Introduction
Chronic inflammatory diseases remain a significant public health challenge [1], [2]. Despite substantial progress in their detection and treatment, these advances come
at a considerable cost, significantly contributing to increased health expenditures.
The primary goals of treatments for chronic inflammatory diseases are reducing inflammation
and pain and preserving functionality. Such treatments are specific to each condition
and include pharmacological interventions, lifestyle modifications, and patient education
regarding disease management [3], [4].
In vitro and in vivo studies provided essential insights into the molecular mechanisms underlying inflammatory
processes, enabling the identification of key mediators and the development of targeted
therapies [5]. Several inflammatory mediators and signaling molecules are dysregulated in chronic
inflammatory diseases, presenting viable targets for current treatments. However,
existing therapies often fail to provide consistent efficacy across all patients due
to heterogeneity and the dynamic nature of the pathogenic process [6].
Medicinal plants have been traditionally used worldwide as alternative or complementary
treatments for inflammatory diseases [7]. Plants and animals share intrinsic intracellular regulatory processes and mediators,
and numerous plant-derived compounds exert significant biological effects on animal
cells (e.g., digitalis, colchicine, and opioids) [8], [9]. Recently, there has been a growing interest in the bioactive compounds in plants,
notably polyphenols, for their potential to treat chronic inflammatory conditions
[10]. Herbal treatments can be prepared through simple decoctions from plant extracts
or by combining multiple plant types. However, the low concentrations of active compounds
obtained through basic processing methods may limit their full therapeutic potential
[11].
Sumac, a genus (Rhus) comprising over 250 species of flowering plants in the family Anacardiaceae, is
widely used as a spice and herbal remedy in traditional medicine for its diverse properties
[12]. Members of the Anacardiaceae family, including the Rhus species, are predominantly trees and shrubs, with occasional subshrubs and lianas
found in tropical, subtropical, and limited temperate regions [13] ([Fig. 1 a]). The economic importance of this plant family stems from its ornamental cultivars
(e.g., Schinus spp.) and fruit- and seed-producing species, such as Pistacia vera (pistachio), Anacardium occidentale (cashew), Mangifera indica (mango), and Rhus spp. (sumacs) [14]. In the Americas, Rhus species (subgenera: Lobadium and Rhus) are closely related to other Rhoeae species, such as
Actinocheita, Cotinus, Malosma, Schinus, Searsia, and Toxicodendron. In Mexico, representatives of these plants include Cardenasiodendron, Cotinus, Toxicodendron, and 35 different species of Rhus
[15], [16] ([Fig. 1 b]).
Fig. 1 Representative images of (a) Rhus trilobata from the Anacardiaceae Family, (b) distribution of plants of genus Rhus in North America, and (c) mainly molecules isolated from Rhus plants.
Research into the anti-inflammatory mechanisms attributed to plants or their components
has expanded remarkably in recent years. These studies aim to support and promote
complementary and alternative medicine or identify and characterize specific anti-inflammatory
components for therapeutic use in chronic inflammatory diseases [17]. Plants of the genus Rhus exhibit antioxidant [18], antimicrobial, anti-aging [19], anticancer [20], [21], and antidiabetic [22] properties. Additionally, bioactive components of Rhus spp. have been investigated, with some molecular mechanisms already described. The anti-inflammatory
properties of Rhus spp. are of particular interest. While specific mechanisms have been partially reviewed
for Rhus verniciflua Stokes
[23],
further experimental strategies, in vitro, in vivo, and human trials, are necessary to understand these effects comprehensively.
Despite the promising therapeutic potential of Rhus spp., knowledge gaps remain regarding their mechanisms of action, optimal dosages,
and the potential risks associated with their use. Addressing these gaps is crucial
for the safe and practical application of Rhus-based treatments in managing inflammatory conditions. Therefore, this review aimed
to compile studies conducted in in vitro, in vivo, and human clinical trials that evaluate the effects of plants of the genus Rhus or their isolated components on inflammatory conditions. The goal was to identify
and describe the potential anti-inflammatory mechanisms attributed to this plant.
Results
Study selection and risk of bias assessment
The article selection process using the PRISMA guide is shown in [Fig. 2], and from the 2351 articles initially identified using the keywords, duplicates
and articles older than five years were eliminated. Then, the titles and abstracts
of 748 articles were reviewed to meet the inclusion criteria. Of these, 704 articles
were excluded because they were review or meta-analysis studies, were not in English
or Spanish, did not evaluate Rhus plants in any in vitro or in vivo studies, or did not evaluate anti-inflammatory effects. Of the 44 potentially relevant
articles, after a detailed review of the complete text, 9 were excluded because they
did not assess inflammatory mediators. Finally, 35 articles that fulfilled the inclusion
criteria were included. No published systematic review was found regarding the effect
of Rhus genus plants on inflammatory mediators in vitro, in vivo, or in humans.
Fig. 2 Flow chart of study selection according to the Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) guidelines.
The risk of bias assessment in the included studies is shown in [Fig. 3]. Overall, 57.7% of the articles were classified as low-risk bias for selection.
The selection bias was divided into two components: random sequence generation, which
showed 21.5% high risk, and allocation concealment, for which no high risk was found
(0%). However, most studies (88.9%) were classified as an unclear risk for allocation
concealment. Performance biases were classified as low risk (43.5%) or unclear risk
(34.5%) because the articles did not specify the information sufficiently. Detection
biases were of unclear risk in 76.9%, low risk in 19.4%, and only 3.7% were classified
as high risk. Incomplete outcome data (attrition bias) was a low or unclear risk bias
in 37.5% and 52.1% of the studies. More than 80% of the articles were classified as
low risk for reporting bias biases. Reporting biases were of low risk for all the
included articles.
Fig. 3 Risk of bias of the articles included in the review. (n = 35). The potential risk
of bias for each article was assessed with the SYRCLE risk of bias tool. Each item
was scored using the nominal scale “yes,” “no,” or “unclear”. Subsequently, the risk
percentages of each bias of the included articles were graphed.
Anti-inflammatory effects of Rhus genus plants in vitro
Nineteen articles that evaluated the anti-inflammatory effects of Rhus genus plants in vitro were included ([Table 1]). The plants studied for their anti-inflammatory effects were Rhus verniciflua, Rhus chinensis Mill, Rhus coriaria L, Rhus succedanea, Rhus tripartite, Rhus trilobata Nutt., and Rhus crenata.
Table 1 Characteristics of the studies in vitro evaluating the anti-inflammatory effects
of plants of genus Rhus.
|
Plant
|
Author, year. Country
|
Cell line
|
Groups of study and treatment
|
Techniques to determine inflammatory mediators
|
|
ADAMTS: A disintegrin and metalloproteinase with thrombospondin motifs; C/ebpα: CCAAT enhancer binding protein α̧ Fabp4: Fatty acid-binding protein 4; CD11b: Cluster of differentiation molecule
11B; CD36: platelet glycoprotein 4; COL2: Collagen type II; COX2: Cyclooxygenase type
2; CXCR4: G-protein-coupled chemokine receptor; DMSO: Dimethylsulfoxide; EGCG: Epigallocatechin-3-gallate.;
ELISA: Enzyme-Linked ImmunoSorbent Assay; Emr-1: adhesion G protein-coupled receptor
E1; ERK: Extracellular-Signal-Regulated Kinase; GFAP: Glial fibrillary acidic protein;
HSP90: heat shock protein 90; Iba 1: Allograft inflammatory factor-1; ICAM: intercellular
adhesion molecules; IF: Immunofluorescence; IHC: Immunohistochemistry; IKKa: IκB kinase α; IL: Interleukin; INF: Interferon; iNOS: Inducible nitric oxide synthase; IκB: Inhibitor of NF-κB; IκBα: Inhibitor of nuclear factor-κB α; JAK: Janus kinase; JNK: Jun
N-terminal kinase; LPS: Lipopolysacharide; MCP: Membrane cofactor protein: MMP: Matrix
metalloproteinases; MEK: Mitogen-activated protein kinase kinase; MIP-1α: Macrophage inflammatory protein-1α; MMP: Matrix metalloproteinase; NF-κB: nuclear enhancer factor of kappa light chains of activated B cells; p38: Mitogen-activated
protein kinases; PGE2: Prostaglandin E2; Pparγ: Peroxisome proliferator-activated receptor gamma; qPCR: quantitative polymerase
chain reaction; Raf: Rapidly accelerated fibrosarcoma; RT-qPCR: Quantitative reverse
transcription polymerase chain reaction; SOCS: Suppressor of cytokine signaling proteins;
SOX: Supercritical Oxygen; STAT3: signal transducer and activator of transcription
3; TNF: Tumor necrosis factor; TNFR: Tumor Necrosis Factor Receptor; TRAF3: TNF receptor-associated
factor; Tyr705: Phospho-Stat3; VEGF: Vascular endothelial growth factor; WB: Western
blot
|
|
Rhus verniciflua Stokes
(Isolated butein)
|
Roh K. et al., 2020.
