Rotundine/L-THP Revealed an Anti-Allergic Asthma Effect Through MRGPRX2

M. D. Foysal Uddin Sarker Shanto, M. D. Roknuzzaman Faisal, Mahdi Nikbakht, MST Umma Fatama, M. D. Shorif Uddin, Ashiquer Rahman Tonmoy, Abul Kalam,

doi:10.5281/zenodo.15166269

Review Paper | Open Access
Volume 03 | Issue 04 | Article Id IJPS/250304001

Rotundine/L-THP Revealed an Anti-Allergic Asthma Effect Through MRGPRX2
M. D. Foysal Uddin Sarker Shanto* M. D. Roknuzzaman Faisal Mahdi Nikbakht MST Umma Fatama M. D. Shorif Uddin Ashiquer Rahman Tonmoy Abul Kalam
^1,2,3,4,5,7School of Pharmaceutical Science, Zhengzhou University, Henan, China.
⁶School of Nursing and Health, Zhengzhou University, Henan, China.

Abstract

Background: Allergic Asthma is a chronic inflammatory disorder that can be characterized by airway hyperresponsiveness, inflammation, and remodeling. Despite many modern advancements in treatment, still there remains a need for more effective and targeted therapies. Recent studies have identified MRGPRX2 (Mas-Related G Protein-Coupled Receptor X2) as a key factor in mast cell-mediated allergic disease, this makes it a promising therapeutic target. Rotundine, a natural compound with known anti-inflammatory properties, has shown potential in modulating MRGPRX2 activity in mast cells. This review aims to investigate the anti-allergic effects of Rotundine (L-THP, Levo-tetrahydropalmatine) and how it can benefit allergic-asthma patients through its interaction with MRGPRX2, addressing the unknown in current knowledge regarding MRGPRX2-mediated pathways and their therapeutic potential ability. By collecting knowledge from existing literature, this review study will explore the mechanisms underlying Rotundine’s effects, its efficacy in relieving asthma symptoms, and its potential ability as a novel therapeutic treatment for allergic asthma. Objectives: The objective of this systematic review is to demonstrate an overview knowledge of the role of MRGPRX2 in allergic asthma pathogenesis, synthesize and critically evaluate the available evidence regarding the mechanisms by which Rotundine/L-THP modulates MRGPRX2 signaling in mast cells, and its efficacy in alleviating allergic asthma symptoms. Design and Methods: This review synthesizes findings from preclinical and clinical studies, focusing on the mechanisms by which Rotundine/L-THP modulates MRGPRX2 activity and allergic asthma symptoms. A comprehensive search of relevant databases such as PubMed, Web of Science, Google Scholar, and Frontiers. Studies focusing on MRGPRX2, mast cell activation, allergic asthma pathophysiology,and the pharmacological properties of Rotundine/L-THP were analyzed. Emphasis was placed on experimental and clinical studies that investigate the interaction between Rotundine and MRGPRX2, as well as its potential therapeutic applications. Results: This review summarizes results on how Rotundine/L-THP reduces the release of histamine, tryptase, and pro-inflammatory cytokines, hence preventing MRGPRX2-mediated mast cell activation, which in turn has anti-allergic asthma benefits. It minimizes airway inflammation by suppressing Th2 immune responses by lowering IL-4, IL-5, and IL-13 levels as well as by downregulating NF-?B and MAPK pathways. Preclinical research reveals that it successfully lowers immune cell infiltration and airway hyperresponsiveness in animal models. While these outcomes suggest that Rotundine/L-THP is a promising therapeutic target to treat allergic asthma. Moreover, further research is needed to confirm its direct interaction with MRGPRX2 and validate its clinical potential.

Keywords

Rotundine, L-tetrahydropalmatine(L-THP), Mast cell, MRGPRX2, Allergic Asthma.

