Global Trends in Research of Treatment on Bladder Cancer with Chinese Medicine Monomer from 2000 to 2021: A Bibliometric Analysis

Bladder cancer is a malignant tumor that occurs on the mucous membrane of the bladder. It is the most common malignant tumor of the urinary system and one of the top ten common tumors in the whole body. This bibliometric analysis was applied to identify the characteristics of global scientific output, the hotspots, and frontiers about treatment on bladder cancer with Chinese medicine monomer over the past 22 years. We retrieved publications published from 2000 to 2021 and their recorded information from Web of Science Core Collection (WoSCC). VOSviewer and CiteSpace were used to analyze bibliometric indicators and visualize the trend and hotspots of researches on bladder cancer with Chinese medicine monomer. Altogether, 658 original articles were reviewed, and the results showed that the annual number of publications (Np) shows an upward trend over the past 22 years as a whole. The US produced the most papers, and the number of citations (Nc) and H-index of the US ranked first. Johns Hopkins University and BJU International were the most prolific affiliation and journal, respectively. Recently, the keywords “NF-kappa B” appeared frequently. Besides, quercetin is the most thorough research in the treatment of bladder cancer with Chinese herbal compound, but whether quercetin is the most potent compound needs further study.


Introduction
Bladder cancer is the most common and high incidence rate malignant tumor in urinary system [1], and the full name is bladder urothelial cell carcinoma, which mainly occurs in the bladder mucosa [2]. The prevalence of male is higher than that of female, and the incidence rate is increasing year by year, which has a serious impact on patients' health [3]. Bladder cancer is characterized by metastasis and recurrence [4]; however, surgery and chemotherapy-based therapies are difficult to improve the metastasis or recurrence of bladder cancer [5]. Moreover, the serious adverse reactions of surgery and chemotherapy have a great impact on the quality of life and prognosis of patients. Therefore, it is very important to find and develop new methods and drugs for the effective treatment of needle bladder muscle cancer. Medicinal plant resources are very abundant all over the world, and a large number of studies have shown that traditional Chinese medicine monomer or extract has good antitumor activity. In addition, it has many advantages such as high selectivity, small body damage, and low toxic and side effects, which has attracted the attention of more and more researchers [6]. For instance, Chen et al. confirmed that isoquercitrin inhibits the progression of bladder cancer in vivo, and the molecular mechanism of this inhibition may be closely related to PI3K/Akt and PKC signaling pathway [7]. Yan et al. demonstrated that berberine may inhibit the metastasis and invasion of bladder cancer cells by blocking the expression of heparinase, so it can be used to reduce the recurrence of bladder cancer in clinic [8]. Li et al. showed that fluoxetine is a new, effective, and safe drug for bladder chemotherapy [9]. Over the past few decades, there were more and more studies on the treatment of bladder cancer with Chinese herbal monomers. In addition, more and more scholars and professors have made great efforts and published many papers so far, but there is a lack of summary comments. Research in such studies must contribute to obtaining data or information on the latest state of research, measuring current practice, and identifying gaps [10]. Therefore, we believe that it is necessary to make a comprehensive review of this field in order to benefit both new and old researchers in this research field.
Although the traditional literature review is a timeconsuming and labor-consuming manual task, which can only provide sampling insights into a certain research field, researchers can conduct bibliometric analysis on a certain research field in order to obtain quantitative and profound knowledge in a relatively short time [11]. Bibliometrics is a convenient new method for qualitative and quantitative analysis of publications [12]. The knowledge graph drawing tools represented by VOSviewer and CiteSpace, through the organic combination of multidisciplinary methods such as applied mathematics, statistics, bibliometrics, and informatics, intuitively show the development process and research hotspot of a research field [13]. Using this method, researchers can quickly and deeply study the theme evolution, main research fields, and new research directions in a certain research field [14]. Over the years, bibliometric analysis has been applied to aristolochic acid [15], health-related quality of life [16], tuberculosis [10], podocyte [12], butyrophilins [17], macrophages associated with acute lung injury [18], and other research areas. However, bibliometric studies on the treatment of bladder cancer with Chinese herbal monomers are still blank. Therefore, the purpose of this study is to systematically analyze the research of Chinese herbal monomer in the treatment of bladder cancer, in order to evaluate the research status and hotspot in this field.  )). The unstable nature of tannin makes the traditional Chinese medicine preparation easy to precipitate and change color and turbidity, thus affecting the quality of the preparation. Therefore, tannin is regarded as an impurity in many traditional Chinese medicines; therefore, tannin was excluded from the search term of this study. Only original articles and reviews written in English were included among various publication types. In total, 658 articles were ultimately analyzed in our research. The detailed screening is shown in Figure 1.