Korea [24]
|
Peritoneal macrophage from BALB/c mice under inflammatory stimulus (100 ng/mL LPS)
|
|
-
ELISA (TNF-α)
-
RT-qPCR (Pparγ, C/ebpα, Fabp4, CD36)
-
WB (Pparγ, C/ebpα, Fabp4)
|
|
Rhus verniciflua Stokes
(Isolated butein)
|
Liu Y. et al., 2020.
China [25]
|
SH-SY5Y neuroblastoma cells under inflammatory stimulus (BV2 cells + 10 µg/mL LPS
culture supernatants)
|
-
Rhus compound (1, 10, and 30 µg/mL)
-
Non-treatment control
-
Non-inflammatory stimulus control
|
-
IHC (NF-κB p65)
-
qPCR (IL-1β, IL-6, TNF-α, ERK, MEK, Raf-1, NF-κB p65)
-
WB (Erk, MEK, Raf-1, NF-κB p65)
|
|
Rhus verniciflua Stokes
(NS)
|
Kim, B. et al., 2018.
Korea [26]
|
Peritoneal macrophage cells under inflammatory stimulus (100 ng/mL LPS)
|
|
|
|
RAW264.7 cells
|
|
|
|
Rhus verniciflua Stokes
(Isolated dihydrofisetin)
|
Li, K. K. et al., 2018.
China [27]
|
RAW 264.7 cells under inflammatory stimulus (1 mg/mL LPS)
|
-
Rhus compound (10, 20, and 40 µg/mL)
-
Non-treatment control
-
Non-inflammatory stimulus control
|
-
ELISA (PGE2, IL-1β, IL-6, MCP-1, TNF-α)
-
WB (iNOS, COX-2)
|
|
Rhus verniciflua Stokes
(NS)
|
Zheng, W. et al., 2017.
China [28]
|
Primary human osteoarthritis chondrocytes under inflammatory stimulus (10 ng/mL IL-1β)
|
|
-
ELISA (NO, PGE2, TNF-α, IL-6)
-
qRT-PCR (COX-2, iNOS, MMP-1, MMP3, MMP-13, IL-6, TNF-α, ADAMTS-4, ADAMTS-5, SOX-9, COL-2)
-
WB (COX-2, iNOS, MMP-13, COL-2, SOX-9, P65, IκB-α)
|
|
Rhus chinensis Mill.
(Isolated Gallic acid)
|
Liao et al., 2023.
China [29]
|
GES-1 cells under inflammatory stimulus (3 × 105 mol/L of N-methyl-N′-nitro-N-nitrosoguanidine)
|
|
|
|
Rhus chinensis Mill
(Herbal mix and isolated pyrogallol)
|
Chantarasakha K. et al., 2022. Thailand [30]
|
THP-1 and RAW 264.7 macrophages under inflammatory stimulus (10 ng/mL LPS)
|
-
Mix with Rhus compound (25 to 500 µg/mL) for THP-1 cells
-
Mix with Rhus compound (12.5 to 250 µg/mL) for RAW 264.7 cells
-
Non-treatment control
-
Non-inflammatory stimulus control
|
|
|
Rhus chinensis Mill
(NS)
|
Zhou G. et al., 2021.
China [31]
|
HT-29 Human colon cancer cells under inflammatory stimulus (50 ng/mL rhIL17A and 20 ng/mL
TNF-α)
|
-
Mix with Rhus compound (10, 33, 100, and 300 µg/mL)
-
Non-treatment control
-
Non-inflammatory stimulus control
|
-
ELISA (IL-17A, IL-1β, IFN-γ, TNF-α)
-
IHC (IL-17A)
-
qPCR (TNFR, IL-17RA, IL-17A, HSP90)
-
WB (IL-17A, TRAF3, ERK, P38, JNK)
|
|
Rhus chinensis Mill
(NS)
|
Yu, T. et al., 2021.
China [32]
|
Caco-2 cells under inflammatory stimulus (1 mg/mL LPS)
|
-
Mix with Rhus compound (10, 33, 100, and 300 µM)
-
Salazosulfapyridine control (20 mg/100 mg)
-
Indigo control (100 mg/kg)
-
Gallic acid control (100 mg/kg)
-
Indirubin and Ginsenoside Rg1 control
-
Non-treatment control
-
Non-inflammatory stimulus control
|
-
ELISA (IL-6, IL-1β, IL-2, IL-4, IL-5, IL-10, IL-13, IL-18, IFN- γ, TNF-α)
-
WB (Tyr705, STAT3, JAK, SOCS3)
|
|
Rhus chinensis Mill
(Isolated 1,2,3,4,6 penta-O-galloyl-β-D-glucose)
|
Mendonca P. et al., 2017.
United States [33]
|
BV-2 microglia cells under inflammatory stimulus (1 mg/mL LPS and 200 ng/mL IFNγ)
|
|
|
|
Rhus coriaria L.
(Fruits)
|
Martinelli, G. et al., 2022.
Italy [34]
|
Human GES-1 gastric epithelial cells under inflammatory stimulus (10 ng/mL TNF-α or bacterium: cell ratio of 50 : 1 of H. pylori)
|
-
Rhus compound (5, 10, 25, and 50 µg/mL)
-
Non-treatment control
-
Non-inflammatory stimulus control
|
-
ELISA (IL-6, IL-8)
-
IF (NF-κB)
-
WB (NF-κB)
|
|
Rhus coriaria L.
(Fruits)
|
Khalil M. et al., 2021.
Lebanon [35]
|
BV-2 cells under oxidative stress (50 µM H2O2)
BV-2 under inflammatory stimulus (1 µg/mL LPS)
|
|
|
|
Rhus coriaria L.
(Fruits)
|
Khalilpour S. et al., 2019.
Malaysia [36]
|
HaCaT cells under inflammatory stimulus (10 ng/mL TNF-α)
|
-
Rhus extract (10, 25, and 50 µg/mL)
-
10 µM Quercetin control
-
20 µM Curcumin and EGCG control, respectively
-
50 µM pf Resveratrol control
-
Non-treatment control
|
|
|
Rhus coriaria L.
(Fruits)
|
Momeni, A. et al 2019.
Iran [37]
|
Synoviocyte cells from horseradish under inflammatory stimulus (20 ng/mL LPS)
|
-
Rhus compound (0.01, 0.09, 0.1, 0.9, 1, 9, 10, and 90 µg/mL)
-
Rhus compound (10 µL) and non-inflammatory stimulus
-
Ibuprofen (50 – 100 nM)
-
Non-treatment control
|
|
|
Rhus succedanea L.
(Isolated rhoifolin)
|
Yan, J. et al., 2021.
China [38]
|
Chondrocytes from Sprague–Dawley rats under inflammatory stimulus (125, 26 y 35 270 ng/mL
IL-1β)
|
-
Rhus compound (5, 10, 20 µM)
-
Non-treatment control
-
Non-inflammatory stimulus control
|
|
|
Rhus succedanea L.
(Isolated fisetin)
|
Xu M – X. et al., 2020.
China [39]
|
Primary astrocytes from C57BL/6 mice under inflammatory stimulus (contaminated air
with PM2.5 particles)
|
-
Rhus compound (5, 10, and 20 µg/mL)
-
Non-treatment control
-
Non-inflammatory stimulus control
|
-
qPCR (IL-1β, TNF-α, IL-6, IL-8, Emr-1, MIP-1α, CXCR4, GFAP, CD11b, IKKα, IκBα, Iba-1, MCP-1)
|
|
Rhus tripartite
(Leaves, roots, and stems)
|
Ben-Barka Z. et al., 2018.
Belgium [40]
|
Caco-2 cells under inflammatory stimulus (25 ng/mL IL-1β, 50 ng/mL TNF-α, 50 ng/mL IFN-γ, and 1 µg/mL LPS)
|
-
Rhus extract (0.8, 1.6, 3.2, and 6.5 µg/mL)
-
EGCG treatment control
-
Non-treatment control
-
Non-inflammatory stimulus control
|
|
|
Rhus trilobata Nutt.
(Stems)
|
Rodriguez-Castillo et al., 2024.