Introduction

Asthma is a chronic inflammatory lung disease that causes hyperreactivity on a physiological level and recurring episodes of coughing, chest tightness, or wheezing on a clinical level[1-4]. The incidence of asthma increases by 50% every 10 years on average worldwide[5]. More than 300 million people currently suffer from asthma worldwide[6, 7]. An estimated 262 million people globally had asthma in 2019[8]. The two types of asthma are intermittent and chronic, with the latter being mild, moderate, or severe. Asthma patients can also be categorized as cough variant asthma, aspirin-exacerbated respiratory disease, occupational asthma, cough virus, immunoglobulin E-mediated asthma, cough-type asthma, allergic asthma, and nonallergic asthma, which is frequently brought on by viral upper respiratory tract infections or has no known cause[1]. Allergic asthma, also known as Type 2-high asthma, is the most common clinical phenotype of asthma[9, 10]. It is an inflammatory disease of the airways characterized by recurrent episodes of wheezing and bronchoconstriction. It results from complex gene-environment interactions, with flare-ups frequently triggered by allergen exposure, airway hyperresponsiveness, chronic inflammation, and accumulation of immune system cells, and is triggered by endogenous and environmental stimuli[3, 9, 11]. Allergic asthma is a common phenotype and one of the most critical disorders in the world regarding the extent and duration of the disability[12], affecting up to 90% of the pediatric asthma population and up to 50% of adults. Its severity varies from mild to severe, with flare-ups frequently triggered by allergen exposure[13]. Immunologically, the main clinical features of allergic asthma result from the action of different cytokines secreted from activated CD4⁺ T-helper 2 (Th2) cells[14-16]. Th2 cytokines (IL-4, IL-5, IL-13) contribute to key features such as eosinophilic inflammation, mucus hypersecretion, airway hyperresponsiveness, and elevated IgE levels[2, 12, 17, 18]. Th2 cells, through the production of cytokines, further amplify the allergic inflammatory response, leading to conditions like allergic asthma[19]. Rotundine (molecular formula: C₂₁H₂₅NO₄), also known as L-tetrahydropalmatine(L-THP) and its chemical name is 5,8,13,13a-tetrahydro-2,3,9,10-tetramethoxy-6h-dibenzo[a,g] quinolizine, Molecular Weight: 355.43[20, 21], is an isoquinoline alkaloid extracted mainly from the active ingredients of Stephania Epigaea Lo and Corydalis yanhusuo W. T. Wang [22-24]. It is widely used for its analgesic and hypnotic effects, and its pharmacological effects include anti-inflammatory, anti-virus, and anti-tumor effects on melanoma, leukemia, and breast cancer [22, 24, 25]. It can also block calcium channels and inhibit pathogenic bacteria and conditioned reflexes[3]. Recent studies suggested that L-THP is a promising compound for treating dysmenorrhea, drug addiction, inflammatory diseases, neuropathic pain, cancer, brain edema, and acute global cerebral ischemia-reperfusion injury, analgesia, antitussive, antiarrhythmia and antihypertension[21, 26]. Mast cells (MCs) play a key role in the early stages of allergic asthma[27] by migrating toward inflamed tissues and stimulating the contraction of bronchial smooth muscle bundles, which plays an important role in the pathophysiology of allergic asthma[3]. MCs caused allergic asthma by releasing pro-inflammatory and airway-constrictive mediators like histamine, tryptase, serotonin, cysteinyl-LTs, LTB4, and PGD2[24]. Their activation is primarily driven by IgE-FcεRI crosslinking with allergens, with IL-4, IL-5, and IL-13 as key cytokines. IL-4 and IL-13 are essential for IgE class switching[28-30]. Mast cells (MCs) are tissue-resident immune cells and are critical for host defense against microbial infection, pathogen clearance, immune-cell recruitment, and inflammatory-mediated pain[31], but they are best known for their roles in allergic disorders such as Allergic Asthma[32]. The Mas-related G protein-coupled receptor (MRGPRs) family consists of 7 transmembrane domain receptors involved in cell proliferation, development, metabolism, survival, and neuronal signaling. MRGPRX2, a 37-kDa GPCR with 330 amino acids, is primarily expressed in mast cells (MCs)[33]. In 2006, Tatemoto et al.provided the first demonstration that MRGPRX2 is expressed in MCs[34]. MRGPRX2 has been proposed to play an important role in mast cell-driven diseases[35]. Recently, it has been identified as a potential biomarker for allergic asthma, and targeting it may help alleviate the disease, as shown in previous studies [3, 24, 33, 36]. However, the canonical receptors for the peptides identified as ligands for MRGPRX2 are expressed in the neurons[37]. MRGPRX2’s knockdown in human MCs resulted in a significant abolishment of MC degranulation and allergic reactions[36]. At present, the reagents used to treat asthma are mainly bronchospasm-relieving drugs, inhaled corticosteroids, such as β2-receptor agonists and theophylline, anticholinergics, and leukotriene antagonists or anti-inflammatory drugs, which include hormones and leukotriene regulators[38-40]. Most of these drugs reveal several adverse reactions with long-term use. There are a variety of antibody drugs, such as Benralizumab, Mepolizumab, Reslizumab, Dupilumab, and anti-asthma monoclonal antibody (omalizumab), that have significant effects in the treatment of severe asthma[2, 3, 6]. Allergen-specific immunotherapy is an effective treatment for common allergic conditions[41].

