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Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jethpharm

Review

“Shanghuo” increases disease susceptibility: Modern significance of an old

TCM theory
Ming-Hai Pana,b,c,1, Si-Rui Zhua,b,c,d,1, Wen-Jun Duana,b,c, Xiao-Hui Maa,b,c, Xiang Luoa,b,c,
Bo Liue, Hiroshi Kuriharaa,b,c, Yi-Fang Lia,b,c,∗∗, Jia-Xu Chenf,∗∗∗, Rong-Rong Hea,b,c,∗
a
Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China
b
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632,
China
c
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College
of Pharmacy, Jinan University, Guangzhou, 510632, China
d
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangdong, Guangzhou, 510006, China
e
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, And Collaborative Innovation Center for Biotherapy, Chengdu, 610041,
China
f
College of Chinese Medicine, Jinan University, Guangzhou, 510632, China

A R TIC L E INFO A B S TR A C T

Keywords: Ethnopharmacological relevance: “Shanghuo”, a concept based on Traditional Chinese Medicine (TCM) theory,
Shanghuo describes a status of Yin-Yang imbalance when Yang overwhelms Yin. The imbalance of Yin-Yang resembles the
Disease susceptibility breaking of homeostasis and manifests by the impaired physiological functions, which leads to the onset, re-
Emotional stress currence, and progression of diseases. Since ancient times, Chinese Materia Medica (CMM), such as herbal tea,
Yin-Yang
has been applied as a treatment for “Shanghuo”.
Chinese materia medica
Aim of the study: This review is aimed to describe the origin of “Shanghuo” from the Yin-Yang theory in TCM, as
well as explore the relevance and correlations between “Shanghuo” and diseases susceptibility from the per-
spective of modern medicine. We also propose several strategies from CMM to improve the status of “Shanghuo”
for the purpose of treating diseases.
Methods: Systematic research of articles with keywords including Shanghuo, Yin-Yang, emotional stress and
disease susceptibility was done by using the literature databases (Web of Science, Google Scholar, PubMed,
CNKI). Related books, PhD and master's dissertations were also researched. Full scientific plant names were
validated by “The Plant List” (www.theplantlist.org).
Results: To date, a large number of publications have reported research on sub-health status, but studies about
the theory or intervention of “Shanghuo” are rarely found. The articles we reviewed indicate that accumulated
emotional stress is critical for the cause of “Shanghuo”. As a status similar to sub-health, “Shanghuo” is also
manifested by impaired physiological functions and decreased nonspecific resistance, which increase suscept-
ibility to various diseases. What's more, some studies highlight the importance of TCM treatment towards
“Shanghuo” in maintaining normal physiological functions, such as immunity, lipid metabolism and ROS
clearance.
Conclusions: Researches on “Shanghuo” and its mechanism are every rare currently and are in need of in-
vestigation in the future. Studies on disease susceptibility recently are mostly about susceptible genes that relate
to a few parts of people, however, for most of the people, accumulated emotional stress or other stressors is
accountable for the susceptibility of diseases. Given that emotional stress plays an important factor in the
causation of “Shanghuo”, we reviewed the articles about this relevance and discussed the connection of
“Shanghuo” with disease susceptibility in a novel perspective. In addition, we have reviewed the disease sus-
ceptibility model of restraint stress from its biochemical manifestation to application in CMM assessment.
Although it would be a breakthrough in evaluating CMM efficacy of attenuating disease-susceptibility,

∗
Corresponding author. Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
∗∗
Corresponding author. Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
∗∗∗
Corresponding author. Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
E-mail addresses: liyifang706@jnu.edu.cn (Y.-F. Li), chenjiaxu@hotmail.com (J.-X. Chen), rongronghe@jnu.edu.cn (R.-R. He).
1
These authors contributed equally to this review.

https://doi.org/10.1016/j.jep.2019.112491
Received 10 September 2019; Received in revised form 16 December 2019; Accepted 17 December 2019
M.-H. Pan, et al.

understanding the comprehensive theory and establishing more models of “Shanghuo” would be required in
further investigation.

Abbreviations DA dopamine
GC glucocorticoid
AIDS acquired immune deficiency syndrome GHT Guangdong herbal tea
ANS autonomic nerves system HPA axis hypothalamus-pituitary-adrenocortical axis
AMP adenosine monophosphate NADPH nicotinamide adenine dinucleotide phosphate
ATP adenosine triphosphate NAFLD non-alcoholic fatty liver disease
CA catecholamine ROS reactive oxygen species
cAMP cyclic adenosine monophosphate s-IgA secreted immunoglobulin A
cGMP cyclic guanosine monophosphate SIRT3 sirtuin 3
CMM Chinese materia medica SHS sub-health status
CNS central nervous system TCM traditional Chinese medicine
CRH corticotropin-releasing hormone 5-HT 5-hydroxytryptamine
CVD cardiovascular disease

1. Introduction acceleration of pace of modern life and the competitive pressure of

Traditional Chinese medicine (TCM) is a system of medical science,
which has been used in diagnosing and treating diseases or disorders for
more than 2000 years. The theory of TCM contains rich integrated
thoughts, and it can be regarded as a holistic approach to health that
attempts to bring the body, mind and spirit into harmony. As essential
elements of TCM theory, Yang represents for active and aggressive
factors, while Yin represents for inhibitory and depressive factors.
Therefore, the Yin-Yang balance (阴阳平衡) (homeostasis) plays an
important role in maintaining the harmony, and the disequilibrium of
Yin-Yang may cause diseases. Herein, striking the balance between Yin
and Yang puts forward the idea of “Zhi Weibing” (治未病) (prophylactic
treatment or prevention treatment) (see Glossary), also called pre-
ventive treatment of diseases, and the concept of “Weibing” (未病)
(Korea: Mibyeong (Lee et al., 2013), Japan: Mibyou (Yamamoto et al.,
2011)), which has a lot in common with sub-health (BOX 1).
“Shanghuo” (上火) (disorders in homeostasis with abnormal non-
specific response) (see Glossary) is an expression of the special status
of the body refers to an imbalanced situation based on the dialectical
Yin-Yang theory, in which predominant Yang makes Yin disordered.
The reasons can involve environmental factors, self-life habits, mental
stress, etc. With the further study of “Shanghuo” and understanding of
stress response, it is found that emotional factors such as the
society are particularly important in the formation of “Shanghuo” (He
and Hiroshi, 2008).
Recently, sub-health status (SHS) has become a new challenge to
public health in the world. As an intermediate state between health and
disease, SHS is mainly characterized by a general decline in health, non-
specific weakness, and decreased energy (Wang et al., 2013).
“Shanghuo” status also manifests as reduced strength and a decline in
functions and adaptability as like SHS, and both do not indicate any
current diagnostic criteria for diseases, however, increase the suscept-
ibility to diseases. Therefore, studying the relationship of “Shanghuo”
and disease susceptibility not only improves SHS through TCM but also
reveals connections between Chinese and western medicine.
Unfortunately, studies on “Shanghuo” and its intervention methods
are relatively rare currently. Some disease models on animals are not
even clearly characterized or validated. Definitive clinical character-
izations of traditional oriental medicine are also scarce to explain the
concept and mechanism of “Shanghuo”. Herein, to address this chal-
lenge and improve human health conditions, explanation of the corre-
lativity between “Shanghuo” and disease susceptibility is essential. In
this review, we present and discuss the TCM theory and modern med-
ical researches, study the TCM intervention and mechanism of
“Shanghuo”, meanwhile explore the relevance and correlated me-
chanism between the “Shanghuo” symptoms and disease susceptibility.

BOX 1
“Yin-Yang Balance” and Diseases in TCM theory

Yin-Yang is an ancient Chinese philosophical theory used to explain the occurrence, development and change of the universe, it is a world view
and methodology for ancient Chinese people to explore the origin and explain the changes of the universe. As an abstract concept, Yin and
Yang can represent both the things or phenomena in nature that are interrelated but opposed to each other and the two aspects of the same
thing that are opposed to each other (Table I).

