Molecular mechanism and promising treatments of chronic prostatitis/chronic pelvic pain syndrome: An exploratory bibliometric analysis and literature review of preclinical studies

Abstract

Background: As one of the most common diseases in urology, a large number of preclinical studies have been accumulated to explore the etiological mechanism and potential intervention of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

Methods: In this study, we systematically evaluated the current status of preclinical research on CP/CPPS through bibliometrics analysis using VOSviewer and Citespace. Characteristics of publication such as year, country/region, institution, author, journal, citation, and keywords were analyzed. Based on the bibliometrics analysis results of keywords, we summarized the possible mechanisms and promising treatments for CP/CPPS narratively.

Results: According to the results of this study, the most common mechanisms involved in CP/CPPS were as follows: Disturbed immune and inflammation mediators, immune cell dysfunction, oxidative stress, dysregulated signaling pathways, apoptosis, gut microbiota, and testosterone metabolism. Traditional Chinese Medicine and extracorporeal shock wave therapy have important potential in the treatment of CP/CPPS.

Conclusion: Further translational studies targeting the above mechanisms and validating the objective efficacy of potential treatments indicated by preclinical studies in clinical patients are needed in the future.

Graphical abstract

Keywords

bibliometrics / chronic prostatitis/chronic pelvic pain syndrome / mechanism / treatment

1 INTRODUCTION

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is one of the most common urologic diseases in men which is mainly characterized by painful symptoms[1]. Currently, there is still a lack of efficient and lasting treatment for CP/CPPS. Patients with CP/CPPS often face the stress of a rate of recurrent episodes which might cause long-term mental and psychological issues[2]. This clinical dilemma may be attributed to the complex pathogenesis of CP/CPPS and the lack of efficient etiological diagnosis[2].

Bibliometrics is a widely used approach to obtain the research status and network of a particular field[3]. Bibliometric analysis could provide researchers with a holistic and essential view of the dynamic research trends by analyzing the basic characteristics of the publications such as publication year, authors, regions, institutions, keywords, and their inner connection[4]. Based on these advantages, bibliometrics holds a crucial role in forecasting the potential research future and can be helpful for policy-making authorities of the government in funding decisions as well as some other pertinent areas[5,6].

During the past decades, many preclinical studies have been published to explore the potential mechanism and potential treatments of CP/CPPS. These studies provided a good insight into the optimization of future clinical treatment regimens for CP/CPPS. Some studies have focused on the research status of generalized urologic chronic pelvic pain syndrome and prostatitis[7,8]. However, to our knowledge, there is no bibliometrics analysis focusing specifically on the molecular mechanism and potential candidate treatments of CP/CPPS. Therefore, in this study, bibliometrics analysis of only preclinical studies related to CP/CPPS was conducted. Within the research framework, the key mechanisms and the most promising candidate therapeutic options suggested from the preclinical stage will be revealed.

2 METHODS

2.1 Literature search

The Web of Science Core Collection (WoSCC) was retrieved to identify the pertinent literature from inception to October 20, 2023, as previous studies[5,9,10]. By referring to a previously published article[11], the search strategy was set as follows: (TS = (CP/CPPS OR CP-CPPS OR chronic prostatitis/chronic pelvic pain syndrome OR chronic prostatitis with chronic pelvic pain syndrome OR chronic abacterial prostatitis)) AND TS = (animal OR rat OR mouse OR mice OR cell OR RWPE-1 OR disease model). Only articles and review publications in English language were included.

2.2 Bibliometric analysis

After retrieval, records in the WoSCC were downloaded as plain text documents. In this study, the following bibliometric indicators were included: country/region, institution, author, journal, and keywords. As reported, the number of publications was used for evaluating productivity while the number of citations was used to measure influence[7,12,13]. The downloaded text was imported into VOSviewer software (version 1.6.17) and Citespace software (version 6.2.R4) for subsequent analysis. The VOSviewer was used for constructing and visualizing the bibliometric network, including country/region, institution, author, journal, and keywords. The Citespace was utilized for exploring the cluster and burst of keywords. GraphPad Prism software (version 8.0.1.244) and Scimago Graphica (version 1.0.36) were used for drawing scatter plots and line plots in some situations.

