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X Use of Angong Niuhuang in Treating Central Nervous System Diseases and Related Research

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In Chinese medicine-based therapeutics, Angong Niuhuang pill (ANP) is one of the three most effective formulas for febrile diseases, and it is also used to treat other diseases. This paper reviews current knowledge regarding the clinical and pharmacological effects of ANP for treating different central nervous system (CNS) diseases to confirm its validity and efficacy. These diseases are like centric fever, coma, stroke, and viral encephalitis. This review reveals that various diseases could be treated using the same agent, which is one of the most important principles of traditional Chinese medicine (TCM). According to the "Same Treatment for Different Diseases" principle, ANP might be efficacious in other CNS diseases.
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Review Article
Use of Angong Niuhuang in Treating Central Nervous System
Diseases and Related Research
Yu Guo,1,2 Shaohua Yan,1Lipeng Xu,1,2 Gexin Zhu,1Xiaotong Yu,1,2 and Xiaolin Tong1
1Endocrinology Department of Guang An Men Hospital, China Academy of Chinese Medical Science, Beijing 100053, China
2Beijing University of Chinese Medicine, Beijing 100029, China
Correspondence should be addressed to Xiaolin Tong; xiaolintong@sina.com
Received  August ; Revised  October ; Accepted  December ; Published  December 
Academic Editor: Paul Siu-Po Ip
Copyright ©  Yu Guo et al. is is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
In Chinese medicine-based therapeutics, Angong Niuhuang pill (ANP) is one of the three most eective formulas for febrile
diseases, and it is also used to treat other diseases. is paper reviews current knowledge regarding the clinical and pharmacological
eects of ANP for treating dierent central nervous system (CNS) diseases to conrm its validity and ecacy. ese diseases are
like centric fever, coma, stroke, and viral encephalitis. is review reveals that various diseases could be treated using the same
agent, which is one of the most important principles of traditional Chinese medicine (TCM). According to the “Same Treatment
for Dierent Diseases” principle, ANP might be ecacious in other CNS diseases.
1. Introduction
e premier description of Angong Niuhuang pill (ANP) is in
Shang Jiao,VolumeOneoftheTreatise on Dierentiation and
Tre atment o f Epidemic Febrile Diseases,writtenbyWu Jutong
in the Qing Dynasty.
CNS diseases manifest mainly at the neural tube, neural
crest, spinal cord, and brain. Typical clinical manifestations
include high fever, headache, dizziness, unconsciousness,
nausea and vomiting, diculty moving, hemiplegic paralysis,
language disorders, weakness, neck rigidity, and epilepsy. In
ancient times ANP was known as the pill that could rescue
the patient immediately and help revive those who were on
the brink of death. It was named “one of the three treasures,
and was used to treat high fevers []. Today, ANP has the
potential to provide new breakthroughs for the treatment of
CNS diseases such as stroke, coma, centric fever, and viral
encephalitis, as well as the design of clinical studies of these
diseases.
2. Clinical Applications
2.1. Stroke. Strokes can be categorized as ischemic or hemor-
rhagic. Cerebral hemorrhage is a brain parenchymal nontrau-
matichematomathatisprimarilycausedbyhypertensionand
the subsequent clogging of arteries. It normally causes intrac-
erebral hematoma; however, the blood sometimes penetrates
the brain parenchyma, which results in intraventricular and
subarachnoid hemorrhage. e clinical features of this type
of stroke are dizziness, headache, vomiting, loss of con-
sciousness, hemiplegia, hemidysesthesia, and hemianopsia
[]. On the contrast, hypoxic-ischemic encephalopathy is
caused by circulatory or respiratory diseases, which results in
an insucient oxygen supply to the brain. If the brain arterial
oxygen partial pressure falls below  kPa, a lack of oxygen
diusion will result in collateral damage to the brain [].
However, in the theoretical system of traditional Chinese
medicine, stroke that results from impaired function of the
liver,kidney,heart,spleen,andothervisceraproducesa
series of pathological changes including wind (mainly in
liver), internal heat (liver and heart heat), phlegm (wind
and wet phlegm), qi (deciency,reverse ow,andstagna-
tion), and blood (deciency and stasis). Stroke disturbs qi-
movement and leads to a qi-blood imbalance,whichareall
the results of external wind,emotionalchanges,improper
diet, too much physical and mental labor, or excessive sexual
activities []. She and Gao [] ascribed the basic theory
of ANP to wind-yang excess.eyfoundthatwind phlegm
and phlegm re disturbed the upper body, which aroused
mental confusion. e key steps of treatment can bring down
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Evidence-Based Complementary and Alternative Medicine
Volume 2014, Article ID 346918, 9 pages
http://dx.doi.org/10.1155/2014/346918
Evidence-Based Complementary and Alternative Medicine
a fever, detoxifying and resolving turbidity and inducing
resuscitation.
Zhan [] randomized  intraventricular hemorrhage
patients into an observation group and a control (C) group.
In addition to conventional treatment, the observation group
was also given with Xing Nao Jing injections, ANP, and
acupuncture. e results showed that intracerebral pressure,
temperature, and the time to recover consciousness were
signicantly better in the observation group than in the C
group (𝑃 < 0.05). Aer  days of treatment, the nerve
function defect grade and the scores of TCM syndrome were
all lower in the observation group than in the C group (𝑃<
0.01).
Moreover, Zhang and Li [] divided  cerebral hemor-
rhage cases in average into two groups, which were treated
with biomedicine or a combination of biomedicine and
Angong and Qingkailing injections. e results revealed
an increased curative eect and treatment ecacy in the
combination group compared with the biomedicine group
(𝑃 < 0.05). e level of disability and death rate in the
combination group were also lower than in the biomedicine
group (𝑃 < 0.05). ese ndings suggest that combining
TCM and biomedicine is eective for reducing the mortality
rates aer cerebral hemorrhage.