Settings:

This review primarily includes studies done in Asian Countries where Rotundine has been traditionally used and extensively studied for its medicinal properties.

Rotundine/Tetrahydropalmatine and Contribution of MRGPRX2 to Allergic Asthma

Chemical Characteristics and Plant Sources of Rotundine/Tetrahydropalmatine:

THP (molecular formula: C₂₁H₂₅NO₄), an isoquinoline alkaloid, widely exists in Chinese herbal medicine preparations excreted from Corydalis yanhusuo[42]. In the 1960s, Hsu and Kin were the first to isolate l-tetrahydropalmatine (l-THP) from Corydalis yanhusuo and did the first pharmacological characterization of the compound[43]. THP has four–OCH₃ groups at the 2, 3, 9 and 10 positions. THP has a chiral center in its structure, and its levorotatory form [(-)-tetradropalmatine (-)-THP] is also known as Rotundine. In L-THP, the N⁺ cation is downward, and the chiral (C₁₄)-H is upward. Therefore, it is also known as (13aR)-5,8,13,13a-tetrahydro-2,3,9,10-tetramethoxy-6Hdibenzo[a,g]quinolizine hydrochloride (IUPAC name). THP has several derivatives with similar structures, such as corydaline (Figure 1)[26].

Figure 1: Chemical structural formulae of Rotundine/THP and its main related derivatives.

In particular, the levo isomer of THP (l-THP; structure shown in Figure 1 appears to contribute to many of the therapeutic effects such as sedative, neuroleptic, analgesic properties, anti-coagulant, anti-nociceptive, anti-hyperalgesic, anti-oxidant, anti-viral, and anti-inflammatory activities[44-46]. Mounting evidence from biochemical, immunohistochemical, behavioral, electrophysiological, and pharmacological studies suggest that THPBs mainly exert their neuropharmacological effects through dopamine (DA) receptors, with preferential affinity toward D₁ and D₂ receptors in the nigrostriatal and mescorticolimbic DAergic pathways[43, 47, 48]. Recent research has revealed that THP demonstrates anti-inflammatory and antioxidant properties. It can suppress osteoclastogenesis by inhibiting the NF-κB and MAPK pathways and can attenuate intracellular accumulation of ROS under the stimulation of irradiation[49]. Rotundine/L-THP has been found to alleviate headache, chest pain, hypochondriac pain, and abdominal pain in humans and inflammatory and neuropathic pain in experimental animals[50]. However, the mechanism underlying L-THP analgesic effect remains poorly understood.

Exploring the Contribution of MRGPRX2 to Allergic Asthma:

The family of Mas-related G protein-coupled receptors (MRGPRs) is a family of 7-transmembrane domain receptors that regulate cell proliferation, development, metabolism, survival, and neuronal signal transmission. MRGPRX2 is a 37-kDa G protein-coupled receptor (GPCR) that consists of 330 amino acids and is expressed on mast cells (MCs)[33]. Many US Food and Drug Administration-approved drugs activate human MCs and induce hypersensitivity reactions through a novel GPCR, known as MRGPRX2[51]. In the past 10 years, MRGPRX2 has emerged as a significant MC receptor responsible for non-IgE-mediated allergic reactions[52]. In a detailed study, An, Lee, et al. showed that serum MRGPRX2 levels were significantly higher in asthma patients than in healthy subjects. In particular, they were higher in the allergic asthma group than in the nonallergic asthma group. Additionally, high levels of MRGPRX2 were significantly associated with allergic asthma requiring moderate-to-high ICS doses and those with good responses (well-controlled) to ICS for the 12-month follow-up period (especially those with MRGPRX2 value ≥ 100 ng/mL). Furthermore, we confirmed that MGRPRX2 is an independent biomarker for predicting asthma control status with ICS response for the 12-month follow-up in allergic asthmatic patients. Interestingly, MRGPRX2 concentrations were higher in the well-controlled group than in the uncontrolled group, probably because there were more patients with a stronger nature of nonallergic asthma (usually difficult to control) among the allergic asthmatic patients[53].

