcription-factor level, expression of the Th1-associated transcription factor T-bet and the regulatory T-cell-associated transcription factor Foxp3 increased, whereas expression of the Th2-associated transcription factor GATA-3 and the Th17-associated transcription factor RORγt decreased.

Consistent with these changes, levels of IFN-γ and IL-10 increased, whereas levels of IL-4, IL-5, IL-13, and IL-17 significantly decreased. A reduction in serum IgE levels was also reported.

These findings suggest that HQH can influence both Th1/Th2 and Treg/Th17 immune balance in these experimental models.

Importantly, these findings were obtained using HQH rather than purified Huaier alone, and the observed immune changes should therefore be interpreted in the context of this multi-ingredient formulation.

Potential Applications in Veterinary Medicine

[How to Utilize in Clinical Practice]

The broad immunoregulatory effects summarized in this review provide a scientific rationale for further investigation of Huaier and Huaier-derived preparations in veterinary medicine.

Potential areas for future investigation include oncology, inflammatory disorders, immune-mediated diseases, and renal disease.

However, the evidence reviewed in this article was derived primarily from human clinical studies, rodent disease models, and in vitro experiments.

In addition, some of the evidence concerning renal and allergic diseases was obtained using HQH, a multi-ingredient formulation, rather than Huaier alone.

Accordingly, the reviewed evidence does not establish clinical efficacy in dogs or cats.

At present, these findings are best regarded as hypothesis-generating evidence that may support future veterinary studies rather than as evidence supporting specific treatment recommendations in small-animal practice.

[Comparison With Existing Treatments]

Conventional treatments for malignant, inflammatory, and immune-mediated diseases include chemotherapy, corticosteroids, immunosuppressive drugs, and other established therapies, depending on the disease.

The review discusses studies in which Huaier or Huaier-containing preparations were investigated in combination with, or alongside, established treatments.

Some studies reported protective effects against treatment-associated adverse effects, including myelosuppression or nephrotoxicity, while others reported changes in immune parameters or clinical outcomes.

The authors also discuss the possibility that Huaier-related preparations may exert context-dependent immunoregulatory effects rather than producing uniform immunosuppression or immune stimulation.

However, the reviewed evidence is heterogeneous in terms of study design, preparation, disease, dose, and outcome measures.

Therefore, it cannot be concluded from this review that Huaier consistently reduces treatment-associated toxicity or preserves the therapeutic efficacy of established treatments.

Rather, these findings provide a rationale for further investigation of Huaier-related preparations as potential adjunctive approaches.

[Study Limitations and Critical Appraisal]

One important limitation of the reviewed evidence is the complex composition of Huaier preparations.

Several purified components have been isolated and studied, but a single principal active component responsible for the reported biological and clinical effects has not been definitively identified.

As a result, detailed pharmacokinetic information remains limited, including data on absorption, distribution, metabolism, and excretion. This also creates uncertainty regarding the scientific basis for optimal dose selection.

Another important limitation is the heterogeneity of the evidence summarized in the review.

The included studies used different Huaier preparations, purified compounds, extraction methods, compound formulations such as HQH, doses, routes of administration, experimental models, and clinical populations.

Findings obtained with one preparation should therefore not automatically be extrapolated to another.

The review also suggests that the immunological effects associated with Huaier-related preparations may differ depending on the underlying disease and immune environment.

Accordingly, Huaier should not simply be characterized as either an immune stimulant or an immunosuppressant on the basis of the currently available evidence.

These limitations are particularly important when considering veterinary applications.

Species differences must be considered when extrapolating findings from human studies and rodent models to dogs or cats.

Direct veterinary studies are required to establish efficacy, safety, appropriate dosing, and clinically relevant treatment strategies in companion animals.

Mini-Glossary for Readers

TLR4:
Abbreviation for Toll-like receptor 4. It is a receptor involved in innate immune recognition and can activate intracellular pathways associated with inflammatory and immune responses.

NF-κB:
Nuclear factor kappa B, a major transcriptional regulator involved in inflammatory responses, immune signaling, and cell survival.

Podocyte:
A specialized epithelial cell in the renal glomerulus that plays a central role in maintaining the glomerular filtration barrier.

Th1/Th2 Balance:
The relative activity of different helper T-cell responses. Changes in this balance can contribute to immune-mediated and allergic diseases.

Treg/Th17 Balance:
The relationship between regulatory T cells and Th17 cells, two T-cell populations involved in immune regulation and inflammatory responses.

Link to the full article: https://doi.org/10.3389/fimmu.2023.1147098