Mexico [41]
|
Macrophage J774-A under inflammatory stimulus (5 µg/mL LPS)
|
|
-
RT-qPCR (IL-6, IL-1β, TNF-α)
-
Metabolites determination in culture supernatant (PGE2)
|
|
Rhus crenata
(Isolated butein)
|
Ohmoto et al., 2024
Japan [42]
|
RAW264 cells co-cultivated with 3 T3-L1 adipocytes under inflammatory stimulus (LPS
at 5 µM and 10 ng/mL)
|
-
Non-inflammatory stimulus control (3 T3-L1 adipocytes alone negative control)
-
Non-inflammatory stimulus control (co-cultures of 3 T3-L1 adipocytes and RAW264 cells
without LPS and treatment as negative control)
-
Rhus compound group (co-cultures of 3 T3-L1 adipocytes and RAW264 cells with LPS and treatment
at 2 and 5 µM, respectively)
|
-
RT-qPCR (β-actin, PPARγ, C/EBP α, adiponectin, aP2, TNFα, IL-6, MCP-1, iNOS, GLUT4, IRS-1)
|
The preparation methods for Rhus treatments varied across studies. Three studies involved testing plant-infused extract
[30], [31], [32]; one used nearly the entire Rhus tripartita plant, including stems, leaves, and roots, preparing an ethanolic extract of its
components [40]. Chantarasakha et al. [30] prepared an ethanolic extract (v/v) but combined different plants, including Rhus chinensis Mill. Kim et al. [26] used only the bark of Rhus verniciflua to prepare a simple aqueous extract tested on the cellsʼ supernatant. Four studies
tested Rhus coriaria L. fruits using phenolic [35], aqueous [36], and ethanolic [34], [37] fractions extracted from fruits,
and one study on Rhus chinensis Mill. [43]. Moreover, the aqueous ethanol, ethanol-water (ethanol: water 50 : 50 v/v), ethanol
macerate (plant material subjected to maceration with pure ethanol for 48 h), acetone,
and ethyl acetate extracts have also been evaluated [34].
Compounds isolated from the plants were evaluated in eight in vitro studies. Components such as butein, chemically described as 2′,3,4,4,4′-tetrahydroxichalcone
([Fig. 1 c]) [44], a chalcone derivative produced by species from several diverse botanical families,
including the Anacardiaceae to which Rhus verniciflua belongs. Liu et al. [25] and Zheng et al. [28] obtained 98% pure butein from SIGMA and confirmed previous findings about the potential
health benefits of compounds of Rhus verniciflua. Roh et al. [24] also investigated the chemical synthesis of various butein derivatives to enhance
compound 1, a phenolic fraction, as a starting point.
Dihydrofisetin, also named fustin ([Fig. 1 c]) [45], a polyphenol derived from wild and edible herbs and traditional Chinese medicines,
including Rhus verniciflua Stokes, was another compound analyzed in the included studies. Li et al. [27] used it on macrophages, observing reduced levels of proinflammatory mediators.
Gallic acid (GA), or 3,4,5-trihydroxybenzoic acid, acts as an astringent, antioxidant,
plant metabolite, and geroprotector. It inhibits cyclooxygenase-2, and the arachidonate
15-lipoxygenase induces apoptosis and exhibits antitumor activity [46]. A recent study on GA from Rhus chinensis showed its concentration-dependent inhibition of GES-1 cell proliferation via G0/G1
cell cycle arrest. RNA sequencing revealed that GA modulates multiple biological pathways,
including the Wnt/β-catenin pathway, by suppressing Wnt 10B and β-catenin expression. This regulation likely reverses MNNG-induced epithelial-mesenchymal
transition [29].
The compound 1,2,3,4,6 penta-O-galloyl-β-D-glucose (PGG) derived from Rhus Chinensis Mill, which has five galloyl groups in the 1-, 2-, 3-, 4- and 6-positions ([Fig. 1 c]) [47], was also tested. Mendonca et al. [33] demonstrated the anti-inflammatory effects of PGG on microglial cells.
Rhoifolin, a 7-O-neohesperidoside derivative of apigenin, features an alpha-(1 → 2)-L-rhamnopyranosyl-beta-D-glucopyranosyl
group at the 7-hydroxy position. Classified as a dihydroxyflavone and a glycosyloxyflavone,
rhoifolin was first isolated from Rhus succedanea in 1952 [48], [49]. Yan et al. [38] demonstrated that rhoifolin reduced inflammatory cytokines (iNOS, COX-2) and cartilage
degradation markers (MMP13, ADAMTS5) while enhancing collagen II expression, mitigating
IL-1β-induced cartilage damage. It inhibited the phosphorylation of JNK, P38, PI3K, AKT,
and mTORkey proteins in inflammation and autophagy regulation and improved histological
outcomes [38].
Butin, a trihydroxyflavonone, protects against mitochondrial dysfunction induced by
oxidative stress and functions as an antioxidant, protective agent, and metabolite
[50]. In the reviewed study, butin treatment significantly reduced lipid peroxidation
(p < 0.001) compared to the D-GalN group and restored antioxidant enzyme activities
(GSH, SOD, and CAT). It also prevented the elevation of proinflammatory cytokines
(TNF-α, IL-1β, and IL-6) induced by D-GalN (p < 0.05). Additionally, butin (25 and 50 mg/kg) markedly
reduced MPO activity compared to the D-GalN control group (p < 0.001) [51].
Three in vitro assays were performed on cell cultures subjected to proinflammatory lipopolysaccharide
stimulation. Two of these assays utilized Pyrogallol ([Fig. 1 c]), a benzenetriol with hydroxy groups at positions 1, 2, and 3 [52], derived from Rhus chinensis Mill. Chataraska et al. [30] demonstrated its anti-inflammatory effects ([Table 2]). The third assay used an aqueous extract from the infused stems of Rhus trilobata Nutt. [41].
Table 2 Modulation of intra- and extracellular mediators by plants of genus Rhus in vitro.
|
Plant
|
TNF-α
|
IL-1β
|
IL-6
|
IL-8
|
COX-2
|
iNOS
|
NF-κβ P65
|
INF-γ
|
MIP-1a
|
Other
|
|
ADAMTS: A disintegrin and metalloproteinase with thrombospondin motifs; CD11b: Cluster
of differentiation molecule 11B; CD36: platelet glycoprotein; COL2: Collagen type
II; COX2: Cyclooxygenase type 2; CXCR4: G-protein-coupled chemokine receptor; Emr-1:
adhesion G protein-coupled receptor E1; ERK: Extracellular-Signal-Regulated Kinase;
GFAP: Glial fibrillary acidic protein; HSP90: heat shock protein 90; Iba 1: Allograft
inflammatory factor-1; ICAM: intercellular adhesion molecules; IKKa: IκB kinase α; IL: Interleukin; INF: Interferon; iNOS: Inducible nitric oxide synthase; IκBα: Inhibitor of nuclear factor-κB α; JAK: Janus kinase; JNK: Jun N-terminal kinase; MCP: Membrane cofactor protein; MMP:
Matrix metalloproteinases; MEK: Mitogen-activated protein kinase kinase; MIP-1α: Macrophage inflammatory protein-1α; MIP-1α: Macrophage inflammatory protein-1α; NF-κB: nuclear enhancer factor of
kappa light chains of activated B cells; NO: Nitric oxide; p38: Mitogen-activated
protein kinases; p65: ribosome-associated protein; Pparγ: Peroxisome proliferator-activated receptor gamma, C/ebpα: CCAAT enhancer binding protein α; Raf: Rapidly accelerated fibrosarcoma; SOCS: Suppressor of cytokine signaling proteins;
SOX: Supercritical Oxygen; STAT3: signal transducer and activator of transcription
3; TNF: Tumor necrosis factor; TNFR: Tumor necrosis factor receptor; TRAF3: TNF receptor-associated
factor; Tyr705: Phospho-Stat3; VEGF: Vascular endothelial growth factor
|
|
Rhus verniciflua stokes [24]
|
↓
|
|
|
|
|
|
|
|
|
↓ PPAR-γ, CD36. C/ebp-α, Fabp-4
|
|
Rhus verniciflua stokes [25]
|
↓
|
↓
|
↓
|
|
|
|
↓
|
|
|
↓ ERK, MEK, Raf-1
|
|
Rhus verniciflua stokes [26]
|
↓
|
|
↓
|
|
|
|
|
↑
|
|
↑ IL-12 p70
|
|
Rhus verniciflua stokes [27]
|
↓
|
↓
|
↓
|
|
↓
|
↓
|
↓
|
|
↓
|
↓ PGE2
|
|
Rhus verniciflua stokes [28]
|
↓
|
|
↓
|
|
↓
|
↓
|
|
|
|
↓ PGE2, MMP-13, ADAMTS-5, MMP-1, κBα, ADAMTS-4, NO, SOX-9, COL-2, p65
|
|