Table I
Yin and Yang attribute classification

Attribute Temperature Character Motion State System Hormone Cytokine Second Messenger

Yang Warm Clear, Gaseous Rise, Move, Excitation, activate Sympathetic Thromboxane, cortisol IL-1β, TNF-α c-AMP
Yin Cold Turbid, Shaped Fall, Quiet, Inhibition, decline Parasympathetic Prostacyclin, testosterone IFN-β, IL-2 c-GMP

Yin-Yang Balance is a complex interplay between body and mind, which reflected at all levels, ranging from the biochemical component
perspective to the energetic system control of the physical body. It is the reflection of natural health principle “correspondence between man
and universe,” the concept of holism of “body-soul unity”. If the change of Yin and Yang goes beyond a certain limit and range, the dynamic
balance will be destroyed, and diseases will occur in the human body. Therefore, in the TCM theory, “the disequilibrium of Yin-Yang” is
considered as the pathogenesis of all diseases, and maintaining or restoring the dynamic balance of the Yin-Yang movement has become the
supreme principle of TCM treatment and regimen.
M.-H. Pan, et al.
Taken together, these findings would provide reference in improving
the SHS as well as preventing or curing diseases.
2. “Shanghuo” in Chinese and western medicine theory
According to Chinese philosophy, Yin and Yang are two opposing
principles in nature: the former negative or resting, the latter positive or
active. From a holistic point of view in TCM, the balanced Yin and Yang
means health whereas an excess or deficiency of one or the other
usually induces disease, and “Shanghuo” means a Yin-Yang imbalance
which Yang overwhelms Yin. Although Yin-Yang theory is regarded as
an ideology without definite physical meaning before, gradually,
people found that Yin-Yang theory is a model that can be applied to any
natural system (e.g. human body, cell, medicinal plants, etc.) in order to
understand its complexity better. The dual concept of Yin and Yang is
now widely used by the scientists in describing the balance and im-
balance of various biological or biochemical process, such as im-
munoregulation, autoimmunity, inflammation (Mills and Bhatt, 2004;
Zhang et al., 2007), gene expression (Xu et al., 2013), cause and de-
velopment of cancer (Wang et al., 2004).
It has been proposed that the Yin-Yang theory, which includes the
concept of balance, harmony and homeostasis, is actually the anti-
oxidation–oxidation balance described in western medicine (Ou et al.,
2003). The researchers suggested the analogy of Yin-Yang balance with
that of antioxidation-oxidation, in which Yin represents antioxidation
and Yang represents oxidation. Scientists also declared that Yin-Yang
balance is a balance in autonomic nerve with Yin representing the
parasympathetic nervous system which helps to calm and rest the body,
and Yang representing sympathetic system which helps to excite and
activate the body (Ye, 2015). In autonomic nervous system (ANS), the
concentration of the cyclic nucleotides cAMP and cGMP fluctuate and
they appear to have mutually antagonistic actions like Yin and Yang
(Chen, 2009). Accordingly, “Yin-Yang theory” has been applied to the
regulation of second messenger, with Yang deficiency corresponding to
a decrease in cAMP and Yin deficiency to an increase in cAMP (Seki
et al., 2005).
Except for corresponding syndromes resulted from antioxidation-
oxidation imbalance and autonomic dysfunction, there are many non-
specific symptoms of “Shanghuo” can be found in the whole body. As a
typical manifestation of Yin-Yang imbalance in TCM, “Shanghuo” is a
sub-health status of internal environment disorder involving systems
such as gastrointestinal tract micro ecological system (Melinder et al.,
2018), nervous system (McCarty, 2016), endocrine system (Siddiqui
et al., 2015), cardiovascular system (Esler, 2017), etc. Therefore, our
research group previously established a concept that “Shanghuo” is a
psychological and physiological uncoordinated response in the stress-
loaded organism (He and Hiroshi, 2008). It not only manifests as
mental and physical fatigue that goes beyond the normal range of
physiological regulation, but also shows a physical and mental stress
syndrome that impacts various physiological functions, and its clinical
feature varies with different individuals.
Typically, TCM physicians diagnose “Shanghuo” through inspec-
tion, listen, inquiry, and palpation, which are usually based on the
clinicians' subjective judgment, but not quantified objective diagnostic
parameters. Assessment of biological indicators related to the nervous,
endocrine, and immune systems in individuals with SHS may, to some
extent, help clarifying the mechanisms of “Shanghuo”. Then, in the
modern medical diagnostic research of “Shanghuo”, some specific
physiological and molecular indicators are brought up. For instance,
decreased serum testosterone/cortisol (T/C) ratio may be an objective
indication of "Shanghuo" (Wang et al., 2013), because it shows sub-
health with physiological fatigue (decreased performance, loss of ap-
petite, changes in heat rate, etc.), psychological disorders (con-
centrating difficulty, depression, apathy, etc.) and immunological de-
ficiency which resembles “Shanghuo” syndrome (Fry et al., 1991;
Angeli et al., 2004). Changes in some other neuroendocrine and
immunological indicators (gene network of plasma norepinephrine,
level of CD4 naive T cell, etc.) may also explain some of the “Shanghuo”
symptoms, including malaise, increased disease susceptibility and poor
work performance attributable to persistent fatigue (Holmes et al.,
1988; Milrad et al., 2018; Nguyen et al., 2019). It is also reported that
diagnosing “Shanghuo” using SHSQ-50 questionnaire or a combination
of diagnostic score tables and s-lgA levels is with good reliability and
validity (Zhao et al., 2012; Liu et al., 2014). What's more, the oral
ailments associated with “Shanghuo” syndrome including oral dryness,
mucosal ulcer, and gum bleeding, swelling, and pain, are similar to
recurrent aphthae, gingivitis, periodontitis, and caries of Sjogren syn-
drome (Yan et al., 2012), which provides reference value for the con-
nection between western medicine and TCM. However, in western
medicine, the manifestations remain vague for the diagnosis of
“Shanghuo”. It is of necessity to dig more clinical disorders that are
related to “Shanghuo” from the sight of Yin-Yang balance.
Lately, similar to integrated thoughts in TCM, a novel analytical
technique, metabolomics (or metabonomics), reflects the function of
organisms from terminal symptoms of the metabolic network and me-
tabolic changes caused by interventions in a holistic level (Wang et al.,
2011). Herein, in pharmacological studies on the intervention of
“Shanghuo”, metabolomics focuses on the holistic monitoring of me-
tabolic changes and responses to a xenobiotic intervention, permits the
study of the system-wide effects of “Shanghuo” intervention such as
herbal tea, as well as provides an in-depth understanding of its me-
chanisms of action and health benefits (You et al., 2014).
3. “Shanghuo” increases disease susceptibility
3.1. Emotional stress is an important factor in “Shanghuo”
TCM has recognized the important role of “Internal injury due to
emotional disorder” in the early stages of the disease, and it is believed
that the emotional stimulation can physiologically disorder the balance
of Yin and Yang, which respectively represent by Xue (血) (blood and
energy) and Qi (气) (spirit and pneuma) (see Glossary). As a result,
Xue, as running liquid in the vessels with energy, becomes incapable of
loading Qi, and then, leads to Qi stagnation under emotional stress.
Finally, dominated Yang (stagnated Qi) transforms into “Huo” (火)
(excessive heat), also called “Extreme changes of five minds causing
Huo” (五志过极化火) (see Glossary) or emotion disease theory in TCM
(Wang and Guo, 2012). “Huo”, the origin of this so-called unhealthy
heat, ensues once an excess of Yang or deficiency of Yin occurs and
leads to the “Shanghuo” status.
According to the logic and methodology of TCM, analogizing from
similarities between the appearances of diseases and natural phe-
nomena is one of the common approaches. Therefore, hydropenia such
as dry eye syndrome, parched mouth, scorched tongue, brown urine
and constipation, as well as inflammation symptoms like swelling,
aphtha, sore throat and fever, burning pain, are comparable to
“Shanghuo” symptoms. “Shanghuo” is also used to describe the uneasy,
anxious and irritable emotional state. In the perspective of western
medicine, these symptoms are also considered as compensatory ad-
justment against the breaking of diverse homeostasis (Fan et al., 2011).
Additionally, traditional emotion disease theory and modern psy-
chological stress theory have something in common in epistemology
that they all included systemic non-specific response caused by psy-
chological factors: the stress response. It is psychological and physio-
logical alterations in systems like central nervous system (CNS), endo-
crine system and immune system when the body is affected by stressors,
and the authors called the stress response induced by emotion factors
emotional stress response. XQ Li et al., (2002) found that the emotion of
patients with syndrome of liver fire flaring up in TCM contains dis-
composure and anxiety caused by neurological dysfunction and sym-
pathetic hyperactivity. Some symptoms of “Shanghuo” such as canker
sores (Gallo et al., 2009), constipation (Devanarayana and Rajindrajith,
M.-H. Pan, et al.
2010) can either be explained as an emotional stress response. The
authors’ previous studies also confirmed that stress response caused by
restraint and other psychological stress could partially simulate the
pathological changes of emotion diseases in TCM (Zhu et al., 2018) (“Qi
stagnation transforming into Huo” (气郁化火)). We thereby proposed
that “Huo” mostly comes from emotional factors, and emotional stress
response can partly explain “Shanghuo” as a kind of comprehensive
response without specific physiological indicators when the body loses
stability during emotional abnormalities (Fig. 1).
3.2. Emotional “Shanghuo” increases disease susceptibility
Nowadays, SHS is considered as an unhealthy condition but non-
disease, and traditional medicine believes that, “Shanghuo” is not a
disease, while diseases come from it. Researches also showed that the
Fig. 1. “Extreme change of five minds” and emotional stress, the patho-
genesis of “Shanghuo” in TCM and modern medicine theory
In the perspective of Traditional Chinese Medicine (TCM), extreme change of
five minds will lead to the imbalance of Yin-Yang, then the imbalance of Qi-
Blood, which alters the motion of Qi, and induce Qi stagnation. Under Qi
stagnation, dominated Yang will turn into "Huo", and finally cause “Shanghuo”.
In modern medicine theory, emotional stress will impair the central nervous
system (CNS), inducing the neuroendocrine disorder. With the hormone se-
cretion disorder, many effects such as immune inhibition ensue, and then break
the homeostasis, lead to Shanghuo syndrome, finally let body under a sub-
health state of Shanghuo.
stress status caused by emotional factors is not a disease but an inducer
of increased disease susceptibility (Priyadarshini, 2016). With the
pressure of society, the population with “Shanghuo” status in urban
area is on the rise, and they are suffering from impairments in the CNS,
endocrine system, immune system, and metabolism caused by emo-
tional stress which are closely related to disease susceptibility. Diseases
with high morbidity and mortality such as cancer, AIDS, cardiovascular
disease (CVD), Parkinson's disease, depression and alcoholism have
considerable association with emotional stress due to the increased
pressures (Becker, 2017). It has been proved that 70% of the diseases
are related to psychological stress. Except for the CNS disease, people
with clinical depression or anxiety are more vulnerable to CVD, cancer
or secondary autoimmune diseases such as allergic asthma (Meisel
et al., 2005; Cohen et al., 2007; Ohno, 2017). In addition, many studies
at present have shown that mood swings, depression and other stress
can affect the normal development of embryos, even lead to miscarriage
of pregnant women (Hunter et al., 2017). With the rise of clinical re-
ports about emotional stress-related diseases or disorders, further in-
vestigations are developed in a systematic level and cellular level.
In general, under the emotional stress, hyperactivity of the hy-
pothalamic-pituitary-adrenal (HPA) axis, alterations of ANS character-
ized by sympathetic overactivity and neuroendocrine dysfunction, as
well as hypofunction of immunity, may contribute to increased sus-
ceptibility to diseases. Additionally, we investigated that emotional
stress damages the functions of various tissues through oxidative stress,
thereby elevating disease susceptibility. Hence, “Shanghuo” caused by
emotional stress not only promotes the incidence of insomnia, depres-
sion and other mental diseases, but also significantly increases the
susceptibility to pathogen infection diseases, and notably induces and
aggravates metabolism, cardiovascular and tumor-related clinical
symptoms (Fig. 2).
Under the emotional “Shanghuo” status, neuroendocrine
system changes will increase susceptibility to neuropsychiatric
diseases and endocrine diseases. When people refer to “Shanghuo”,
they mainly associate it with clinical symptoms such as upset, insomnia,
irritability, forgetfulness and other emotional problems. Under chronic
stress, adrenal glands become larger with hyperplasia, increasing the
susceptibility to hyperthyroidism (Kanczkowski et al., 2015). HPA axis
over-excitement may lead to CNS dysfunction, depression, anorexia,
and even suicidal tendencies (Baumeister et al., 2014), and the reason is
that the stress response is mediated through the CNS and thus can di-
rectly affect the susceptibility of neuropsychiatric disorders. Recent
studies confirmed that long-term emotional stress will disorder neuro-
hormones in vivo, leading to insomnia (Olini et al., 2017). In the clin-
icopathological studies of “Shanghuo” epidemiology, Shen JF et al.
(Shen and Yan, 2007) found that patients with stagnation of liver Qi
transforming into “Huo” syndrome are prone to insomnia caused by
hypothalamus-pituitary-target gland hormone secretion disorders.
What's more, the fatigue caused by insomnia will further aggravate the
“Shanghuo”. Lack of sleep also boosts levels of Alzheimer's disease as-
sociated proteins like amyloid beta or tau/p-tau (Lucey et al., 2017). In
recent years, it is found in the clinical depression study on patients that
there is a significant correlation between the incidence of depression
and aggravate stress load (Guo et al., 2014). Moreover, emotional stress
induces memory impairment and cognitive dysfunction by affecting
various functions of the hippocampus (Sanchez-Hidalgo et al., 2016;
Bhakta et al., 2017), leading to an increased susceptibility to Alzhei-
mer's disease. Alzheimer's disease incidence shows the trend of a
younger age because of emotional stress (Garcia-Blanco et al., 2017). In
addition, long-term chronic stress will increase prefrontal inhibition
(McKlveen et al., 2016), then change the structural function of the
brain's prefrontal cortex, resulting in behavioral disorders (de Araújo
Costa Folha et al., 2017), making adverse effect on the adolescent brain
development. High-pressure stress will induce visual cortex and tha-
lamus brain atrophy then impacts on eyesight (Yoshii et al., 2017).
Another study insisted that stress regulates the function of brain
M.-H. Pan, et al.

