The Web of Science (WoS) database was used to find papers published in all years containing the subject term “Neuromedin U.” The final search was performed on December 16, 2021. After all data were independently extracted by the two authors, the final inclusion of the research literature was determined. The dataset was derived from original research articles, meta-analyses, reviews, and case reports. Bibliometric indices used for literature data extraction included author names, keywords, nationalities, research institutions, and citation frequencies.

We reviewed publication characteristics by generating a “WoS Literature Analysis Report” online, including countries/regions, institutions, journals, authors, and their number of annual publications, citation frequency, and “H-index.” The H-index can reflect both the quantity and quality of an author's publications, and is considered a reliable method for predicting future research success (11). Using the mapping function of the Microsoft Excel software, we compared the number of publications, citations, and H-index among different countries and institutions.

The VOSviewer software was used to visually analyze the trends in the publications (12). Author, institution, and country coupling analyses were performed using the “document coupling analysis” function, and analysis diagrams were derived. In these diagrams, the size of the circle reflects the degree of connection between published studies. Visual analysis of co-occurrence helps understand the research trends and current hot spots, which is of great significance in predicting future research dynamics (13).

According to keyword clustering, current NMU research directions could be divided into six categories: central-nervous-system, homeostasis, energy metabolism, cancer, immune inflammation, and food intake depicted by different colors (Figure 6). In the central-nervous-system, commonly used keywords included “corticotropin-releasing hormone,” “porcine spinal-cord,” “protein-coupled receptor,” “smooth-muscle,” and “central nervous system;” in the homeostasis cluster, commonly used keywords included “energy,” “homeostasis,” “secretory,” “gastrointestinal-tract,” and “hormone”; in the energy metabolism cluster, commonly used keywords included “body-weight,” “obesity,” “angiotensin,” “reward,” and “paraventricular nucleus”; for cancer cluster, commonly used keywords included “cancer,” “gene,” “metabolism,” and “therapeutic target”; in the immune-inflammatory system, commonly used keywords included “innate lymphocytes,” “tuft cells,” “inflammation”; and for food intake cluster, commonly used keywords included “leptin,” “feeding-behavior,” “glucagon-like peptide-1,” and “brain.” The keywords related to each system were both different and interrelated.

Bibliometric analysis revealed that most NMU research to date has been basic research, and these published articles mainly focus on animal experiments and review articles, as well as a few reports on clinical trials. Although NMU research has made great progress in various aspects, clinical research on NMU remains minimal.

Neuromedin U was first discovered and isolated from the pig spinal cord by Minamino et al. (15). In 1987, the Fujii group attempted to synthesize NMU-8 and NMU-25 using the deprotecting reagent trimethylsilyl trifluoromethanesulfonate (16). Subsequently, NMU has been detected in several species, including various fish (17–19), guinea pigs (20), dogs (21), chickens (22), rabbits (23), various frogs frogs (24, 25), and humans (26), etc. Neuromedin U has maintained a highly conserved amino acid sequence during evolution, especially in its five C-terminal amino acids (-Phe-Arg-Pro-Arg-Asn), which are preserved in almost all mammals and ensure maintenance of the protein's important physiological functions (27). However, the expression levels and functions of NMU differ between tissues and species.

Visualization of keyword co-occurrence revealed that NMU research to date has focused on six topics: central-nervous-system, homeostasis, energy metabolism, cancer, immune inflammation, and food intake. These themes are both independent and concomitant, and form an intricate network structure that reflects the versatility of NMU. Neuromedin U was first discovered based on its ability to because it can stimulate uterine contractions, and was subsequently confirmed to act as a contractile stimulator in the gastrointestinal tract and genitourinary system (14, 28). Neuromedin U has a variety of physiological functions, which are mainly related to the corresponding NMU receptors (NMURs). Typical NMURs are NMUR1 and NMUR2, both of which are of the orphan class A rhodopsin G protein-coupled receptor family (1). NMUR1 is predominantly distributed in peripheral tissues such as the gastrointestinal tract, genitourinary system, pancreas, bone marrow, lymphatic tissue, and lungs; therefore, it mainly mediates the physiological functions of NMU in peripheral tissues (1, 27). Conversely, NMUR2 is expressed in the central nervous system (mainly in the medulla oblongata, pontine network, anterior pituitary, spinal cord, and thalamus), and therefore mediates the role of NMU at these sites (27, 29). In other tissues, NMUR1 and NMUR2 are co-expressed.

