Anti-inflammatory and/or immunomodulatory activities of Uncaria tomentosa (cat’s claw) extracts: A systematic review and meta-analysis of in vivo studies

Background: Uncaria tomentosa (Willd. ex Schult.) DC. (Rubiaceae) is traditionally used by Amazonian indigenous groups to treat inflammatory diseases. To date, there are no systematic reviews and meta-analyses on the use of U. tomentosa for inflammation control in animals supporting the traditional knowledge about this species. This study was conducted to evaluate the effect of U. tomentosa extracts in modulating inflammatory mediators and to determine which types of inflammatory diseases can be treated by this species.

Methods: We conducted a systematic review and meta-analysis of preclinical studies published before 26 July 2023, identified in PubMed, Embase, and Scopus. Four independent reviewers extracted the data and assessed the risks of bias. The effects of U. tomentosa on inflammatory diseases and the inflammatory mediators involved were extracted from the studies. Standardized mean differences (SMD) and 95% confidence intervals (95%CI) of the outcomes were estimated. The meta-analyses were conducted using RevMan 5.4 (Cochrane Collaboration). This protocol was registered in PROSPERO (CRD42023450869).

Results: Twenty-four of 523 studies were included. U. tomentosa extracts decreased the cytokines interleukin (IL)-6 (SMD: −0.72, 95%CI: −1.15, −0.29, p = 0.001) and transcription factor nuclear factor kappa-B (NF-κB) (SMD: −1.19, 95%CI: −1.89, −0.48, p = 0.001). However, the extracts did not significantly alter IL-1 (SMD: −0.16, 95%CI: −0.87, +0.56, p = 0.67), IL-10 (SMD: −0.05, 95%CI:–0.35, 0.45, p = 0.80), or tumor necrosis factor-alpha (TNF-α) levels (SMD: 0.18, 95%CI: −0.25, 0.62, p = 0.41).

Conclusion: Many extracts of stem bark, roots, and leaves of U. tomentosa, mostly aqueous and hydroethanolic, exhibited anti-inflammatory and/or immunomodulatory activities and low toxicity. The extracts decreased NF-κB and IL-6. These findings suggest that this species has the potential to treat inflammatory diseases in which these markers are increased, according to the ethnopharmacological use. These activities are not related to a specific class of compounds.

Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=450869, Identifier CRD42023450869.

Highlights

• Uncaria tomentosa (cat’s claw) extracts decreased IL-6 and NF-κB.

• Cat’s claw did not alter IL-1, IL-10, or TNF-α.

• Cat’s claw extracts have low toxicity.

• Cat’s claw improves parameters of chronic inflammatory diseases.

1 Introduction

Uncaria tomentosa (Willd. ex Schult.) DC. (Rubiaceae), commonly known as cat’s claw or “unha de gato,” is widely used in Peruvian and Brazilian traditional medicine as an anti-inflammatory, antinociceptive, and antiasthmatic agent, and to prevent diseases (Reinhard, 1999; Valente, 2013; Valdiviezo-Campos et al., 2020; Obregon Vilches, 1997). This species is distributed in Brazil in the states of Acre, Amapá, Amazonas, and Pará (Honório et al., 2016). It is included in the National List of Essential Medicines (Relação Nacional de Medicamentos Essenciais, RENAME), which is provided by the Brazilian Ministry of Health to all municipalities through the National Health System (Sistema Único de Saúde, SUS) (Brazil, 2022).

U. tomentosa is rich in alkaloids, including tetracyclic indole, tetracyclic oxindole, pentacyclic indole, pentacyclic oxindole, and glycoindole alkaloids (Laus et al., 1997; Keplinger et al., 1999; Falkiewicz and Lukasiak, 2001). It also contains triterpenoids derived from quinovic acid and polyphenols (Hoyos et al., 2015). Mitraphylline and isopteropodine are considered the chemical markers of this species (USP, 2023). Pharmacological studies using different U. tomentosa extracts have confirmed their antiasthmatic, antidiabetic, antimicrobial, anticancer, antioxidant, and anti-inflammatory properties, as well as their neuroprotective effects against Parkinson’s and Alzheimer’s diseases (Sandoval et al., 2002; De Martino et al., 2006; Ciani et al., 2018; Xu et al., 2021; Blanck et al., 2022).

