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\begin{document}

\title{Traditional Medicine Combination Therapy Is A Promising Strategy for
MRSA Infection}



\author[1]{Bo Wen}%
\author[1]{Xiaoyu Feng}%
\author[1]{Lulu Zhang}%
\author[1]{Li Li}%
\author[1]{Yuwen Xia}%
\author[1]{Weifeng Yang}%
\author[2]{Yung-Chi Cheng}%
\author[3]{Tariq Mahmood}%
\author[1]{Yan Ma}%
\author[4]{Chunyan Jiang}%
\author[1]{Cheng Lu}%
\author[1]{Yong Tan}%
\affil[1]{China Academy of Chinese Medical Sciences}%
\affil[2]{Yale University}%
\affil[3]{Quaid-i-Azam University Faculty of Biological Sciences}%
\affil[4]{Capital Medical University Affiliated Beijing Hospital of Traditional Chinese Medicine}%


\vspace{-1em}



  
  \date{May 30, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Methicillin-resistant Staphylococcus aureus (MRSA) is a superbug that
often causes serious inflammation-related injuries. Host immune defense
against MRSA infection and MRSA immune evasion strategies are the main
mechanisms of these injuries. Conventional drugs, such as antibiotics,
optimized antibiotics and vaccines, can treat MRSA infections, but their
use is limited because of drug-resistance and impairment of immunity.
Traditional medicine (TM) therapies, presently used to address these
unmet clinical needs and treat injuries, are regarded as a potential
solution to combat MRSA infection. This review systematically summarizes
the immune mechanisms of MRSA infection, analyzes the efficacy
characteristics and corresponding mechanisms of conventional and TM
therapies in treating injuries, and discusses the potential advantages
of combined therapy. Furthermore, several appropriate immune
responses-related conditions that could be treated with the combination
therapy were summarized, and new perspectives on the clinical and basic
research on this combination therapy were proposed. This review lays a
foundation for the development of anti-MRSA therapies and provides novel
strategies and methods for the treatment of inflammation-related
injuries caused by multiple drug-resistant bacteria.%
\end{abstract}%



\sloppy


\textbf{1 Introduction}

Methicillin-resistant \emph{Staphylococcus aureus} (MRSA), a worldwide
prevalent superbug, usually causes immune
injuries\textsuperscript{{[}1{]}}. These immune injuries are attributed
to the interaction between the host's immune responses and MRSA immune
evasion\textsuperscript{{[}2{]}}. Conventional drugs, such as
antibiotics, optimized antibiotics and vaccines, are currently used to
treat injuries. Since the emergence of resistant strains and immune
evasion, the efficacy of antibiotics has decreased and their adverse
effects limit their use \textsuperscript{{[}3, 4{]}}. Optimized
antibiotics are new favorite in drug research due to their superior
potency, efficacy, and specificity. However, high production costs
hinder its extensive use. Vaccine development often suffers from
challenges in technique, cost, and other difficulties. It is therefore a
burning issue to improve treatment methods for MRSA immune injuries.

Traditional medicine (TM) is used to treat bacterial infection and
immune injuries, because it not only inhibits and kills bacteria, but
also relieves immune injuries, partly overcomes drug resistance, and
alleviates the adverse effects caused by conventional
therapies\textsuperscript{{[}5-8{]}}. Studies have shown that TM
enhances host immunity. For example, it activates Peyer's batches and
regulates neutrophil phagocytosis \textsuperscript{{[}9-11{]}}. A study
has suggested that herbal formulae combined with antibiotics exert
better bacteriostatic efficacy than antibiotic use
alone\textsuperscript{{[}12{]}}.

This study aims to review the efficacies and corresponding mechanisms of
both conventional drugs and TM in combating MRSA, and to explore the
potential of their combination. Additionally, the research ideas and
methods on the combination medication are discussed. This review will
lay a foundation for the development of a new strategy to treat MRSA
infection.

\textbf{2 MRSA infection and its immune mechanisms}

MRSA infection has three stages: colonization, adaptation and invasion.
Its high pathogenicity is attributed to the invasiveness, virulence and
variability \textsuperscript{{[}13{]}}. MRSA has virulence factors that
increase its invasiveness, allowing the bacteria to adhere and invade to
host cells \textsuperscript{{[}14{]}}. The variability of MRSA includes
antigenic variation and phase variation. Antigenic variation enables
resistance to commonly used antibiotics without reducing the
pathogenicity of MRSA, and can alter the immunoreactivity of its encoded
products, thereby evading the host's immune
response\textsuperscript{{[}15, 16{]}}. Phase variation helps MRSA
immune evasion by promoting MRSA biofilm (MRSA-BF) formation and
assisting bacteria survival within the ``Trojan
horse''\textsuperscript{{[}17{]}}. In MRSA infection, the human immune
system evolves several efficient mechanisms to eliminate MRSA, and MRSA
evolves immune evasion strategies against host immunity (Fig.
1)\textsuperscript{{[}2{]}}.

2.1 Host immune defense against MRSA infection

As shown in Fig. 1, there are three lines of defense against MRSA
infection, the body's mucosal immune system (MIS), the innate immune
system (IIS) and the adaptive immune system (AIS). As a physical and
immune defense barrier, MIS maintains immune homeostasis in the vast
epithelial surface areas from the nasal cavity and respiratory tract to
the intestine \textsuperscript{{[}18{]}}. The formation of secretory IgA
(SIgA) is the key strategy of the MIS \textsuperscript{{[}19{]}}. SIgA
is released into the nasal passage and intestinal tract, binding and
``coating'' offending pathogens, thus blocking pathogens invasion (Fig.
1) \textsuperscript{{[}20{]}}. The IIS is rapidly triggered during
infections, which involves the activation of the complement system and
the recruitment and activation of dedicated immune cells such as
neutrophils and macrophages (Fig. 1) \textsuperscript{{[}21{]}}. The
activated complement system usually exerts phagocytosis by binding with
the complement receptor (CR), and it triggers serial chemotactic and
proinflammatory responses to facilitate neutrophil migration to the
infection site \textsuperscript{{[}22, 23{]}}. Neutrophils are activated
and stimulate bacterial clearance by phagocytosis and
bactericide\textsuperscript{{[}24, 25{]}}. As pathogens are degraded,
antigenic peptides are processed by specific antigen-presenting cells
such as DCs and M\selectlanguage{greek}φ\selectlanguage{english}s, further triggering the AIS, which plays a major
role in both the treatment and control of chronic infections (Fig.
1)\textsuperscript{{[}26, 27{]}}.

2.2 MRSA immune evasion

To establish infection successfully, MRSA deploys several immune evasion
strategies to prevent the host's three lines of defense. (Table 1.). The
analysis of molecular structures reveals the mechanism by which a
bacterial pathogen evades SIgA-mediated immunity via Staphylococcal
superantigen-like protein-7 (SSL-7) in the mucosal immune response,
which facilitates survival in mucosal environments and then contributes
to systemic infections \textsuperscript{{[}28{]}}.

To evade attack from innate immune responses, MRSA secretes virulence
factors that prevent complement initiation, digest complements and
inhibit the cleavage of complement cleavage fragments, further evading
opsonization of the complement system and causing inhibition of
subsequent neutrophil effects (Table 1) \textsuperscript{{[}25,
29-38{]}}. Other virulence factors prevent neutrophils from functioning
by blocking them from arriving at infected sites, inhibiting their
phagocytosis, and even killing them \textsuperscript{{[}32, 39-41{]}}.
MRSA also impairs macrophages mainly via the formation of mature
MRSA-BF\textsuperscript{{[}40, 42{]}}. It survives in macrophages and
enters the general circulation, leading to other tissue damage, which is
called the ``Trojan horse'' \textsuperscript{{[}43{]}}. Finally, MRSA
directly causes macrophage death through pore-forming toxins (PFTs),
particularly PVL. MRSA also manipulates the AIS, for example,
interfering with B-cell activation and proliferation, and impeding the
humoral response\textsuperscript{{[}44, 45{]}}.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1. Overview of immune response mechanisms during MRSA infection.
The body has three lines of defense against MRSA infections. (A) Mucosal
immune response. The mucosal surface is in direct contact with
pathogens. The key strategy of the mucosal immune response is to
generate antigen-specific IgA antibodies in the external secretions.
This process occurs at Peyer's patches (PP), and its key function is the
sampling of antigens. To facilitate this sampling, microfold (M) cells,
specialized phagocytic cells in the PP, can directly swallow and
transport antigens in the nasal or intestinal cavity to DCs via
phagocytosis. In the PP, through antigen presentation, IgA-committed
B-cell (IgA+ B cells) are induced to develop and finally produce dimeric
(or polymeric) forms of IgA after proliferation and differentiation at
effector sites. Ultimately, these forms of IgA become secretory IgA by
binding to polymeric Ig receptors (SCs). SIgAs are then released into
the nasal passage and intestinal tract, binding and ``coating''
offending pathogens, thus blocking pathogen invasion. (B) Innate immune
response. The complement system is activated through the classical
pathway, lectin pathway and alternative pathway. Some complement
fragments, such as C3b formed by C3 convertases cleaving the C3 protein,
can exert phagocytosis through binding with the complement receptor
(CR). The membrane attack complex (MAC) is formed and directly leads to
cell lysis. Moreover, other complement fragments, such as C3a and C5a,
can trigger a series of chemotactic and proinflammatory responses to
facilitate neutrophil migration to the site of infection. Neutrophils
recruit and migrate to infection sites along a concentration gradient of
chemokines secreted or released by activated host cells or complement
components such as C5a. Finally, neutrophils are primed, activated and
stimulate bacterial clearance by phagocytosis and bactericide.
Gradually, the invading bacteria are killed, and any remaining
neutrophils die off via apoptosis and are cleared by macrophages. (C)
Adaptive immune response. As pathogens are degraded, antigenic peptides
can be presented by dedicated antigen-presenting cells, such as DCs and
M\selectlanguage{greek}φ\selectlanguage{english}s, to T-lymphocytes, further activating the host adaptive immune
response. When stimulated directly or indirectly, B cells differentiate
and produce antibodies, which specifically bind with bacteria to
eliminate pathogens. When bacteria enter the cells, antigen-specific T
cells are stimulated and differentiate into CD8+ T cells. These cells
recognize and specifically bind to infected cells (targeted cells)
invaded by antigens, activate lysosomal enzymes in targeted cells, and
finally lead to the lysis and death of targeted cells. The antigens in
the cells lose are bound and immobilized by the antibodies and are then
phagocytosed. Ultimately, MRSA infection is inhibited.