Fig. 2. “Shanghuo” caused by emotional stress, can affect the normal function of the body at systemic level and cellular level, increasing disease sus-
ceptibility
“Shanghuo” caused by emotional stress, can affect the normal function of the body at systemic level and cellular level. At the systemic level, hyperactivation of
hypothalamus-pituitary-adrenocortical axis (HPA axis) and sympathetic nervous system (SNS) under emotional “Shanghuo”, will cause the over secretion of glu-
cocorticoid (GC), corticotropin-releasing hormone (CRH), catecholamine (CA) and mineralocorticoid as well as rise in heart rate (HR), cardiac output (CO), blood
pressure (BP) and function of renin-angiotensin system. These alterations will impair the nervous system, endocrine system, immune system, and metabolism,
increase the susceptibility to certain diseases. As for the cellular level, under the “Shanghuo” status, the balance between oxidation and antioxidation will be broke,
excessive oxidative species (OS) will impair the function of cells even lead to its death, which finally increase the susceptibility to diseases. AD: alzheimer's disease;
AIDs: acquired immune deficiency syndrome; CNS: central nervous system; HPG axis: hypothalamic-pituitary-gonadal axis.

synapses and contributes to behavioral adaptation and psycho-
pathology (Timmermans et al., 2013). The above evidences indicated
that emotional stress can lead to an increase of disease susceptibility in
neurodegeneration diseases, neuropsychiatric diseases and endocrine
diseases that involves the damage of brain, and hyperactivation of HPA-
axis was regarded as an important indicator of emotional “Shanghuo”.
Undergoing emotional “Shanghuo” and excessive ingestion of
hot food increase the susceptibility to metabolic diseases and as-
sociated complications. Enhanced metabolic rate, increased decom-
position and decreased synthesis are characteristics of the population
under the “Shanghuo” status. Studies have found that the “Huo” sig-
nificantly interfered the body's energy metabolism (Liu, 2000; Xiao
et al., 2008). In patients with liver fire, the ratio of AMP/ATP increased,
while the total adenine nucleotide and the energy charge decreased,
indicating that emotional “Shanghuo” resulted in undue metabolism
(Zhu et al., 1996). In addition, excessive metabolic rate is very detri-
mental to the body. For example, catecholamine (CA) and glucocorti-
coid (GC) long-term over-secretion will increase glucose and lipid
metabolism, leading to stress-induced hyperglycemia or stress diabetes
(Siddiqui et al., 2015). There is an emerging evidence that psycholo-
gical stress factors play a role in the pathogenesis of diabetes: a variety
of negative psychosocial factors have (for the most part) been shown to
increase the risk of diabetes in initially healthy population (Hackett and
Steptoe, 2016). Increasing fatty acids and ketone body in blood also
increases the body's susceptibility to metabolic diseases (Du et al.,
2018; Sikder et al., 2018). Stressful life events will reduce insulin se-
cretion, increase blood glucose, and ultimately deteriorate into diabetes
(Rains and Jain, 2011). Negative emotions or mental disorders may
increase obstacle of blood glucose control and complications of diabetes
(van Donkelaar et al., 2014). Besides, high levels of protein metabolism
will force the body to undergo negative nitrogen balance (Schutz, 2011;
Tipton, 2011) and damage physiological functions. Moreover, in-
creasing epinephrine related to emotional stress will weaken the anti-
acid function of gastrointestinal mucosa and hydrogen ions reverse
dispersion thus increase susceptibility to gastric ulcer (Fomenko et al.,
2014). Taken together, it is highlighted that emotional stress will lead
M.-H. Pan, et al.
to disorder in energy metabolism in accordance with the excessive heat
concept of “Huo”. Under this “Shanghuo” state, the disordered glucose,
lipid and protein metabolism will result in the increased susceptibility
towards various kinds of metabolic diseases.
The relationship between emotional stress and obesity rates has
drawn much attention in recent years. Obesity and “Shanghuo” are
mutually causal and mutually reinforcing. Obesity is gaining accep-
tance as a serious primary health burden that impairs the quality of life
due to its associated complications, including diabetes, CVD, cancer,
asthma, sleep disorders, hepatic dysfunction, renal dysfunction, and
infertility (Masters et al., 2013). It is known that negative emotion,
especially depression, anxiety and pressure, will significantly affect the
appetite, lead to emotional over-eating and then promote risk to obesity
(Luca et al., 2015). It can be ascribed to stress acted on the ingestion
center neurons in hypothalamus (Kakoschke et al., 2015; Ulrich-Lai
et al., 2015). Furthermore, chronic stress response not only acts on the
brain's nervous system and indirectly affect metabolism by control
people's dietary behavior (Didarloo et al., 2014), but also directly affect
metabolism by affecting glucose and lipid metabolism. For example,
persistent stress will induce energy storage through the release of glu-
cocorticoids and neuropeptide Y (Savini et al., 2013), so that the body is
under a “Shanghuo” status of disordered energy metabolism, leading to
obesity (Rabasa and Dickson, 2016). In the previous study, we dis-
covered that the blood insulin levels and glycogen synthesis ability of
mice significantly reduced after 20 h' restraint stress. While after glu-
cose loading, the blood glucose levels increased due to the decreased
blood glucose clearance rate (Chen et al., 2011b). In addition, we ob-
served that the impact of lipid metabolism under emotional stress also
appears the same situation: the lipase activity was significantly lower in
mice loaded with restraint stress, meanwhile the clearance rate of
plasma triglyceride was significantly reduced after the Intralipid
(emulsion used for clinical injection) administration (He et al., 2009a).
These results indicated that stress directly affected the body's glucose
metabolism and lipid metabolism, and the decreased body's glucose
metabolism and lipid metabolism will raise the risk of lifestyle-related
diseases such as type II diabetes, hyperlipidemia and obesity. Since only
a few people related these symptoms with “Shanghuo”, the mentioned
indicators like glucocorticoids and neuropeptide Y levels as well as li-
pase activity are considerable to deem as clinical manifestations of
emotional stress-induced “Shanghuo”.
Chinese people, based on the TCM concept, classify foods that are
roasted, fried, high in fats or sugars as Hot foods, and believe that ex-
cessive intake can cause “Shanghuo” (Zhao et al., 2009). Likewise, these
Hot foods are also included in the World Health Organization's list of
unhealthy foods that cause sub-health. Excessive intake of these Hot
foods will bring about the “Shanghuo” or sub-health status and thus
affect the susceptibility to metabolic diseases. People under pressure
prefer to eat baked, fried, high sugar, fat and other Hot foods which can
easily form hydrogen bonds with water, releasing too much energy and
free radicals, as a result lead to “Shanghuo” (Zeng, 1997). It was
showed that the “Huo” of spleen and stomach as well as the “Huo” of
liver can significantly affect the body's energy metabolism (Yang,
2011). Recently, some researchers explore the relationship between
“Shanghuo” and intestinal microflora from the perspective of energy
metabolism and mucosal immunity (Pan et al., 2015). They concluded
that people suffering from “Shanghuo” have problems of energy me-
tabolism and disorders of mucosal immunity. Impaired intestinal mu-
cosal immune function leads to inflammatory state, which causes im-
balance of gut microflora, changes the ecological balance of intestinal
flora and affects the absorption of nutrients. In the epidemiology, it is
also found that with the increase of life pressures, chronic stress such as
diet and sleep irregularity will elevate the incidence of gastric ulcer and
simple obesity (Zhang et al., 2012). Accordingly, we found western
medicine clues in illustrating the diet factor of “Shanghuo” in TCM,
marked that “Shanghuo” can be explained as metabolism and mucosal
immune disorders which increase susceptibility to metabolic diseases.
One of the reasons for the increased susceptibility to diseases is
also the reduction in the immunological status under the emo-
tional “Shanghuo”. Emotional “Shanghuo” will reduce the immunity,
increase the susceptibility to viral diseases and tumor. Immune function
and neuroendocrine regulation are closely related to stress, and in-
hibited immunity will increase the incidence of viral infections and
cancer (Benaroya-Milshtein et al., 2011). Virus-infected diseases belong
to the category of Warm-Disease (温病) (epidemic diseases) in TCM and
“attacked by pestilential qi (疫气) (infectious and pathogenic patho-
gens) " in the study of TCM pathogeny. In TCM theory, “Shanghuo”
significantly influences the occurrence and development of “warm-
disease”, while in western medicine, emotional “Shanghuo” increases
the susceptibility to virus infection is interpreted as negative emotions
such as tension, anxiety and depression will significantly lower the
immunity, improve the herpes virus recurrent infection rate and in-
fluenza virus susceptibility (Chen et al., 2017a). Our preliminary find-
ings indicated that restraint stress enhances the body's sensitivity to
influenza virus, aggravates the infection rate of influenza virus and
upregulates the amount of influenza virus in the body, thus accelerates
the occurrence and development of influenza subsequent pneumonia as
well as increases the incidence rate and mortality (Tang et al., 2014; Cai
et al., 2015). Under the long-term stress load, sustained harmful stimuli
will gradually deplete the body's resistance, affect the internal en-
vironment balance (Cohen et al., 2007), weaken the immune system
and increase the viral infection risk (He et al., 2011b) through trig-
gering the fatigue (Silverman et al., 2010). Results of other studies
manifested signs of immune disturbance in patients with chronic fa-
tigue syndrome, especially in the form of elevated proinflammatory
cytokine levels (Patarca-Montero et al., 2001; Patarca, 2001), such as
IL-6 and TNFα in serum and cerebrospinal fluid (Straus et al., 1989;
Borish et al., 1998). Above evidences have expounded the theory of
“attacked by pestilential qi (疫气) (infectious and pathogenic patho-
gens) " with decreased immune function. However, apart from occur-
rence, the latency and relapse of viruses are also of great importance in
the study of viral diseases. Further researches about emotional
“Shanghuo” facilitating latency and relapse of viruses is of priority.