Inflammation is a multifactorial condition that involves several mediators. The latter are potent chemical substances found in the body tissues, such as lymphokines, leukotrienes, prostaglandins, prostacyclins, interferon-alpha (IFN-α) and gamma (IFN-γ), interleukins (ILs) (Ricciotti and FitzGerald, 2011; Cerami, 1992; Serhan and Levy, 2018), histamine, 5-hydroxytryptamine (5-HT), and tumor necrosis factor-alpha (TNF-α) (Holtmann and Neurath, 2004; Branco et al., 2018). It is therefore challenging to find a drug that simultaneously acts on multiple targets and attenuates the damage caused by chronic inflammation (Chen et al., 2018). There is a constant search for plants and substances that are more effective in treating inflammatory diseases by acting on multiple targets with fewer side effects. The anti-inflammatory properties of many substances from medicinal plants have been described (Gandhi et al., 2022a; Gandhi et al., 2022b; Zhao et al., 2023), but their safe clinical use has not yet been proven.

Therefore, the present systematic review aimed to synthesize the knowledge on the preclinical anti-inflammatory and/or immunomodulatory activities of different extracts of U. tomentosa evaluated in different in vivo models and on their main mechanisms of action, including a meta-analysis of their effects on selected inflammatory mediators.

2 Methods

2.1 PICOS question and strategy

The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Page et al., 2021) and was previously registered in PROSPERO (CRD42023450869).

The research questions were as follows: against which inflammatory diseases are U. tomentosa extracts effective, as assessed in in vivo models, and which inflammatory mediators are involved?

The PICOS strategy (problem, intervention, control, outcomes, and study design) was built as follows: P: inflammatory diseases; I: treatment with U. tomentosa extracts; C: no treatment or placebo (vehicle); O: levels of inflammatory mediators; and S: in vivo preclinical studies.

2.2 Data sources and bibliographic searches

Searches were performed in the PubMed, Scopus, and Embase databases in September 2023 using a combination of keywords, MeSH terms, and their synonyms, as follows: for Embase: (‘inflammation'/exp OR ‘acute inflammation’ OR ‘inflammation’ OR ‘inflammation reaction’ OR ‘inflammation response’ OR ‘inflammatory condition’ OR ‘inflammatory lesion’ OR ‘inflammatory process’ OR ‘inflammatory reaction’ OR ‘inflammatory response’ OR ‘inflammatory syndrome’ OR ‘reaction, inflammation’ OR ‘response, inflammatory’ OR ‘inflammatory disease'/exp OR ‘inflammatory disease’ OR ‘disease, inflammatory’ OR ‘cytokine'/exp OR ‘cytokine’ OR ‘cytokines’ OR ‘interleukin’ OR ‘interferon'/exp OR ‘cl 884′OR ‘cl884′OR ‘endogenous interferon’ OR ‘exogenic interferon’ OR ‘ifn’ OR ‘interferon’ OR ‘interferon 1′OR ‘interferon i' OR ‘interferon type i' OR ‘interferone’ OR ‘interferonogen’ OR ‘interferons’ OR ‘interferron’ OR ‘tumor necrosis factor'/exp OR ‘tnf alfa’ OR ‘tnf alpha’ OR ‘cachectin’ OR ‘cachetin’ OR ‘human recombinant tumour necrosis factor alpha’ OR ‘mhr 24′OR ‘recombinant tumour necrosis factor alpha’ OR ‘tissue necrosis factor’ OR ‘tumor necrosis factor’ OR ‘tumor necrosis factor alfa’ OR ‘tumor necrosis factor alpha’ OR ‘tumor necrosis factor-alpha’ OR ‘tumor necrosis factors’ OR ‘tumor necrosis serum’ OR ‘tumour necrosis factor’ OR ‘tumour necrosis factor alfa’ OR ‘tumour necrosis factor alpha’ OR ‘tumour necrosis factor-alpha’ OR ‘tumour necrosis factors’ OR ‘tumour necrosis serum’) AND (‘uncaria tomentosa'/exp OR ‘uncaria tomentosa’ OR ‘cat`s claw’ OR ‘uncaria tomentosa extract'/exp OR ‘uncaria tomentosa extract').