Data Collection and
Cleaning. First, raw data is extracted from WoSCC. Information recorded includes number of papers and citations, H-index, year of publication, country/ region, institution, author, journal, references, and keywords. Although inaccurate analysis may not be completely avoided due to the multiple editions of the cited literature, the same acronyms of different authors, and the different forms of the cited journals, we believe that most of the original data are reliable. Prior to data analysis by VOSviewer v.1.6.15.0 (Research Centre for Science and Technology, Leiden University, Leiden, Netherlands), CiteSpace was used to combine several duplicates into a single word, correct misspelled elements, and remove useless words. Finally, the cleaned data was imported into VOSviewer and CiteSpace for bibliometric analysis.

Bibliometric Analysis.
In this study, VOSviewer (version 1.6.10) and CiteSpace (version 5.8.R3) were used for bibliometric analysis. VOSviewer [19] is used to visualize complex cocitation networks, such as cooperation and time trends among countries, institutions, and individuals. The size of the node represents the number of publications; the thickness of the line represents the strength of the connection; the colors of the nodes represent different clusters or times. CiteSpace is used to facilitate visual analysis of knowledge domains and emerging trends, including cluster analysis, timelines, and keyword bursts. In addition, we analyzed the number of publications (Np), the number of unself-cited citations (Nc), and the H-indices of authors, countries, journals, and institutions. In addition, the impact factor (IF) obtained from the latest edition of the Journal Citation Report (JCR) is regarded as one of the main indicators to measure the quality and impact of medical journals [20].    Figure 2(b) shows the annual Np related to treatment on bladder cancer with Chinese medicine monomer. Despite fluctuations over the 22-year period, the number of annual papers increased from 177 in 2011 to 413 in 2020, with Np peaking in 2020. Since 2011, the annual Np of the United States and Japan has remained stable, while that of China has increased rapidly. Overall, these findings indicate that research on treatment on bladder cancer with Chinese medicine monomer is still a lot of room for development. On the whole, there is a small amount of literature, and further research is needed. Figure 3 shows the top ten countries in the number of documents issued. The number of documents issued by each country fluctuated in these 22 years.