Table 1. Differences between clinical characteristics and optimal serum MRGPRX2 levels in allergic asthmatic patients[53]

	Serum MRGPRX2<100 ng/mL (n=85)	Serum MRGPRX2 ≥100ng/mL (n=79)	Total (n=164)	P value
Age, years	46.0±13.9	41.6±14.1	43.9±14.1	0.047
Female sex, n (%)	56 (65.9)	47 (59.5)	103 (62.8)	0.494
Smoking status, n (%)

Current	10 (11.8)	9 (11.4)	19 (11.6)	0.901
Former	21 (24.7)	22 (27.8)	43 (26.2)
Never	54 (63.5)	48 (60.8)	102 (62.2)
Age at onset, n (%)
<40y	36 (42.4)	50 (63.3)	86 (52.4)	0.008
≥40y	49 (57.6)	29 (36.7)	78 (47.6)
Exacerbations over 12 mo†, n (%)
no	13 (68.4)	13 (65.0)	26 (66.7)	0.823
yes	6 (31.6)	7 (35.0)	13 (33.3)
ICS use at registration, n (%)
No (naïve)	57 (66.3)	55 (69.6)	112 (67.9)	0.647
yes	29 (33.7)	24 (30.4)	53 (32.1)
Required dose of ICS‡, n (%)
Low	11 (39.3)	5 (20.8)	16 (30.8)	0.155
Moderate to high	17 (60.7)	19 (79.2)	36 (69.2)
Response to ICS over 12 mo§, n (%)
Well-controlled	14 (56.0)	21 (84.0)	35 (70.0)	0.033
Uncontrolled	11 (44.0)	4 (16.0)	15 (30.0)
Blood eosinophil, absolute count, n (%)
<300 cells/μL	22 (32.4)	29 (41.4)	51 (37.0)	0.271
≥300 cells/μL	46 (67.6)	41 (58.6)	87 (63.0)
Sputum eosinophil, n (%)
<2%	4 (22.2)	3 (15.8)	7 (18.9)	0.622
≥2%	14 (77.8)	16 (84.2)	30 (81.1)
FEV1, pred, n (%)
FEV1≥80%	36 (42.4)	32 (40.5)	68 (41.5)	0.960
60%≤FEV1 <80%	31 (36.5)	29 (36.7)	60 (36.6)
FEV1 <60%	18 (21.1)	18 (22.8)	36 (22.0)

As shown in table 1 above, the allergic asthma group was classified into two subgroups with high and low MRGPRX2 levels using the optimal cutoff value of 100 ng/mL. Distributions of clinical variables between these two subgroups are summarized in Table 1. Patients with higher MRGPRX2 levels were significantly associated with an onset age higher than 40 years (P = .008) and well-controlled responses to ICS (P = .033) compared with their counterparts. Otherwise, no significant variables associated with MRGPRX2 levels existed. MRGPRX levels did not correlate with absolute blood eosinophil count (r = .008, P = .929), sputum eosinophil percentage (r = −.318, P = .582), C-reactive protein (r = .118, P = .32), and FEV1 (r = .001, P = .986)[53].

Anti-allergic asthma effects of Rotundine/L-THP through MRGPRX2:

So far, no cure for allergic diseases is available. Current medicines such as anti-histamines, immunosuppressants and mast cell stabilizers primarily focus on relieving allergic symptoms and reducing the pain of allergic reaction. However, these medications often come with side effects and do not address the root cause of the diseases[54, 55]. Mast cells (MCs) are key mediators in allergic reactions, playing a central role in the pathogenesis of allergic asthma. They contribute to allergic responses by secreting histamine and a variety of inflammatory and immunomodulatory substances. In allergic pathologies, histamine triggers acute symptoms due to its rapid effects on the vascular endothelium, bronchial smooth muscle cells, and other tissues. This leads to vasodilation, vascular hyperpermeability, bronchoconstriction, hypotension, itching, cramping, diarrhea, and cutaneous wheal and flare responses[56]. MRGPRX2 is the key receptors that mediate MC activation and induce allergic reactions. Unlike the IgE-FcεRI pathway, it triggered MCs activation, operates independently, and is characterized by rapid degranulation. This process is associated with a quick and transient peak of intracellular calcium, followed by the secretion of individual granules[57]. Mrgprx2 can be activated by a variety of basic compounds, peptides, and amines such as substance P, and mastoparan. and is related to MC activation through an IgE- IgE-independent pathway, which is a crucial target for anti-allergy drug therapy. This receptor is linked to mast-cell activation through an IgE-independent pathway, which makes it a crucial target for anti-allergy drug therapy[56]. Rotundine/L-THP has been shown in previous research to exhibit anti-inflammatory and mast cell-stabilizing properties[22, 23]. By inhibiting mast cell degranulation, Rotundine/L-THP could reduce the release of histamine, tryptase, and pro-inflammatory cytokines, which are the key drivers of allergic asthma symptoms in patients. MRGPRX2-mediated mast cell activation is associated with a rapid increase in intracellular calcium levels. Besides, Rotundine/L-THP has been reported to block calcium channels[3], which also could inhibit the calcium influx required for MRGPRX2-triggered degranulation. Moreover, Rotundine/L-THP has demonstrated immunomodulatory effects[56], through which it can suppress the Th2 cytokines such as IL-4, IL-5, and IL-13. Since Th-2 cytokines contribute key features to allergic asthma[2, 12, 19] Rotundine/L-THP could reduce symptoms by modulating these immune responses. Furthermore, Rotundine/L-THP has been shown to inhibit NF-κB and MAPK signaling pathways[49], which are downstream of MRGPRX2 activation. By disrupting these pathways, Rotundine/L-THP could successfully reduce the production of pro-inflammatory mediators and attenuate airway inflammation. Roundine/L-THP, with its alkaloid structure[22, 24, 42], may act as a functional antagonist of MRGPRX2, preventing ligand-induced activation and subsequent inflammatory responses.

DISCUSSION:

Rotundine/L-THP exhibits several pharmacological properties, including mast cell stabilization[54], calcium channel blockade[3], immunomodulation[56], and inhibition of NF-κB/MAPK signaling pathways[49] that potentially align with mechanisms involved in MRGPRX2 modulation. Given its alkaloid structure, Rotundine/L-THP may behave as a functional antagonist of MRGPRX2, blocking ligand-induced activation and subsequent inflammatory responses. While these mechanisms provide a compelling rationale for Rotundine/L-THP’s potential anti-allergic effects through MRGPRX2, it is important to acknowledge that this remains largely theoretical.

Limitations of Current Evidence:

Despite extensive literature searches, we didn’t find any direct studies that have established a bridge linking Rotundine/L-THP to MRGPRX2 modulation. Firstly, there is a gap in direct evidence demonstrating a clear signaling role from Rotundine/L-THP to MRGPRX2. Secondly, while Rotundine/L-THP is a known compound to stabilize mast cells, the specific mechanisms of how it does this effect remain unclear. Thirdly, no direct evidence was found regarding this matter that Rotundine/L-THP has effects on the release of specific mast cell mediators, such as histamine and tryptase, in other contexts of MRGPRX2 activation.

CONCLUSION:

Allergic asthma remains a significant health challenge all over the world, the current existing therapies often failing to address the root causes of the allergic diseases, particularly non-Ig-E mediated pathways. In this review article, we investigated a natural compound Rotundine/Levo-tetrahydropalmatine (L-THP)’s potential as a new treatment for allergic diseases specifically allergic asthma, focusing on its most possible relationship with mas-related G protein-coupled receptor X2 (MRGPRX2). Since allergic asthma is a chronic inflammatory illness, current treatments that target not only IgE-dependent but also IgE-independent mast cell activation pathways are required. Besides, MRGPRX2 has become a key participant in the allergic process and for this, it is a potential therapeutic target. Rotundine/L-THP shows promising anti-allergic asthma potential effects via a variety of mechanisms, such as immunomodulation, calcium channel blockage, mast cell stability, and suppression of NF-κB/MAPK signaling pathways. According to these pharmacological characteristics, Rotundine/L-THP might interrupt the activation of mast cells by MRGPRX2, and also plays a crucial route in non-IgE-mediated hypersensitivity reactions. Since IgE-FcεRI signaling is the primary target of currently used asthma medicines, investigating MRGPRX2 as a therapeutic target offers a possible and unique way to manage allergic asthma in patients, especially when traditional treatments are ineffective. Moreover, most of the existing data demonstrating Rotundine/L-THP’s anti-allergic actions via MRGPRX2 is an indirect and theoretical study. Besides, the absence of strong proof which will show the direct interaction of Rotundine/L-THP’s with MRGPRX2, unclear mechanisms of how mast cells stabilize, and a lack of information on its effect on histamine and tryptase release are some of its main disadvantages. Therefore, to fill up these gaps, we highly suggest that future research emphasize a thorough and multifaceted approach. The following pathways should be included. Preclinical in vitro and vivo experiments using MRGPRX2-transferred mast cells and animal models of allergic asthma are needed to evaluate Rotundine/L-THP’s effects on mast cell degranulation, cytokine release, and airway inflammation. Mechanistic investigations in the lab should identify the specific molecular mechanisms by which Rotundine/L-THP stabilizes mast cells and inhibits downstream signaling pathways. Additionally, clinical trials (at the beginning in small groups) are essential to find out the safety, efficacy, and optimal dosing of Rotundine/L-THP in human patients with allergic asthma. The potential of combining Rotundine/L-THP with existing anti-asthma medications to enhance therapeutic outcomes should also be investigated. Furthermore, molecular docking studies and bioinformatics analyses should be employed to predict Rotundine/L-THP’s binding to MRGPRX2 and identify the potential interaction sites. Finally, these preclinical and clinical studies will determine whether the Rotundine/L-THP can possibly develop into a safe and effective therapeutic agent for allergic asthma, which will offer a novel approach to targeting MRGPRX2-mediated pathways. The findings from such research studies would not only advance our understanding of MRGPRX2-mediated pathways but also open the way for innovative treatments that will improve the quality of life for asthma patients globally.

Lists of Abbreviations:

DA: Dopamine

FEV1: Forced Expiratory Volume in 1 Second

GPCR: G Protein-Coupled Receptor

ICS: Inhale Corticosteroids

IgE: Immunoglobulin E

IL: Interleukin

L-THP: Leve-Tetrahydropalmatine

MRGPRX2: Mas-Related G Protein-Coupled Receptor X2

NF-κB: Nuclear Factor Kappa B

ROS: Reactive Oxygen Species

Th2: T=helper 2

THP: tetrahydropalmatine

Conflicts of interest:

The authors declared no conflicts of interest.

ACKNOWLEDGEMENT:

The authors would like to express their heartiest gratitude to Mr. MD Foysal Uddin Sarker Shanto for providing the necessary resources and facilities that enabled the completion of this review study. We are also deeply indebted to Mr. Abdul Kalm for his invaluable mentorship, insightful guidance, and constructive feedback throughout the project. Additionally, we extend our sincere appreciation to our fellow authors who contributed to this project and dedicated their valuable time and energy to make it complete. Without the advice and complete honesty of each author, this paper would never have reached its potential.

Credit authorship contribution statement:

Mr. Md Foysal Uddin Sarker Shanto: Literature Review, Conceptualization, collecting data, Methodology, writing original draft, Figure input, Software. Mr. Abul Kalam: Methodology, formal analysis, mentorship, and correcting the original draft. Mr. Md Roknuzzaman Faisal: Formal analysis, data curation, and writing the original draft. Mr. Mahdi Nikbakht: Data Curation, correcting grammatical errors. Mrs. Mst Umma Fatima: Correcting Grammatical errors and further software correction. Mr. MD Shorif Uddin: Further Review and add corrections. Mr. Ashiquer Rahman Tonmoy: Further Review and add correction

Ethics approval and consent to participate: Not Applicable

Consent for publication: Not Applicable

Availability of data and material: all the data used in our article are available from publicly accessible sources, such as PubMed, Elsevier, Web of Science, Springer, etc.

Competing interests: The authors declare that they have no competing interests.

Funding: No funding received.

Studies involving plants: this review discusses Rotundine/L-THP, a natural alkaloid derived from plants. All information regarding these plants is derived from publicly accessible sources, such as PubMed, Elsevier, Web of Science, Springer, etc.

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