Rhus chinensis Mill. [29]
|
|
|
|
|
|
|
|
|
|
↓ TGFβ, p53
↑ VEGF, Wnt, IL-17, MAPK
|
|
Rhus chinensis Mill. [30]
|
↓
|
|
↓
|
|
↓
|
|
|
|
|
↓ IL-1α
|
|
Rhus chinensis Mill. [31]
|
↓
|
↓
|
|
|
|
|
|
↓
|
|
↓ IL-17A, IL17RA, TNFR, ERK, HSP90, TRAF3, p38, JNK
|
|
Rhus chinensis Mill. [32]
|
↓
|
↓
|
↓
|
|
|
|
|
↓
|
|
↓ IL-10, IL-18, IL-2, IL-4, IL-13, IL-5, JAK2, STAT3, Tyr705, SOCS-3
|
|
Rhus chinensis Mill. [33]
|
|
|
|
|
|
|
|
|
|
↓ MMP-9, MCP-5
|
|
Rhus coriaria L. [34]
|
|
|
↓
|
↓
|
|
|
↓
|
|
↓
|
NA
|
|
Rhus coriaria L. [35]
|
↓
|
|
↓
|
|
↓
|
↓
|
↓
|
|
|
↓ IL-10
|
|
Rhus coriaria L. [36]
|
|
|
|
|
|
|
|
|
|
↓ MMP-9, ICAM-1, VEGF1
|
|
Rhus coriaria L. [37]
|
↓
|
↓
|
|
|
↓
|
|
|
|
|
↓ IL-18
|
|
Rhus succedanea
[38]
|
|
↓
|
|
|
↓
|
↓
|
|
|
|
↓ MMP-13, ADAMTS-5
|
|
Rhus succedanea L. [38]
|
↓
|
↓
|
↓
|
↓
|
|
|
|
|
↓
|
↓ Emr-1, CXCR-4, GFAP, MCP1, CD11b, Iκκα, κBα, Iba-1
|
|
Rhus tripartite
[40]
|
|
|
|
↓
|
|
|
|
|
|
NA
|
|
Rhus trilobata Nutt. [41]
|
↓
|
↓
|
↓
|
|
|
|
|
|
|
↓ PGE2
|
|
Rhus crenata
[42]
|
↓
|
|
↓
|
|
|
↓
|
|
|
|
↓ β-actin, PPAR-γ, C/EBP α, adiponectin, aP2, MCP-1, GLUT4, IRS-1
|
Additional plant-derived compounds, including fisetin ([Fig. 1 c]) from Rhus succedanea L., were also tested. Fisetin is an orally bioavailable polyphenol found in many
fruits and vegetables, with potential antioxidant, neuroprotective, anti-inflammatory,
antineoplastic, senolytic, and longevity-promoting activities. Upon administration,
fisetin scavenges free radicals, protects cells from oxidative stress, and can upregulate
glutathione. It inhibits proinflammatory mediators, such as tumor necrosis factor-alpha
(TNF-α), interleukin (IL)-6, and nuclear factor kappa β (NF-κβ) [53]. Xu et al. [39] investigated its effects on primary astrocytes through nanoemulsion formulations
employing various solvents, demonstrating its anti-inflammatory effect ([Table 2]).
The included studies reported nine cell types that tested the anti-inflammatory potential
of Rhus. Macrophage cultures were particularly interesting, comprising three subtypes: RAW
macrophages from the peritoneum [26], [30], macrophages J744-A [41], and THP-1 macrophages [30]. BV-2 microglial cells [25], [33], [35], CaCo2 colon cancer cells [32], [40], gastric epithelial cells (GES)-1 [29], [34], and HT-29 colon cancer cells [31] were also frequently reported. Different cell lines, including HaCaT keratinocytes
[36], SH-SY5Y cells [25], primary astrocytes [39], primary bovine synoviocytes [37], primary rat chondrocytes [38], and primary human cartilage chondrocytes [28] were used in only one study. These studies showed the reduction in various intra-
and extracellular mediators, including proinflammatory cytokines, suggesting the anti-inflammatory
effect of Rhus in all tested cell lines ([Table 2]).
Regarding the treatment doses, most studies tested different treatment concentrations,
with some evaluating eight [37], four [31], [32], [34], [38], [40], three [25], [26], [27], [36], [39], or two [26], [28], [29], [30], [35], [42] different concentrations. Only three studies evaluated a single concentration [24], [33], [41]. A consistent pattern was observed: the highest concentration consistently showed
the most effectiveness in reducing proinflammatory mediators, regardless of the administration
route.
The primary outcomes measured were the changes in the concentration of intra- and
extracellular inflammatory mediators ([Table 1]). The laboratory techniques most frequently used were the enzyme-linked immunosorbent
assay (ELISA), followed by Western blot (WB) and reverse transcription (RT)–qualitative
polymerase chain reaction (qPCR). Immunohistochemistry (IHC), immunofluorescence (IF),
qPCR, and antibody microarray assays were also used. TNF-α was the most commonly measured mediator, with 13 studies demonstrating its reduction
following Rhus treatments. IL-6, the second most evaluated mediator, decreased in 11 studies, while
IL-1β decreased in 8. A decrease in inflammatory mediators was observed in nearly all the
studies, except for Kim et al. [26], where INF-γ and IL-12p70 were increased by Rhus treatment, and Liao et al., where VEGF, Wnt, IL-17, and MAPK pathways were increased
by GA isolated from Rhus plants derivates [29] ([Table 2]).
Anti-inflammatory effects of rhus genus plants in in vivo and human studies
Twenty-three articles were conducted in vivo using animal models of inflammation, and only one was done in humans ([Table 3]). Eight of these also included in vitro assays. The plants used in the in vivo studies were Rhus verniciflua, Rhus chinensis Mill, Rhus coriaria L., Rhus succedanea, and Rhus trilobata Nutt.
Table 3 Characteristics of the studies in vivo and in humans evaluating the anti-inflammatory
effects of plants of genus Rhus.
|
Plant
|
Author, year.
Country
|
Animal Model
|
Groups of study and treatment
|
Techniques to determine inflammatory mediators
|
|
5HT3A: 5-Hydroxytryptamine Receptor 3A; Ac-FOX01: Acetyl forkhead box protein O; Ac – p53:
acetyl-tumor suppressor protein; ACT1: Nuclear factor-kappa-B activator 1; AKT: Protein
kinase B; ASC: Apoptosis-associated speck-like protein containing; b.w: body weight;
Bax: Bcl-2-associated X protein; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma
2; Bcl2: inhibitor of the anti-apoptotic protein B-cell lymphoma 2; BSEP: bile salt
export pump; C/ebpα: CCAAT enhancer binding protein α̧ CD36: platelet glycoprotein 4; CASP: Caspase; CD11b: Cluster of differentiation
molecule 11B; CD36: platelet glycoprotein 4; COX2: Cyclooxigenase type 2; CXCR4: C – X-C
chemokine receptor type 4; CYP2E1: Cytochrome P450 family 2 subfamily E; d.w: drinking
water; ELISA: Enzyme-Linked ImmunoSorbent Assay; Emr-1: adhesion G protein-coupled
receptor E1; ERK: Extracellular-signal-regulated kinase; EX-527: Selisistat, Sirtuin
Inhibitor; Fabp4: Fatty acid-binding protein 4;
GFAP: Glial fibrillary acidic protein; HO-1: Heme oxygenase 1; Hsp90: heat shock protein
90 kDa; Iba 1: Allograft inflammatory factor; IF: Immunofluorescence; IFN-ϒ: Gamma
interferon; IHC: Immunohistochemistry; IKKa: IκB kinase α; IKKβ: Inhibitor kappa-B kinase β; IL: Interleukine; iNOS: Inducible nitric oxide synthase; IκBα: inhibitor of nuclear factor kappa B; IκBα: Inhibitor of nuclear factor-κB; JAK2: Janus kinase; JNK: Jun N-terminal kinase; LPS: Lipopolysacharide; MCP: Membrane
cofactor protein; MIP-1α: Macrophage inflammatory protein-1α; MMP9: Matrix Metallopeptidase 9; MRP2: Multidrug resistance-associated protein 2;
NF-κB: nuclear enhancer factor of kappa light chains of activated B cells; NQO1: NAD(P)H
quinone dehydrogenase 1; Nrf2: Nuclear factor erythroid-derived 2-like 2; NS: Not
specified; p38: mitogen-activated protein kinases; PI3K: Phosphatidylinositol-3-kinase;
Pparγ: Peroxisome proliferator-activated receptor gamma; qPCR: quantitative polymerase
chain reaction; SERT: serotonin transporter protein; SIRT1: Sirtuin 1; SOCS: Suppressor
of cytokine signaling proteins; STAT3: signal transducer and activator of transcription
3; TGF-β: transforming growth factor; TGF-β: Transforming growth factor beta; TIMP2: Tissue inhibitor of metalloproteinases 2;
TNF: Tumor Necrosis Factor; Tyr705: Phospho-STAT3; WB: Western blot.; α-SMA: alpha smooth muscle Actin
|
|
Rhus verniciflua Stokes
(Isolated butein)
|
Althurwi et al., 2023
Saudi Arabia [51]
|
Hepatic injury in Wistar rats (21 days)
|
|
|
|
Rhus verniciflua Stokes
(Bark)
|
Kim S. et al., 2021.
