Bibliometric analysis of recent research on the association between TRPV1 and inflammation

ABSTRACT TRPV1 channel is a sensitive ion channel activated by some noxious stimuli and has been reported to change many physiological functions after its activation. In this paper, we present a scientometric approach to explore the trends of the association between TRPV1 channel and inflammation and our goal is to provide creative directions for future research. The related literature was retrieved from Web of Science Core Collection and then analyzed by CiteSpace and VOSviewer. A total of 1533 documents were screened. The most productive country, institution, journal, author, cited journal, cited author, and references were the United States, University of California, San Francisco, Pain, Lu-yuan Lee, Nature, Michael J. Caterina, and Caterina MJ (Science, 2000), respectively. The most influential country and institution were Switzerland and University of California, San Francisco, respectively. The cooperation among countries or institutions was extensive. Amounts of documents were distributed in molecular, biology, genetics. TRPV1-associated neurons, neuropeptides, neuropathic pain, neuroinflammation, and neurogenic inflammation were mainly hotspots in this field. The research has presented valuable data about previous studies in the link of TRPV1 channel and inflammation.

Transient Receptor Potential (TRP) channels belong to nonselective cation channels and were divided into six subfamilies including TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), and TRPA1 (ankyrin) channels in human [1]. Among these channels, TRPV1 channel has been widely studied. TRPV1 also called as capsaicin receptor. As the name suggests, TRPV1 is very sensitive to capsaicin and the latter activates TRPV1 channel by acting on binding sites [2,3]. A well-known researcher in TRPV1 field is David Julius, one of 2021 Nobel Prize in Physiology or Medicine winners. His pioneer work has contributed to our present understanding of this channel. Most strikingly, his lab isolated a functional cDNA encoding a capsaicin receptor from sensory neurons named VR1 (that is TRPV1) using an expression cloning strategy based on calcium influx [2], which threw light on the nature of TRPV1 channel. Based on hydrophilicity analysis, TRPV1 channel was firstly reported to be a polytopic protein containing six transmembrane domains with an additional short hydrophobic stretch between transmembrane regions 5 and 6 [2]. Afterward, he participated in unraveling the structure of TRPV1 channel by single particle electron cryo-microscopy, which is very important for the study of its function [4].
Many studies have shown that TRPV1 channel was activated by several exogenous (noxious heat (>~43°C) [2], acidic pH [5], protons [6], toxin [7]) and endogenous agonists (bradykinin [8], lipid [9], diacylglycerol [10]). For this, TRPV1 activation in neuronal and non-neuronal cells could exert various physiological functions and has been extensively studied by researchers from different scientific fields. TRPV1 has been widely expressed in neurons, especially neurons of small to medium size in the dorsal root and trigeminal ganglia [2], and it was responsible for nociception transduction and inflammatory thermal hyperalgesia as a thermosensor [11]. Also, TRPV1 channel was functionally expressed in non-neuronal cells. For instance, TRPV1 in vascular smooth muscle cells could mediate vasoconstriction of the resistance arteries [12]. Activated TRPV1 signaling increased cell proliferation of gingival epithelial cells [13]. Prevotella melaninogenica, a pathogenic bacteria that causes a variety of anaerobic infections, was found to be able to activate the TRPV1 channel in our study. Additionally, the results showed that TRPV1 activation promoted inflammation, which raised the possibility of a link between the production of inflammation and TRPV1 channel activation [14].
Inflammatory response is a complicated physiological and pathological processes from trigger, physiological purpose to pathological consequences [15]. More and more researchers have focused on the association between TRPV1 channel and inflammation. Many reports have revealed that TRPV1 could trigger inflammatory response by releasing inflammatory neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) in neuronal cells [16]. SP and CGRP exerted their pro-inflammatory role by interacting their receptors in many types of cells including T lymphocytes, macrophages, mast cells [17][18][19], thus arousing immune responses. During inflammation, TRPV1 channel participated in the process of heat, mechanical, and cold hyperalgesia [20]. Aberrant expression and activation of TRPV1 have been reported to be involved in inflammatory diseases such as oral lichen planus (OLP) [21], psoriasis [22], atopic dermatitis [23], airway inflammation [24], inflammatory bowel diseases (IBD) [25], and pancreatitis [26]. In nonneuronal cells, TRPV1 activation by capsaicin in keratinocytes promoted the release of interleukin-8 and prostaglandin E2, resulting in inflammation [27]. TRPV1/CGRP pathway induced inflammatory response in Hacat and THP-1 cells challenged with Propionibacterium acnes [28]. Considering its important role both in neurons and non-neuronal cells, some scholars proposed that TRPV1 may be a keystone for neurogenic inflammation [29][30][31].
Bibliometric analysis was an effective method to review prominent publications, to analyze current research and predict research trends in the future [32]. It can be useful for researchers to have access to data on the frequency and distribution of countries/regions, institutions, authors, journals, cocited authors, and journals in a certain field. Bibliometric analysis has become popular in recent years across a number of medical specialties, including rehabilitation medicine [33], neurology [34], anesthesiology [35], respiratory system [36], and oral medicine [37]. A free computer tool called VOSviewer makes it simple to create and analyze bibliometric maps [38]. Another bibliometric tool for evaluating and visualizing trends and hotspots in a knowledge domain is CiteSpace [39], which is widely used in bibliometric analysis. Although the TRPV1 channel and inflammation are popular topics in several research areas, no bibliometric studies have yet established a connection between the two. Here, we explored the trends and potential association between TRPV1 channel and inflammation by a bibliometric approach, aiming to provide a scientific collaboration network and new directions for future research.