2.3 Study selection and eligibility criteria

Three independent reviewers (GA, PPGA, and AMSP) analyzed the search results and selected potentially relevant studies after reading their titles and abstracts, and using the Rayyan software (Ouzzani et al., 2016). Disagreements were resolved by consensus among the reviewers, with the assistance of a fourth reviewer (JSC), when necessary. The following inclusion criteria were applied: in vivo study of inflammatory diseases in animals, administration of U. tomentosa extracts versus placebo or no treatment, assessment of effects on inflammatory mediators or cytotoxic effects, and published in English, Portuguese, or Spanish. Studies using U. tomentosa extracts mixed with other species or isolated substances, non-controlled studies, narrative or scoping review articles, abstracts, conference papers, editorials/letters, and case reports were excluded. Additionally, the reference lists of all selected studies were hand searched to identify additional primary studies for inclusion.

2.4 Data extraction

The following data were extracted from the included articles: author, part of the plant used, type of extract (solvent, method, and extraction time), concentration and/or dose, animal species, results (cytotoxicity and inflammatory mediators), and conclusions. Treatment effects for continuous outcomes were extracted as mean differences (MD) plus standard deviations (SD), which could also be estimated from standard errors or confidence intervals. In the studies where such values were not reported, they were estimated from charts using ImageJ software (National Institutes of Health, Bethesda, USA). The authors of the included studies were contacted when necessary (when some data or articles were not available).

2.5 Quality assessment

For the risk of bias, two investigators (AMSP and FC) independently reviewed the selected studies according to a modified CAMARADES checklist (Macleod et al., 2004) and reported the risks of bias in a table. After the initial analysis, the authors reassessed the articles analyzed previously by each other. Any discrepancies were resolved by a third author (GMA) after discussion with the team. The information is presented as a risk of bias summary (Table 2).

2.6 Statistical analysis

Review Manager 5.4 (Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) was used for statistical analysis. Heterogeneity was evaluated using Cochrane’s Q test and I² statistics, with a p-value <0.10 and I² > 50% being considered significant, respectively. We built a fixed-effects model for endpoints with I² < 50% (low heterogeneity). In the case of pooled outcomes with high heterogeneity, a random-effects model was applied. The results were reported as standardized mean differences (SMD) and their respective 95% confidence intervals (95%CI). We also performed a subgroup analysis to assess the effects of different extracts (aqueous, hydroethanolic, and ethanolic) on the outcomes.

3 Results

3.1 Study selection and characteristics

The initial search retrieved 523 studies published between 1989 and 2023; of these, 124 were found in PubMed, 279 in Embase, and 120 in Scopus. There were 217 duplicated articles, and 273 were excluded after reading the title and the abstract. Thus, 33 studies were selected for full-text reading. Two additional articles were later excluded because they were conference abstracts, whereas seven could not be obtained in full. The final number of articles was 24 (Figure 1).

Figure 1

Figure 1. PRISMA flow diagram of study screening and selection.

Research workers from eleven countries across the American, European, and Asian continents have published preclinical studies with extracts of U. tomentosa, demonstrating the scope of interest and use of this plant in the world. The countries that have contributed most to the publications of in vivo studies are Brazil (41.6%), the United States (12.5%), and Peru (12.5%).

The results of the included studies show that U. tomentosa extracts are well tolerated by the animals and have little or no toxicity at the doses evaluated (Table 1).

Table 1

Table 1. Characteristics of the included studies regarding plant part, type of extract, disease model, treatment, and main results.

3.2 Meta-analysis of selected inflammatory mediators

3.2.1 Interleukin-1 (IL-1)

Three studies that used four animal models and aqueous and hydroethanolic extracts of U. tomentosa were analyzed. The results showed no effect on IL-1 levels (SMD: −0.16, 95%CI: −0.87, +0.56, p = 0.67). The overall assessment of the data revealed high heterogeneity (p < 0.001, I² = 90%) (Figure 2).

Figure 2

Figure 2. Forest plot of the efficacy of Uncaria tomentosa extracts on levels of interleukin (IL)-1.

3.2.2 Interleukin-6 (IL-6)

Six studies showed that the aqueous extract tended to increase IL-6, whereas hydroethanolic extracts significantly reduced IL-6 levels (SMD: −0.72, 95% CI: −1.15, −0.29, p = 0.001). The overall assessment of the data showed high heterogeneity (p = 0.002, I² = 66%) (Figure 3).

Figure 3

Figure 3. Forest plot of the efficacy of Uncaria tomentosa extracts on levels of interleukin (IL)-6.

3.2.3 Interleukin-10 (IL-10)

The effect of U. tomentosa on IL-10 was analyzed in three studies. The results showed that the extracts did not significantly alter IL-10 levels (SMD: −0.05, 95%CI:–0.35, 0.45, p = 0.80). The overall assessment of the data revealed significant heterogeneity (p = 0.004, I² = 63%) (Figure 4).