3 RESULTS

3.1 Overview of preclinical publications on CP/CPPS

A total of 352 documents were retrieved in the WoSCC firstly based on the above search strategy. After excluding publication type of meeting abstract, retraction, and reprint, as well as non-English literature, 338 records were left. Then the remaining records were further checked to exclude clinical studies. As a result, 53 records were excluded, leaving 285 records for final analysis. The detailed screening procedure was presented in Figure 1. The 285 records generated a total of 5507 citations, among which 4290 citations were not self-cited while per article generated 19.32 citations on average. The collective H-index of all records was 37.

3.2 Publication and citation numbers sorted by years

As shown in Figure 2A, the number of publications presented an upward trend year by year basically while publications in 2023 significantly reduced because the year is not yet over. The period of publication was from 1994 to 2023. The largest number of articles were published in 2022 (29 papers) and none of the articles were published in 1995. As shown in Figure 2B, the number of citations also climbed year by year in recent years. And as the year 2023 has not yet ended, citations have declined to some extent. These articles were cited from 1996 onwards, with the highest number of citations in 2021 (650 citations).

3.3 Bibliometric analysis of countries/regions and institutions

From 1994 to 2023, a total of 35 countries/regions contributed to publishing papers in this field. Table 1 presents the top 10 productive countries/regions. China and the United States have significantly more publications and citations than other countries. The United States published fewer articles (n = 73) than China (n = 130) but had the most citations (n = 2239) and the highest degree of cooperation (total link strength = 16). Although the publication outputs of Italy were not so much (n = 15), it occupied an important position in the cooperation network (total link strength = 14) which was second only to the United States while China was the third. The global collaboration of countries/regions in this field was visualized in Figure 3A.

In total, 371 institutions participated in the preclinical field of CP/CPPS. As shown in Table 1, Anhui Medical University from China published the most articles (n = 28), followed by Northwestern University from the United States (n = 22). China Pharmaceutical University (n = 17), Shanghai Jiao Tong University (n = 15), Nanjing Shuiximen Hospital (n = 12), and Southeast University (n = 12) which were all from China followed closely by more than 10 publications, respectively. The top 5 cited institutions were Northwestern University from the United States (n = 567), Medical University of Vienna from Austria (n = 353), University of Florence from Italy (n = 346), Temple University from the United States (n = 256), and China Pharmaceutical University from China (n = 245). Although Anhui Medical University contributed the largest number of articles, the number of citations ranked only sixth (n = 240). Figure 3B presents the global collaboration map of institutions. China Pharmaceutical University (total link strength = 52), Southeast University (total link strength = 39), and Nanjing Shuiximen Hospital (total link strength = 37) showed closer collaboration with other institutions.

3.4 Bibliometric analysis of authors and co-cited authors

All these papers involved 1196 authors in total. As shown in Table 2, the top 10 most productive authors were from China and the United States while the top 5 authors who output the largest number of articles were Chaozhao Liang, Li Zhang, Praveen Thumbikat, Anthony J. Schaeffer, and Xianguo Chen. Figure 4A presented the collaboration network of the authors. The 10 most co-authors were also presented in Table 2, and the cocitation authors' network was shown in Figure 4B. J. Curtis Nickel ranked first in all cocitation authors with 327 citations, followed by John N. Krieger and Ruben D. Motrich with 202 and 140 citations, respectively.

3.5 Bibliometric analysis of journals and co-cited journals

All the documents were published in 128 journals. Table 3 exhibits the top journals with the most publications in this field. And the top 5 most productive journals were Prostate (n = 24), Journal of Urology (n = 18), Andrologia (n = 14), Urology (n = 12), and Asian Journal of Andrology (n = 7). The citation network of journals was shown in Figure 5A. The results of the cocitation analysis of journals were also presented in Table 3. The top 5 co-cited journals were Journal of Urology (n = 1500), Urology (n = 750), Prostate (n = 457), European Urology (n = 359), and BJU International (n = 314). And the cocitation network of journals was exhibited in Figure 5B.