Data collection
A search for related articles up to 2021 was conducted in the Web of Science Core Collection (WOSCC). The data were downloaded directly from the database as secondary data without further animal experiments, and thus, no ethical approval was required. The data search was conducted on 15 September 2022 and collected in 1 day to avoid any potential bias due to the daily updating of the database. The search formula was TS = [TS = ("Inflammation" OR "Inflammations" OR "Innate Inflammatory Response" OR "Inflammatory Response, Innate" OR "Innate Inflammatory Responses")] AND [TS = ("TRPV1" OR "TRPV-1" OR "vanilloid receptor 1" OR "transient receptor potential cation channel subfamily V member 1 protein" OR "transient receptor potential vanilloid 1" OR "transient receptor potential V1" OR "capsaicin receptor")]. The document language was set to English. In total, 1533 publications were analyzed. The retrieving process was shown in Figure S1.

Data analysis
CiteSpace software (6.1 R3) and VOSviewer were used to perform a bibliometric analysis including authors, keywords, countries/regions, references, co-cited authors, and journals. Visualization maps consist of nodes and links. Different nodes represent elements such as an author, keyword, country/region, reference, journal, and links between nodes represent collaboration or cooccurrence or co-citations among them. The color of nodes and lines represents different years. The parameters of CiteSpace were set as follows: time slicing (1993-2021), years per slice (1), term source (all selection), node type (choose 1 at a time), pruning (pathfinder) and visualization (cluster view-static, show merged network). For country/region, institution, keyword, cited author, and journal, the TOP N was set 50. For author, the TOP N was set 10. The purple circle represented centrality, nodes with high centrality were usually considered as pivotal points or key points in a specific field [40,41]. The distribution of countries and institutions was drawn using Microsoft Excel 2019 (Microsoft Office for Windows, USA). See Supplementary material Table S1 for details.

General information and annual publication output
We searched a total of 1925 records based on the search terms, of which 1533 met the requirements including 1283 articles and 250 reviews. On the whole, the number of published articles presented a steady upward trend from 1993 to 2021 and the published documents in 2021 increased by 134 times compared to that in 1993 with an average annual publication of 52.9 documents and a compound annual growth rate of 18.4% ( Figure 1). The increase in the number also shows that there have been more and more researches in this field and scholars paid more attention to it.