Korea [54]
|
Helicobacter pylori-induced gastritis model in C57 BL/6 J mice (49 days)
|
-
Rhus extract (3, 4, 6, 8, and 16 mg/mL d. w.)
-
Metronidazole (400 mg/kg) + Omeprazole (20 mg/kg) + Clarithromycin (250 mg/kg) + Rhus
extract mixed d. w. control
-
Non-treatment control
|
|
|
Rhus verniciflua Stokes
(Isolated butein)
|
Roh, K. et al., 2020.
Korea [24]
|
Lymphedema model in BALB/c mice (7 days)
|
|
|
|
Rhus verniciflua Stokes
(Isolated butein)
|
Zhu, Y. et al., 2019.
China [55]
|
Sepsis-induced brain injury model in C57BL/6 mice (48 h)
|
-
Rhus compound (10 mg/kg b. w.)
-
Rhus compound (10 mg/kg b. w.) + EX-527 (5 mg/kg b. w.)
-
EX-527 (5 mg/kg b. w.) control
-
Non-treatment control
-
Non-inflammation and Rhus compound treatment control
|
-
ELISA (IL-6, TNF-α, IL-1β)
-
WB (Bcl2, Bax, SIRT1, Ac-FOXO1, NF-κβ, Ac – p53, SIRT1)
|
|
Rhus verniciflua Stokes
(NS)
|
Kim, B. et al., 2018.
Korea [56]
|
Peritonitis-induced model in BALB/c mice model (6 days)
|
|
|
|
Rhus verniciflua Stokes
(Isolated dihydrofisetin)
|
Li, K. K. et al., 2018.
China [27]
|
Carrageenan-induced paw edema model in mice (4 h)
|
|
-
ELISA (IL-6, TNF-α)
-
WB (iNOS, COX-2)
|
|
Rhus verniciflua Stokes
(NS)
|
Kim, H. et al., 2017.
Korea [57]
|
Emesis and gastrointestinal inflammation-induced model in Sprague–Dawley rats (5 days)
|
-
Rhus extract (25, 50, and 100 mg/kg mg/kg b. w.)
-
Metoclopramide control (25 mg/kg b. w.)
-
Non-treatment control
-
Non-inflammation control
|
-
ELISA (TNF-α, IL-6)
-
qPCR (5HT3A, SERT)
|
|
Rhus chinensis Mill.
(Isolated tannic acid)
|
Wang et al., 2024.
China [58]
|
DSS-induced colitis model in SPF mice (16 days)
|
-
Non-inflammation control
-
Non-treatment control
-
Rhus compound (0.1, 1, 3 mg/ml d. w.)
-
Non-inflammation + Rhus compound control
|
-
PCR (IL17F, IL-1β, TNF-α)
-
IHC (IL17F, NFκβ)
-
RT-qPCR (TNF-α, IL-1β, NFκβ p65, Uhrf1, MettI17, Asf1b)
-
WB (Asf1b, Mett17b)
-
Transcriptome profiles (Chil1, S100A8, S100A9, SphK1, Mmp11, Mmp14, Ccl3, TNF-α, IL1β, IL6, IL17A, IL17F, IL17ra e IL17rb)
|
|
Rhus chinensis Mill.
(Fruits)
|
Ma et al., 2023
China [59]
|
Acetaminophen-induced liver injury in BALB/c, mice BALB/c (7 days)
|
|
-
WB (CYP2E1, p-NF-κB/NF-κB, N-NF-κB, COX-2, p- JNK/JNK, p-ERK/ERK, p-P38/P38, p-Akt/Akt, Bax, Bcl-2)
|
|
Rhus chinensis Mill.
(Fruits)
|
Liao et al., 2023.
China [29]
|
Gastric precancerous lesions in BALB/c mice (20 weeks)
|
|
-
IHC (Wnt 10B, β-catenin)
-
WB (Wnt 10B, β-catenin, E-cadherin, N-cadherin, and vimentin).
|
|
Rhus chinensis Mill.
(Fruits)
|
Zhang et al., 2022.
China [43]
|
Necrotizing enterocolitis model in Sprague–Dawley rat pups (4 days)
|
|
-
IF (Occludin, ZO-1, NrF2)
-
WB (NQO1, NrF2, NF-κB, pNF-κB, iNOS, Bax, Bcl-2, Caspase-3)
-
IHC (TLR4, pNF-κB)
|
|
Rhus chinensis Mill.
(Fruits)
|
Ma et al., 2022.
China [60]
|
Indomethacin-induced gastric ulcer in Kunming mice (28 days)
|
|
-
IHC (p-NF-κВ)
-
IF (Nrf2 and p-NF-κВ)
-
WB (IKB-α, p-IKB-α, NF-κB, p-NF-κB and iNOS).
-
Biochemical indicators in plasma (IL-1β, IL-6, TNF-α, AOPP and PGE2)
|
|
Rhus chinensis Mill.
(Fruits)
|
Sun, Y. et al., 2022.
China [61]
|
Cholestasis model in C57 BL/6 J mice (30 days)
|
|
-
ELISA (IL-6, TNF-α, IL-1β)
-
IHC (TGF-β y α-SMA)
-
WB (NF-κB, IκBα, BSEP y MRP2)
|
|
Rhus chinensis Mill.
(Fruits)
|
Sun Y. et al., 2023.
China [62]
|
Isoniazid+ rifampicin-induced liver injury in BALB/c, mice (28 days)
|
|
-
ELISA (IL-6, TNF-α, IL-1β)
-
WB (Nrf2, HO-1, NQO1, CYP2E1, Bax, Bcl-2)
|
|
Rhus chinensis Mill.
(NS mix)
|
Zhou G. et al., 2021.
China [31]
|
Colitis-induced model in BALB/c mice (7 days)
|
-
Mix with Rhus compound: gallic acid, lutein, and quercetin (50, 100, and 200 mg/kg b. w., respectively)
-
Gallic acid 50 mg/kg b. w. control
-
Lutein 100 mg/kg b. w. control
-
Quercetin 200 mg/kg b. w. control
-
5-aminosalicylic acid at 200 mg/kg b. w. control
-
Non-treatment control
-
Non-inflammation control
-
Non-inflammation and Mix with Rhus compound treatment control
|
-
qPCR (IL-17A, ACT1, Hsp90)
-
ELISA (IL-10, TNF-α, IL-1β, IFN-ϒ, IL-17A)
-
IHC (IL-17A)
-
qPCR (IL-17A, ACT1, Hsp90)
-
WB (IL-17A, Hsp90, ERK, JNK, P38, IκBα, and iNOS)
|
|
Rhus chinensis Mill.
(NS mix)
|
Yu, T. et al., 2021.
China [32]
|
Ulcerative colitis model in Sprague–Dawley rats (24 h)
|
-
Mix with Rhus compound (140 and 280 mg/kg b. w.)
-
2,4,6-Trinitrobenzenesulfonic acid control
-
Non-treatment control
-
Non-inflammation control
|
-
ELISA (IL-6)
-
qPCR (TNF-α, IL-6, IL-1β)
-
WB (Tyr705, STAT3, JAK2, SOCS3, SOCS1, CASP1, IL-1β, ASC)
|
|
Rhus chinensis Mill.
(Fruits)
|
Sun Y. et al., 2021.