Table 1. MRSA virulence factors that contribute to immune evasion and
their functions in host immune responses\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
Evasion proteins against mucosal immune & Target & Function/ effect on
immune system & Ref.\tabularnewline
\midrule
\endhead
\emph{Staphylococcal} superantigen-like protein-7 (SSL-7) & SIgA & It
enhances the ability to colonize in mucosal environments such as the
nasal passage by binding to SIgA. &
\textsuperscript{{[}28{]}}\tabularnewline
Evasion proteins against innate immune & Target & Function/ effect on
immune system & Ref.\tabularnewline
Proteins including extracellular adherence protein (Eap),
collagen-binding protein (Cna) and serine-aspartate repeat protein E
(SdrE) & C1q in classical pathway, lectin pathway, alternative pathway &
They inhibit the activation of the complement system by blocking these
three pathways. & \textsuperscript{{[}36-38{]}}\tabularnewline
\emph{Staphylococcal} Protein A (SpA) & IgG & It results in the inverted
tagging and blocking of the C1q binding sites, preventing complement
initiation. & \textsuperscript{{[}30{]}}\tabularnewline
& B cells & It interferes in B-cells activation and proliferation,
reducing the phagocytosis of MRSA, impeding antibody production and
causing disordered activation, finally leading to the death of the B
cells. & \textsuperscript{{[}44, 45{]}}\tabularnewline
\emph{Staphylococcal} complement inhibitor (SCIN) & C3 convertases & It
binds and stabilizes C3 convertases, interfering with the activation of
the complement system. & \textsuperscript{{[}32{]}}\tabularnewline
Extracellular fibrinogen-binding protein (Efb); its homolog
extracellular complement-binding protein (Ecb) & C3 & They prevent C3
from recognition by macrophages. &
\textsuperscript{{[}33{]}}\tabularnewline
Second Immunoglobulin-binding protein (Sbi) & IgG & It avoids
neutrophil-mediated opsonophagocytosis. &
\textsuperscript{{[}46{]}}\tabularnewline
& C3 & It binds to complement, leading to the cleavage and consumption
of complement Factor C3. & \textsuperscript{{[}34{]}}\tabularnewline
Factor I & C3b & It mediates C3b cleavage to iC3b, inhibiting initiation
of the alternative pathway as well the activation of the terminal
complement cascade. & \textsuperscript{{[}35{]}}\tabularnewline
Staphylokinase (SAK) & Complement & It digests IgG and complement. &
\textsuperscript{{[}25{]}}\tabularnewline
chemotaxis inhibitory protein of staphylococci (CHIPS) & C5aR & It binds
to C5aR to evade complement. & \textsuperscript{{[}29{]}}\tabularnewline
& FPR1 & It binds to FPR1 to block the chemotaxis of neutrophils. &
\textsuperscript{{[}47{]}}\tabularnewline
\emph{Staphylococcal} superantigen-like protein-7 (SSL-7) & C5 & It
inhibits the opsonization of bacteria by inhibiting the cleavage of C5.
& \textsuperscript{{[}31{]}}\tabularnewline
Proteases, e.g., staphopain A (Scp A), aureolysin (Aur) & Complement &
They degrade complement preventing opsonization and bacteria lysis. &
\textsuperscript{{[}30{]}}\tabularnewline
& Neutrophils & ScpA inhibits the chemotaxis and activation of
neutrophils. & \textsuperscript{{[}48{]}}\tabularnewline
\emph{Staphylococcal} superantigen-like 5 (SSL5) & P-selectin
glycoprotein ligand 1 (PSGL-1) & It binds to PSGL-1 of sialyl Lewis X,
thus blocking PSGL-1 interaction with the natural ligand P-selectin and
abrogating neutrophil rolling on endothelial cells. &
\textsuperscript{{[}39{]}}\tabularnewline
Proteins including extracellular adherence protein (Eap) & Intercellular
adhesion molecule 1 (ICAM-1) & It binds to ICAM-1, blocking the
neutrophil recruitment to the infection site. &
\textsuperscript{{[}32{]}}\tabularnewline
\emph{Staphylococcal} complement inhibitor (SCIN), chemotaxis inhibitory
protein of staphylococci (CHIPS) & Neutrophils & They impair neutrophil
recruitment as chemotaxis inhibitors. &
\textsuperscript{{[}49{]}}\tabularnewline
Nuc & NETs & It is a nuclease produced by MRSA to evade NETs. &
\textsuperscript{{[}50, 51{]}}\tabularnewline
Panton-Valentine leukocidin (PVL) & Neutrophils & It causes neutrophil
lysis at the dose of 0.04 \selectlanguage{greek}µ\selectlanguage{english}g/mL. &
\textsuperscript{{[}52{]}}\tabularnewline
Phenol-soluble-modulins (PSMs) & Neutrophils & They directly kill
neutrophils mainly by disrupting the membrane. &
\textsuperscript{{[}41{]}}\tabularnewline
\bottomrule
\end{longtable}

\textbf{3 Challenges of conventional drugs for the treatment of MRSA
infection}

3.1 Antibiotics

Antibiotics are used for MRSA infection. Long-term use of antibiotics
causes resistance, which is due to the immune evasion strategies of
bacteria. The use of antibiotics also impairs phagocytic bactericidal
functions and weakens the host's immunity \textsuperscript{{[}3{]}}.
Additionally, oral antibiotic treatment can disrupt the normal
intestinal flora, affecting lung or other tissue immunity to
bacteria\textsuperscript{{[}53{]}}. Antibiotic resistance and side
effects limit its utilization.

3.2 Optimized antibiotics

Optimized antibiotics, including antibody-antibiotic conjugate (AAC) and
antibiotic adjuvants, have been proposed to combat MRSA
infection\textsuperscript{{[}16, 54{]}}. AAC is an anti-MRSA antibody
linked to an antibiotic using a protease-sensitive
linker\textsuperscript{{[}55{]}}. When MRSA is opsonized by the antibody
and is phagocytized by immune cells, the linker is cleaved by host cell
proteases, and the antibiotic is released close to the bacteria and in
the compartment with antibiotic tolerant
bacteria\textsuperscript{{[}55{]}}. Optimized antibiotics, with superior
potency, efficacy, and specificity, are more effective the antibiotics
alone for the treatment of secondary MRSA
infection\textsuperscript{{[}55{]}}. Moreover, AAC can combat
antibiotic-tolerant bacteria more effectively and can improve the
permeability of antibiotics into host cells. However, high production
costs hinder their clinical translation \textsuperscript{{[}56{]}}.
Antibiotic adjuvant (AA) is another strategy for developing novel
antibiotics. To date, AAs mainly contain efflux pump inhibitors and
\selectlanguage{greek}\emph{β} -\selectlanguage{english}lactamase inhibitors\textsuperscript{{[}16{]}}. Efflux pumps
can actively extrude antibiotics, increasing their minimum inhibitory
concentration (MIC) or even losing their antimicrobial activity. Using
efflux pumps as therapeutic targets, efflux pump inhibitors (EPIs) were
developed. EPIs, with no antibacterial activity on their own, inhibit
efflux pumps by interfering with efflux gene expression, adding
functional groups to the drug substrate, and developing small-molecules
as substrate analogues to hinder identification, or to interfere with
the assembly of channel proteins \textsuperscript{{[}57{]}}. EPIs can
increase the activity of antibacterial drugs subject to efflux, maintain
the drug concentration at the therapeutic dose and shorten the treatment
duration\textsuperscript{{[}58{]}}. However, its use requires high-dose
administration, which could be toxic \textsuperscript{{[}16{]}}. This
high-dose administration makes it difficult to widely develop
EPIs.\selectlanguage{greek}\emph{β} -\selectlanguage{english}Lactamase can deactivate
antibiotics\textsuperscript{{[}16{]}}. Thus, \selectlanguage{greek}\emph{β} -\selectlanguage{english}lactamases
inhibitors (BLIs), capable of inactivating most\selectlanguage{greek}\emph{β} -\selectlanguage{english}lactamases, are
a proper antibiotic adjuvant. These inhibitors are mainly used in
treating G- bacterial infection, while their use in G+ bacteria still
needs to be developed\textsuperscript{{[}59{]}}.

3.3 Vaccines

Vaccination to prevent MRSA infection acquisition is the main treatment
strategy. Vaccination can decrease the occurrence and transmission of
resistant strains \textsuperscript{{[}60{]}}. Vaccines usually induce
the immune system to react to multiple targets, which makes it more
difficult for bacteria to evade the immune response induced by
vaccination, namely, it restricts the mutation of bacterial resistance
genes \textsuperscript{{[}61{]}}. Vaccines do not increase antibiotic
resistance, and most vaccines still work after long-term use. Moreover,
vaccination can restrict the ability of bacteria to colonize and
establish an infection by enhancing immunity \textsuperscript{{[}62{]}}.
However, these vaccines have had limited or no success in human
trials\textsuperscript{{[}63, 64{]}}.

\textbf{4 TM for anti-MRSA infection}

TM has exerted its unique efficacies in inhibiting MRSA
infection\textsuperscript{{[}6, 12{]}}. However, the bacteriostatic
ability of TM is weaker than that of antibiotics.TM regulation of the
body's immunity might be a promising strategy to combat MRSA infection.
In TM, single herbs and their active components as well as formulae play
a key role in regulating host immunity. The mechanisms of these herbs
and formulae were systematically analyzed and summarized (Table 3, Fig.
2).