Active countries/regions and institutions
Many countries and institutions contributed to this research. We analyzed the countries and institutions of publications over the past 29 years (1993-2021) including a total of 62 countries/ regions, and the cooperation between them constituted 272 links. As for countries/regions, the United States (USA) (n = 548) dominated this field, followed by China (n = 257), Germany (n = 142), England (n = 139), and Japan (n = 138) in publication amount. From a centrality perspective, Switzerland (centrality = 0.69) topped the list, followed by Romania (centrality = 0.63), Finland (centrality = 0.55), Germany (centrality = 0.48), and the United States (centrality = 0.44) ( Table 1). Among these, there were close cooperation among the United States, Japan, South Korea, and Germany (Figure 2a and b). In terms of institutions, there were 1509 nodes and 3753 links. Among these, University of California, San Francisco (n = 35) ranked first, followed by Duke  Table 2). Among these institutions, there was close collaboration (Figure 2c and d). As for influence, University of California, San Francisco (centrality = 0.18) ranked first, followed by University of Florence (centrality = 0.12), National Cancer Institute (centrality = 0.12), New York University (centrality = 0.11), and Consiglio Nazionale delle Ricerche (centrality = 0.10) ( Table 2). Of particular note is that the communication and cooperation among countries or institutions were very necessary.

Active journals and co-cited journal
Dual-map overlay map of journals showed that a large number of the papers were distributed in molecular, biology, genetics, and some were health, nursing, medicine, and dermatology, dentistry and surgery ( Figure 3).
Totally, 499 journals published documents about TRPV1 and inflammation and journals were shown in Figure 4a. Among these, Pain (n = 50) was the most frequent journal in this field, followed by Molecular Pain (n = 45), Journal of Neuroscience (n = 42), British Journal of Pharmacology (n = 40) and Neuroscience (n = 32). The most citation was from Journal of Neuroscience (n = 4689) with the citations per paper (111.64). The impact factor of top 10 journals was from 3.37 to 9.473 and JCI quartile included 40% Q1, 40% Q2 and 20% Q3 (Table 3). Some documents were published in well-known journals, such as Nature (n = 3), Cell (n = 3) and Science (n = 1).
The network of co-cited journals included 340 nodes and 1701 links (Figure 4b) and the top 10 was shown in Table 4. The most co-cited journal was Nature with 1123 citations, followed by Journal of Neuroscience

Active authors and cited authors
Total 7678 authors contributed to the related documents in TRPV1 and inflammation, 1237 of which were shown in the author-network map (Figure 5a). The map showed that the most prolific authors. As shown in Table 5, Lu-yuan Lee, a well-known professor from Department of Physiology, University of Kentucky Medical Centre in USA, participated in the publication of 18 articles, ranking first, as the most productive author, has made remarkable achievements on the research about TRPV1 channel and sensory neurons. In his highest cited related articles (n = 88), he illustrated that allergen-induced chronic inflammation in airway could promote the sensitivity to capsaicin of vagal bronchopulmonary myelinated afferents, which probably resulted from an increased expression of TRPV1 in these sensory nerves [42], which emphasized the promotion of inflammation for TRPV1 activation. From the Figure 5a, it was seen that the collaborations among authors was little. For cited authors in these articles, a network was shown in Figure 5b including 691 nodes and 2664 links and the collaborations among them was visible. The most frequently cited author is Caterina MJ with a total of 880 citations followed by Tominaga M (n = 404), Szallasi A (n = 359), Davis JB (n = 299), and Jordt SE (n = 231) ( Table 6). According to their articles, many great contributions has been made to the research on TRPV1 channel and inflammation. For example, the essential role of TRPV1 channel in pain sensation was proved [43]. It was also reported that the p38 MAPK activation in the DRG increased translation and transport of TRPV1 to the peripheral nociceptor terminal, leading to the maintenance of inflammatory hypersensitivity [44], which closely linked TRPV1 and inflammatory hypersensitivity, providing strong support and guidance for the subsequent exploration. Moreover, it was also identified that TRPV1 in concert with TRPA1 were required for bradykinin-evoked thermal hyperalgesia in inflammatory pain [45].