Among the researches of susceptibility to neoplastic disease, psy-
choneuroimmunology study demonstrated that stress-induced stress
response promotes tumor growth and decreases patient survival by
inhibiting immune function in patients with breast cancer (Zhao and
Cheng, 2013). Besides, emotional “Shanghuo” with emotional over-
reaction often results in staying up late (Bassett et al., 2015), and
staying up late was regarded as a 2A-level carcinogenic factors in 2007
by the World Health Organization. Although the view that staying up
late is carcinogenic remains controversial, the turmoil in biological
clocks caused by staying up late can prompt cancer was proved in an-
imal experiments. Without turning off the lights at night or frequent
changes in the long-term load not only affect the tumor blood flow, but
also significantly promote tumor growth (Hori et al. 1992, 1995). Re-
cent years, the role of the light-biological clock in the treatment of
cancer and critically ill patients has drawn much attention and has been
extensively studied and practiced (Annane, 2016). In our common
knowledge, cancer is caused by a gradual accumulation of genetic
mutations, but today an idea shows that the declining immune system is
another important factor that triggers an increase in the incidence of
cancer (Palmer et al., 2018). In addition to the decreased levels of
immunity in stress state, it is also suggested that elevated corticotropin-
releasing hormone (CRH) concentrations are closely linked to increased
susceptibility towards some diseases (Sapolsky et al., 1987). Increased
CRH secretion allows viral genes and oncogenes to promote viral re-
plication and oncogene transcription through the activation of proo-
piomelanocortin transcription factors, thereby increasing human sus-
ceptibility to certain diseases.
Emotional “Shanghuo” can affect body fluid metabolism and
vascular function, and further increase the susceptibility to CVD.
“Shanghuo” and stress response often come with dry mouth and eyes,
M.-H. Pan, et al.
dry stool and other dryness symptoms by influencing intracellular and
extracellular ion concentrations, as well as reducing exocrine gland
osmotic pressure and excretion volume, which eventually affect the
secretion of saliva, sweat, tear, digestive juice, etc. (Su and Sun, 2015).
These phenomena are related to sympathetic activity and acetylcholine
levels under environmental changes or stress (He et al., 2013). What's
more, changes in body fluids also directly affect the circulatory system
and urinary system, increasing the susceptibility to CVD and nephro-
pathy (Bedogni et al., 2003). It is claimed that essential hypertension is
a multifactorial disease not only genetically related but also closely
linked with obesity, smoking, alcoholism and stress caused by stressful
and unhealthy habits (Ushakov et al., 2016). Additionally, stress-in-
duced abnormal increase of angiotensin II controlled by neuroendo-
crine system, is generally accepted as an potential attribution to es-
sential hypertension (Markou et al., 2015). Therefore, the articles
revealed the relationship that “Shanghuo” related hydropenia will mess
the circulatory system and urinary system and increase susceptibility to
CVD, which indicated that “Shanghuo” people are liable to suffer from
CVD (Munakata, 2018).
Through the HPA axis, negative psychological stress not only alters
the plasma lipoprotein level (Vries et al., 2017), but also adversely af-
fects peripheral vascular endothelial function (Chen et al., 2017b), in-
creasing the risk of CVD. Chronic stress promotes vascular endothelial
cell senescence while increasing the formation of atherosclerotic pla-
ques (Lagraauw et al., 2015), which thereby facilitating the incidence of
coronary heart disease and myocardial infarction. In addition, the in-
flammatory response caused by chronic stress can easily induce myo-
carditis, then further leads to myocardial ischemia (Hammadah et al.,
2018). Emotional stress stimulates the secretion of CA and then pro-
motes coagulation ability, therefore increases the incidence of throm-
bosis and disseminated intravascular coagulation (Stampfli et al.,
2014). The trend of younger age groups in patients with CVD is also
related to the emotional stress caused by the growing social environ-
ment pressure (Bertuccio et al., 2011). Nevertheless, further studies in
exploring the indicators of endothelial cell senescence and defining the
level of CA, CRH and other hormones that can indicate abnormalities
are of vital necessity in diagnosing “Shanghuo” and preventing CVD.
In addition to HPA axis and SNS pathways innervate patholo-
gical changes, a variety of stress-induced oxidative stress that in-
hibit cellular immune responses are also relevant to “Shanghuo”
and disease susceptibility. Oxidative stress is caused by the excessive
production of reactive oxygen species (ROS), or dysfunction of anti-
oxidant defense system when suffers various stimuli, and finally results
in the oxidative damage of cells and tissues by increasing of free radi-
cals in vivo. It is suggested that psychological stress is associated with
increased oxidant production and oxidative damage. Thus, long-term
exposure to psychological stressors may increase the risk of many dis-
eases (Hayashi and Cortopassi, 2015).
Oxidative stress in different parts of body can lead to increased
susceptibility in different diseases, such as neurodegenerative diseases
(Moniczewski et al., 2015), CVD (Polimeni et al., 2015), diabetes
(Kayama et al., 2015), etc. For effects on the brain, there are some
studies about chronic restraint stress-induced peroxidation injury of
nerve cells, causing learning and memory impairments or forgetfulness
(Wang et al., 2014). Additionally, oxidative stress plays a significant
role in the pathogenesis of Alzheimer's disease (Chen and Zhong, 2014).
Moreover, a recent study found that mood affects the circadian rhythms
of the brain and tissues, and thus disorders the rhythmic transcription
of genes linked with susceptibility to at least 140 diseases (Mure et al.,
2018). As for the effects on the metabolism and digestive system, oxi-
dative stress increases susceptibility to obesity, obesity per se in turn
induces systemic oxidative stress through various biochemical me-
chanisms, such as superoxide generation from NADPH oxidases, oxi-
dative phosphorylation, glyceraldehyde auto-oxidation, protein kinase
C activation, and polyol and hexosamine pathways (Manna and Jain,
2015). There are some other factors that contribute to oxidative stress
in obesity including low antioxidant defense, chronic inflammation,
and postprandial reactive oxygen species generation (Rajendran et al.,
2014). In addition, emotional consumption of high-calorie foods in
large quantities leads to excessive energy intake and disturbance of
metabolic environment in the body and induces intestinal “Shanghuo”-
like inflammation through oxidative stress (Qiao, 2014). About the ef-
fects on the vessel, emotional stress will evoke the occurrence of oxi-
dative stress damage and then vascular dysfunction, which eventually
leads to increased susceptibility of CVD like stroke and renal vascular
disease (Siti et al., 2015). Other than the above, oxidative stress in
immune cells directly damages the body's immune function and leads to
more diseases and disorders (Maes, 2009) like chronic intestinal in-
flammation (Leonardi et al., 2018). Although the researches above
declared that emotional stress itself and emotion-induced overeating
will evoke “Shanghuo”-like inflammation, CVD and neurodegeneration
diseases, understanding specific origin of ROS in accordance with
“Huo” in TCM theory is a new challenge for the modernization of
“Shanghuo”.
3.3. Molecular biology mechanisms of emotional “Shanghuo” increased
disease susceptibility
Since it has been widely accepted that adverse psychological factors
will lead to sub-health, increase susceptibility to various diseases and
thus affect human physiological health. Studies on the mechanism of
“Shanghuo” caused by emotional stress have also made some pro-
gresses, and emotional “Shanghuo” is undoubtedly regarded as the re-
sult of mental factors affecting on the body homeostasis.
The authors studied the relationship between “emotional stress” and
“susceptibility to diseases” using restraint stress mouse model, and
claimed that emotional stress provokes unspecific responses of neuro-
transmitters such as histamine, serotonergic and dopaminergic neuro-
transmitters (Abe and Kurihara, 2011), and then induce a marked in-
crease in the level of plasma corticosterone (Li et al., 2012).
Simultaneously, it is discovered that after restraint stress load, the mice
will appear an immune-disable-process, leading to the increased sus-
ceptibility to diseases such as bacterial or viral infections and cancer
(Tang et al., 2011). In the study of susceptibility to influenza virus
under restraint stress conditions, restraint stress increases the plasma
corticosterone content, as a result upregulates the expression level of
Mitofusin-2 (MFN2) and inhibits the antiviral signaling pathway of
mitochondria antiviral signaling protein (MAVS), which leads to the
increase of influenza susceptibility in the body (Chen, 2015). Likewise,
we also found that the increase of GC caused by restraint stress will
create more glucocorticoid-glucocorticoid receptor compound, which
transfers into cell nucleus and downregulates the function of SIRT3,
subsequently leads to the peroxidation of free fatty acid (Wang et al.,
2018) and inhibition of autophagy (Li et al., 2018), ultimately increase
the susceptibility to diseases like non-alcoholic fatty liver disease and
Senility. Other than the alterations of hormone levels, our previous
study showed the restraint stress-mediated inhibition of glucose trans-
porter1/3 expression will result in less transport of glucose through the
blood-brain barrier, whereafter the meditated activation of lactate de-
hydrogenase will lead to the release of lactic acid and then break the 5-
HT/DA balance which finally increases the susceptibility to central fa-
tigue (Li et al., 2015).
Otherwise, there are some stress-induced molecules such as free
radicals involved in the pathogenesis of emotional “Shanghuo”. They
will attack the unsaturated fatty acids in the bio-membrane and lead to
lipid peroxidation, which evokes the destruction of fatty acid chains
thereby damaging cell membrane and biological macromolecules of
living organisms. What's more, the degradation products of lipid per-
oxidation like 4-HNE and MDA, will also twist the physiological func-
tion of cells through forming crosslink between proteins and DNA
(Gaschler and Stockwell, 2017). The authors, in previous studies, con-
firmed that stress-induced loss of immune function in experimental
M.-H. Pan, et al.