Figure 4

Figure 4. Forest plot of the efficacy of Uncaria tomentosa extracts on levels of interleukin (IL)-10.

3.2.4 Tumor necrosis factor-alpha (TNF-α)

Six studies using aqueous and hydroethanolic extracts of U. tomentosa were analyzed. The extracts did not significantly alter TNF-α levels (SMD: 0.18, 95%CI: −0.25, 0.62, p = 0.41). Overall evaluation of the data showed high heterogeneity (p < 0.00001, I² = 80%) (Figure 5).

Figure 5

Figure 5. Forest plot of the efficacy of Uncaria tomentosa extracts on levels of tumor necrosis factor (TNF)-α.

3.2.5 Nuclear factor-kappa-B (NF-κB)

Four studies using aqueous and hydroethanolic U. tomentosa extracts showed a significant reduction in NF-κB (SMD: −1.19, 95%CI: −1.89, −0.48, p = 0.001). Overall evaluation of the data revealed moderate heterogeneity (p = 0.05, I² = 55%) (Figure 6).

Figure 6

Figure 6. Forest plot of the efficacy of Uncaria tomentosa extracts on levels of tumor necrosis factor kappa B (NF-κB).

3.3 Quality assessment

There was a high risk of bias regarding sample size calculation, missing outcome data (excluded animals), and possible conflicts of interest, and a moderate risk of bias for temperature control, the number of animals appropriate to the model, and compliance with animal welfare regulations. The risk of bias was low for peer reviewing and the disease model (Table 2). Publication bias was high for IL-6 as the funnel plot is shifted toward the left (data not shown).

Table 2

Table 2. Risk of bias among the included studies.

4 Discussion

In this systematic review and meta-analysis, U. tomentosa decreased the levels of IL-6 and NF-κB but not of IL-1, IL-10, or TNF-α, in animal models of inflammatory diseases. These models included asthma, diabetes, arthritis, obesity, gastric ulcers, and intestinal diseases (Azevedo et al., 2018; Mendes et al., 2014; Castilhos et al., 2015; Araujo et al., 2018; Sandoval et al., 200; Sandoval-Chacón et al., 1998). Although some ethnic groups use this species for religious purposes only, such as the Asháninkas (Keplinger et al., 1999), our findings confirm the anti-inflammatory and/or immunomodulatory activities of the species, as advocated by other indigenous groups of the Amazon.

Inflammatory diseases are usually accompanied by a significant production of reactive oxygen and nitrogen species, as well as the expression of pro-inflammatory cytokines, most notably IL-1, IL-6, and TNF-α; the anti-inflammatory cytokine IL-10; and the activation of NF-κB (Hata et al., 2004; Kany et al., 2019). The studies using extracts of U. tomentosa included in this review show decreases in levels of IL-6. These findings explain, at least in part, the anti-inflammatory activity of this species. Most of the in vivo studies have demonstrated, directly or indirectly, that the inhibition of the activity of the transcription factor NF-κB by the extracts was accompanied by decreased levels of IL-1 or IL-6 (Aguilar et al., 2002; Sandoval et al., 2002; Sandoval et al., 2002; Lozada-Requena et al., 2015; Araujo et al., 2018; Azevedo et al., 2018; Elgawish et al., 2019; XU et al., 2021). Targeting IL-6 is an important strategy to treat inflammatory diseases. Therapeutic monoclonal antibodies against cytokines or their receptors, such as tocilizumab (Ohsugi, 2020), are among the most effective, yet very expensive, therapies.

In general, U. tomentosa extracts have an antioxidant activity that always potentiates their anti-inflammatory activity in the models tested (Sandoval-Chacón., 1998: XU et al., 2021; Desmarchelier et al., 1997; Azevedo et al., 2019; Saghir et al., 2023). Selective inhibitory activity against cyclooxygenase-2 (COX-2) has also been observed, confirming anti-inflammatory properties (Aguilar et al., 2002).

Another important aspect to be considered is that U. tomentosa extracts preserve CD4⁺ and CD8⁺ T cells and possibly stimulate cytokines that favor the polarization of CD4⁺ Th2 cells. These cells play an important role in autoimmune diseases, such as rheumatoid arthritis, by modulating the excessive activity of Th1 cells (Domingues et al., 2011a; Domingues et al., 2011b; Lozada-Requena et al., 2015; Azevedo et al., 2018). In fact, an extract of U. tomentosa was superior to placebo in 50 patients with rheumatoid arthritis, decreasing the number of painful joints, morning stiffness, pain intensity, and joint edema (Mur et al., 2002). Therefore, U. tomentosa should be more broadly investigated for the treatment of autoimmune diseases.