Co-citation analysis
We performed an analysis of references using CiteSpace and VOSviewer. A total of 47,472 documents were included. The top three cited references including Caterina MJ (Science, 2000), Davis JB (Nature, 2000) and Bautista DM (Cell, 2006) and has more than 60 citations ( Table 7). The cocitation density and network were shown in Figure 6a (Figure 6c). Timeline of cited references were generated by CiteSpace and 19 clusters in regions with different colors comprised of #0 euphorblum, #1 TRPA1, #2 itch, #3 airway, #4 neuroinflammation, #5 sensory TRP ion channels, #6 vr1, #7 TRPV1, #8 smoking, #9 dorsal root ganglion, #10 sensitive sub-populations, #11 psoriasis, #12 exercise, #13 agonist, #14 hippocampus, #15 species-related differences, #16 particulate matter, #19 adrenal cortex, #20 neuropathic pain, and #21 UV-b. It was found that documents related to TRPA1, smoking, exercise, and agonists were gathered in 2000-2010, documents related to itch, airway, neuroinflammation, psoriasis, and neuropathic pain were concentrated on 2010-2020 (Figure 6d). Combined analysis of burst detection and timeline revealed that different topics of references were in different phases. In the early explora-tion, some fundamental findings about TRPV1 channel in inflammation have been published. TRPV1 was increased after inflammation and it was required for inflammatory thermal hyperalgesia [11,43,44,46,47], which revealed the importance of TRPV1 in regulation of inflammatory pain. The synergistic role of TRP channels (such as TRPV1 and TRPA1) in inflammation and pain was reported [48][49][50]. In recent years, TRPV1 was  reported to mediates neuroinflammation in microglia [51] and regarded as a potential treatment target for neuropathic pain [52].

Keyword co-occurrence and burst
To some extent, the analysis of keywords could reflect the direction and interest of research in this field. Keyword network and density were generated by CiteSpace and VOSviewer (Figure 7a-c). The frequency of keywords can represent the trends of research. It was found that the most frequent keywords in TRPV1 and inflammation were TRPV1 channel (n = 858), inflammation (n = 351), dorsal root ganglion (n = 279), pain (n = 238), calcitonin generelated peptide (n = 178), neurogenic inflammation (n = 173), substance p (n = 163), TRP channel (n = 156), capsaicin (n = 125), and nerve growth factor (n = 125) (  (Figure 7d). As well, the timeline view presented these clusters over time and it was shown that many influential research subjects occurred in the early phase such as pain, thermal hyperalgesia, and substance p (Figure 7e On the whole, the researchers mainly focused on TRPV1-associated exploration, such as TRPV1 agonist capsaicin, neuropeptides (substance P, CGRP), some other ion channels and neurogenic inflammation and neuropathic pain. From a perspective of burst detection and overlay network, we predicted the following five important hotspots in this field: (1) TRPV1 expression: As a sensitive ion channel, many studies showed that TRPV1 was expressed in dorsal root ganglion (DRG). Blockade of TRPV1 in DRG was considered  as a potential method in cardioprotection [53], irritable bowel syndrome [54], psoriasis [22], prostatitis [55], neuropathic pain [56], cystitis [57]. (2) Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel: The structure of TRPA1 is similar with TRPV1 [58], and they shared many similarities in the mechanism of oxidative stress [59], inflammation [60], and pain [61]. However, they were different. It was reported that 97% (100/103) of TRPA1-positive neurons also express TRPV1, while 30% (100/336) of TRPV1-positive neurons express TRPA1 [62]. Although they were both temperaturesensitive channels, TRPA1 was sensitive to cold temperature instead of heat like TRPV1 [63].
(3) Neuropathic pain: TRPV1 could induce neuropathic pain in many situations. For example, as a target of miR-338-3p, TRPV1 induced neuropathic pain via interacting with N-terminal EF-hand Ca 2+binding proteins 2 [64]. Also, Pirt together with TRPV1 is involved in the regulation of neuropathic pain [65]. TRPV1 could affect their intrinsic electrical properties and synaptic strength in cortex of mice suffering from neuropathic pain [66]. Moreover, blocking TRPV1 channel could be considered as a way in clinical treatment. Zinc suppressed both acute nociception and chemotherapy-induced chronic neuropathic pain through inhibiting TRPV1 [67]. As well, noopept, a nootropic dipeptide, attenuated diabetes-mediated neuropathic pain through inhibition of TRPV1 channel [68]. (4) Neurogenic inflammation: Neurogenic inflammation is a complex process through the release of the neuropeptides CGRP and SP and subsequent vascular and nonvascular inflammatory responses including vasodilation, plasma extravasation, edema, and mast cell degranulation [69]. TRPV1 could induce neurogenic inflammation by promoting the release of neuropeptides SP and CGRP upon activation [30]. In airways, ethanol could stimulate airway sensory  Huai-Hu Chuang 175 10 Narender R Gavva 170 nerves through TRPV1 channels, resulting in the release of sensory neuropeptides and the consequent inflammatory responses [70]. In trigeminal sensory neurons, the activation of TRPV1 channels lead to CGRP release and activate NF-κB nuclear translocation, contributing to the inflammation [16], and inflammatory mediators could activate TRPV1 ion channels, leading to the release of neuropeptides, thereby inducing or enhancing neurogenic inflammatory processes [71]. (5) Substance P (SP): As mentioned above, TRPV1 activation could result in the release of neuropeptide substance P [72]. SP was expressed in many cell types such as neurons [73], immune cells (T cells, macrophages) [74,75] and exerted its proinflammatory role through interacting with its receptors [76]. SP could be regarded as a very important bridge for researchers to study the crosstalk between TRPV1 and inflammation.