animals was associated with a significant increase of lipid peroxidation
levels in immune cells (Pu et al., 2012). Immune cells are sensitive to
oxidative stress due to quantities of poly unsaturated fat acids that
regulate their homeostasis (Marion-Letellier et al. 2015). Hence, the
ROS generated by stress load may inhibit the immune function of
natural killer cells, T cells, and other immune cells (Duan et al., 2016),
significantly decrease the index of immune organs and the total number
of spleen lymphocytes in mice (He et al., 2009b), as well as suppress the
phagocytosis function of peritoneal macrophages (Li et al., 2012). The
products of oxidative stress injury in immune cells significantly in-
creases, and oxidation capacity significantly reduces (He et al., 2011b).
Besides, the authors demonstrated that mitochondrial dysfunction in
immune cells caused by stress load triggers an excessive release of
H2O2, indicating the occurrence of cellular oxidative stress, which re-
sults in apoptosis or necrosis (Li et al., 2015), and finally decreases the
number of immunocytes and diminishes the activity of immune

Fig. 3. The mechanisms of emotional

“Shanghuo” increased disease sus-
ceptibility
As emotional stress response can partly
explain the pathology of “Shanghuo”,
we adapt emotional stress as a model of
emotional “Shanghuo”. Under the
emotional stress, alteration in many
signal pathways are involved, which
will lead to the increase of disease
susceptibility. In the brain, emotional
stress will inhibit the expression of
GLUT1/3, making brain lack of glu-
cose, simultaneously, it will activate
LDH which increases the level of Lactic
acid through anaerobic respiration
when the brain is lack of nutrition, and
then breaks the balance of 5-HT/DA,
eventually leads to central fatigue, in-
creases the susceptibility to some cen-
tral nervous diseases. In the body,
emotional stress will active the HPA
axis and increase the release of gluco-
corticoids. The glucocorticoids (GCs)
will combine with glucocorticoid re-
ceptors (GRs), and this compound will
induce several kinds of process related
to diseases. The GC-GR compound will
activate MFN2, and the activation of
MFN2 will inhibits MAVS, then inhibits
the following activation of IFR3 and
release of IFN-β, so that increasing the
susceptibility to virus. In addition, the
GC-GR compound can translocate into
the nuclei, impact the gene expression,
downregulate the level of SIRT3, a mi-
tochondrial protein deacetylase, and
then inhibit the following deacetylation
of LCAD and phosphorylation of APMK,
which increase the susceptibility to
metabolism diseases like NAFLD and
Senility. With the dysfunction of mi-
tochondria and attack from exogenous
stress, the production of ROS is on the
rise, excessive ROS will attack the
plasma membrane with PUFAs, lead to
lipid peroxidation, and increase the
toxic metabolites of PUFA-OOH such as
4-HNE and MDA, which induce cell
death and increase susceptibility to
several diseases. AMPK: AMP-activated
protein kinase; DA: dopamine; GLUT1/
3: glucose transporter1/3; GRE: gluco-
corticoid response element; HPA axis:
hypothalamic-pituitary-adrenal axis;
IKK: IκB kinase; IκB: inhibitor of NF-κB;
IFN-β: interferon beta; IRF3: interferon
regulatory factor 3; LCAD: long-chain
acyl coenzyme A dehydrogenase; LC3: microtubule-associated protein light chain 3; LDH: lactate dehydrogenase; MAVS: mitochondrial antiviral-signaling protein;
MDA: malondialdehyde; MFN2: mitofusin-2; NAFLD: non-alcoholic fatty liver disease; NF-κB: nuclear transcription factor-kappa B; PE: phosphatidylethanolamine;
PUFAs: polyunsaturated fatty acids; RIG-I: retinoic acid-inducible gene I; SIRT3: sirtuin 3; STING: stimulator of interferon genes; TBK1: TANK binding kinase 1; 4-
HNE: 4-hydroxynonenal; 5-HT: 5-hydroxytryptamine.