3.6 Bibliometric analysis of references

As shown in Table 4, we presented the 10 most cited articles which had been referenced 1301 times (23.62%)[14–23]. The review published by Prof. Kramer in 2007 was cited the most (n = 353)[14], followed by Pontari et al. 2004 (n = 167)[15], and Fibbi et al. 2010 (n = 165)[16]. Among the top 10 most cited articles, eight articles were reviews while only two articles from Prof. Penna 2006 (n = 93)[18] and Prof. Rudick 2008 (n = 68)[23] were original research. The two research explored the therapeutic effects and potential mechanisms of vitamin D receptor agonist elocalcitol for experimental autoimmune prostatitis (EAP) mice, and the histopathological changes and molecular mechanisms of EAP mice, respectively.

3.7 Bibliometric analysis of keywords

We explored the frequency and co-occurrence of keywords through VoSviewer first. The top 30 keywords were presented in Table 5. The most frequent keywords were pelvic pain syndrome (n = 104), followed by inflammation (n = 85), chronic prostatitis (n = 81), prostatitis (n = 74), and men (n = 67). The co-occurrence network of keywords was exhibited in Figure 6A. Then we conducted a cluster analysis of the keywords (Figure 6B). The Modularity Q-value = 0.4042, and the Silhouette S-value = 0.7499. The results showed that all keywords grouped into nine clusters: Chronic pelvic pain syndrome, chronic prostatitis, pelvic pain, therapy, benign prostatic hyperplasia, chlamydia trachomatis, experimental autoimmune prostatitis, interstitial cystitis, and pain mechanisms. In addition, we presented a visualization of the keyword evolution over time (Figure 7A). Finally, the keywords' citation bursts were also detected and we presented the top 25 keywords with the strongest citation bursts in Figure 7B. Nonbacterial prostatitis had the highest burst strength (5.85), followed by chronic abacterial prostatitis (4.83), steroid binding protein (4.71), symptoms (4.41), and model (4.3). Notably, the chronic pelvic pain (3.07), double blind (3.01), experimental model (2.56), and chronic prostatitis (2.41) bursts continued in 2023, indicating that they are still hot topics.

3.8 The molecular mechanism involved in CP/CPPS

Through bibliometric analysis of keywords and systematical collation, some mechanisms were summarized and described below.

3.8.1 Disturbed immune and inflammation mediators

Various cytokine and immune mediator-related keywords were identified, indicating that disturbed immune and inflammation mediators were one of the main molecular immune mechanisms of CP/CPPS. Murphy et al. reviewed the immune mediators involved in CP/CPPS and proposed that these abnormal mediators lead to immune dysregulation and immune cell dysfunction[24]. Chen et al. systematically reviewed the immunological alterations of patients with CP/CPPS and the EAP model, and they found tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), IL-6, and IL-8 were the four immune mediators that elevated in most of the samples derived from patients with CP/CPPS and the EAP models[25]. Meanwhile, many chemokines and their receptors such as CCL2, CCL3, and CXCR4 were found to be involved in the development and pain maintenance of CP/CPPS[26–28].

3.8.2 Immune cell dysfunction

Many studies had established a wide range of links between various immune cells and CP/CPPS. Done et al. found elevated mast cell tryptase in prostatic secretions of CP/CPPS patients, and increased total and activated mast cells in the prostate of EAP mice[29]. And they found treating EAP mice with a mast cell stabilizer combined with a histamine 1 receptor antagonist could result in a synergistic decrease in chronic pelvic pain. Later, the team investigated the role of mast cell mediator tryptase-β and its cognate receptor PAR2 in CP/CPPS, and they found the tryptase-PAR2 axis was an important mediator of pelvic pain in EAP mice[30]. Then the group found that PAR2 activation in the prostate might also contribute to EAP-induced lower urinary tract dysfunction[31]. Recently, Pattabiraman et al. identified a subgroup of CP/CPPS patients with mast cell dysfunction and found the mast cell stabilizer cromolyn sodium combined with cetirizine dihydrochloride could reduce symptoms and modulate the immune inflammatory environment of CP/CPPS patients[32].

