Intercultural Usage of Mori Folium: Comparison Review from a Korean Medical Perspective

Objectives. A review on studies related to the use of Mori folium, the leaves of Morus alba, was conducted with the goal of identifying new clinical applications in Korean medicine. Methods. Global literature search was conducted using three electronic databases up to January 2015 with the term Morus alba and its Korean terms. KM literatures including textbooks and standard pharmacopoeia were separately hand-searched and reviewed to provide comparison. Data were extracted according to predetermined criteria, and clinical uses were standardized with ICD-10 categories. Results. 159 potentially relevant studies were identified, and 18 articles including 12 ethnopharmacologic and 6 clinical studies were finally included in this analysis. Ethnopharmacologic studies from 8 countries provided 17 clinical uses. We found that five out of six clinical trials were related to diabetes and suggested a moderate short-term to mild long-term effect. And 43 Korean texts also provided 156 clinical uses in 35 categories including ocular and respiratory disorders. Discussion and Conclusions. Though majority of the clinical uses were also found in Korean medicine literature, treatment of infertility, jaundice, cognitive disorder, and hyperpigmentation was found to be effective and diabetes with Morus alba was recognized to have clinical importance.


Introduction
Morus alba Linne is a deciduous tree that belongs to the Moraceae family. Mulberry trees are usually grown throughout the world including Korea and have been used in many ways in traditional medicine for a long time [1].
Mori folium is also used agriculturally for feeding the silkworms, and in many countries like Turkey and Greece, Mori fructus has a role in food supply [2]. In Asia, Africa, Europe, and South and North America, Morus alba is widely used to treat diseases for its antimicrobial and antioxidant properties [3,4], however, mainly for antidiabetic, immunomodulatory, antimicrobial, antioxidant, and anticancer purposes [5]. The major phytochemical component of Mori folium is rutin, and Mulberry leaves are known to have antipyretic, antitussive, anti-inflammatory, and hepatoprotective effects [6]. Mori folium is also frequently used in Korea for treating common cold, cough, headaches, and red swollen eyes [6]. Korea has a dual medical system of conventional Western medicine and indigenously developed traditional Korean medicine (KM) and tries to combine these for more integrative medical services [7]. Traditional Korean medicine has a clinical experience of more than five thousand years and has influence of traditional Chinese medicine with more emphasis on Person-Centered Medicine [8]. A 2014 nationwide survey by the Korean Ministry of Health and Welfare found that 27.1% of the general respondents received KM treatment within the past 3 years, and 68.8% were found to have intention to use KM for treatment [9]. Considering that Mori folium is an abundant, economical, and versatile herbal resource, expanding its clinical application range in the KM system would therefore be beneficial both economically and 2 Evidence-Based Complementary and Alternative Medicine medically. There is a difference in applications of Mori folium in KM and other medical systems, but studies addressing this gap are not available yet.
The current study thus aims to identify potential clinical areas of additional use of Mori folium in KM practice by reviewing ethnopharmacologic and clinical literature from other medical systems and comparing the results with a narrative review of Korean medical literatures. The specific procedures and methods are described in the following section. Herbs are usually administered as a multiherbal prescription and seldom used as single herb in KM. Assessment of full texts provided only one Korean ethnopharmacologic study of Mori folium in single herb. Since this was deemed insufficient to serve as a basis for comparison, a narrative review on effect of Mori folium in KM was separately performed.

Inclusion and Exclusion Criteria.
Ethnopharmacologic studies providing uses and effects attributed specifically to Mori folium alone were included, but multiherbal prescriptions were excluded. Studies providing secondhand information only were excluded to avoid duplication.
Clinical studies on isolated substances from Mori folium were excluded for this review since they cannot represent the whole range of substances present in the material as used in KM practice. Research on Mori folium products with certain fortified substances was included only when new substances were not included. Case reports were excluded since they were deemed not to represent usage. Other disputes were settled through consensus among authors.
Out of 3,421 articles identified in the search process, one KM ethnopharmacologic field study was analyzed separately in the KM narrative review, and 18 articles were included in this review.

Data Extraction.
All articles were independently reviewed by three reviewers (Jeon, Lim, and Joh) and data was extracted by predefined criteria (see Table 1). These criteria were modified from previous reviews on ethnopharmacology and/or clinical trials of similar nature [10,11]. Due to disparities in description of quality and cultural context, uses were standardized and coded as the closest matching category listed on the 10th International Classification of Diseases (ICD-10) [12]. Only firsthand data was used from each study.