Contributions of Countries/Regions to Global Publications.
We ranked the 10 high-producing countries/regions by Np for all authors ( Table 1). The United States published the most articles (165), followed by China (115) and Japan (54). Papers from the United States were cited 7,287 times, accounting for 39.25 percent of total citations, followed by China (2,197) and Canada (1945). In addition, the United States had the highest H-index (44), more than twice that of any other country except China. Although the Np of Canada is the lowest, the Nc is higher than other countries except the United States and China and has the highest average per item, indicating that the quality of papers published by Canada in this field is very high. Figure 4(a) shows the geographical distribution of global output. Figure 4(b) shows the network of country cooccurrence. The United States and China have the largest number of posts, indicating the highest number of publications. Furthermore, we performed a visualized timeline for clusters, and there were four clusters including antiproliferative activity, desert date Balanites aegyptiaca, low-dose inorganic arsenic, and European prospective investigation. Figure 4(d) shows the most representative countries in terms of burst strength, burst duration, and burst time. Egypt has the highest burst in recent years.  Table 2 shows the top 10 affiliates with the largest number of publications related to TCM monomer therapy of bladder cancer.
Johns Hopkins University has the highest Np [17], followed by the Egyptian Knowledge Base (EKB) [16] and the University of Texas System [15]. The University of Texas System ranked first in Nc (1097), and Jilin University had the highest H-index. Although the Egyptian Arab Republic KB EKB has a relatively high Np, its H -index lags far behind the University of Texas System, University, Porto, University of California System, and AGREST New Zealand. Figure 5(a) shows the cooccurrence of the relational network. Among its Chinese affiliates, Xi'an Jiaotong University performs well. Figure 5(b) shows the subordinate clusters, the first four of which are modulation, polymorphism, fruit, and nicotinamide adenine dinucleotide phosphate. Table 3 lists the top 10 prolific authors. He published 94 papers, accounting for 14.29% of the total. Miyamoto of the University of Rochester ranked first in the research field of TCM monotherapy for bladder cancer, followed by Munday, CM and Munday, R of Ruakura Agr Res Ctr of New Zealand. As shown in Table 3 Table 4, BJU International (9 publications, IF: 5.588) published the most papers on TCM monomer therapy of bladder cancer, followed by carcinogenic effects (9 publications, IF: 4.944) and molecules (8 publications, IF: 4.412). 11.25% were published in the top 10 academic journals (74/11.25%). Of the top 10 journals, all but the International Journal of Nutrition and Cancer (IF: 2.9) and Cancer Research (IF: 2.48) had a high IF (defined as greater than 3000). It is noteworthy that the International Journal of Molecular Science (IF = 5:924) has a lower citation rate and H-index. However, the impact factors of the top ten journals are lower than 10, which indicate that the depth of research in this field needs to be strengthened.
3.6. Analysis of Cocitation. Cocitation refers to when two authors' academic papers are cited by the same paper at the same time. Being able to form a cocitation shows that the concepts, methods, and theories of the two authors for a certain research are related. Therefore, mining the cocitation relationship between authors is helpful to find authors with similar research directions, so as to form a collection of similar scholars. Cocitation analysis can also be used for magazine and literature analysis. The analysis of cocitation is shown in Figure 6. The top ten cocited authors were Miya-  The top ten cocited journals were cancer res (865 times), carcinogenesis (516 times), j urology 506 (times), int j cancer (402 times), j biol chem (395 times), p natl acad sci usa (394 times), j clin oncol (367 times), eur urol 329 (times), brit j cancer (317 times), and cancer lett (292 times), Furthermore, we performed a visualized timeline for clusters ( Figure 6(d)). We found that "urothelial cancer risk," "nqo1 genotypes smokings," "isothiocynante," and "3-nitrobenzanthrone"    In addition to exploring the therapeutic mechanism of compounds for bladder cancer, the toxicological aspects of compounds are also described. Cluster 4 was mainly about applications of modern biotechnology, such as genomics, metabonomics, and epigenetics in bladder cancer. The top frequent occurrences of keywords were "cancer," "apoptosis," "bladder cancer," "expression," "in-vitro," "carcinoma," and "activation," suggesting that the researches related to treatment on bladder cancer with Chinese medicine monomer mainly focused on basic studies. As shown in Figure 8(b), the timeline of clustering showed that "urinary tract tumor cell" and "wyc 0209 target" were the most important areas of treatment on bladder cancer with Chinese medicine monomer. As shown in Figure 8(c), we found that "glutathione Stransferase" and "nad(p)h quinone oxidoreductase" had the highest burst strength. In addition, we also found that "therapy" and "in vitro" were the keywords that emerged in the last 5 years.