Various studies suggested that T lymphocytes significantly influenced the pathogenesis of CP/CPPS[33,34]. Kouiavskaia et al. found a higher rate of recognizing the self-prostatic proteins prostatic acid phosphatase and prostate-specific antigen (PSA) of CD4 T cells from patients with CP/CPPS compared to those from normal male blood donors[35]. Subsequently, a series of special types of T cells: Foxp3⁺ CD4⁺ Treg cells[36], Th1 cells[37,38], Th2 cells[39], Th17 cells[40], and Treg cells[41] were found to be involved in the pathological process of CP/CPPS. These cells might interact with each other to regulate the local inflammation reaction of the prostate.

As key performers of downstream effects in immune response, macrophages were also found to be involved in the pathological process of CP/CPPS. Desireddi et al. found monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 alpha could serve as possible biomarkers for CP/CPPS[42]. And Hua et al. found that CXCL10 was an important molecule involved in inflammatory infiltration and pain symptoms of prostatitis by promoting the migration of macrophages and secretion of inflammatory mediators via CXCR3-mediated ERK and p38 mitogen-activated protein kinase (MAPK) activation[43]. Similarly, microglia, resident immune cells of the central nervous system which have the phenotypic similarity of microglia to peripheral blood monocytes/macrophages and dendritic cells[44], were also found abnormally activated and correlated with pain and depressive symptoms as well as cognitive impairment of EAP animals[45–48].

3.8.3 Oxidative stress

Oxidative stress which could cause tissue damage is a result of the imbalance between reactive oxygen species (ROS) and antioxidants in the organism. Oxidative stress holds a significant role in the pathogenesis of CP/CPPS[49,50]. Evidence demonstrated that oxidative stress-related indicators GSH, CAT, MDA, SOD, NADPH, and ROS were abnormal in EAP models[51,52]. Currently, the improvement of oxidative stress was often used as an indicator to evaluate the efficacy of specific interventions in animal experiments[53].

3.8.4 Dysregulated signaling pathways

Many studies suggested that multiple pathways might be involved in the onset and development of CP/CPPS. Meng et al. proposed that the nuclear factor κB (NF-κB) and MAPK signaling pathways were activated in the CFA-induced CP/CPPS rat model, and they would further regulate the expression of various cytokines to promote the progression of inflammation[54]. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway plays a key role in pathophysiological processes such as inflammation and oxidative stress, and anomalies in this pathway could lead to the start and control of immune response and inflammation in CP/CPPS rats[55,56]. Studies showed that the expression of CXCR3 on specific T cells is essential for homing to the prostate gland in the EAP model, and it could consequently activate the downstream ERK1/2 and p38 MAPK signaling pathways to be involved in inflammatory infiltration and pain symptoms of prostatitis[37,43]. Additionally, Zhang et al. found that upregulation of the NGF/TrkA pathway in the spinal dorsal root (DRG) might cause pelvic organ cross-sensitization by upregulating the expression of TRPV1 in the prostate, bladder, and DRG[57]. And Roman et al. found the TRPV1 channel is a key mediator in persistent pelvic pain in EAP and targeted therapy with a TRPV1 antagonist may alleviate CP/CPPS symptoms[58]. Additionally, a novel peptide (T2) isolated from another TRP channel protein: TRPM8 was found to induce severe prostatitis in rats indicating a potentially significant role of TRPM8 in CP/CPPS[59]. Zhu et al. demonstrated that TLR4 is increased in estradiol-induced CNP rats and downregulated after treatment[60].

3.8.5 Apoptosis

The process of apoptosis is known as programmed cell death[61]. Abe et al. compared the expression of apoptosis-related protein Bcl-2 in the prostatic fluid from acute bacterial prostatitis and nonbacterial prostatitis, and no statistically significant difference was found[62]. Jeon et al. found another apoptosis-related protein caspase-3 was elevated in the prostate of EAP rats[63]. However, Song et al. found that in the LPS-induced RWPE-1 cell model, apoptosis was inhibited, accompanied by increased Bcl-2 levels and downregulation of BAX and the ratio of cleaved caspase-3/caspase-3[52]. Hu et al. found that the apoptosis in corpus cavernosum detected by the Tunel assay of EAP rats was significantly increased compared with the normal rats[64]. These results suggest that the role of apoptosis in CP/CPPS may be complex and needs to be further explored.