As a multifunctional neuropeptide, NmU plays a variety of roles in different cells and tissues, transmitting central signals and directly stimulating tissues or cells to perform its jack-of-all-trades function. For the six themes mentioned above, a great deal of research has been carried out by scholars in different fields. Neuromedin U selectively regulates behaviors in different areas of the brain. For example, when NMU is injected into the nucleus accumbens shell, it can prevent acute alcohol-induced motor stimulation behavior and induce memory recovery as part of the alcohol reward pathway (30). Furthermore, a recent study found that NMUR1 and NMUR2 were expressed in the rat hippocampus, and their activation contributed to the excitation of gamma-aminobutyric acid neurons in the hippocampal CA1 zone (31). Neuromedin U is highly expressed in the paraventricular nucleus of the hypothalamus, which participates in stress-related behaviors and regulates the activation of the hypothalamic-pituitary-adrenal axis (27). The NmU gene is located near the clock circadian regulator gene (CLOCK) and is expressed in the suprachiasmatic nucleus, where it helps to regulate the circadian rhythm through rhythm-matched oscillations in its expression level (32, 33). Neuromedin U participates in the regulation of food intake through the brain-gut axis, and intracerebroventricular administration of anti-NMU IgG into rats mediated leptin to induce satiety, decrease food intake, and improve energy consumption (34). Similar studies have shown that an NMUR2 agonist can inhibit food intake and attenuate body weight in diet-induced obese (DIO) rats (35, 36). In addition, peripherally given NMU enhanced glucose tolerance and improved white adipose tissue beiging in DIO mice (37). Neuromedin U is highly expressed in a variety of inflammatory models. It promotes the release of inflammatory factors by binding to receptors on the surface of immune cells, thereby inducing inflammatory reactions (38–42). Neuromedin U activated lung ILC2s by NMUR1, which further promoted IL-17A secretion and IL-17A-dependent γδ T cell amplification, which in turn exacerbated sepsis (43). However, the mechanisms by which NMU affects tumors are relatively complex. For example, NMU expression is significantly reduced or completely silenced in esophageal squamous cell carcinoma and other squamous cell carcinoma cell lines. Further functional tests showed that NMU treatment for cancer cells reduced tumor colony formation (44, 45). Therefore, NMU inhibits the growth of these tumor cells. However, in bladder cancer (46), endometrial carcinoma (47, 48) and breast cancer (49), lung adenocarcinoma (50), NMU overexpression can promote tumor cell growth, enhance tumor formation and metastasis, and increase tumor drug resistance. The latest study found for the first time that NMUR2 activation promoted signaling in colorectal cancer (CRC) cells, and that NMU improves the mobility and invasiveness of NMUR2-positive CRC cells (51). The specific mechanisms behind these differing effects are not clear, but may be related to the tumor type, positive, and negative regulation of oncogenes, and the tumor microenvironment.

The WoS database contains all documents published about NMU since 1987. The United States had the highest number of publications, followed by Japan. Accordingly, of the top 10 institutions, four were from Japan and four were from the United States; among them, the top three most highly cooperative institutions were National Cerebral and Cardiovascular Center Research Institute (Japan), Miyazaki University (Japan), and University of Texas Medical Branch (USA). Miyazato Mikiya, Mori Kenji, and Kangawa Kenji were identified as outstanding scientific leaders in this field. These results emphasize the major contributions of Japan and the United States to this field. Japan was the first country to discover and synthesize NMU, and has the most research institutions currently conducting research on the topic. Although the United States was approximately 20 years behind Japan in contributing to this research field, it currently maintains a dominant position in terms of number of publications, citation frequency, and H-index. This could be due to many factors, including the research institutions, the strength of the publishing journal, academic influences, funding support, and language differences. China is the only developing country in the top five, which included one North American country, one Asian country, and two European countries. In contrast, China ranked third in the number of publications, and ranked fifth in citation frequency and H-index. This could be due to a lack of close team cooperation or a language disadvantage. Although the trend appears to be changing, English is more difficult to publish in for Chinese researchers.

NMU-related studies have been published in a variety of high-impact journals, such as Cell (IF = 41.582), Nature (IF = 49.962), Cell Metabolism (IF = 27.287), Blood (IF = 22.113), and Immunity (IF = 31.745). This indicates advanced research quality in the NMU field, highlighting its importance in biomedicine. Four NMU studies were highly cited, three of which were published in Nature and describe NMU's regulation of ILC2s involved in the inflammatory response. Independent studies showed that NMU was produced by cholinergic neurons in the gastrointestinal tract and lungs of mice, and are adjacent to ILC2s, which selectively express NMUR1. The activated ILC2s proliferate rapidly and release T helper 2 (Th2)-like inflammatory factors, such as interleukin (IL)5, IL13, and amphiregulin. When NMUR1 is knocked out, the Th2 inflammatory response is attenuated (38, 40, 42), suggesting that the NMU-NMUR1 axis plays a key role in the inflammatory response, and confirming that neuropeptides that bypass traditional immunological mechanisms are involved in the regulation of specific immune responses. Exploring the relationships between neuroimmunity, inflammation, allergy, and other diseases has become a promising research direction in the field.

It is worth noting that most of the functions of NMU are performed via NMUR1 and NMUR2. However, other receptors can play regulatory roles as well, such as MAS-related GPR family member X2 (MRGPRX2) (52); NMUR2S (a splice variant of NMUR2) is thought to have a negative regulatory effect on NMU (53). Interestingly, NMUR1 and NMUR2 have been reported to be heterodimers of the growth hormone secretagogue receptor 1b (GHSR1b) and the neurotensin receptor 1 (NTSR1) (54). When considering NMU as a target for disease treatment, mutual cooperation or antagonism between its multiple receptors should be considered.

Based on the advantages of bibliometric systematization and quantification, this study combined the VOSviewer software to draw a scientific map of the field of NMU in order to evaluate the global distribution characteristics, research hotspots, and frontier trends. Our study will help researchers and institutions to better grasp the research dynamics, so as to promote the research progress and translation of results in the field. However, the study also has some limitations. Firstly, the data cannot be analyzed comprehensively across databases, and therefore we have not combined our dataset with data from the PubMed, Scopus, and EMBASE databases for integrated analysis. Moreover, NMU related datas were retrieved from the WoS database, which is recognized as the best database for bibliometric analysis. The data are objective and comprehensive, reflecting the current NMU research situation and its trends. Secondly, this research lacked depth compared with basic research, but this quantitative approach presented a more intuitive overview of topical issues and emerging trends in the field. Thirdly, owing to the short publication time of recently published high-quality literatures, the citation frequency is not high, and the literature quality level will have a certain deviation. In addition, peer review of conference abstracts is considered inferior to that of published papers and there may be positive results bias; on the other hand, conference abstracts are timely and innovative.

Despite these limitations, we believe that the bibliometric method is worth adopting in order to guide the selection of basic and clinical research directions, and improve the quality of future research within the NMU field.