Interestingly, U. tomentosa extracts can either stimulate or inhibit the release of different cytokines, depending on the animal’s health status or the modeled disease. This was observed for IL-1: in the study by Eberlin et al. (2005), a sepsis model, U. tomentosa increased IL-1 levels throughout the infection; in the study by Araujo et al. (2018), a non-alcoholic fatty liver disease model, extracts of U. tomentosa decreased IL-1 levels. Some authors refer to this regulatory effect as immunomodulation (Domingues et al., 2011a; Domingues et al., 2011b; Lozana-Requena et al., 2015; Elgawish et al., 2019; Aldayel et al., 2021; Xu et al., 2021). In our study, U. tomentosa did not alter IL-10 levels in a sepsis model, suggesting immunomodulatory activity in infectious diseases.

Regarding the effectiveness of pentacyclic oxindole alkaloids in reducing inflammatory processes, the results are conflicting. Some authors claim that ethanolic extracts enriched with these alkaloids have better anti-inflammatory activity than aqueous extracts (Aguilar et al., 2002; Domingues et al., 2011a; Farias et al., 2011; Lozada- Requena et al., 2015; Xu et al., 2021). However, the anti-inflammatory activity of aqueous extracts of U. tomentosa is well documented (Roque et al., 2009; Castilhos et al., 2015; Azevedo et al., 2018; Elgawish et al., 2019; Aldayel et al., 2021), and extracts without alkaloids have been shown to maintain their anti-inflammatory activity (Sandoval et al., 2002).

The chemical composition of U. tomentosa extracts is often diverse. In addition to alkaloids, the presence of other compounds such as quinovic acid and polyphenols, which contribute to the pharmacological activity of the species, has been reported (Aquino et al., 1991; Yépez et al., 1991; Dietrich et al., 2014). Furthermore, synergism between different compounds usually contributes to the pharmacological effect of medicinal plants (Carmona and Pereira, 2013).

Interestingly, 54% of the studies included in this review used extracts directly related to traditional formulations (aqueous and hydroethanolic extracts). So important is the traditional use that only these studies could be included in the meta-analysis. On the other hand, although 46% of the studies have used extracts not directly related to traditional formulations, they are important because they can help elucidate mechanisms of action (Table 1).

Overall, the studies were at high risk of bias because most of them did not report sample size calculations, the number of excluded animals, or possible conflicts of interest. The main limitation of this study is the small number of studies included in the meta-analysis. Therefore, as more studies are conducted, other pharmacological effects of this species might be demonstrated. Another limitation is the considerable variation in the plant parts used and in the chemical profiles of the extracts, which is a fact that makes interpretation of these results challenging. Nevertheless, as preclinical studies confirmed the anti-inflammatory and/or immunomodulatory effects and the low toxicity of U. tomentosa extracts, clinical studies should be encouraged.

5 Conclusion

Extracts of the stems, stem barks, roots, and leaves of U. tomentosa, mostly aqueous and hydroethanolic extracts, exhibited anti-inflammatory and/or immunomodulatory activities and low toxicity. These extracts decreased NF-κB and the cytokine IL-6 without altering IL-1, IL-10, or TNF-α. These findings suggest that this species has the potential to treat inflammatory diseases associated with increased IL-6 and/or NF-κB, according to the ethnopharmacological use. These activities are not related to a specific class of compounds.

Data availability statement

The raw data supporting the conclusion of this article will be made available by the authors, without undue reservation.

Author contributions

GA: conceptualization, data curation, investigation, methodology, validation, and writing–original draft. PA: data curation, investigation, methodology, software, validation, and writing–original draft. MM: methodology, resources, validation, and writing–original draft. ER: investigation, methodology, validation, and writing–original draft. SF: investigation, methodology, validation, visualization, and writing–review and editing. JC: investigation, methodology, validation, and writing–review and editing. FC: conceptualization, formal analysis, investigation, resources, software, supervision, visualization, writing–original draft, and writing–review and editing. AP: conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, supervision, validation, visualization, writing–original draft, and writing–review and editing.

Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The publication of this article was financially supported by the University of Ribeirao Preto (UNAERP).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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