Methodological Quality Assessment.
There is currently no validated tool for assessing ethnopharmacologic research quality and methodological quality of clinical studies was assessed with JADAD scale [13]. The JADAD scale has been used for assessing the methodological quality of randomized controlled clinical trials depending on its description of randomization, blinding, and others with score range of 0 to 5 [13]. Studies with 3-5 points were regarded as good methodological quality and 0-2 points were poor methodological quality.

Data
Analysis. The data analysis was conducted using the following process. Clinical uses and nationality or cultural origin of research subjects in ethnopharmacologic studies were analyzed and summarized. Clinical trials were first grouped according to ICD-10 subchapters of usage. Subsequently, exploration of the significant factors for the clinical characteristics of each group was conducted.

KM Literature Review.
A literature review was separately performed as previously mentioned in Section 2.1. KM pharmacology textbooks currently used in one or more colleges and 10 classics recognized by Korean Food and Drug Administration as standard pharmacopoeias were searched for uses of Mori folium. Literature from the previous database search containing first-or secondhand information on KM use of Mori folium, including one ethnopharmacologic field study, was also retrieved for review in this part. Furthermore, the references in all the located articles were manually searched for additional relevant article search. Data extraction was performed according to the predefined criteria in Table 1, with the exception of originating culture since all pertained to KM.
Clinical usage data attributed to Mori folium were extracted, but effects of multiherbal prescriptions were excluded. To preserve the cultural intonations of the data, uses were first standardized into 2nd Korean Standard Classification of Diseases-Oriental Medicine (KCD-OM2) codes which employ KM diagnostic terminology and then translated into pertaining ICD-10 category codes based on the diagnosis matching chart of KCD-OM2. Closest matches were used in both coding steps. The same ICD-10 categories appearing multiple times in a single text were counted as one use.

Results
3421 potentially relevant articles for the global literature review were found on initial search of databases. Figure 1 shows the data extraction process, and the results are summarized in Tables 2 and 3. The detailed analyses were presented in the following sections.

Ethnopharmacologic
Research. 17 records of clinical uses in 13 categories were found from 12 non-Korean ethnopharmacologic studies with 8 cultural origins. Table 2 provides a summary for these.   Mori folium was used in multiple studies for respiratory tract disorders at Pakistan. It was used in 3 instances such as an expectorant and sore throat treatment [14] and to relieve cough due to throat pain [15]. Two studies described the clinical use for ocular disorders including relieving effect on sore and inflamed eyes [14] and blindness treatment [16]. Substances in Mori folium such as rutin, choline, and folic acid have anti-inflammatory effects which might be a reason for these clinical effects [6].
acid plays a role in cancer prevention and protection in animal models [29], possibly through increasing DNA repair rates. Folic acid is an important substance in the reproductive process of both men and women [30]. Folic acid also plays a controversial role in cancer patients; diets high in folate are associated with decreased risk of colorectal cancer [31], but the quickly multiplying cancer cells require folate for growth and reducing its availability to cancer cells is a major pathway in mechanisms of commonly used chemotherapy agents such as methotrexate. The actions of these substances might provide at least some parts of medicinal effects of Mori folium in humans.

Clinical Trials.
Six clinical trials within predetermined criteria were found and had small or moderate sample size. Five studies were on diabetes or postprandial glucose suppression, and one study was on cognitive function. Table 3 provides a summary of these clinical trials. Various Mori folium-derived products were used around the globe in herbal supplements for blood glucose management, and the present results reflected this fact. The key active substance for this application is the glucose analogue 1-deoxynojirimycin (DNJ). It is the most abundant iminosugar in Mori folium and is an -glycosidase inhibitor [32]. HPLC fluorescent detection of DNJ in Mori folium from Morus alba L. showed the content to be at 0.12% [33]. Most of the studies attempted to use materials with higher concentrations of DNJ, ranging from 0.36% to 1.5% of dry weight. Single dose studies for postprandial glucose suppression had more robust results, while long-term studies on plasma glucose provided weaker results.
The single study on cognitive function was a randomized clinical trial with poor methodological quality. It suggested a possible improvement of cognition in mild cognitive impairment patients [34], but the small number of subjects and poor methodological quality made the evidence weak.