4.1 Single Herbs and active components

4.1.1 \emph{Glycyrrhiza glavra} (\emph{Glycyrrhiza} polysaccharides)

\emph{Glycyrrhiza glavra} (\emph{G. glavra} , licorice) is an herbal
medicine with various bioactivities. It has been used to treat lung
injury and bacterial infection \textsuperscript{{[}65{]}}. Its
components including glycyrrhizin (GL) and its hydrolysis product
18-\selectlanguage{greek}β-\selectlanguage{english}glycyrrhetinic acid (18-\selectlanguage{greek}β-\selectlanguage{english}GA), as well as licorice flavonoids, can
restrain bacterial infection \textsuperscript{{[}65{]}}. GL has
anti-inflammatory and immunomodulatory
activities\textsuperscript{{[}66{]}}. Neutrophils are its primary
targets. By down-regulating the expression of endothelial adhesion
molecules in neutrophils (ICAM-1 and P-selectin), GL prevents neutrophil
adhesion, partly curbing local injuries \textsuperscript{{[}67{]}}. It
also decreases myeloperoxidase (MPO) levels. MPO, an enzyme mainly
stored in azurophilic neutrophil granules, has potent antibacterial
activity, and it is a marker of neutrophil migration and infiltration,
as well inflammation and tissue injury \textsuperscript{{[}66, 68,
69{]}}. GL can inhibit neutrophil phagocytosis, and it can treat the
initial phase of lung inflammation. It decreases the secretion of
inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and
pro-inflammatory cytokines (TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-1\selectlanguage{greek}α, \selectlanguage{english}IL-6) by regulating NF-\selectlanguage{greek}κ\selectlanguage{english}B
signaling molecules\textsuperscript{{[}66{]}}. Both iNOS and COX-2 are
induced by inflammatory stimuli and play important roles in MRSA
pneumonia\textsuperscript{{[}70{]}}. Altogether, GL inhibits MRSA
pneumonia in the initial phase, mainly by preventing the adhesion,
migration, recruitment, infiltration and phagocytosis of neutrophils.

18-\selectlanguage{greek}β-\selectlanguage{english}GA can combat MRSA immune evasion and improve host
immunity\textsuperscript{{[}71{]}}. It markedly reduces MRSA immune
evasion to alleviate infection via down-regulating the key virulence
factors, saeR, hla, RNAIII, mecA, and sbi \textsuperscript{{[}72{]}}.
Additionally, it can regulate the functions of neutrophils and DCs. In a
mouse model of MRSA skin infection, 18-\selectlanguage{greek}β-\selectlanguage{english}GA reduces neutrophil
recruitment by down-regulating KC and granulocyte colony-stimulating
factor (G-CSF) to alleviate skin infection \textsuperscript{{[}72{]}}.
It also activates adaptive immune responses to anti-MRSA infection by
targeting DCs\textsuperscript{{[}73{]}}. In a mouse model of
lipopolysaccharide (LPS)-induced inflammation, at doses of 1 mg/mL and
10 mg/mL, 18-\selectlanguage{greek}β-\selectlanguage{english}GA increases CD40 expression levels in DCs
\textsuperscript{{[}73{]}}. The interaction of CD40 and its ligand CD40L
can promote T cells activation and inflammatory cytokine (IL-1, IL-6 and
IL-12) production and induce DC maturation and activation, thereby
promoting immune responses\textsuperscript{{[}73{]}}.18-\selectlanguage{greek}β-\selectlanguage{english}GA modulates
the Th1/Th2 response through up-regulating Th1 responses. During the Th1
response, it also enhances the secretion of IL-10 by CD4+ T cells, and
IL-10 limits Th1 responses in a regulatory-feedback loop
\textsuperscript{{[}73, 74{]}}. This process suggests that 18-\selectlanguage{greek}β-\selectlanguage{english}GA may
suppress excessive inflammatory-responses or terminate immune responses
after pathogen eradication by upregulating IL-10. These results shed new
light on the possibilities of exploiting these herbs and compounds for
the treatment of infectious diseases by regulating DC maturation and
T-cell differentiation. Besides its single use, GL exerts synergistic
effects when combined with antibiotics. Licorice flavonoids can increase
the sensitivity of MRSA strains to oxacillin, a \selectlanguage{greek}\emph{β} -\selectlanguage{english}lactam
antibiotic\textsuperscript{{[}75{]}}.

4.1.2 \emph{Panax ginseng} (Ginseng polysaccharide)

\emph{Panax ginseng} (Pg) is known for invigorating and maintaining
physical vitality \textsuperscript{{[}76{]}}. Pg contains ginsenoside,
polysaccharides and peptides. It exerts antibacterial and
immunoregulatory functions and has been widely used for the treatment of
infectious diseases \textsuperscript{{[}76{]}}. Heat-processed Pg (at
100 \selectlanguage{ngerman}°C) enhances the antimicrobial activity against \emph{S. aureus} ,
which is due to increased levels of the ginsenoside Rg3, a major
compound against \emph{S. aureus} infection \textsuperscript{{[}77{]}}.
HPLC analysis shows that Rg3 penetrates the bacterial cell membrane more
easily than other compounds, thereby inhibiting bacterial
growth\textsuperscript{{[}77, 78{]}}. Pg is an adjuvant for pneumococcal
vaccines, which can enhance vaccine efficacy and increase the survival
rate after lethal bacterial challenge \textsuperscript{{[}79{]}}. Pg
extracts and Rb1 ginsenosides also show an adjuvant effect on
immunization against MRSA. Rb1 can promote both lymphocyte proliferation
and antibody production specific for MRSA
antigens\textsuperscript{{[}80{]}}.

Ginsan is a polysaccharide extracted from Pg \textsuperscript{{[}81{]}}.
It can protect mice from \emph{S. aureus} -induced sepsis by
bidirectionally modulating the IIS, mainly phagocytosis. It suppresses
MRSA-induced sepsis by increasing the bactericidal activity of
macrophages by increasing nitric oxide (NO) levels. Moreover, it
restricts excessive inflammation by suppressing TLR2, TLR4, TLR9 and
MyD88 levels, decreasing related downstream molecule (p38 MAPK and
JNK1/2) phosphorylation, and reducing NF-\selectlanguage{greek}κ\selectlanguage{english}B activation and inflammatory
cytokine (TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-1\selectlanguage{greek}β \selectlanguage{english}and IL-6) levels. In conclusion, ginsan not only
enhances immune responses but also avoids the pathologic inflammatory
response to increase survival in MRSA-infected
mice\textsuperscript{{[}81, 82{]}}. It also induces a high humoral
immune response against \emph{S. typhimurium} with increasing serum
IgG1, IgG2 and SIgA levels \textsuperscript{{[}8{]}}. Western blot and
RT-PCR confirmed that combined with an orally delivered antigen, ginsan
specifically up-regulates the expression of COX-1, COX-2 and CCL3 mRNA
in Peyer's patches \textsuperscript{{[}8{]}}. COX-1 and COX-2 are two
inflammation mediators and can modulate MRSA
inflammation\textsuperscript{{[}70{]}}. They promote DC migration to the
Peyer's patch via CCL3, a chemo attractant for DCs
\textsuperscript{{[}8{]}}. Consequently, ginsan may serve as a potent
vaccine supplement for oral immunization.

Ginsenoside, another ingredient of Pg, combats MRSA infection by
stimulating immune responses and disrupting immune evasion. A Pg extract
mainly consisting of ginsenoside can modulate the mRNA levels of TLR2/4,
trigger the activation of the MyD88-dependent pathway and NF-\selectlanguage{greek}κ\selectlanguage{english}B
signaling, and increase the mRNA levels of TNF-\selectlanguage{greek}α \selectlanguage{english}and IL-1\selectlanguage{greek}α, \selectlanguage{english}finally
promoting monocytes-macrophage recruitment to combat the
infection\textsuperscript{{[}83{]}}. Ginsenosides isolated from Korean
red ginseng can disrupt the structure of bacterial BFs and inhibit MRSA
immune evasion \textsuperscript{{[}84{]}}. The combination of
ginsenosides and kanamycin/cefotaxime (conventional antibiotics) elicits
synergistic or additive effects according to FICI indexes, which can be
linked to altered cell membrane permeability \textsuperscript{{[}85{]}}.
When ginsenosides interact with MRSA-BF, the permeability of the plasma
membrane to kanamycin could be increased \textsuperscript{{[}85{]}}.
Ginsenoside not only attenuates bacterial toxicity but also promotes the
influx of antibiotics, which effectively inhibits immune evasion.

Ginseng oligopeptides (GOP), a dietary supplement derived from Pg, has
immunomodulatory activities \textsuperscript{{[}86{]}}. Oral
administration of GOP can enhance the IIS and AIS, which may be due to
increased macrophage phagocytosis and NK cell activity and the
stimulation of Th cells (Th1 and Th2 cells) followed by antibody
production (serum IgA, IgG1, IgG2b and intestinal SIgA) and cytokine
secretion. Increased Th1 responses trigger IL-2 and IL-12 secretion,
increased Th2 responses trigger IL-6 secretion and increased proportions
of Tregs inhibit TNF-\selectlanguage{greek}α \selectlanguage{english}\textsuperscript{{[}86{]}}.