China [63]
|
Acetaminophen-induced liver injury in BALB/c mice (7 days)
|
|
-
ELISA (IL-6, IL-1β, TNF-α)
-
IF (anti-Nrf2)
-
WB (Nrf2, HO-1, NQO1, CYP2E1, NF-κB, COX-2, JNK, ERK, P38, PI3K, Akt, Bax and Bcl-2)
|
|
Rhus chinensis Mill.
(Fruits)
|
Wu et al., 2020.
China [64]
|
Nonalcoholic fatty liver disease in rats Sprague–Dawley (12 weeks)
|
|
-
WB (PPAR-α, CPT1, PPAR-γ, β-Actin, CYP2E1, P38, p-P38, p-NFκβ, iNOS, COX-2, β-Actin)
-
IF (p-NFκβ)
|
|
Rhus chinensis Mill.
(Fruits)
|
Zhou J. et al., 2020.
China [65]
|
Liver fibrosis-induced model in Kunming mice (6 weeks)
|
|
-
ELISA (IL-1β, IL-6, TNF-α)
-
IF (anti-MMP9 and anti-TIMP2)
-
IHC (p-NF-κB, p-P38, PPAR-γ)
-
qPCR (TNF-α, TGF-β1, Bax, Bcl-2)
-
WB (TGF-β1, α-SMA, COX-2, iNOS, Bax, Bcl-2)
|
|
Rhus coriaria L.
(Fruits)
|
El-Elimat et al., 2023.
Jordan [66]
|
Paracetamol-induced liver toxicity in a male Wistar rat model of hepatotoxicity (29
days)
|
-
Rhus 25 mg/kg + paracetamol
-
Rhus 50 mg/kg + paracetamol
-
Negative control
-
Hepatotoxic control (paracetamol 3 g/kg)
-
Silymarin positive control (silymarin 100 mg/kg + paracetamol).
|
-
qPCR (TNF-α and IL-6)
-
IHC (TNF-α and IL-6)
|
|
Rhus coriaria L.
(Fruits)
|
Hariri, N. et al., 2020.
Iran [67]
|
Women with depression and obesity (6 weeks)
|
|
|
|
Rhus coriaria L.
(NS)
|
Isik, S. et al., 2019.
Turkey [68]
|
Necrotizing enterocolitis-induced model in rats (4 days)
|
|
|
|
Rhus succedanea L.
(Isolated fisetin)
|
Xu M. et al., 2020.
China [39]
|
Neuroinflammation-induced model in C57BL/6 mice (14 weeks)
|
-
Rhus extract (5, 10, and 20 mg/kg b. w.)
-
Non-treatment control
-
Non-Inflammatory stimulus and Rhus extract treatment control
|
-
qPCR (IL1β, IL-6, TNF-α, IL-8, Emr-1, MIP-1α, CXCR4, GFAP, CD11b, IKKα, IκBα, Iba-1, MCP-1)
-
WB (IKKβ, IκBα, NF-κβ, GFAP)
|
|
Rhus trilobata Nutt.
(Stems)
|
Rodriguez-Castillo et al., 2024.
Mexico [41]
|
LPS-induced paw edema model in Wistar rats (24 h)
|
-
Rhus compound at 500, 750, or 1000 µg, respectively (50 µL of 10 mg/mL)
-
Non-treatment control
-
Dexamethasone control (500 µg)
-
Non-inflammatory stimulus control
|
|
Compounds isolated from the Rhus genus were used in six in vivo studies [24], [27], [39], [51], [55], [58]; however, most included studies did not fully detail the active compounds tested,
including those in which aqueous or methanol extract or a macerate or fermented components
were used [26], [41], [43], [54], [57], [59], [61], [64], [66], [67], [68], [69], [70], [71], [72]. Two studies tested a mixture of plants that included Rhus
[31], [32].
Four different rodent strains were reported to be used to evaluate the anti-inflammatory
effect of Rhus in vivo; additionally, one study was carried out in humans [67] ([Table 2]). Inflammation models in BALB/c [24], [26], [29], [32], [59], [69] and C57BL/6 [39], [54], [55], [61] mice were the most used, followed by the Sprague–Dawley rats used in three studies
[32], [43], [54], two studies used Wistar rats [41], [51], one was conducted under Specific Pathogen Free [58], and Kunming mice were used in two studies [70], [71].
The inflammation models and the treatment durations with Rhus are shown in [Table 3]. The most common inflammation models were those of the gastrointestinal tract [29], [31], [32], [54], [57], [58], [62], [68], [71] and liver [51], [61], [62], [64], [66], [69], [70]. However, the effect of Rhus was also evaluated in models of edema [24], [27], [41], neuroinflammation [39], [55], and periodontitis [56]. Treatment durations ranged from hours to weeks, with the shortest being 4 hours
in the carrageenan-induced paw edema model and the longest being 20 weeks in the gastric
precancerous lesions in BALB/c mice ([Table 3]).
Compounds isolated from the plants were evaluated in seven in vivo studies, including butin [51], butein [24], [55], dihydrofisetin [27] isolated or derived from Rhus verniciflua Stokes, tannic acid [58] from Rhus Chinensis Mill., and fisetin [39] derived from Rhus succedanea L. Notably, all of these compounds showed effects in reducing the inflammatory process.
Additionally, two studies tested mixed compounds formulated from various plants containing
Rhus Chinensis
[31], [69].
As in in vitro studies, most in vivo studies tested different treatment doses, with studies evaluating four [54], three [31], [39], [41], [57], or two [26], [27], [29], [32], [43], [51], [59], [61], [65], [66], [69], [71], [73] doses and some using a single concentration [24], [55], [67], [68]. The doses were applied in various ranges,
from 5 to 800 mg/kg body weight when injected, as reported by most studies, or from
0.1 to 16 mg/ml when administered in drinking water, as reported by two studies. The
most commonly used doses were 400 and 800 mg/kg body weight ([Table 3]). In the reviewed studies, a consistent pattern was observed regardless of dose:
the highest concentration consistently proved to be the most effective in reducing
proinflammatory mediators, irrespective of the administration route.
The laboratory techniques for assessing the modification of cytokines and other inflammatory
mediators used in vivo included predominantly protein detection by ELISA followed by WB and, less frequently,
IF. As in in vitro studies, the inflammatory mediator most commonly measured in the experiments was
TNF-α, followed by IL-6 and IL-1β, although 54 different molecules were evaluated. No specific pattern of inflammatory
mediators was observed in the models of acute inflammation (hours or days) or chronic
inflammation (weeks).
As shown in [Table 4], the anti-inflammatory effect of all the Rhus species, through any form of administration (components, dosage, and route of administration),
was shown to decrease the expression of the classic inflammatory mediators TNF-α, IL-1β, and IL6. Moreover, the potential of Rhus to reduce more than 50 extra- and intracellular mediators, including receptors, signal
molecules, and transcriptor factors, was demonstrated.
Table 4 Modulation of intra- and extracellular mediators by plants of genus Rhus in vivo
and in human studies.