Korean Medical Literature Review.
One ethnopharmacologic study provided a record of treatment of sore throat [35]. 40 classics and contemporary texts retrieved from the references of a literature review on Mori folium provided the majority of clinical uses [36]. 156 mentions of clinical uses in 35 ICD-10 categories were found from 43 texts. The most prevalent uses were for ocular disorders ( = 33), respiratory disorders ( = 24), analgesic purposes ( = 16), treating excessive sweating ( = 15), joint disorders ( = 11), and gastrointestinal tract disorders ( = 11). Table 4 provides a summary of the literature review.

Discussion
The current study examined global and Korean literature on medical use of Mori folium to discover additional clinical applications in traditional Korean medicine. In traditional Evidence-Based Complementary and Alternative Medicine 5 RCT, randomized controlled trial; CR, crossover; CC, case-controlled. All medications were taken orally. †  Evidence-Based Complementary and Alternative Medicine    Korean medicine (Table 4), Mori folium clears heat of the lungs which can be understood as the inflammation or congestion in the upper body, respiratory system, and skin. The anti-inflammatory effects might explain the clinical reports in the world, which showed antipyretic, analgesic, antivenom, antihypertensive, and anti-infertility properties that can be used in respiratory and ocular disorders, neuritis, jaundice, and hyperpigmentation (Tables 2 and 3). These clinical uses can be easily understood when we compare the reports using the standardized ICD-10 codes. However there are some other clinical uses uniquely for traditional Korean medicine including treatment of hyperhidrosis, gastrointestinal tract, and joint disorders and use as hair tonic that can be adopted in other medical systems. Along with these, treatments of infertility [19], jaundice [24], cognitive disorder [34], and hyperpigmentation [25] were not or seldom described in Korean medical classics and texts (Tables 3 and 4).
There have been many clinical reports of Mori folium on blood glucose and diabetes (Tables 3 and 4). Though different research settings and low research quality of these reports lower the reliability of these, they showed strong possibility of dose-dependent suppression of postprandial glucose elevation that can have long-term effect on patients with severe glucose metabolism impairment. There still lies a need for well-designed clinical study, which may provide pivotal methods for diabetes treatment.
As for the summary and analysis in this study, the authors coded reported clinical uses into ICD-10 categories to compare their clinical effects. Though ethnopharmacologic studies sometimes have used ICD-10 chapters to categorize medicinal effects [37][38][39], the present study used categories since chapters and subchapters were too broad to incorporate all the clinical uses of Mori folium in the world. Also, the classification into chapters would cause overrepresentation of the system chapter since many ethnopharmacologic records were just simple mention of symptom names.
Although the ICD-10 coding system has universal use and usefulness for comparing studies from the world in scientific ways, there might be inevitable losses during the translation due to the nature of Western medicine underneath the coding system. For example, ICD-10 does not differentiate fever caused by liver heat and kidney deficiency, which has different accompanying signs and symptoms, and warrants completely different ways of treatment. Therefore, it should be noted that the findings in this study should be thoroughly explored with respect to their originating culture or nationality before the clinical application. And, the indicators of clinical importance and reliability were also not provided for the majority of studies. Therefore, all the potential clinical uses found in this review should be reexamined with further studies regardless of citation frequencies in here.
In this study, we excluded the clinical reports with multiherbal decoction including Mori folium as one of the ingredients and rather included description from medical textbooks, classics, and pharmacopoeia, since clinical action and effectiveness of a given herb may vary according to its role in the prescription and so it is hard to analyze its clinical usefulness. As the medical herbs are usually used as a multiherbal decoction in traditional Korean and Chinese medicine, there would be a possibility that Korean ethnopharmacologic usage and Chinese clinical studies might be unsatisfactory in this review [40]. Also, limitation with accessible clinical research databases might also have happened as for the local literatures with other languages not included here.
In conclusion, we performed a review on clinical use of Mori folium with three database and traditional Korean medical textbooks and pharmacopoeia and analyzed its clinical use with ICD-10 code. From 159 relevant studies and 17 clinical usages, infertility, jaundice, cognitive disorder, and hyperpigmentation were identified as potential clinical uses, and diabetes was the one deserving more emphasis. This study would contribute to the thorough understanding on the clinical usefulness of Morus alba and Mori folium with carefully designed researches on its clinical applications.