4.1.3 \emph{Panax quinquefolius} (aqueous extract of \emph{P.
quinquefolius} )

A patented aqueous extract from \emph{Panax quinquefolium} (\emph{P.
quinquefolius} ), CVT-E002, is used to treat upper respiratory tract
infection \textsuperscript{{[}87{]}}. An \emph{in vivo} study showed
that it can improve the function of immune organs. It increases the NK
cell numbers in mouse spleen and bone marrow \textsuperscript{{[}88,
89{]}}. It also stimulates the proliferation of B-lymphocytes in the
spleen of mice, and at doses of 10--500 Ag/mL, it increases IL-2 and
IFN-\selectlanguage{greek}γ \selectlanguage{english}levels in the spleen in a dose-dependent
manner\textsuperscript{{[}87, 90{]}}. In addition, it activates
peritoneal exudate macrophages (PEM), leading to increases in NO, IL-1,
IL-6 and TNF-\selectlanguage{greek}α \selectlanguage{english}levels \textsuperscript{{[}90{]}}. Additionally, it
stimulates\emph{in vivo} IgG production in treated
mice\textsuperscript{{[}90{]}}.

4.1.4 \emph{Ophiopogon japonicus} (\emph{O. japonicus} )

\emph{Ophiopogon japonicus} (\emph{O. japonicus} ) has various
bioactivities, including anti-inflammatory and immunoregulatory
activities. Its rhizome, as the primary medical portion, has been used
to treat inflammatory diseases \textsuperscript{{[}91{]}}.

Ruscogenin (RUS) is a major effective steroidal sapogen in \emph{O.
japonicus} \textsuperscript{{[}92{]}}. It exerts immunoregulatory
activities mainly by inhibiting neutrophil infiltration and phagocytosis
as well as blocking cell apoptosis, thus alleviating acute lung injury
(ALI) and pneumonia caused by committee- or hospital-acquired MRSA (CA-
or HA-MRSA) infection \textsuperscript{{[}93{]}}. At doses of 0.3 kg/mL,
1.0 kg/mL and 3.0 kg/mL, RUS reduces neutrophil infiltration by
decreasing MPO levels, thus inhibiting LPS-induced ALI in
mice\textsuperscript{{[}94{]}}. Additionally, it inhibits neutrophil
phagocytosis \textsuperscript{{[}94{]}}. This process might be
associated with the suppression of NF-\selectlanguage{greek}κ\selectlanguage{english}B p65 phosphorylation and
activation \textsuperscript{{[}94, 95{]}}. Moreover, RUS inhibits the
apoptosis of cells. Apoptosis is a common inflammatory characteristic of
MRSA pneumonia and is critical for improving MRSA clearance as well as
alleviating lung injuries \textsuperscript{{[}96, 97{]}}. At a dose of
1 mg/kg, RUS inhibits LPS-induced apoptosis of pulmonary endothelial
cells (PECs) by suppressing Bax and cleaved caspase-3 levels and by
up-regulating Bcl-2 \textsuperscript{{[}96{]}}. The high ratio of
Bax/Bcl-2 is a well-recognized indicator of apoptosis. Bax accelerates
apoptosis, and Bcl-2 inhibits apoptosis \textsuperscript{{[}98{]}}.
Cleaved caspase-3 is a pro-apoptosis marker \textsuperscript{{[}98{]}}.
The anti-apoptotic effects of RUS on PECs are accomplished by
restraining NF-\selectlanguage{greek}κ\selectlanguage{english}B activation. This action occurring by inhibiting TLR4
and MyD88 expression, which then inhibits NO, IL-6 and TNF-\selectlanguage{greek}α
\selectlanguage{english}production\textsuperscript{{[}96{]}}. TLR4 and its adapter protein MyD88
play an important role in the pulmonary inflammatory
response\textsuperscript{{[}93{]}}. MyD88 deletion can weaken the
endocytosis of pathogens by neutrophils and decrease ROS and cytokines
levels\textsuperscript{{[}99{]}}. Taken together, RUS combats MRSA
infection, especially MRSA-induced lung injuries by blocking neutrophil
function and exerting anti-apoptosis effects.

\emph{Ophiopogon} polysaccharide (OPS), another ingredient of O.
japonicus, exhibits immune-enhancing activity in which macrophages are
its main targets. It can induce the migration and recruitment of immune
cells to infected sites by up-regulating IL-1\selectlanguage{greek}β, \selectlanguage{english}TNF-\selectlanguage{greek}α \selectlanguage{english}and other
cytokines \textsuperscript{{[}100{]}}. Additionally, it enhances the
phagocytic function of macrophages by increasing iNOS and NO levels,
ultimately enhancing the ability to kill
pathogens\textsuperscript{{[}100{]}}. Furthermore, OPS induces CD14 and
MHC-II expression to promote macrophage activation and exert
antigen-presenting functions, thus accelerating the initiation of the
AIS\textsuperscript{{[}100{]}}. Recently, immunological enhancement of
OPS was markedly promoted by a drug delivery system via encapsulation
with liposomes (OPS liposomes, OPSLs) \textsuperscript{{[}100{]}}.

4.1.5 \emph{Cordyceps sinensis} and \emph{Cordyceps militaris}
(\emph{C. sinensis} , \emph{C. militaris} )

\emph{Cordyceps sinensis} (\emph{C. sinensis} ) and \emph{Cordyceps
militaris} (\emph{C. militaris} ) are representative species
of\emph{Cordyceps} mushrooms \textsuperscript{{[}101, 102{]}}. \emph{C.
sinensis} exerts anti-inflammatory and immunoregulatory
properties\textsuperscript{{[}101{]}}. It can attenuate LPS-induced
pulmonary inflammation and fibrosis \emph{in vivo}
\textsuperscript{{[}101{]}}. In LPS-induced ALI mice, \emph{C. sinensis}
extract (CSE) can improve pathological damage of lung tissue and reduce
the degree of pulmonary edema in a dose-dependent manner. It reduces the
number of neutrophils and macrophages, as well as MPO levels, thus
alleviating inflammatory cell exudation, which is related to NF-\selectlanguage{greek}κ\selectlanguage{english}B
signaling\textsuperscript{{[}101{]}}. By inhibiting the phosphorylation
of NF-\selectlanguage{greek}κ\selectlanguage{english}B p65 and downstream factors of NF-\selectlanguage{greek}κ\selectlanguage{english}B signaling (COX-2, iNOS),
CSE down-regulates NO, TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-6 and IL-1\selectlanguage{greek}β, \selectlanguage{english}thus inhibiting the
inflammatory response \textsuperscript{{[}101{]}}.

\emph{C. militaris} is another representative species of this genus and
shows immunomodulatory effects \textsuperscript{{[}102{]}}. Cordycepin
(Cor) is the representative component \textsuperscript{{[}102{]}}. Cor
regulates the secretion of inflammatory mediators and pro-inflammatory
cytokines by affecting the TLR4/NF-\selectlanguage{greek}κ\selectlanguage{english}B pathway in
macrophages\textsuperscript{{[}103{]}}. It can inhibit neutrophil
exudation and phagocytosis by decreasing MPO levels and down-regulating
iNOS/NO expression and improve lung edema and inflammatory responses by
regulating inflammatory cytokines, including TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-6, HMGB1 and
IL-10. This regulation occurs through the up-regulation of heme
oxygenase-1 (HO-1) in a dose-dependent manner \textsuperscript{{[}104,
105{]}}. HO-1, an antioxidative enzyme, can reduce free hemoglobin with
pro-inflammatory activity \emph{in vivo} , and produce by-products
possessing anti-inflammatory activities \textsuperscript{{[}106{]}}. Cor
can increase the mRNA and protein levels and enzymatic activity of HO-1
in a dose-dependent manner, inhibiting inflammatory
responses\textsuperscript{{[}105{]}}. HO-1 can further attenuate
inflammation and injuries in the lung through down-regulating TNF-\selectlanguage{greek}α,
\selectlanguage{english}IL-6 and HMGB1 and up-regulating IL-10 \textsuperscript{{[}105{]}}.
IL-10 can inhibit inflammation \textsuperscript{{[}104{]}}. HO-1 and
IL-10 promote each other's expression and cooperate to inhibit
inflammation. HMGB1, an inflammatory cytokine, is recognized by TLR4 and
induces inflammation, which is promoted by nucleocytoplasmic
translocation of HMGB1\textsuperscript{{[}107{]}}. In conclusion, Cor
exerts a protective effect by increasing Nrf2/HO-1 signaling and
decreasing NF-\selectlanguage{greek}κ\selectlanguage{english}B signaling\textsuperscript{{[}104, 105{]}}. Nrf2 is an
upstream regulator of HO-1. The expression of Nrf2 in the cytoplasm and
nucleus before and after Cor intervention shows that Nrf2 activation and
transformation from the cytoplasmic into the nucleus are the mechanisms
for the induction of HO-1 expression \textsuperscript{{[}104, 105{]}}.

