Clinical effects and mechanisms of actions of the Chinese herbal formula (RCM-104) for weight management: literature reviews and computational analysis
Creators: name: Yuen, Heidi
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 420803
subject: Traditional Chinese medicine and treatments
classificationCode: 420899
subject: Traditional, complementary and integrative medicine not elsewhere classified

description: Background

Overweight and obesity is a major global health issue, characterised by higher dietary energy intake than energy expenditure. Statistics from the World Health Organisation (WHO) indicated that in 2016, more than 1.9 billion adults were overweight and 650 million of them were obese (WHO, 2021). Apart from being a disease in itself, obesity is a major risk factor for a number of other conditions such as type-2 diabetes, high blood pressure, heart diseases, stroke, certain types of cancer, sleep apnoea, osteoarthritis, fatty liver disease, kidney diseases and pregnancy problems (NIDDK, 2018).
 
Currently, pharmacotherapy is being used as the first line of treatment for patients with overweight and obesity. However, anti-obesity pharmacotherapies have been unsafe and minimally efficacyious, and some anorectics were withdrawn from the market due to severe adverse side effects (Marcus &amp; Wildes, 2013; Pi-Sunyer, 2009). Therefore, there is a need to seek solutions outside the regime of current pharmacotherapy. Thus, more and more patients are seeking alternatives for weight management, such as Chinese herbal medicine (CHM) (Xiao &amp; Luo, 2018; Yeh et al., 2017).

Aim

RCM-104 is a weight management CHM formula developed in RMIT University (Lenon et al., 2012) which comprises three Chinese herbs: Jue ming zi (JMZ, Cassiae Semen), Lu cha ye (LCY, Green tea, Camellia Sinensis leaf), and Huai hua (HH, Sophora Flos). The clinical effects of RCM-104 were evaluated with a 12-week randomised controlled trial (RCT) with placebo as control. The results of the RCT have shown that RCM-104 is effective in reducing weight, body mass index and body fat content in obese individuals. However, the pharmacological and molecular mechanisms of actions of the RCM-104 ingredients are still unknown.
 
The aim of this research project was to investigate the clinical effects and mechanisms of actions of RCM-104 for the treatment of simple obesity, through systematic reviews of classic and modern literatures, as well as computational analysis. 

Methods

This research project contains three phases: Phases I and II are review of classical and modern literature respectively and Phase III is computational analysis.

A comprehensive review of classical literature was conducted in phase I to understand the interpretation of obesity in ancient China and to collect information concerning properties, actions and indications of the ingredients of weight-loss CHM formula RCM-104. A two-stage process was used in the classical literature search: A CD-ROM database named Zhong Hua Yi Dian (ZHYD; Encyclopaedia of Traditional Chinese Medicine) was first used to locate any related citations. This was then followed by cross-referencing to hardcopy authenticated editions of the books in Zhong Guo Ben Cao Quan Shu (ZGBCQS; The Complete Collection of Traditional Texts on Chinese Materia Medica) to verify the retrieved information.
 
Phase II was divided into IIa and IIb. Phase IIa was to investigate the phytochemistry, pharmacological profiles and clinical applications of the herbal ingredients in formula RCM-104. Comprehensive searches were performed on seven English databases and three Chinese databases for publications on original experiments related to phytochemistry, pharmacology, and toxicology of the herbs from their earliest available records to 30 April 2020.

Phase IIb was to identify the required data as input for next phase, computational analysis. The possible anti-obesity targets were identified through online database search including Herb Ingredients’ Targets (Ye et al., 2011), Traditional Chinese Medicine Systems Pharmacology database (Ru et al., 2014), the Protein Data Bank (Berman et al., 2000) and DrugBank (Wishart et al., 2008; 2018). Known drugs for weight management were searched through the online database Monthly Index of Medical Specialities for drugs available in Australia, and DrugBank and the Metabolomics Innovation Centre for drugs available in the United States, Canada and the European Union. Herbal compounds of RCM-104 were identified through (1) Encyclopaedia of Traditional Chinese Medicine (Zhou et al., 2012), (2) textbooks (Bensky et al., 2004; Chen et al., 2004), (3) an open chemistry database: PubChem, and (4) a database of systems pharmacology for drug discovery from herbal medicines—Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. Keywords overweight and obesity were used in the screening process. Additionally, literature search was conducted to identify any compounds missed from books and online databases and new compounds discovered through in vitro experiments.
 