Discussion
In this study, VOSviewer and CiteSpace software were used to make a bibliometric analysis of the research trends and hotspots in the treatment of bladder cancer with TCM monomaterial in WoSCC database. We searched 658 original articles and reviews published between 2000 and 2021.
According to the polynomial fitting curve, the number of annual publications generally showed an upward trend, rising rapidly in the second half of the period, especially after 11 Journal of Oncology 2013. Among the top countries/regions, the United States ranked first in Np, indicating that the United States was the country with the highest production in this field, the possible reason is that the United States' scientific and technological strength, economic strength, innovation ability, investment, and research depth in this field are much higher than those of other countries. Four American branches and three Chinese authors were among the top 10, which means the US has the world's top research institutions and China has the world's most professional researchers, which partly explains why China and the US have made rapid progress in this field in the past 22 years. Canada, however, had the highest average per item. This shows that Canadian scholars' research in this field is of high quality and more in-depth than that of other countries in the world. This suggests that scholars and affiliated institutions in other countries should make more efforts to improve the quality of papers in this field. Similarly, there is a contradiction between quantity and quality of publications in France.
Notably, seven of the 10 most productive journals had higher IF. This means that it is not a challenge to publish a study on the treatment of bladder cancer with Chinese herbal monomers.
With the deepening of research, people have found signaling pathways involved in various mechanisms. Keyword mapping revealed that nuclear transcription factor (NF-κB) plays a key role in the pathogenesis of bladder cancer. Nuclear factor κB (NF-κB) has been identified as a regulator of the κB light chain in mature B cells and plasma cells [21]. NF-κB plays an important role in the development and progression of cancer [22]. Bladder cancer is the second most common cancer of the urinary system, and NF-κB involvement in the development of superficial or muscle infiltrating disease and cancer recurrence is preliminary at best [23]. Constitutive NF-κB activation was observed in high-grade bladder cancer [24,25]. Geng et al.'s research suggest that the NF-κB pathway regulates the expression of bladder EMT and CSC markers induced by tobacco smoke, as well as the protective effect of tobacco smoke that NF-κB pathway regulates the expression of bladder EMT and CSC markers and the protective effect of DATS induced by tobacco smoke [26]. Multiple molecules could enhance bladder cancer cell migration, invasion, and proliferation by activating NF-κB signaling [27,28]. Some compounds can also inhibit bladder cancer by inhibiting NF-kappa B [25,26,29]. This study shows that quercetin is the most studied monomer compound in all traditional Chinese medicine. Quercetin is a natural flavonoid from plants. It has good therapeutic effect on many diseases and has good antiinflammatory and antioxidant effects [30], which is a widely distributed plant secondary metabolite. Quercetin widely exists in daily diet and nature. It can produce toxicity to cancer cells without damaging healthy cells and has therapeutic effects on a variety of cancers. Quercetin is lipophilic and can smoothly cross the cell membrane and play an antitumor role. Its main mechanism is to block the invasion and metastasis of cancer cells, induce apoptosis of cancer cells, and regulate and inhibit the expression of oncogenes. The study of Adami et al. demonstrated that quercetin had anti-tumor effect on human bladder cancer cells, and the activity and proliferation of T24 cells decreased. Biophysical and morphological analyses showed that this effect was the result of quercetin-induced apoptosis, as the treated T24 cells showed morphological changes characteristic of apoptosis. In addition, quercetin-treated T24 cells showed no plasma membrane damage, suggesting that cell death was not due to necrosis but to apoptosis. Further NMA analysis showed that T24 cells showed fewer normal nuclei and more nuclear changes common during early apoptosis, senescence, and other nuclear damage, thus confirming the apoptotic effect of quercetin. Finally, AFM analysis revealed a pattern of cell damage after treatment with different quercetin concentrations, gradually beginning with irregular small contours, increasing the number of holes and pits and cell shrinkage, and eventually causing tumor cell collapse. Finally, our study shows for the first time the morphological and mechanical characteristics of quercetin-treated bladder cancer T24 cells and suggests that it has antitumor effects. We hope this study will serve as a starting point and support for other studies to analyze quercetin for bladder cancer [31]. Ma et al. demonstrated that quercetin inhibits the growth and proliferation of bladder cancer cells and induces apoptosis, which is associated with reduced DNA methylation levels of P16, RASSF1A, and Erβ genes and reduced expression of mutP53 and Survivin proteins. Quercetin is a potential chemoprophylaxis and chemotherapy agent for bladder cancer. Further studies of demethylation genes and downstream molecular mechanisms associated with the cell cycle are needed [32]. The study of Orsolic showed that quercetin can inhibit the proliferation and colony formation of human bladder cancer cells by inducing DNA damage, and quercetin may be an effective chemoprophylaxis and chemotherapeutic agent for papillary uroepithelial bladder cancer after transurethral resection [33]. All these suggest that quercetin may be the most promising monomer for the development of bladder cancer drugs. Another well-studied compound is silibinin. Silibinin is a silymarin extracted from the fruit of silymarin, which is a mixture of active flavonoid lignin and flavonoids [34], which has many physiological functions, such as protecting myocardium, reducing blood lipid, protecting liver, scavenging free radicals, and antioxidation. [35] Silibinin can induce apoptosis of human bladder cancer cell line T24 and 5637, thus inhibiting cell invasion and proliferation [36]. Silibinin can reduce the proliferation and increase the apoptosis of TP53 mutant cells. In both RT4 and T24 cell lines, increased early apoptosis rate, primary DNA damage, and reduced cell colonies in clonal survival tests were detected. Expression of FRAP/mTOR, AKT2, FGFR3, DNMT1, and miR100 were downregulated in RT4 cells. Regulation of miR203 was observed in both cell lines [37].

Conclusion
This analysis of bibliometric reveals that researches on treatment on bladder cancer with Chinese medicine monomer is still much room for development, and the current research literature is less at present. The United States is a major 12 Journal of Oncology producer and has made many outstanding breakthroughs in this field. The BJU International and Carcinogenesis published the latest research and new advances in this field. In recent years, the role of NF-κB molecular pathway has become a focus of research. Moreover, quercetin has been studied most, and it may be a promising new drug in treating bladder cancer.

Data Availability
The data could be acquired from the corresponding author.

Conflicts of Interest
The authors have no conflicts of interest to declare.