4.1.6 \emph{Atractylodes} species Atractylodis Rhizoma (Atractylodes
macrocephala polysaccharide)

\emph{Atractylodes} species are composed of two major
groups,\emph{Atractylodes lancea} (Thunb.) DC. (\emph{A. lancea} )
and\emph{Atractylodes macrocephala} Koidz. (\emph{A. macrocephala} ).
Extracts from Atractylodes species including lactones and
polysaccharides, exert anti-inflammatory, antibacterial and
immunomodulatory activity and improve gastrointestinal
function\textsuperscript{{[}108{]}}. \emph{A. macrocephala} extract at
1.562 mg/mL, 3.125 mg/mL and 6.25 mg/mL concentrations can inhibit MRSA
in a dose-dependent manner \textsuperscript{{[}109{]}}. Atractylenolide
I (AO-I), a major bioactive component isolated from \emph{A.
macrocephala} , has anti-inflammatory
effects\textsuperscript{{[}110{]}}. It exerts a protective effect on
LPS-induced ALI mice by inhibiting the phagocytic activity of
neutrophils and macrophages \textsuperscript{{[}110{]}}. By inhibiting
TLR4, NF-\selectlanguage{greek}κ\selectlanguage{english}B activation and I\selectlanguage{greek}κ\selectlanguage{english}B-\selectlanguage{greek}α \selectlanguage{english}degradation, it decreases MPO levels,
thus suppressing the numbers and phagocytic activities of neutrophils
and macrophages in the BALF. Finally, AO-I exerts anti-inflammatory
activity by inhibiting TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-6, IL-13 and macrophage
migration inhibitory factor (MIF) \textsuperscript{{[}110{]}}. IL-13, a
Th2 cytokine, induces airway inflammation \textsuperscript{{[}111{]}}.
MIF is released by bacterial antigen-stimulated macrophages, promoting
infiltration and phagocytosis of macrophages in response to airway
inflammation \textsuperscript{{[}112{]}}. Notably, MIF shows greater
deleterious effects in chronic inflammation than in acute
one\textsuperscript{{[}113{]}}. Hence, it is necessary for
anti-inflammatory agents to inhibit these cytokines. Additionally, AO-I
can directly up-regulate IL-10 to promote inflammation
resolution\textsuperscript{{[}110{]}}. It also inhibits
antibiotic-induced dysbiosis of the intestinal microbiome
\textsuperscript{{[}114{]}}. Hence, it may be a promising method to
combine \emph{A. macrocephala}with antibiotics for MRSA infection,
because it not only enhances the ability to resist pathogens but also
reduces the disruption to the normal intestinal flora by antibiotics.
\emph{A. macrocephala}polysaccharides (AMPS), another component in
\emph{A. macrocephala} , exert immunoregulatiory activity. In contrast
to AO-I, AMPS induces I\selectlanguage{greek}κ\selectlanguage{english}B degradation, activates NF-\selectlanguage{greek}κ\selectlanguage{english}B and then
up-regulates NO and TNF-\selectlanguage{greek}α, \selectlanguage{english}thus improving the phagocytic activities of
macrophages and enhancing the IIS in a dose-dependent manner
\textsuperscript{{[}115, 116{]}}.

In \emph{A. lancea} , an acidic polysaccharide (ALP-3) is a component
deserving attention. It can modulate macrophage functions, including
promoting macrophage proliferation and phagocytosis, and releasing NO,
TNF-\selectlanguage{greek}α \selectlanguage{english}and IL-6. In addition, it exerts intestinal immune
activities\textsuperscript{{[}117{]}}. It can directly stimulate myeloid
cell proliferation in Peyer's patch cells and induce them to enhance the
production of hematopoietic growth factors (HGF). HGF acts on the
impaired intestinal mucosa and promotes intestinal mucosal
repair\textsuperscript{{[}117{]}}. Briefly, \emph{A. lancea} and
\emph{A. macrocephala} provide a protective effect on MRSA infection,
especially on pulmonary injuries mainly by inhibiting inflammation and
improving MIS.

4.2 Formulae

4.2.1 Zhenqi Capsule

Zhenqi capsule (ZQ) is composed of \emph{Astragalus
membranaceus}(\emph{A. membranaceu} ) and \emph{Ligustrum lucidum} . It
is commonly used to improve immunity, increase leukocyte numbers, and
promote the recovery of normal functions after surgical operation,
radiotherapy, or chemotherapy \textsuperscript{{[}118{]}}. An analysis
of the tissue distribution of the main bioactive components of ZQ
suggests that these components show overall high levels in the spleen
and thymus, suggesting that these components mainly accumulate in organs
associated with the immune response, confirming their immune
effect\textsuperscript{{[}118{]}}. Of these components, astragaloside IV
with its higher tissue concentration and bioavailability \emph{in vivo}
, has become an index of quality control of ZQ
\textsuperscript{{[}118{]}}. The extract from \emph{Ligustrum} lucidum
contains potent immune stimulants and influences immune
restoration\textsuperscript{{[}119{]}}.

\emph{Astragali Radix} (AR) is one of the major tonics in TM. AR
polysaccharide (ARPS), the representative component of AR, has effects
on immune regulation and inflammation \textsuperscript{{[}120{]}}. In
an\emph{Aeromonas hydrophila} -infected mouse model, ARPS balances the
inflammatory status in infected sites. It enhances the phagocytic
activities of phagocytes by stimulating macrophage and NK cell activity.
It also inhibits neutrophil phagocytic activity and reduces MPO levels,
preventing potential poor prognosis due to excessive neutrophil
infiltration \textsuperscript{{[}68{]}}. Additionally, its
immunostimulatory activity is involved in activating T-helper cells and
stimulating cell division and transformation in
lymphocytes\textsuperscript{{[}68{]}}. It lowers the proportion of CD8+
T cells and increases the ratio of CD4+/CD8+ T cells, representing an
increase in immunity \textsuperscript{{[}68{]}}. ARPS induces the
activation of CD4+ T cells in mice with \emph{P. aeruginosa}
infection\textsuperscript{{[}121{]}}.

4.2.2 Yupingfeng San

Yupingfeng San (YPFS) is composed of AR, \emph{A. macrocephala}
and\emph{Saposhnikoviae Radix} (SR). Clinically, YPFS has beneficial
immune-modulatory effects and has been used to prevent and treat
bacterial infection as well as upper respiratory tract
infection\textsuperscript{{[}122{]}}. Based on its network pharmacology
analysis, it is associated with the bacterial invasion of epithelial
cells and other bacterial infections, which is consistent with its
clinical uses\textsuperscript{{[}123{]}}. It is also linked with
aminoacyl-tRNA biosynthesis, which is a representative pathway to
reflect the inhibitory effect of an herbal formula in combination with
antibiotics on MRSA-BF infection \textsuperscript{{[}12, 123{]}}.
Furthermore, it is involved in the NF-\selectlanguage{greek}κ\selectlanguage{english}B signaling pathway, chemokine
signaling pathway, leukocyte trans-endothelial migration, endocytosis
and antigen processing and presentation \textsuperscript{{[}123,
124{]}}.

The bidirectional regulatory effect on the expression of inflammatory
factors is one of the features of this formula. It helps the immune
system achieve a balance between the expression of pro-inflammatory and
anti-inflammatory cytokines in the process of combating MRSA infection.
In acute inflammation models (LPS-induced for 3 hours), YPFS activates
NF-\selectlanguage{greek}κ\selectlanguage{english}B by enhancing the degradation of I\selectlanguage{greek}κ\selectlanguage{english}B-\selectlanguage{greek}α, \selectlanguage{english}inducing the mRNA and
protein expression of pro-inflammatory cytokines (IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-6 and TNF-\selectlanguage{greek}α\selectlanguage{english})
in a dose-dependent manner, with maximal induction reaching
approximately 2- to 20- fold of the original\textsuperscript{{[}124{]}}.
However, when in chronic inflammation models (for 24 hours), it
suppresses these cytokines, exerting anti-inflammatory effects
\textsuperscript{{[}124{]}}. In this process, it is key events to
bidirectionally regulate these inflammation mediators (iNOS, COX-2)
\textsuperscript{{[}125{]}}. It depresses iNOS and COX-2 levels in
macrophages at the 3-hour time point; however, at the 24-hour time
point, it exerts the opposite\textsuperscript{{[}125{]}}. The iNOS, an
enzyme in macrophages, assists macrophages in combating pathogens.
However, when MRSA-BF is formed after 24 hours, it helps MRSA evade
attack by the immune system, which promotes macrophages toward
anti-inflammatory or profibrotic M2 phenotype polarization
\textsuperscript{{[}42, 126{]}}. One of the features of a typical M2
macrophage response is decreased iNOS levels, which promotes profibrotic
responses and abscess production during chronic MRSA infection
\textsuperscript{{[}42, 127{]}}. Similarly, COX-2 is an inducible
enzyme, and its expression is up-regulated in the initial stages of
inflammation and tissue injury such as MRSA-induced acute skin injury.
If this high expression continuously occurs, it can lead to severe
damage to the body \textsuperscript{{[}70{]}}. Therefore, moderate
expression of iNOS and COX-2 plays a protective role against MRSA
infection. Overall, YPFS balances complex immune responses against MRSA
infection by exerting bidirectional modulating functions, which is
hardly found in conventional drugs \textsuperscript{{[}128{]}}.

In addition, AR, \emph{A. macrocephala} and SR have bidirectional
regulatory effects on cytokines, including COX-2 and
iNOS\textsuperscript{{[}124, 129{]}}. The glycoprotein derived from
\emph{A. macrocephala} stimulates TNF-\selectlanguage{greek}α \selectlanguage{english}production in splenocytes, yet
other components of \emph{A. macrocephala} , AO-I and III, exert
anti-inflammatory activities by suppressing TNF-\selectlanguage{greek}α
\selectlanguage{english}production\textsuperscript{{[}130, 131{]}}. SR water extracts can
up-regulate iNOS. However, the other three SR-derived active ingredients
inhibit iNOS expression \textsuperscript{{[}125, 132{]}}. Thus, a single
herb may exhibit a greater immune stimulation effect than YPFS.
Bidirectional regulation is a unique advantage of herbal formulae. Apart
from enhancing the IIS, YPF-PS derived from YPFS enhances T lymphocyte
proliferation. It promotes lymphocyte entry into S and G2/M phases, and
thus effectively increases the percentages of CD4+ and CD8+ T cells,
greatly potentiating the cell immune
responses\textsuperscript{{[}133{]}}.