|
Plant
|
TNF-α
|
IL-1β
|
IL-6
|
COX-2
|
iNOS
|
NF-κβ P65
|
Bax
|
Bcl-2
|
p38
|
Other
|
|
5HT3A: 5-Hydroxytryptamine Receptor 3A; ACT1: Nuclear factor-kappa-B activator 1;
AKT: Protein kinase B; ASC: Apoptosis-associated speck-like protein containing; Bax:
Bcl-2-associated X protein; C/ebpα: CCAAT enhancer binding protein α; CASP: caspase protein; CD11b: Cluster of differentiation molecule 11B; CD36: platelet
glycoprotein 4; COX: Cyclooxygenase type 2; CXCR4: C – X-C chemokine receptor type
4; CYP2E1: Cytochrome P450 family 2 subfamily E; Emr-1: adhesion G protein-coupled
receptor E; ERK: Extracellular-signal-regulated kinase; Fabp4: Fatty acid-binding
protein 4; GFAP: Glial fibrillary acidic protein; Hsp90: heat shock protein 90 kDa;
Iba 1: Allograft inflammatory factor; IFN-ϒ: Gamma interferon; IKKa: IκB kinase α; IL: Interleukin; IκBα: Inhibitor of nuclear factor-κB; JAK2: Janus kinase; JNK: Jun N-terminal kinase; MIP-1α: Macrophage inflammatory protein-1α; MMP9: Matrix Metallopeptidase
9; NA: Not apply; NF-κB: nuclear enhancer factor of kappa light chains of activated B cells; NQO1: NAD(P)H
quinone dehydrogenase 1; Nrf2: Nuclear factor erythroid-derived 2-like 2; p38: mitogen-activated
protein kinases; p53: tumor suppressor; PI3K: Phosphatidylinositol-3-kinase; Pparγ: Peroxisome proliferator-activated receptor gamma; SERT: serotonin transporter protein;
SIRT1: Sirtuin 1; SOCS: Suppressor of cytokine signaling proteins; STAT3: signal transducer
and activator of transcription 3; TGF-β: Transforming growth factor beta; TIMP2: Tissue inhibitor of metalloproteinases 2;
TIMP2: Tissue inhibitor of metalloproteinases 2; TNF: Tumor necrosis factor; Tyr705:
Phospho-STAT3; α-SMA: alpha smooth muscle actin
|
|
Rhus verniciflua Stokes [51]
|
↓
|
↓
|
↓
|
|
|
|
|
|
|
NA
|
|
Rhus verniciflua Stokes [54]
|
↓
|
|
|
|
|
|
|
|
|
↓ Pparϒ, C/ebpα, Fabp4, CD36
|
|
Rhus verniciflua Stokes [24]
|
|
↓
|
|
|
|
|
|
|
|
NA
|
|
Rhus verniciflua Stokes [55]
|
↓
|
↓
|
↓
|
|
|
↓
|
↓
|
↑
|
|
↓ SIRT1, p53
|
|
Rhus verniciflua Stokes [26]
|
↓
|
|
↓
|
|
|
|
|
|
|
NA
|
|
Rhus verniciflua Stokes [27]
|
↓
|
|
↓
|
↓
|
↓
|
|
|
|
|
NA
|
|
Rhus verniciflua Stokes [57]
|
↓
|
|
↓
|
|
|
|
|
|
|
↓ 5HT3A, SERT
|
|
Rhus chinensis Mill. [58]
|
↓
|
↓
|
↓
|
|
|
↓
|
|
|
|
↓ IL-17F, Chil1, S100A8, S100A9, SphK1, Mmp11, Mmp14, Ccl3, IL17A, IL17F, IL17ra e
IL17rb
|
|
Rhus chinensis Mill. [59]
|
|
|
|
|
|
|
|
|
|
↓ Wnt 10B, β-catenin, E-cadherin, N-cadherin, vimentin
|
|
Rhus chinensis Mill. [29]
|
↓
|
↓
|
↓
|
|
↓
|
↓
|
|
|
|
↓ IKB-α, p-IKB-α, AOP, PGE2
↑ Nrf2
|
|
Rhus chinensis Mill. [43]
|
↓
|
|
↓
|
|
↓
|
↓
|
↓
|
↑
|
|
↓ TOS, MPO, MDA, TLR4, cleaved CASP-3
↑ TAS, SOD, GSH-Px, NQO1, Nrf2
|
|
Rhus chinensis Mill. [60]
|
↓
|
↓
|
↓
|
|
↓
|
↓
|
↓
|
↑
|
|
↓ PGE2, AOPP, p-IκBα/IκBα, p-NF-κB/NF-Κb, CASP-3
↑ Nrf2, HO-1 y NQO1
|
|
Rhus chinensis Mill. [61]
|
↓
|
↓
|
↓
|
|
|
|
|
|
|
NA
|
|
Rhus chinensis Mill. [69]
|
↓
|
↓
|
↓
|
↓
|
|
↓
|
↓
|
↑
|
|
↓ Nrf2, HO-1, NQO1, CYP2E1, p-JNK JNK, p-ERK, ERK, p-P38, P38, PI3K, p-PI3K, Akt,
p-Akt
|
|
Rhus chinensis Mill. [31]
|
↓
|
↓
|
|
|
↓
|
|
|
|
↓
|
↓ IL-10, IFN-γ, IL-17A, ERK, JNK, IκBα, ACT1, HSP90
|
|
Rhus chinensis Mill. [32]
|
↓
|
↓
|
↓
|
|
|
|
|
|
|
↓ STAT3, Tyr705, SOCS1, SOCS3, CASP-1, JAK2, ASC
|
|
Rhus chinensis Mill. [62]
|
↓
|
↓
|
↓
|
↓
|
|
↓
|
↓
|
↑
|
↓
|
↓ IL-8, ERK, JNK, Nrf2, NQO1, CYP2E1, Akt, PI3K
|
|
Rhus chinensis Mill. [64]
|
|
|
|
↓
|
↓
|
↓
|
|
|
↓
|
↓ PPAR-α, CPT1, PPAR-γ, β-Actin, CYP2E1, p-P38, β-Actin
|
|
Rhus chinensis Mill. [65]
|
↓
|
↓
|
↓
|
↓
|
↓
|
↓
|
↓
|
↑
|
↓
|
↓ Pparγ, MMP-9, TGFβ, α-SMA, TIMP2
|
|
Rhus coriaria L. [66]
|
↓
|
|
↓
|
|
|
|
|
|
|
NA
|
|
Rhus coriaria L. [67]
|
↓
|
|
↓
|
|
|
|
|
|
|
NA
|
|
Rhus coriaria L. [68]
|
↓
|
|
↓
|
|
|
|
|
|
|
↓ CASP-3, CASP-8, CASP-9
|
|
Rhus succedanea L. [74]
|
↓
|
↓
|
↓
|
|
|
↓
|
|
|
|
↓ IκBα, Emr-1, CXCR4, GFAP, CD11b, IKKα, IKKβ, Iba-1, MIP-1α
|
|
Rhus trilobata Nutt. [41]
|
|
↓
|
|
↓
|
|
|
|
|
|
NA
|
Predicted cellular mechanisms for the anti-inflammatory effect of Rhus plants
We identified 57 different inflammatory mediators in in vitro studies ([Table 2]) and 54 in in vivo studies to be underexpressed by plants of the genus Rhus or its components. Altogether, 84 inflammatory mediators were identified and subsequently
analyzed in the Reactome bioinformatic platform to obtain the prediction and overrepresentations
of cellular processes and signaling pathways shown in [Fig. 4].
Fig. 4 Prediction of anti-inflammatory potential of plants of Rhus genus. A list of the mediators modified by Rhus treatment was obtained by combining information from all included studies. Subsequently,
this was analyzed in the REACTOME v83 database (https://reactome.org) and the overrepresentation visualizations for proteins were obtained. Proteins underexpressed
by Rhus were associated with the immune system signaling pathway (d); including innate immune system signaling (b) and cytokine signaling in immune system pathways (c). A more detailed visualization of signaling by interleukins shows the association
within the cytokine-mediated signaling (a). [rerif]
Sixty-nine proteins underexpressed by Rhus were associated with the immune system signaling pathway (p = 1.11E-16, FDR: 1.32E-14)
([Fig. 4 d]). Within this pathway, 23 proteins were related to innate immune system signaling
(p = 7.83E-4, FDR: 4.87E-3) and 63 with cytokine signaling in immune system pathways
(p = 1.11E-16, FDR: 1.32E-14) as shown in [Fig. 4 b] and [c], respectively. A more detailed visualization of signaling by interleukins showed
that signaling from the families of IL-10 (22 proteins, p = 1.11E-16, FDR: 1.32E-14),
IL-4/13 (47 proteins, p = 1.11E-16, FDR: 1.32E-14) and IL-1 (14 proteins, p = 6.3E-10,
FDR: 7.67E-8) was the most significantly associated within cytokine-mediated signaling
([Fig. 4 a]).
Discussion
Research into traditional treatments for inflammatory diseases, mainly herbal medicine,
has garnered increasing attention as a promising strategy for developing more effective
therapies. As a result, scientific evidence regarding the benefits and risks of various
alternative and complementary therapies is now more readily available [80], [81], [82], [83], [84].
This systematic review of research on plants in the Rhus genus reveals that numerous species exhibit significant anti-inflammatory potential,
both in vitro and in vivo, despite variations in purity, dosage, administration routes, and inflammation models.
We confirmed that Rhus extracts can effectively reduce classic inflammatory cytokines, including TNF-α, IL1β, IL6, IFNγ, and others. Rhus plants can modulate intracellular mediators and transcription factors, including
ERK, MEK, p38, JAK, STAT, JNK, Raf, NFκB, IκB, COX-2, iNOS, PPAR, C/EBP, and SOX-9. Extracellular mediators such as MMPs, VEGF,
PGE, and ADAMTS, as well as receptors like TNFR, IL17RA, and ICAM, are also targeted.
Furthermore, the bioinformatics analysis of these inflammatory mediators suggests
that Rhus compounds regulate immune system signaling, diminishing the innate immune response,
and inhibiting critical proinflammatory
interleukins and inflammasome signaling.