Table 1
Representative herbal tea formulae from TCM and their pharmacological actions on “Shanghuo”.
Name Original Plant names in ingredients
Name
Guangdong Herbal Tea 广东凉茶 Ilex asprella (Hook. & Arn.) Champ. ex Benth. (folium),
(GHT) (王老吉凉 Oroxylum indicum (L.) Kurz. (semen), Polygonum
Wanglaoji Herbal Tea 茶) chinense L. (herba), Desmodium styracifolium (Osbeck)
Merr. (herba), Microcos paniculata L. (folium),
Lophatherum gracile Brongn. (folium), Lygodium
japonicum (Thunb.) Sw. (spore), Vitex negundo L.
(fructus), Helicteres angustifolia L. (radix), Rosa
laevigata Michx. (radix)
Boat-Fruited Sterculia 胖大海凉茶 Sterculia lychnophora Hance (semen), Glycyrrhiza
Seed Herbal Tea uralensis Fisch. (radix), etc.
Compound Isatis Root 复方板蓝根 Isatis tinctoria L. (radix), Chrysanthemum abolinii
Herbal Tea 凉茶 (Kovalevsk.) H.Ohashi & Yonek. (flos), Lonicera
japonica Thunb. (flos), Prunella vulgaris L. (spica),
Glycyrrhiza uralensis Fisch. (radix), Crataegus
pinnatifida Bunge (fructus), Mesona chinensis Benth.
(herba), etc.
Shaxi Herbal Tea 沙溪凉茶 Ilex asprella (Hook. & Arn.) Champ. ex Benth. (folium),
Spilanthes acmella (L.) L. (herba), Syzygium jambos (L.)
Alston (velamen and fructus), Clerodendrum philippinum
Schauer (radix and folium), Solanum surattense Burm.
f. (herba), etc.
Deng's Herbal Tea 邓老凉茶 Lonicera japonica Thunb. (flos), Chrysanthemum
abolinii (Kovalevsk.) H.Ohashi & Yonek. (flos),
Imperata cylindrica (L.) Raeusch. (rhizoma), Morus alba
L. (folium), Taraxacum mongolicum Hand.-Mazz.
(capitulum) and Glycyrrhiza uralensis Fisch. (radix),
etc.
Huang Zhenlong's Herbal 黄振龙凉茶 Chrysanthemum abolinii (Kovalevsk.) H.Ohashi &
Tea (Bansha Herbal (斑砂凉茶) Yonek. (flos), Lonicera japonica Thunb. (flos), Morus
Tea) alba L. (folium), Lophatherum gracile Brongn. (folium),
Plantago depressa Willd. (herba), Ophiopogon japonicus
(Thunb.) Ker Gawl. (radix), Lysimachia christinae
Hance (herba), Platycodon grandiflorus (Jacq.) A. DC.
(radix), Houttuynia cordata Thunb. (herba), Imperata
cylindrica (L.) Raeusch. (rhizoma), etc.
24-Flavour Herbal Tea 二十四味茶 Ilex asprella (Hook. & Arn.) Champ. ex Benth. (folium),
Helicteres angustifolia L. (radix) Microcos paniculata L.
(folium), Morus alba L. (folium), Schefflera octophylla
(Lour.) Harms (velamen, bark, radix and folium),
Sapindus mukorossi Gaertn. (semen), Lophatherum
gracile Brongn. (folium), etc.
Function
Used for diseases or disorders like cold,
fever, sore throat, dampness-heat diarrhea,
xerostomia and oliguria
Treatment of disorders and diseases like sore
throat especially hoarseness and loss of
voice, cough, headache, constipation and
slow fecal transit
Treating disorders or diseases such as, oral
ulcer, virus infection syndrome (cold, fever,
cough, etc.)
Used for disorders or diseases like sleepy,
hyperpyrexia, cold, cough, laryngitis (sore
throat, hoarse voice, etc.)
Prevention and treatment for diseases like
flu, fever, sore throat, etc.
Prevention of heat pattern, removal of
dampness, treatment of acne, cold, fever and
sore throats
Prevention and treatment of cold, heliosis.
Resolve summer-heat, removing indigestion
and dampness
M.-H. Pan, et al.
Pharmacological activity and the effects on cellular and Ref
physiological functions
Antimicrobial effect, anti-inflammatory effect, diuretic (Ye et al., 1993; Bao et al., 2008a,
effect at low dose, accelerate gastrointestinal emptying, 2008b; Hu et al., 2008; He et al.
reduce lung and bronchial perfusate flow, improve the 2010, He et al., 2011a)
immunity by adjusting the Tc/Th ratio and increasing
the secretion of IL-2, protect against stress-induced
liver injury, and relieve heat shock, the protection
effect against oxidative stress in stress-loaded
organisms; maximum tolerance is 220 times of clinical
oral dose.
Anti-inflammatory effects in administration of ear (Xia et al., 1996; Ye and Zhang,
edema model in mice. There is also a certain degree of 1996; Ai et al., 2012, Li, 2015)
analgesic and antibacterial activity, which is non-toxic,
and the mutagenicity test results do not show
mutagenicity.
Anti-inflammatory, anti-oxidant effects, anti-virus, (Chen et al., 2011a; Xiao et al.,
anti-bacterial and anti-endotoxin effects. Increase 2014; Ping et al., 2016)
immune function such as spleen index, number of
leukocyte and lymphocyte as well as phagocytosis of
macrophage
Bacteriostatic, anti-inflammatory, anti-influenza virus, (Chakraborty et al. 2004, 2010;
analgesic, antispasmodic and antipyretic activities. Liu et al., 2006; Dubey et al.,
Studies also have shown there is no lethal effect on 2013)
zebrafish under therapeutic dose
Anti-inflammatory, anti-microbial, anti-oxidative (Wan et al., 2007; Deng et al.,
effects. Significantly improve the sub-health symptoms 2011)
in various systems such as boosting immunity.
Mutagenic security in mammals is standard
Anti-inflammatory, anti-oxidative, and anti-bacterial (Fan et al., 2002; Xian and Hang,
effects. Does not show mutagenicity and safe to drink 2005; Deng and Yang, 2013)
Anti-inflammatory and anti-oxidative effects. (Dufay et al., 2014; Lin et al.,
Accelerate gastrointestinal emptying, inhibit 2015)
Cytochrome P450 3A4 in vitro
M.-H. Pan, et al.
function (Duan et al., 2013). Except for immune cells, the lipid perox-
idation will detriment the biology of other types of cells like neurons
through similar mechanisms and increase the susceptibility to certain
diseases (Bradley-Whitman and Lovell, 2015; Liu et al., 2015; Islam,
2017) (Fig. 3).
The fluctuation of bio-indicators mentioned above, such as GC,
SIRT3, MAVS, MFN2, 4-HNE, MDA, etc. was reasonable in manifesting
“Shanghuo”, and was used in the further efficacy study of CMM. While
emotional stress response is a comprehensive process, and detection of
these indicators is not enough in explaining the true state of
“Shanghuo”. Thus, establishing more emotional stress models, finding
more signaling pathways in emotional stress, and setting more specific
parameters to explain the complexity of emotion are future topics for us
to resolve.
4. The intervention of “Shanghuo” through CMM
The concept of sub-health was put forward by the former Soviet
Union scholars in 1980s (Castelnau et al., 1998), while the idea of
preventive treatment of diseases in TCM and the treatment of
“Shanghuo” or other subtypes of Weibing own the history for thousands
of years (Wang et al., 2017). However, there is still lack of modern
medicine researches of SHS on effective prevention and treatment, and
the advantages of TCM in prevention and treatment of disease is
highlighted.
Chinese Materia Medica (CMM), an ancient method of treatment
which has been used for thousands of years, is getting more and more
attention by the world. Specific to emotional “Shanghuo” status, TCM
advocated the idea of emotion adjustment and pressure releasing (He
and Hiroshi, 2008). However, continuous and excessive mental pres-
sure and emotional stimulus will cause dysfunction of body, then
complex and comprehensive clinical syndrome. Therefore, it is neces-
sary to target the special symptoms and apply the corresponding food or
drug therapy. Many CMM have long been used for safeguarding health
and delaying the onset of senility, as like the Ayurveda, the traditional
Indian medicine (Gokani, 2014). Basing on the holistic approach to
health in TCM, with the frequent changes in human disease spectrums,
multicomponent drugs have attracted increasing attention from the
mainstream international medical community. CMM has been deemed
as one of the best choices on treating complex chronic diseases (Wang
et al., 2012). Since “Shanghuo” is a kind of Yin-Yang imbalance status
disrupted by different stressors, and the stress response is not triggered
by a single mechanism but a complicated process involves multiple
systems inside the organism. Thence, it is difficult to treat or improve
“Shanghuo” with the help of only one system within the body. Based on
multi-component treatment, CMM is one of the most important treat-
ments for “Shanghuo” syndrome which includes a complex and com-
prehensive clinical syndrome. For example, people living in the
southeast region of China, usually consume a kind of health drink to
prevent or eliminate “Shanghuo” syndrome (Ke et al., 2012).
This kind of herbal tea is often called Liang (cool) tea (凉茶) at
Lingnan (岭南) (southeast region of China) region, which has the effect
of nourishing Yin and consolidating the body energy. It can be used to