4.2.3 Shengmai San

Shengmai San (SMS) is composed of Pg, \emph{O. japonicas}
and\emph{Schisandra chinensis} (\emph{S. chinensis}
)\textsuperscript{{[}134{]}}. It is a classic tonic prescription for
chronic pulmonary diseases, such as syndromes of weakness and shortness
of breath, with powder and injection commonly used
clinically\textsuperscript{{[}135, 136{]}}. SMS combats MRSA infection
by regulating immunity and inflammation. It is highly recommended for
use in combination with antibiotics for CA-MRSA in clinical guidelines,
with an effective rate up to more than 80\% \textsuperscript{{[}137{]}}.
A meta-analysis showed that when treating chronic obstructive pulmonary
disease (COPD), SMS combined with Western medicine has greater efficacy
than Western medicine alone, which provides a partial basis for SMS
combined with conventional therapies in the treatment of MRSA
infection\textsuperscript{{[}138{]}}. It can also combat sepsis by
protecting the MIS of mice \textsuperscript{{[}139{]}}. At a dose of 1.5
mL/kg, SMS regulates NF-\selectlanguage{greek}κ\selectlanguage{english}B and decreases IFN-\selectlanguage{greek}γ, \selectlanguage{english}TNF-\selectlanguage{greek}α \selectlanguage{english}and IL-2 levels,
thus inhibiting excessive inflammation and exerting its anti-septic
activity\textsuperscript{{[}139{]}}. Metabolomics analysis suggests that
the key mechanism of this activity is embodied in SMS regulating taurine
and taurine metabolism, as well as arginine and proline
metabolism\textsuperscript{{[}139{]}}. These metabolic processes have
also been regulated in Reyanning combined with linezolid against MRSA-BF
infection\textsuperscript{{[}12, 140{]}}. These effects of SMS are
echoed by network pharmacology analysis in which SMS can regulate the
processes of immunity and inflammation \textsuperscript{{[}141{]}}.

\emph{S. chinensis} is one of the herbs in this formula. Schisantherin A
(SA), isolated from the fruit of \emph{S. chinensis} , shows a
protective effect on acute inflammatory lung injuries by improving the
IIS\textsuperscript{{[}142{]}}. It inhibits neutrophil and macrophage
activities and reduces neutrophil
infiltration\textsuperscript{{[}143{]}}. Besides, it inhibits NF-\selectlanguage{greek}κ\selectlanguage{english}B
signaling and MAPKs signaling, and then it decreases TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-6 and
IL-1\selectlanguage{greek}β \selectlanguage{english}levels in the BALF, thus exerting anti-inflammatory effects and
improving pulmonary injuries \textsuperscript{{[}143{]}}.

4.2.4 Buzhongyiqi Tang (Hochu-ekki-to, TJ-41)

Buzhongyiqi Tang, known as Hochuekkito (HET), TJ-41, is a formula in
both traditional Chinese medicine and Japanese Kampo medicine. This
formula comprises 10 herbs, including AR, Pg, \emph{A. lancea}
,\emph{Angelicae radix} , \emph{Zizyphi fructus} , \emph{Aurantii
nobilis pericarpium} , \emph{Bupleuri radix} , \emph{G. glavra} ,
\emph{Cimicifugae rhizome} and \emph{Zingiberis rhizome}
\textsuperscript{{[}144{]}}. HET has anti-infection and
anti-inflammatory effects and exerts trophic support functions
\textsuperscript{{[}145{]}}. It not only directly reduces or prevents
MRSA colonization, but also combats MRSA infection by regulating the
MIS. In a small-scale clinical trial for MRSA carriers' patients, HET
eradicated MRSA successfully with no side effects
\textsuperscript{{[}144{]}}. It also prevents MRSA colonization by
improving serum nutrition levels and enhancing the
IIS\textsuperscript{{[}144, 145{]}}. HET also up-regulates the activity
of splenocytes, which is the major immunomodulation system of
anti-bacterial infection \textsuperscript{{[}144{]}}.\emph{Atractylodes}
rhizome, \emph{Zingiberis rhizoma} and\emph{Bupleuri radix} promote the
immunostimulation of spleen cells.\emph{Atractylodes} rhizome extract
promotes T-cell activity by expressing CD28 in T cells in the spleen
\textsuperscript{{[}144{]}}.\emph{Zingiberis rhizoma} extract stimulates
CD8+ T cells of splenocytes\textsuperscript{{[}144{]}}. \emph{Bupleuri
radix} extract has antimicrobial activity \textsuperscript{{[}146{]}}.
In addition, it also promotes B-cell mitogenic activity in spleen
cells\textsuperscript{{[}144{]}}. Thus, for MRSA carriers who are not
recommended to use conventional drugs, HET seems to be a more effective
option. Additionally, HET decreases vulnerability to MRSA
infection\textsuperscript{{[}147{]}}.

Furthermore, HET exerts immunomodulation by regulating the MIS in the
upper respiratory or intestinal tract to resist bacterial infection.
Specifically, oral administration of HET can increase IgA levels in
intestinal, which is the key indicator to evaluate mucosal antibody
responses \textsuperscript{{[}148{]}}. It can directly enhance mucosal
IgA antibodies by modulating cytokine secretion by intestinal epithelial
cells (IECs). Additionally, it is inferred that HET could increase SIgA
secretion and enhance immune responses \textsuperscript{{[}9, 148{]}}.
DNA microarray and flow cytometry analyses show that oral administration
of HET increases the proportion of L-selectin-positive cells in B
lymphocytes in Peyer's patch cells and peripheral blood mononuclear
cells \textsuperscript{{[}148{]}}. L-selectin promotes the recruitment
of B-lymphocytes to the non-intestinal mucosal effector site, which
partly explains the reason for the enhancement of the IgA immune
response in the nasal mucosa \textsuperscript{{[}148{]}}. In summary,
HET exerts anti-MRSA efficacy by regulating immune organs and the MIS.