While several reviews have examined the anti-inflammatory properties of plants, most
are region-specific, and, to date, none have been focused on Rhus species [17], [85], [86]. Thus, this study represents the first comprehensive peer-reviewed examination of
the anti-inflammatory effects of Rhus fruits, extracts, and compounds. It provides new insights into their potential therapeutic
applications in managing inflammation-related conditions.
Previous research on Rhus plants has explored their chemical composition, ethnobotanical uses, and therapeutic
benefits, with findings suggesting effects beyond placebo [18], [87], [88]. Rhus species have shown antioxidant, antineoplastic, and antimicrobial properties. For
example, Rhus longipes increased antioxidant enzyme activity and hepatic glutathione levels while reducing
malondialdehyde in vivo
[89]. Rhus trilobata extracts reduced tumor growth in ovarian cancer models [90], and Rhus vulgaris inhibited MRSA and Streptococcus mutans growth [91]. Given the role of inflammation and oxidative stress in cancer and infections [92], [93], [94], Rhus’s ability to
decrease these processes may help alleviate inflammation.
The pharmacological effects of herbal drugs vary significantly depending on their
geographic origin, harvesting conditions, and preparation methods [95]. Our results indicate that seven Rhus species have been studied, with Rhus verniciflua and Rhus chinensis being the most extensively researched. These species are primarily distributed in
Asia [96], a region known for their deep-rooted traditions, complementary medicine, and scientific
advancements in this field [97]. However, species such as Rhus trilobata, collected in Mexico [41], have also been investigated, which indicates that the study of Rhus-based medicine is expanding to other parts of the world.
Medicinal plant extracts differ from chemically defined pharmaceuticals due to their
complex composition, where the identities and quantities of active ingredients or
marker compounds are often not fully characterized [98]. Our review highlights the diverse preparations of Rhus used in research, including aqueous and organic extracts and isolated bioactive compounds
such as butein [99], fisetin [100], GA [101], and PGG [102]. Regardless of their origin or the extraction method, Rhus plants consistently exhibited anti-inflammatory activity in both in vitro and in vivo studies. This suggests that the anti-inflammatory properties of Rhus are robust across species and preparation methods, indicating a versatile therapeutic
potential. However, these findings also emphasize the need for further studies
focused on standardization and addressing potential variability in efficacy and safety.
In vitro studies in our review showed that Rhus exhibits a consistent anti-inflammatory effect across different plant species and
extract types compared to untreated controls, with some effects comparable to those
of conventional pharmaceuticals. This effect spans a wide dosage range, from less
than 1 to 500 µg/mL, and in various cell types, suggesting a stable mechanism of action
that is not dependent on specific conditions. These findings indicate that Rhus may address a variety of inflammatory diseases with a broad therapeutic margin, allowing
for dose adjustments. Our review further validates these in vitro results by establishing non-toxic doses subsequently used in murine inflammation
models.
Animal models play an essential role in drug development by evaluating candidate compoundsʼ
safety, efficacy, pharmacokinetics, and pharmacodynamics before human testing [103], [104]. In the reviewed studies, inflammation models cover a range of types of acute and
chronic inflammation affecting the gastrointestinal tract, liver and bile ducts, periodontal
tissues, and conditions like edema and neuroinflammation. This could suggest the widespread
efficacy, stability of the mechanism of action, broad therapeutic potential, and foundation
for clinical research of plants from the Rhus genus.
Different doses ranging from 5 to 800 mg/kg body weight were tested in the in vivo models, demonstrating an effect on the reduction in inflammatory mediators, which
increased as the dose was increased. The duration of models and treatment varied significantly
across the studies, depending on the design used to investigate acute or chronic effects
[105]. Most studies lasted around 7 days, although some involved treatment periods as
short as a few hours. The most prolonged analysis periods extended up to 20 weeks.
All studies demonstrated measurable anti-inflammatory effects, regardless of treatment
duration, suggesting immediate and sustained impacts.
In both acute and chronic inflammation models, TNFα, IL-1β, and IL-6 were the most measured inflammatory mediators, recognized for their predominant
role in inflammation [106]. However, 54 different inflammatory mediators were evaluated, including those of
the NF-κB, MAPK, and JAK-STAT pathways, which play a key role in the pathological progression
of organ inflammatory disease [107]. The heterogeneity between studies prevented the establishment of a differential
or explanatory pattern of the anti-inflammatory effect of Rhus or even the differentiation of mechanisms in acute or chronic inflammation. For this
reason, bioinformatics was employed to establish the potential mechanisms of Rhus more comprehensively.
The in vivo studies also evaluated the toxic effects of the treatments using different strategies,
including liver function tests, organ measurements, and morphological assessments
through histopathology. It is worth noting that the doses tested in the in vivo models were derived from previous in vitro studies that confirmed non-cytotoxic doses through strategies such as the TUNEL assay
and MTT. However, the assessment of adverse effects was limited to a maximum analysis
period of 20 weeks in one murine model study and 6 weeks in the human clinical trial,
underscoring the need for long-term studies to ensure the safe use of the Rhus treatment. Despite these challenges, animal models remain indispensable for understanding
drug effects and optimizing therapeutic interventions [104], [108].
The only clinical study in humans was conducted in women with obesity and depression
[67], showing that a 6-week treatment with Rhus coriaria L. (fruits) at a dose of 1000 mg/kg body weight significantly reduced TNF-α and IL-6 levels compared to the untreated group. No significant adverse events were
reported during this evaluation period. This trial provides a more consistent approach
to using Rhus for human inflammatory conditions.
We conducted a bioinformatics analysis to better understand Rhus’s mechanism using data from studies. The Reactome database was employed to identify
significant associations between inflammatory mediators reduced by Rhus and various signaling pathways. Proteins downregulated by Rhus, both in vitro and in vivo, were linked to immune response signaling, particularly cytokine and interleukin
pathways. The involvement of these molecules in numerous diseases, including rheumatoid
arthritis [109], systemic lupus erythematosus [110], inflammatory bowel disease [111], osteoarthritis [112], obesity [113], diabetes [114], atherosclerosis [115], cancer [92], dermatological immune-mediated diseases [116], neuroinflammation [117], epilepsy [118], and periodontitis [119], is well documented. Many current therapies target the inhibition of specific cytokines,
suggesting that Rhus compounds may offer a potentially adjunctive role in reducing inflammation.
The genes downregulated by Rhus compounds indicate a potential regulatory effect on NLR (nucleotide-binding domain
leucine-rich repeat-containing receptor) signaling pathways involved in inflammasome
activation. Inflammasomes are protein complexes within the innate immune system that
initiate inflammation in response to exogenous or endogenous danger signals. Inflammasome
activation leads to pyroptosis, triggering the release of proinflammatory cytokines
such as IL-1β and IL-18. Dysregulated inflammasome signaling has been implicated in cardiovascular
and metabolic diseases, cancer, and neurodegenerative disorders, making inflammasomes
a promising therapeutic target [120]. Our results demonstrate that Rhus compounds decrease IL-1β, and studies by Yu T. et al. [32] and Momeni A. [37] have shown that Rhus chinensis Mill and Rhus coriaria L. reduce
IL-18 in vitro. Additionally, two in vivo studies in rat models of inflammation reported a reduction in IL-1β and caspase-1 by Rhus chinensis Mill [32], and caspases 3, 8, and 9 by Rhus coriaria L. decrease [68]. These findings suggest that Rhus compounds may target the inflammasome, as evidenced by the association of proteins
such as CASP1, CASP8, CASP9, IKKB, IKKA, ASC, and BCL2 with NLR signaling pathways.
Our review followed PRISMA guidelines [75] to ensure transparency and rigor in the study selection process. We also utilized
the SYRCLE risk of bias tool for animal studies [76] to assess the quality of the included research. While the methodological quality
of the included studies was thoroughly evaluated and multiple anti-inflammatory mechanisms
of Rhus were identified, there are still several limitations to consider. Our SYRCLE analysis
revealed some studies with a risk of performance and detection biases, mainly due
to the lack of details of active compounds tested or the incomplete description of
blinded experimental methodologies, leading to the potential selection, performance,
or detection biases. Therefore, a more thorough chemical characterization of the compounds
is needed to draw more definitive conclusions. Additionally, although we used the
Reactome database to map the mediators modulated by
Rhus, the data were not derived from a single controlled experiment, and the analysis
should be interpreted cautiously. Nevertheless, this bioinformatics approach provides
a broader perspective on Rhus’s effects. Finally, our review primarily focused on anti-inflammatory effects, leaving
room for future research into other potential therapeutic properties of Rhus plants.