Xie-Huo (泻火) (adapt to the disorders in homeostasis or release pa-
thological fire) (see Glossary) and to protect against “Shanghuo”
syndrome in TCM (He et al., 2010). Similar to the concept of Xie-Huo,
western medicine scholars have proposed the concept of adaptogenic,
and adaptogens which have the characteristic of adaptogenic, are
stress-response modifiers that increase an organism's nonspecific re-
sistance to stress by increasing its ability to adapt and survive
(Panossian, 2017). Both the Liang (cool) tea and adaptogen own the
characteristic of Fu zheng culture (扶正文化) (strengthening the body
resistance or strengthening vital Qi) in Chinese medicine, suitable for
features of “adaptability to diversity".
And the most popular Liang (cool) tea is Guangdong herbal tea
(GHT), a branch of Lingnan herbal tea, it is also named Wanglaoji
herbal tea (王老吉凉茶) with over 200 years of history (He et al., 2010).
Our pharmacological activity researches on GHT had revealed that it
has protective effects on lowered immunocompetence, disturbances of
lipid and glucose metabolisms, and organs dysfunctions caused by
stress (He et al., 2008a; He et al., 2008b; Li et al., 2010; He et al.,
2011a). Experiments had also showed that GHT can alleviate lipid
peroxidative status and keep the balance of free radicals and anti-
oxidants inside organisms. Therefore, the mechanism of GHT in im-
proving stress-loaded status can be related to the regulation of anti-
oxidation-oxidation balance of organisms, alleviation of oxidative stress
in cells, and improvement of stress condition so as to achieve Xie-Huo.
Recent researches on adaptogens like herbal extracts also noted the
molecular mechanism in adapting to disorders and increasing resistance
to nonspecific stress response through anti-inflammatory (Panossian
et al., 2019), regulating hormone (Panossian et al., 2018), meditating
molecular chaperons and kinases (Panossian and Wikman, 2009), etc.
In depth research on the comparison of CMM and adaptogens is of great
help for analyzing the scientific connotation of this TCM treatment.
With the increase of social pressure and the improvement of people's
health consciousness, Liang (cool) tea, represented by Guangdong
herbal tea or Wanglaoji, has a large share of the beverage market in
China. Except for GHT, the other common health drinks of CMM for
Xie-Huo such as green tea (Chopade et al., 2008; Yiannakopoulou,
2013), chrysanthemum tea (Kong et al., 2006; Wu et al., 2011), Lonicera
japonica tea (Shang et al., 2011; Chen et al., 2013; Pi et al., 2015), etc.
also significantly improve the immune activity or the antioxidative
activity. Some of the well-known and representative herbal tea for-
mulae were developed into health drinks sold in the market, many
pharmacodynamics and safety studies are also performed (Table 1).
In TCM, multicomponent prescriptions are usually used for treating
diseases. Therefore, complex interactions, such as additive, synergistic,
suppressive and antagonistic interactions are involved in the activities
of the component herbs. These interactions are considered essential in
improving their therapeutic potentiality and reducing the side effects of
certain toxic ingredients. However, the underlying molecular me-
chanism is waiting to be clarified for routine usage of TCM treatment.
Setting emotional stress-induced “Shanghuo” as an breakpoint, the
authors deeply and systematically studied the relevance and correlation
between the emotional stress and diseases susceptibility. It is found that
the antioxidation-oxidation imbalance is one of the biomedical foun-
dations of the emotion-induced disorders in TCM, and it provides a
modern biomedical explanation for the TCM theory of psychogenic
disorders (Ou et al., 2003). Therefore, stressor-mediated oxidative
stress is similar with the “Shanghuo” status or SHS in terms of the
disease initiating stage. Of all the stress models, restraint stress, a model
that may mediate psychological or emotional stress response, seems to
be a more reliable model of the “Shanghuo” status defined by the TCM
theory, and we also call this model "disease susceptibility model". Based
on the accomplishment on the research of traditional “Shanghuo”
theory and model building on the long-term practice results of mutual
corroboration between TCM theory and the efficacy of CMM, the ap-
plication of "disease susceptibility model" is beneficial to reveal the
mechanism of action of CMM and the theory basis of TCM. We used
“disease susceptibility model” to evaluate the efficacy of CMM and the
whole research idea is: (1) reveal the relationship between stress load
and disease occurrence from both animal and cellular level by using
stress load to build disease susceptible animal models; (2) on this basis,
evaluate the role of CMM in preventing and treating diseases by
maintaining the homeostasis of the body; (3) then conduct research on
mechanism of action and target (Fig. 4). Under the guidance of the
above idea, the authors effectively evaluated the efficacy of Chinese
medicine prescriptions and Chinese patent drugs such as KangBingDu
(KBD) oral liquid (抗病毒口服液) (Chen et al., 2017a), Renduning (热毒
宁) (Tang et al., 2014), etc. Except for the multicomponent formula, the
effects of some Chinese herbal monomers like Sarcandra glabra (Thunb.)
Nakai extract (SGE) (Cao et al., 2012), Schisandra (Schisandra chinensis
M.-H. Pan, et al.
(Turcz.) Baill.) lignans (Tang et al., 2011) Anthocyanins of bilberry
(Vaccinium myrtillus L.) (Li et al., 2013), Flavonoids from Herbal Lo-
phatheri (folium of Lophatherum gracile Brongn.) (Lin et al., 2010),
Baicalein (a flavonoid from Scutellaria baicalensis Georgi) (Lee et al.,
2013), Theacrine (a Purine Alkaloid Obtained from Camellia assamica
var. kucha H.T.Chang, H.S.Wang & B.H.Chen) (Li et al., 2015), In-
dirubin (Jie et al., 2017) and Epigoitrin (Luo et al., 2019) (alkaloids
from Isatis tinctoria L.) were also studied using the “disease suscept-
ibility model” of restraint stress. In the articles above, the indicators
mentioned in the previous chapters such as serum cortisol level, MDA
level, cell viability of NK cells, etc. are tested to evaluate the efficacy of
CMM in decreasing disease susceptibility, however, it is hard for us to
identify the type of emotions under emotional stress with current
methodologies and standards.
5. Conclusions and future perspectives
Disease susceptibility as a concept related to the causation of dis-
eases (Kunitz, 2002), is getting more and more attention currently.
Although there are some studies in modern biomedicine on the biolo-
gical mechanism of disease susceptibility, they mostly focus on the
research of susceptible genes related to a few parts of the people (Jiang
et al., 2016; Lin et al., 2016; Rubattu et al., 2016; Jia et al., 2017; Sun
et al., 2017; Zhou and Haina, 2017; Ebrahimiyan et al., 2019). How-
ever, for individuals with the same genotype, the susceptibility to the
same disease is also different under different emotional states or other
stressors. In the sight of TCM, “Shanghuo”, an assemble of non-specific
reactions towards stress like emotional stress, is a Yin-Yang imbalance
state which Yang dominates, and Yin-Yang imbalance as the core of
diseases’ causation in the TCM theory, was deemed as an important
factor in increasing disease susceptibility according to the above in-
troduction. Thus, it provides a novel perspective in researching disease
susceptibility with factors other than gene polymorphism as well as
understanding correlations between disease susceptibility and emotion
state or other stressors in the future.
Since we mentioned “Shanghuo” has correlations with disease sus-
ceptibility, treatments towards “Shanghuo” is of vital importance. Of all
the treatments, the TCM idea of “prevention treatment of disease” is at
Fig. 4. The whole research idea of the “disease
susceptibility model” to evaluate the efficacy
of CMM
This review combines with the advantages of
Traditional Chinese Medicine (TCM) and modern
biomedicine. Basing the relevance to and corre-
lations between “Shanghuo” symptoms from TCM
theory and diseases susceptibility from the per-
spective of modern medicine, we can reveal the
relationship between stress load and disease oc-
currence from whole animal and cellular level
using stress load, and establish disease susceptible
animal models. From this model, we can evaluate