\subsection*{}

{\label{section}}

Table 2. The effect of TM therapies on host immunity and MRSA immune
evasion.\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Name of TM\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Active Ingredient\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Model\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Dosing concentration\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Targets and indicators\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Immunomodulatory action\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Ref.\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{G. glavra}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Glycyrrhizin (GL)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Male CD mice (20--25 g)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
10 mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
ICAM-1, P-selectin\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
It decreases the degree of positive staining and densitometry for ICAM-1
and P-selectin.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textsuperscript{{[}67{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Male specific pathogen-free BALB/c mice (6 weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
50 mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
neutrophils, macrophages, MPO, CD11b positive cells\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
It reduces the numbers of total cells, neutrophils, and macrophages, and
decreases MPO and CD11b levels to inhibit the migration and infiltration
of immune cells.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textsuperscript{{[}66, 67{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-1\selectlanguage{greek}α, \selectlanguage{english}IL-6, COX-2, iNOS, NF-\selectlanguage{greek}κ\selectlanguage{english}B\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It decreases the levels of pro-inflammatory cytokines (TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-1\selectlanguage{greek}α,
\selectlanguage{english}IL-6) and pro-inflammatory mediators (COX-2, iNOS, NF-\selectlanguage{greek}κ\selectlanguage{english}B).\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}66, 67{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
18\selectlanguage{greek}β-\selectlanguage{english}Glycyrrhetinic Acid (GA)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female Crl; SKH1-hrBR hairless mice, subcutaneously inoculated with
MRSA\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
600 \selectlanguage{greek}μ\selectlanguage{english}g/mL\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
saeR, Hla, RNAIII, mecA, sbi\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It reduces MRSA immune evasion by down-regulating MRSA virulence factors
(saeR, Hla, RNAIII, mecA, sbi).\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}72{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
KC, G-CSF\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It reduces the levels of inflammatory cytokines (KC, G-CSF).\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}72{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Male BALB/c and C57BL/6 mice (6 weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1 and 10 mg/mL for 14 hours\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
co-stimulatory molecules CD40, CD86, MHC class II\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It induces phenotypic maturation of DCs by increasing CD40, CD86 and
MHC-II expression in DCs.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}73{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IL-12, IFN-\selectlanguage{greek}γ\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It increases IL-12 levels to promote DC maturation and activates T cells
to differentiate into IFN-\selectlanguage{greek}γ \selectlanguage{english}producing Th1 cells.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}73{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IL-10\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It suppresses excessive inflammatory responses or terminates the immune
responses after pathogen eradication by increasing IL-10 levels.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}73{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{P. ginseng} (Pg)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Ginsan\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Male pyrogen-free BALB/c mice (5--7 weeks, 18--22 g); S. aureus 25923 or
E. coli\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.012, 0.025, 0.5, 25, and 250 mg/kg (intravenous injection)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Macrophage, TLR2, TLR4, TLR9, MyD88, MAPK, JUN 1/2, NF-\selectlanguage{greek}κ\selectlanguage{english}B, TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-1\selectlanguage{greek}β,
\selectlanguage{english}IL-6, IL-12\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
It induces resistance to MRSA septicemia by modulating
monocyte/macrophage-mediated innate immunity.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textsuperscript{{[}82{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
BALB/c mice\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
100 mg/kg (intraperitoneally introduced, once a day)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Serum antibodies, Peyer's patches, COX-1, COX-2, CCL3\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It effectively enhances the humoral immune response to orally delivered
antigen, mediated by CCL3 via COX-1 and COX-2.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}8{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Pg extract, such as ginsenoside\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female mouse mastitis model (lactating mice)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3, 10, 50 mg/mL\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Macrophage, TLR2, TLR4, NF-\selectlanguage{greek}κ\selectlanguage{english}B\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Pg extracts trigger and induce the inflammatory response. Pg modulates
the mRNA levels of TLR2 and TLR4, triggers the activation of the
MyD88-dependent pathway and then leads to the liberation of the NF-\selectlanguage{greek}κ\selectlanguage{english}B
transcription factor.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}83{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Ginsenoside\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
MRSA strains: bacterial cells cultured in a Mueller--Hinton broth\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
100 mg/mL\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
MRSA biofilm\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It not only attenuates bacterial toxicity but also promotes the influx
of antibiotics.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}85{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ginseng oligopeptides (GOP)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
420 Female healthy BALB/c mice\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.0375, 0.075, 0.15, 0.3 and 0.6 g/kg for 30 days (intragastrically
administered)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Macrophage, NK cell, T and Th cells\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It increases macrophage phagocytosis capacity and NK cell activity, and
enhances T and Th cells, as well as IL-2, IL-6 and IL-12 secretion and
IgA, IgG1 and IgG2b production.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}86{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{P. quinquefolius}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
aqueous extract of the \emph{P. quinquefolius} (CVT-E002)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Old mice (8--9 weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
80 mg chow/mouse daily\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NK cell in spleen and bone marrow\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It augments the absolute numbers of NK cells in the spleen and bone
marrow.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}88{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
C57 BL/6 mice\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10, 100, 500 Ag/mL\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
B-lymphocyte in the spleen\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It increases IL2 and IFN-\selectlanguage{greek}γ \selectlanguage{english}levels in B-lymphocytes in a dose-dependent
manner.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}87{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
C57 BL/6 mice (6--8 weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
500, 100 and 10 \selectlanguage{greek}µ\selectlanguage{english}g/mL\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Peritoneal exudate macrophages (PEM)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It stimulates NO, IL-1, IL-6 and TNF-\selectlanguage{greek}α \selectlanguage{english}levels in PEM.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}90{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
BALB/c mice (1 week)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
18, 6 mg per mouse\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Plasma cells\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It increases IgG levels.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}90{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{O. japonicas}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
OPS, OPL\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Peritoneal macrophages isolated from ICR mice (18--22 g)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
62.5, 31.25, 15.625, 7.813 and 3.907 g/mL\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Phagocytes, NO, iNOS\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It improves immune function of macrophages by enhancing phagocytic
function and increasing NO and iNOS levels, finally enhancing the
ability of sterilization.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}100{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IL-1\selectlanguage{greek}β, \selectlanguage{english}TNF-\selectlanguage{greek}α, \selectlanguage{english}MCP-1, MIP1\selectlanguage{greek}β\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It exerts immune activity by promoting IL-1\selectlanguage{greek}β, \selectlanguage{english}TNF-\selectlanguage{greek}α, \selectlanguage{english}MCP-1 and MIP-1\selectlanguage{greek}β
\selectlanguage{english}levels in macrophages.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}100{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
31.25, 15.625 and 7.813 g/mL\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
CD14, MHC-II\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It induces CD14 and MHC-II to promote macrophages activation and
maturation.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}100{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Ruscogenin (RUS)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Male ICR mice (6--8 weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.3, 1.0 and 3.0~mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
MPO\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It reduces neutrophil infiltration by decreasing MPO levels.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}94{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1.0~and~3.0 mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
iNOS, NF-\selectlanguage{greek}κ\selectlanguage{english}B\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It suppresses the inflammatory response by decreasing iNOS levels, which
might be linked with the down-regulation of NF-\selectlanguage{greek}κ\selectlanguage{english}B.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}94{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Male C57BL/6 mice (18-22 g)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.3 and 1 mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NO, IL-6, TNF-\selectlanguage{greek}α\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It alleviates lung injury and inflammation by decreasing NO, IL-6 and
TNF-\selectlanguage{greek}α \selectlanguage{english}levels.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}96{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.1, 0.3 and 1 mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Bax, cleaved caspase-3, Bcl-2\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It inhibits PEC apoptosis by decreasing Bax and cleaved caspase-3 levels
and by increasing Bcl-2 levels.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}96{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.3 and 1 mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
TLR4, MYD88, NF-\selectlanguage{greek}κ\selectlanguage{english}B p65\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It attenuates LPS-induced PEC apoptosis and exerts a protective effect
on lung injury and inflammation by suppressing the TLR4/MYD88/NF-\selectlanguage{greek}κ\selectlanguage{english}B
pathway.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}96{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Cordyceps mushrooms- C. sinensis\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{Cordyceps sinensis}~extract (CSE)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Sixty male adult BALB/c mice (8 weeks, 20 \selectlanguage{ngerman}± 2 g)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10, 30 and 60 mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Neutrophils, macrophages, MPO\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It alleviates inflammatory cell exudation by decreasing the numbers of
neutrophils and macrophages, as well as MPO levels.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}101{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NF-\selectlanguage{greek}κ\selectlanguage{english}B p65, COX-2, iNOS, NO, TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-6, IL-1\selectlanguage{greek}β\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It down-regulates NO, TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-6 and IL-1\selectlanguage{greek}β \selectlanguage{english}by inhibiting the
phosphorylation of NF-\selectlanguage{greek}κ\selectlanguage{english}B p65 and COX-2, iNOS.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}101{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Cordyceps mushrooms- C. militaris\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
cordycepin\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Male specific pathogen-free Wistar rats (8--10 weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1, 10 and 30 mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-6, HMGB1, IL-10, TLR4\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It alleviates anti-oxidative stress injuries by down regulating TNF-\selectlanguage{greek}α,
\selectlanguage{english}IL-6 and HMGB1 as well up-regulating IL-10, which is associated with
inhibiting TLR4 signaling.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}104, 105{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Neutrophils, MPO, NO, iNOS, LDH\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It attenuates~inflammation by decreasing the neutrophil number and
inhibiting their exudation by suppressing MPO, NO, iNOS and LDH
levels.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}105{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Nrf2, HO-1\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It stimulates HO-1 production and alleviates lung injuries by promoting
Nrf2 activation and inducing nuclear translocation of Nrf2.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}104, 105{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Male BALB/c mice (6-8 weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
50, 100 and 200 mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NF-\selectlanguage{greek}κ\selectlanguage{english}B, I\selectlanguage{greek}κ\selectlanguage{english}B\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It prevents I\selectlanguage{greek}κ\selectlanguage{english}B phosphorylation and NF-\selectlanguage{greek}κ\selectlanguage{english}B release to achieve
anti-inflammatory effect.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}104{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Atractylodes species- \emph{A. macrocephala}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Atractylenolide I (AO-I)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Male BALB/c mice (20-24 g)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
5, 10 and 20 mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Neutrophils, macrophages, MPO\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It decreases neutrophil and macrophage numbers in BALF and inhibits
neutrophil infiltration by reducing MPO levels.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}110{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-6, IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-13, MIF, IL-10\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It decreases TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-6, IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-13 and MIF levels, as well as
increases IL-10 levels in a dose-dependent manner.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}110{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
TLR4, NF-\selectlanguage{greek}κ\selectlanguage{english}B, I\selectlanguage{greek}κ\selectlanguage{english}B\selectlanguage{greek}α\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It exerts a protective effect on ALI-induced mice by inhibiting TLR4,
NF-\selectlanguage{greek}κ\selectlanguage{english}B activation and I\selectlanguage{greek}κ\selectlanguage{english}B\selectlanguage{greek}α \selectlanguage{english}degradation.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}110{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Atractylodes macrocephala polysaccharides (AMPS)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
The murine macrophage cell line RAW264.7\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
25, 50, 100 and 200 lg/mL\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Macrophages, NO, TNF-\selectlanguage{greek}α\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It stimulates macrophages to promote phagocytic activity and the
productions of~NO and TNF-\selectlanguage{greek}α.\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}115, 116{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NF-\selectlanguage{greek}κ\selectlanguage{english}B, I\selectlanguage{greek}κ\selectlanguage{english}B\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It induces I\selectlanguage{greek}κ\selectlanguage{english}B degradation and the activation of NF-\selectlanguage{greek}κ\selectlanguage{english}B.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}115, 116{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Atractylodes species- \emph{A. lancea}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
A neutral polysaccharide (ALP-1), an acidic polysaccharide (ALP-3)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
The murine RAW264.7 macrophage cell line, Specific pathogen free BALB/C
mice (6-8 weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
50, 100, 250, 500, 1000 and 2000 mg/mL for 18h\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Macrophages, NO, TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-6\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
They promote macrophages phagocytosis and the release of NO, TNF-\selectlanguage{greek}α \selectlanguage{english}and
IL-6.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}117{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HGF\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
They modulate the intestinal immune system by stimulating Peyer's patch
cells to induce HGF production.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}117{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
water extracts of \emph{A. macrocephala} and \emph{A. lancea}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Murine normal colonic epithelial cell-line MCE301 cells\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
100 \selectlanguage{greek}µ\selectlanguage{english}g/mL\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
G-CSF\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
They promote the intestinal immune system by promoting G-CSF.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}149{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Zhenqi Fuzheng granule (ZQ)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Astragalus polysaccharides (APS)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Male MF1albino mice (5-6 weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
250 mg APS/kg/week for four consecutive weeks\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Spleen, neutrophil and ROS in intestinal\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It increases both in the phagocytic ability of neutrophils and the
intestinal ROS production.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}68{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Yu Ping Feng San (YPFS)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
water-soluble extracts of YPFS\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
RAW 264.7 murine macrophages\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1/mL\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
macrophage\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It increases the phagocytic activity of macrophages.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}124{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1mg/mL; 3h\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-6, TNF-\selectlanguage{greek}α\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It suppresses the production of pro-inflammatory cytokines in
LPS-induced cultured macrophages.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}124{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.03, 0.1, 0.3, 1, 3 mg/mL; 24h\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-6, TNF-\selectlanguage{greek}α\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It induces the production of pro-inflammatory cytokines.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}124{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1mg/mL; 3h \& 24h\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
iNOS, COX-2\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It reduces iNOS and COX-2 levels in macrophages at 3-hour time points.
However, it induces the two at 24-hour time points.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}125{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
SMS\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Filtered SMS solutions\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Healthy specific pathogen-free ICR mice (20--22 g, 6--8 weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.375, 0.75 and 1.5 mL/kg\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IFN-\selectlanguage{greek}γ, \selectlanguage{english}TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-2, NF-\selectlanguage{greek}κ\selectlanguage{english}B\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It inhibits excessive inflammation by regulating NF-\selectlanguage{greek}κ\selectlanguage{english}B and decreasing
IFN-\selectlanguage{greek}γ, \selectlanguage{english}TNF-\selectlanguage{greek}α \selectlanguage{english}and IL-2 levels.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}137{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Schisantherin A\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Male BALB/c mice, (6--8 weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10, 20 and 40 mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
MPO, neutrophils, macrophages\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It improves inflammatory cell infiltration in pulmonary tissue by
inhibiting neutrophils and macrophages, as well as MPO levels.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}143{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-6, IL-1\selectlanguage{greek}β \selectlanguage{english}in the BALF\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It exerts an anti-inflammatory effect through decreasing TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-6 and
IL-1\selectlanguage{greek}β \selectlanguage{english}levels in the BALF.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}143{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NF-\selectlanguage{greek}κ\selectlanguage{english}B p65, I\selectlanguage{greek}κ\selectlanguage{english}B-\selectlanguage{greek}α, \selectlanguage{english}JNK, ERK, p38\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It inhibits the phosphorylation of p65, ERK, p38, JNK, and the
degradation of I\selectlanguage{greek}κ\selectlanguage{english}B-\selectlanguage{greek}α \selectlanguage{english}in a dose-dependent manner.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}143{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Buzhongyiqitang (Hochuekkito)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hochuekkito extract (HET)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female BALB/c mice (6 weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3.4 g/kg/day\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
MRSA, splenocyte\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It inhibits MRSA and promotes murine splenocyte immunological activity
in dose-dependent manners.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}144{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
73 acute stroke patients (41 HET-treated and 32 non-HET-treated)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
7.5~g/day, three divided doses for three months\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
serum nutritional markers\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It improves levels of serum nutritional markers by supporting nutrition
and enhancing innate immunity.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}145{]}}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female C3H/HeJ mice (6-8 weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1000 mg/kg/day\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
mucosal IgA antibody\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
It enhances the IgA immune response.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textsuperscript{{[}148{]}}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