Computational molecular docking and analysis approaches were used in phase III. The objectives were: (1) to understand the anti-obesity pathways of the individual herbs of RCM-104; (2) to evaluate the synergistic effects of the individual herbs of RCM-104 through pharmacological network analysis; (3) to identify active herbal compounds of RCM-104 which could have potential therapeutic effects on weight management; and (4) to understand the interactions of the identified compounds with the relevant anti-obesity targets. Current anti-obesity agents were used as control ligands for comparison with the herbal compounds in the computational analysis. 

Key findings
 
The findings in review of classic literature show that JMZ may assist in maintaining a healthy body weight due to its actions in nourishing the Liver and clearing Liver heat. LCY may assist in maintaining a healthy body weight by eliminating the fat, purging the Gallbladder and reducing the damp-heat and pathogenic fire. HH may assist in weight loss by cooling the Large Intestine, clearing the Liver fire, disperse wind-heat and cooling the blood. Therefore, RCM-104 can help to prevent overeating by reducing the heat from Stomach and Large Intestine, because all the three herbs of RCM-104 are cool in nature with JMZ and HH entering the Yang Ming meridians. In addition, all three herbs enter the Liver channel which are beneficial to the free flow of Qi in the body and clear Liver Qi Stagnation. 

The modern literature review on the phytochemistry, pharmacology and toxicity of the herbal ingredients of formula RCM-104 has demonstrated a profound influence of these herbs and their chemical compounds on various diseases and health conditions apart from overweight and obesity. The results of the search found that JMZ and nine of its active chemical compounds are identified to have weight reduction effects. It was found that JMZ compounds may exert anti-obesity effects via inhibiting amylases and lipases and suppress appetite by 5-HT2C receptor activation. LCY plays a role in weight loss by reducing food intake, interrupting lipid emulsification and absorption, suppressing adipogenesis and lipid synthesis and increasing energy expenditure via thermogenesis, fat oxidation and faecal lipid excretion. HH and its bioactive compounds have demonstrated various potentials to against major obesity-related health risks such as diabetes. In summary, the main pathways of weight loss effect of RCM-104 are reducing food intake through appetite suppression and reducing lipid absorption through inhibition of digestive enzymes.
 
Through extensive search on multiple databases, seven anti-obesity drugs/agents, 38 anti-obesity protein target structures and a total of 147 herbal compounds of formula RCM-104 were identified for the molecular docking of the next phase of the project.

In Phase III computational analysis, the output of the docking process consisted of the binding affinity scores of protein-target pairs and the top 10 most energetically favourable 3D models of each pair. A pharmacological network detailing the interactions between the formula, herbs, chemical compounds and targets was established. This visual presentation has provided insights on the mechanisms of actions of formula RCM-104 towards its specific targets. Further analysis on the interaction of these targets and their selected herbal compounds discovered that a major mechanism of action of formula RCM-104 is to supress appetite by influencing the serotonergic and dopaminergic systems. On the other hand, through analysing the docking results and protein-ligand interactions, it was established that each herb of RCM-104 contains chemical compounds which are effective in inhibiting pancreatic lipase and thus achieve weight-loss by suppressing the absorption of lipids.

Conclusion

In conclusion, the goal of this research has been achieved. The results from this research project suggested that formula RCM-104 is indicated for overweight or obese patients of Stomach Heat syndrome with or without Liver Qi Stagnation. And this project deduced that the two major mechanisms of actions of the formula RCM-104 are suppressing appetite by influencing the serotonergic and dopaminergic systems and suppressing lipid absorption by inhibiting pancreatic lipase activities.