the role of Chinese Materia Medica (CMM) in
disease prevention and treatment. And conduct
research on mechanism of action and target,
which provides a new thinking for the treatment
of complex diseases that western medicines are
unable to treat. HPA axis: hypothalamus-pituitary-
adrenocortical axis; ANS: autonomic nervous
system.
the center of the process. In the view of TCM, the idea of “prevention
treatment of disease” shows that prevention is more important than
therapy (Liang and Yin, 2010; Fan et al., 2018), some recent researches
also reveals prevention treatment such as physical fitness (Kwong et al.,
2015; Alves et al., 2016; Dart et al., 2016; Coletta et al., 2019) and food
therapy (Piemontese, 2017; Bajaj and Manchanda, 2019; Yao and Wu,
2019) are of great effect in preventing various kinds of diseases. “Pre-
venting diseases before it occurs” is going to be a hot topic of human's
health and the modernization of TCM through connecting to prophy-
lactic medicine is considerable in the future.
On the other hand, currently, TCM has attracted attention as an
alternative for the treatment of complex diseases that western medi-
cines are unable to treat. CMM treatment as an major therapy in TCM is
now used with canonical western medicine in combined therapy of
complex diseases (Qi et al., 2015; Zheng et al., 2015; Sun et al., 2016).
Although recent researches on adaptogen noted the mechanism of
phytochemicals in strengthening the body which may provide modern
explains for CMM (Liao et al., 2018), the real efficacy and toxicity of
CMM like herbal drinks are unable to be tested adequately using the
present evaluation paradigm for single chemical compounds.
Studies on emotion and “Shanghuo” highlight that psychological
factors such as extreme change of emotion will lead to a non-specific
stress response which is in accordance with “Shanghuo” syndrome (Li
et al., 2002; Gallo et al., 2009; Devanarayana and Rajindrajith, 2010).
The non-specific stress response involves alterations in various systems
which increases susceptibility to diseases. Therefore, we studied
“Shanghuo” and its correlation with disease susceptibility in an emo-
tional stress model, restraint stress, and we used this model to examine
the protective effects of CMM formulae on mental and emotional stress-
induced oxidative stress (Luo et al., 2019), which provides a new
pathway for the modernization of TCM. Recent studies on emotional
stress have used some other models like exposure to ultrasound of al-
ternating frequencies (Pavlov et al., 2019), food restriction (Anversa
et al., 2019) and empty water bottles (He et al., 2019) to investigate the
physiological dysfunctions and increased susceptibility to a certain
disease or evaluate the efficacy of medicines. However, restraint stress
is only one kind of emotional stress model, and some other models such
as exposure to ultrasound of alternating frequencies are acute
M.-H. Pan, et al.
emotional stress models, which cannot simulate chronic emotional
stress in human. What's more, in “The Inner Canon of Huangdi” (黄帝内
经) (a canonical reference of TCM theory), TCM scholars have classified
emotion into five types (joy, anger, anxiety, melancholy, fear) ac-
cording to the Five viscera theory, and each kind of emotion may in-
crease susceptibility to different diseases. Therefore, the recent emo-
tional stress models still cannot thoroughly represent emotional
“Shanghuo”. So, the topic of establishing more emotional stress models
and more specific parameters in defining and classifying “Shanghuo”
should have priority in the further research on disease prevention and
drug evaluation.
All in all, the clinical research and treatment methods of
“Shanghuo” have been increasing year by year, and certain achieve-
ments have also been made in the laboratory related basic researches.
However, due to the complexity of the cause of “Shanghuo” and the
vagueness of the clinical symptoms, there are relatively few scientific
explanations about the pathogenesis of “Shanghuo” and the patho-
genesis and pathological process of related diseases at present. On the
other hand, the necessity of evaluation system for medicine's quality,
safety and efficacy of CMM is increasing rapidly. We can investigated/
tested the canonical parameters of stress response (serum cortisol level
(Wang et al., 2013), MDA level (Gaschler and Stockwell, 2017), cell
vitality of NK cell (He et al., 2011a), etc.) in emotional “Shanghuo”
model of restraint stress, and find its connection with disease suscept-
ibility. Furthermore, we use this model to evaluate whether a Chinese
herb or formula can alleviate stress response so as to prevent diseases.
However, we cannot investigated/tested the specific emotional type of
the stressed animals without specific parameters. Like almost all other
ethnopharmacology, this kind of limitations in clarifying traditional
medicine theory with current methodologies and standards restrict the
development of TCM in the world. Therefore, how to continue further
studies, reveal the biological mechanism of emotional factors or other
stressors on the body, and reduce their harmful effects to the body has
become a widespread concern topic and need an urgent solution.
Contributions
Ming-Hai Pan and Si-Rui Zhu collected the references and drafted
the primary version of manuscript, figures and tables. Wen-Jun Duan,
Xiao-Hui Ma, Xiang Luo and Bo Liu adjusted the main structure of the
manuscript. Jia-Xu Chen and Hiroshi Kurihara provided professional
advice. Rong-Rongong He, Yi-Fang Li, Ming-Hai Pan and Si-Rui Zhu
revised and checked the manuscript.
Declaration of competing interest
The authors have declared that no competing interest exists.
Acknowledgements
This work was supported, in part, by National Key Research and
Development Program of China (grant number 2017YFC1700400,
2017YFC1700404), Natural Science Foundation of China (grant
number 81622050 & 81573675 & U1801284 & 81673709 &
81873209), the Local Innovative and Research Teams Project of
Guangdong Pearl River Talents Program (grant number
2017BT01Y036) and GDUPS (2019), Guangdong Science and
Technology Foundation for Distinguished Young Scholars (grant
number 2017A030306004), Science and Technology Program of
Guangzhou (grant number 201903010062), Natural Science
Foundation of Liaoning Provence (grant number 20170540364) and
Science Foundation from Education Department of Liaoning Provence
(grant number L2015326).
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Glossary
Zhi Weibing (治未病): Also called “preventive treatment of diseases”, and “Zhi” in Chinese
refers to treat or manage. The measures include following the natural laws, regulating
the mind and emotions as well as maintaining the Yin-Yang balance.
Shanghuo (上火): It manifests as some symptoms of heat in the body and belongs to the
category of TCM heat syndrome. In addition to being literally translated as
“Shanghuo”, it is also translated as Excessive Energy metabolism according to dif-
ferences in its nature and perspective in modern medical research.
Qi and Xue (气血): Qi (spirit and pneuma), a material with very strong vitality and ex-
tremely subtle, owns the function of protection and promotion. Xue (blood and en-
ergy) is the red liquid that contains rich nutrition and has nourishing function in the
vessel, both are the basic substances that constitute the human body and maintain life
activities.
Extreme change of Five minds causing Huo (五志过极化火): Five minds not only refer to five
emotions of joy, anger, anxiety, melancholy and fear, but also refer to a variety of
spiritual activities. In TCM theory, the excess of these activities and hyperactivity of
five emotions will induce Qi stagnation then the symptoms of excessive heat invading
the human body.
Pestilential Qi (疫气): Pestilential Qi generally refers to a kind of highly infectious and
pathogenic pathogens, most of which are transmitted through air and contact and
enter the body through the mouth, nose or skin to cause disease.
Xie-Huo (泻火): First presented in “Compendium of Materia Medica” by Li Shi-zhen, a
famous herbalist, is considered to be the core treatment towards “Shanghuo”. It not
only contains the idea of discharging the excessive heat, but also contains the idea of
nourishing Yin, which is the restrictive factor of Yang. In western medicine, it can
also be explained as an adaption towards changes in homeostasis.