3.8.6 Gut microbiota

Gut microbiome diversity was found to be significantly reduced especially Prevotella in CP/CPPS[65]. Konkol et al. found that EAP rats induced by subcutaneous testosterone and 17β-oestradiol (E2) hormone exhibited different microbial biodiversity from healthy rats which might be regulated by galactoglucomannan-rich hemicellulose extract[66]. Du et al. immunized nonobese diabetic mice twice by subcutaneous injection of prostate antigen and adjuvant to generate the EAP model, and they found abnormal composition of gut microbiota in the EAP mice when compared to the control mice[67]. And they found fecal bacteria transplants from EAP mice, but not from control mice, into the pseudo-germ-free mice, significantly exaggerated host depression-like behaviors[67]. Additionally, Du et al. found that gut dysbiosis contributed to a Th17/Treg differentiation imbalance in EAP mice via the decrease of metabolite propionic acid[68]. Recently, a novel diagnostic model for CP/CPPS based on different gut microbiome compositions was proposed, presenting the promising potential of gut microbiome for noninvasive diagnostic biomarkers and future therapeutic targets for CP/CPPS patients[69]. Furthermore, some potential interventions were found to regulate gut microbiota to relieve prostatitis-related symptoms. Liu et al. found Poria cocos polysaccharides could recover the gut microbiota by targeting the Ruminococcaceae NK4A214 group, and improve the histological damage in the inflamed prostate of EAP rats[70]. Additionally, Liu et al. also found Astaxanthin could upregulate Akkermansia muciniphila to improve inflammatory infiltration and pain in EAP mice[71].

3.8.7 Testosterone metabolism

Studies suggested that testosterone metabolism might influence the immune response of the prostate of EAP rats[72,73].

3.9 Promising treatments for CP/CPPS

Through bibliometric analysis of treatment-related keywords and systematical collation, we summarized the explored treatments for CP/CPPS in Figure 8. As shown in Figure 8A, during the past decades, various treatments have been explored to treat CP/CPPS in preclinical studies, such as phytotherapeutic extract, Traditional Chinese Medicine (TCM), antibiotics, extracorporeal shock wave therapy, botulinum toxin, thermotherapy, adrenergic α-antagonists, hyaluronic acid, nanoparticle-conjugated autoantigen peptide T2, multimodal therapy, 5α-reductase, and elocalcitol. The keyword counts of these treatments were both more than 1. Then we ranked these treatment-related keywords by time interval to analyze the evolution of treatments over time (Figure 8B). As observed, phytotherapeutic extract-related studies peaked in the 2010s. TCM and extracorporeal shock wave therapy-related studies have been increasing gradually since the 2000s until now, indicating that they might be the most promising treatment modalities for CP/CPPS. It is worth noting that quite a few treatment-related keywords appear only once, and the vast majority of them were after the 2010s. It showed that many new therapeutic modalities have been explored to treat CP/CPPS in recent years which should be further validated and promoted in clinical practice.

4 DISCUSSION

In this study, we conducted a bibliometric analysis of preclinical studies related to CP/CPPS to evaluate the current status and hotspots of research in this field and summarized the possible mechanisms and promising treatments of CP/CPPS based on keywords. These results may provide important directions for subsequent research.

The results of bibliometrics suggested that the number of publications and citations of preclinical studies on CP/CPPS basically showed an increasing trend year by year. China and Anhui Medical University were the country and institution with the most publications. However, the United States and Northwestern University were the most cited country and institution, respectively. It indicated that although institutions in China published a relatively large number of articles, these publications were not as influential as those in the United States. Similarly, eight of the top 10 authors are from China, but the authors with the most citations are Praveen Thumbikat and Anthony J. Schaeffer from the United States, indicating that the influence of Chinese scholars' papers still needs to be further expanded. The cooperation network of authors suggested that the cooperation between Chinese scholars and foreign scholars is not enough and needs to be further strengthened in the future. Bibliometric analysis of journals suggested that these studies were most often published in relevant professional journals, reflecting the high level of expertise in this field.