(A) Targets of immune responses in the host's immune defenses.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

(B) Targets of immune responses in MRSA immune evasion strategies.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Figure 2. Main mechanisms of TCM therapies against MRSA infections. (A)
Targets of immune responses in the lung and mucosa. 1a. Acting on PMNs;
1b. Acting on promoting or inhibiting inflammation; 1c. Acting on
adaptive immune responses. 2. Acting on mucosal immunity. (B) Targets of
immune responses in MRSA immune evasion strategies. PMN,
polymorphonuclear leukocyte. ICAM-1, Intercellular adhesion molecule 1.
GL, glycyrrhizin. 18-\selectlanguage{greek}\emph{β} -\selectlanguage{english}GA, 18-\selectlanguage{greek}\emph{β} -\selectlanguage{english}glycyrrhetinic acid.
RUS, Ruscogenin. CSE, \emph{C. sinensis} extract.
AO-I,\emph{Atractylenolide} I. APS, \emph{Astragalus} polysaccharides.
SMS (SA), Shengmai San (\emph{Schisantherin A} ). Cor, cordycepin. GOP,
Ginseng oligopeptides. CVT-E002, a patented aqueous extract
from\emph{Panax quinquefolium} (\emph{P. quinquefolius} ). OPS,
Ophiopogon polysaccharide. AMPS, \emph{A. macrocephala} polysaccharides.
M\selectlanguage{greek}φ, \selectlanguage{english}macrophage. HET, Hochuekkito. YPF-PS, polysaccharides derived from
Yupingfeng San. Green arrows represent promotion. Red arrows represent
inhibition.

Briefly, MRSA infection is closely associated with neutrophil function,
inflammation, immune responses, and MRSA immune evasion. In this
section, the main mechanisms of TCM immune therapies for anti-MRSA
infection are summarized and analyzed, suggesting that they can regulate
multiple biological processes to modulate the host's immune responses
and MRSA immune evasion (Fig. 2). As is shown in Fig 2. 1a, regarding
the aspects of regulating the function of PMNs, GL and 18-\selectlanguage{greek}β-\selectlanguage{english}GA inhibit
PMN adhesion and recruitment \textsuperscript{{[}67, 72{]}}. RUS, CSE,
AO-I and APS inhibit PMN infiltration by reducing MPO
levels\textsuperscript{{[}68, 94, 101, 110{]}}. With respects to
modulating inflammation, various TM therapies exert their therapeutic
effect on MRSA infection by regulating TLR4/NF-\selectlanguage{greek}κ\selectlanguage{english}B signaling (Fig. 2.
1b). Ginsenoside, AMPS, CVT-E002 and other therapies increase the
phagocytic functions of immune cells to promote inflammation through
activating TLR4/NF-\selectlanguage{greek}κ\selectlanguage{english}B signaling. OPS also contributes to enhancing the
functions of macrophages. GL, Cor, CSE, RUS, SMS and other active
compounds inhibit excessive inflammation by blocking this signaling. In
addition, RUS inhibits cell apoptosis by blocking this signaling to
improve MRSA clearance and alleviate lung injuries. Cor also inhibits
excessive inflammation by activating Nrf2/HO-1 signaling. These herbs
and formulae exhibit anti-MRSA infection functions by regulating
inflammation (Fig 2. 1b). Besides innate immune responses, TM therapies
act on the adaptive immune response (Fig 2. 1c). For example, GOP plays
immunomodulatory activities by stimulating the secretion of cytokines
and the production of antibodies. YPF-PS significantly enhances T
lymphocyte proliferation to potentiate cell immune responses. Moreover,
ginsan and HET act on mucosal immunity to promote SIgA formation and
secretion, significantly preventing MRSA invasion (Fig. 2. 2). Apart
from regulating host immunity, TCM therapies act on MRSA virulence
factors (Fig 2. 1d). 18-\selectlanguage{greek}β-\selectlanguage{english}GA directly inhibits MRSA virulence factors.
Ginsenoside can disrupt MRSA-BF structure and inhibit MRSA immune
evasion against MRSA infection.

\textbf{5 Combination therapy with conventional and TM immune therapies}

The effects characteristics and mechanisms of conventional and TM immune
therapies against MRSA infection are comprehensively analyzed and
summarized here. In the prevention phase of MRSA infection, vaccination
is the main measure. However, no safe and effective vaccine for MRSA
infection is currently available. Some herbs or formulae, such as HET,
can prevent MRSA colonization by modulating the mucosal immune response.
In the treatment phase, conventional therapies usually focus on
inhibiting or killing bacteria. TM immune therapies usually account for
both killing bacteria and regulating host immunity to combat MRSA immune
injuries. In the recovery phase, TM therapies exert immune enhancement
function to help MRSA infection recovery. As shown in Table 3, these two
therapies show different mechanisms. Hence, it is inferred that combined
conventional and TM therapies hold great potential for the treatment of
MRSA infection.

Table 3. Differences in the mechanisms of the two therapies\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
Conventional Therapies\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
TM Immune Therapies\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Mucosal immune response\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Oral vaccines have not been developed.\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
They enhance Peyer's batches activation and increase the production of
IgA+B cells and SIgA.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Innate immune response\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
(a) The development and research of vaccines are mainly based on
inhibiting the bacterial immune evasion from innate immune responses,
for example, targeting virulence factors by blocking the complement
system and killing neutrophils. (b) AAC therapy facilitates bacterial
uptake by phagocytic cells through opsonizing by antibodies.\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
(a) Targeting the complement system: They influence the complement
system to regulate the development of MRSA infection. (b) Targeting
neutrophil phagocytosis: They act on neutrophil migration and
recruitment, chemokine expression, macrophage activity and antigen
presentation.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Adaptive immune response\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
The development and research of passive immunotherapy also targets the
molecules or components mediated immune evasion.\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
(a) Targeting T-cell activation: They stimulate T-cell activation and
enhancing T-lymphocyte proliferation. (b) Targeting antibodies: They
increase B-cell activation and antibody titers. (c) Targeting MRSA
immune evasion strategies: They inhibit the formation of bacterial
BFs.\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{6 Conclusion and Prospective Studies}

Conventional therapies are insufficient to treat MRSA infection, and are
even likely to weaken host immunity. TM therapies can regulate the
host's immune responses independently to combat MRSA infection. The
combination of two therapies is a promising strategy and may display
greater efficacy in bacterial infection treatment (Table. 2).

What conditions can combination therapy be used for? Generally,
combination therapy can be used to prevent MRSA infection in specific
populations. For HA-MRSA patients, especially permanent users of medical
devices, removing contaminated devices may lead to the risk of bacterial
infection. Combination therapy can reduce this risk. For the population
with weakened~immune~systems, such as neonates and the elder. TM
therapies can enhance their immunity. For patients with congenital and
acquired diseases caused by impaired neutrophils number and function,
combination therapy can increase the number and function of
neutrophils\textsuperscript{{[}150{]}}. Combination therapy can also
prevent MRSA colonization. It can also be used for the treatment of MRSA
infection. It can treat patients with low immunity who are infected by
MRSA\textsuperscript{{[}68, 86, 145{]}}. Additionally, combination
therapy is a promising therapy for MRSA-BF
infection\textsuperscript{{[}5, 6, 12{]}}.

Current findings have confirmed the synergistic effects of combination
therapy \textsuperscript{{[}7, 8, 85{]}}. However, most of these studies
were performed \emph{in vitro} and in animal models. Few clinical
studies have been performed. Moreover, the corresponding mechanisms of
combination therapy are not revealed. Real-world, multiple-center,
international large-sample randomized controlled clinical trials should
be conducted. In these trials, populations of different ethnicities are
enrolled, and internationally unified efficacy evaluation standards and
evaluation norms are adopted, which will aid the global recognition of
this research. Network pharmacology techniques based on big data and
multi-omics integration analysis approaches have marked advantages for
revealing the mechanism of action of these herbs and formulae by
integrating and analyzing the relationships among proteins, genes and
metabolites. In summary, combination therapy is a promising
immunotherapy strategy for MRSA infection, and the mechanisms need to be
further elucidated.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

Figure 3. Overview of the combined efficacy of conventional therapies
and TM therapies against MRSA infection. Combination with conventional
therapies and TM therapies combats MRSA infection not only by inhibiting
planktonic MRSA and MRSA-BF but also by regulating host immunity. The
combination therapy may exert three effects: additive, synergistic and
attenuating. Combination therapy can be used for both MRSA infection
prevention and treatment. Furthermore, international multi-center CTs
should be performed to confirm curative effects and multi-omics
integration analysis should be used to elucidate the corresponding
mechanisms.

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