Recent research
With the deepening of research, more and more researchers have focused on the role of TRPV1 in treatment. Since 2022, nearly half of the literature has presented TRPV1 as a potential target or TRPV1 antagonists as potential therapeutics.
A clinical trial showed that topical application of Asivatrep cream (TRPV1 antagonist) improved clinical signs and symptoms of atopic dermatitis [77]. Another TRPV1 antagonist, cis-Jasmone was reported to have a topical anti-inflammatory effect in skin inflammation [78]. On the other hand, as a potential target, TRPV1 could be regulated by some drug agents (Berberine [79], Shixiao San [80], plant extracts (Lycium barbarum Polysaccharides [81], Paeoniflorin [82], and electroacupuncture [83,84] for relieving pain and/or anti-inflammatory effect. In cancer therapy, TRPV1 hyperactivation promoted tumor initiation and progression and lead to alterations in tumor microenvironment during colorectal tumorigenesis. Due to this, TRPV1 was suspected to be a potential target for the immunotherapy of colorectal cancer [85]. The researchers also discovered a novel capsaicin-loaded CaCO3 nanoparticle for potential cancer treatment [86]. Additionally, the study about TRPV1 activation and pain still goes on. For example, the synthetic chemical 1,4-dioxane could cause hyperalgesia through TRPV1 activation [87]. The arachidonic acid metabolites, 20-hydroxyeicosatetraenoic acid could activate TRPV1 and cause neurogenic inflammation in the skin as an endogenous ligand [88]. TRPV1+ nociceptor-microglia interactions can cause persistent visceral pain following colitis [89]. From this, we can conclude that there are still many mysteries about TRPV1 waiting for us to unravel. The exploration of its molecular mechanism and clinical application will be of great significance to human health.

Strength and limitations
This is a different style from the traditional review to perform a bibliometric and visualized analysis of TRPV1 channel in inflammation field. This method helps us to focus more easily on critical subjects and creative ideas in this field. However, there are existing some limitations for our study   1  TRPV1 channel  858  11  nociception  122  2  inflammation  351  12  primary sensory neuron  117  3  dorsal root ganglion  279  13  TRPA1 ion channel  113  4  pain  238  14  hyperalgesia  111  5  calcitonin gene-related peptide  178  15  spinal cord  78  6  neurogenic inflammation  173  16  oxidative stress  74  7  substance p  163  17  protein kinase c  69  8  TRP channel  156  18  primary afferent neuron  68  9  capsaicin  125  19  thermal hyperalgesia  61  9 nerve growth factor 125 20 inflammatory pain 51 . Firstly, we just analyzed the documents in English from WOSCC database, but not in other languages (Chinese, for example) or other database sources. Secondly, we just extracted data from WOSCC database for that many commonly used databases, for example, PubMed, do not provide full text and citation analyses, which are necessary for bibliometric analysis. Thirdly, recent articles could not acquire sufficient attention due to publication time and this may result in missing some new high-quality articles. Despite these limitations, we still believe that our findings can reflect the trend in the field associated with TRPV1 channel and inflammation at a global level. We believe that the limitations will be solved in the future studies.

Conclusions
In summary, this study analyzed the research of TRPV1 channel in inflammation by the means of bibliometric tools and provided historical retrospect on this field from many aspects including research countries, institutions, authors, journals, citations, trends and hotspots. We hope that this paper can provide some insight and ideas for this research field.

Author contributions
Pan Xu: conceived the concept of the review, data collection and wrote the manuscript. Ru-ru Shao: Design for figures. Yuan He: conceived the concept of the review and revised the manuscript.