In this study, we summarized the potential molecular mechanism of CP/CPPS by collating keywords in this field. Notably, in the past decades, diverse molecular mechanisms were proposed to explain the etiology of CP/CPPS. However, the clinical translational research based on these mechanisms is still less carried out. Targeted mast-cell therapy may be a case in the making of clinical translation. In the past decade, Thumbikat's team focused on the possible mechanism of mast cell in CP/CPPS and had already validated the potential therapeutic effect of targeting mast cells in a small sample of clinical CP/CPPS patients[29–32,74]. This might be a promising therapy in the future. And Yang et al. developed pH/ROS dual-responsive dexamethasone (Dex) nanoformulations which might regulate oxidative stress, and found it was effective for the management of CP/CPPS mice and alleviation of depression in mice[75]. Although these mechanisms were widely used in preclinical studies to explore some interventions for the treatment of CP/CPPS, such as electroacupuncture might regulate TLR4/NF-κB signaling pathway to relieve pelvic pain and attenuate prostatic inflammation in estradiol-induced CNP rats[60], Poria cocos polysaccharides could alleviate CNP by regulating the gut microbiota[70], and low-intensity extracorporeal shock wave therapy might reduce inflammation and pain in EAP rats via PI3K/AKT/FOXO1 pathway[51], translational studies based on these mechanisms were actually quite rare. In fact, treatments such as acupuncture and low-energy shock waves had already been used clinically[76,77], and these mechanisms were used only to explain the biological basis behind their clinical efficacy. However, it is undeniable that more targeted therapies based on these mechanisms might be needed to better control the symptoms of CP/CPPS in the future.

We have summarized the potential treatments for CP/CPPS based on an analysis of treatment-related keywords in this study. To be able to summarize the potential evolution of treatments, the same categories of interventions were combined. For example, TCM includes Chinese patent medicine, Chinese herbs, Chinese medicinal formulae, acupuncture, and so on. As noticed, many interventions had been explored to treat CP/CPPS in the past decades. This demonstrates the efforts of researchers to expand CP/CPPS treatment options. As an important part of TCM, acupuncture has been extensively studied in CP/CPPS. Some studies had observed the potential efficacy of acupuncture for CP/CPPS in animal models[78,79]. And some studies have validated the efficacy of acupuncture for CP/CPPS in clinical trials[77,80]. Similarly, extracorporeal shock wave therapy had also shown objective efficacy in the treatment of CP/CPPS in both preclinical and clinical studies[51,81]. These clinical to basic studies demonstrated the potential of acupuncture and extracorporeal shock wave therapy for CP/CPPS which were consistent with our bibliometrics results. In recent years, these interventions have also been promoted clinically. However, it cannot be ignored that many interventions explored in preclinical studies did not achieve clinical transformation, without even trying to test in clinical patients after literature retrieval. This suggested an important direction in the field of CP/CPPS treatment to verify the effectiveness of interventions explored in the preclinical phase in clinical trials and achieve clinical transformation.

Notably, our study had several limitations. First of all, only the WoSCC database was searched in this study, which inevitably resulted in the omission of some important studies due to the relatively single literature source. However, the journals included in the WoSCC were considered to be the world-leading journals with greater specialization and higher international influence[3,9,82]. Therefore, our data selection was reliable to a certain extent. Second, researchers manually excluded articles that were not relevant to the research objectives and only analyzed articles in English, which may have led to selection bias to some extent. Finally, our research results may have a certain lag, because the update speed of the WoSCC database is very fast, which leads to the development trend of related fields is not static. Nevertheless, our study conducted a thorough analysis of preclinical studies of CP/CPPS from 1994 to 2023, which helped researchers better understand the molecular mechanisms of CP/CPPS and explore new research directions.

5 CONCLUSION

This study analyzed the preclinical studies related to CP/CPPS via bibliometric analysis. Although Chinese scholars and institutions have published a large number of papers, it is necessary to further enhance their academic influence and enhance cross-international cooperation in this field in the future. Based on the analysis of keywords, eight common molecular mechanisms of CP/CPPS were summarized, which were disturbed immune and inflammation mediators, immune cell dysfunction, oxidative stress, dysregulated signaling pathways, apoptosis, gut microbiota, and testosterone metabolism. Further translational studies targeting these mechanisms are needed in the future. TCM and extracorporeal shock wave therapy-related studies have been increasing in recent years indicating their important potential in the treatment of CP/CPPS. To be emphasized, the potential treatments indicated by preclinical studies need to be validated in clinical patients in the future to achieve generalization.

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