In addition, Xing et al. []randomizedpatientswith
cerebral paralysis into a treatment (T) group, which was given
with Angong dissolved in warm water using a nasogastric
tube as well as regular emergency treatment, and a C group,
which received cytidine diphosphate choline, tranquilizers,
and glucocorticoids plus cooling. T group exhibited a cooled
fever (𝑃 < 0.01), coma (𝑃 < 0.05), and convulsions compared
withCgroup.
Wu et al. [ ] conrmed the benets of combining ANP
with biomedicine to treat damaged nerve function in patients
with acute cerebral infarction. Aer treatment, plasma brain
natriuretic peptide (BNP) and C-reactive protein (CRP)
levelsweredecreasedmoremarkedlyinthecombination
treatment group compared with the C group (𝑃 < 0.05).
ese authors stated that use of ANP to reduce plasma BNP
and CRP levels positively aected the neural function of
patients with acute cerebral infarction.
Research regarding the clinical ecacy and safety of ANP
as an adjuvant treatment for moderate or severe neonatal
hypoxic-ischemic encephalopathy (NHIE) revealed that it
aects NHIE. Specically, it could promote patients recovery
anddecreasetheoccurrenceofcomplications[]. Huang
et al. [] reported the clinical eects of ANP during the
treatment of hypoxic-ischemic encephalopathy. Sixty patients
with hypoxic-ischemic encephalopathy were randomized
into a C group given conventional Western medical treatment
and an observation group that also received ANP. Conscious
recovery time, temperature, the occurrence of seizures, the
outcome of the Glasgow Coma Scale (GCS), and clinical e-
cacy were compared between groups. e observation group
had higher GCS scores (𝑃 < 0.02)thantheCgroup.e
observation group also had more stable body temperatures
andshowedfewerconvulsionscomparedwiththeCgroup.
All comparisons were statistically signicant (𝑃 < 0.05). Xiao
[] randomized  patients with ischemic stroke and a
diagnosis of phlegm-heat syndrome into either a comparison
group, which received Western medical treatment, or an
observation group that was administered the basic Western
treatment as well as ANP (one pill orally twice a day). e
TCM syndrome scores that evaluated routine daily living
activities, assessed changes in neurological function, and
analyzed the standards of clinical ecacy revealed that the
basic characteristics of the two groups were not signicantly
dierent. Following treatment, the TCM syndrome scores
of the observation group regarding neurological function,
daily activities, and overall eciency were %, .%, and
.%, respectively, compared with %, .%, and % in
the comparison group. e results revealed that ANP was
highly eective for curing ischemic stroke and phlegm-heat
syndrome.
2.2. Coma. During a coma the depression of cortical and
subcortical mesh structures and functions results in severely
disturbed consciousness. Patients might become semicon-
scious or unconscious, which is apparently a lack of reaction
to pain stimuli and of voluntary movement. Because of
the suppression of higher nerve activity, various external
stimuli are unable to trigger actions including motor reexes,
swallowing, and reaction to light []. ere are two etiologies
of coma. One results from a primary injury to the cerebral
cortex, diencephalon, midbrain, and the top of the pons,
whereas the other might result from brain injury, secondary
systemic toxicity, metabolic blocks, or an endocrine imbal-
ance [].
2.2.1. Coma Caused by Brain Trauma. Skull damage results in
intracranial hemorrhage, intracranial hematoma, increased
intracranial pressure, ischemia caused by decreased cere-
bral blood ow, hypoxia, cerebral edema, the inammatory
response, and apoptosis, which together give rise to brain
damage and coma. A delay in treating a skull damage-induced
comamightleadtotheformationofacerebralhernia,
which has the highest mortality and disability rate among
all bodily injuries []. Chen and Wang []randomized
comatose traumatic brain injury patients to either treatment
(𝑛 = 133)orcontrol(𝑛 = 1790) groups. Patients in both
groups received the same standard care, but patients in T
group were also given ANP twice daily (g each) for a week.
e outcomes of Glasgow Coma Scale (GCS) and Acute
Physiology and Chronic Health Evaluation II (APACHE II)
showed that T group had signicantly lower level of high-
sensitivity CRP and less severe epilepsy. erefore, it was con-
cluded that ANP had a signicant eect on the treatment of
comatose traumatic brain injury patients. Wang []divided
 comatose traumatic brain injury patients with GCS scores
< into treatment and control groups of  patients. Both
groups received treatment to prevent dehydration, maintain
hemostasis, reduce intracranial pressure, and prevent infec-
tion. Patients in the treatment group were given additional
treatments including ANP and head electroacupuncture
combined with hyperbaric oxygen therapy. Aer  weeks the
T group had a better sober rate (𝑃 < 0.001)andGCSscores
(𝑃 = 0.002) than the control group. Furthermore, the T group
had signicantly lower rates of gastrointestinal bleeding
Evidence-Based Complementary and Alternative Medicine
(𝑃 = 0.005) and pulmonary infection (𝑃 = 0.015)thanthe
control group, which suggests that the addition of ANP and
head electroacupuncture plus hyperbaric oxygen therapy to
the normal treatment increased the therapeutic eectiveness
anddecreasedtherateofcomplications.
Lin et al. [] treated comatose traumatic brain injury
patients by using naloxone only in the control group and
naloxone together with ANP in the treatment group. ey
reported signicant dierences in sobriety and intense coma
(mortal) rates between the two groups (𝑃 < 0.05). ere
was also a big dierence in GCS between the treatment
(35.6 ± 1.8)andcontrol(19.3 ± 1.2,𝑃 < 0.01)groups.
Data revealed that the combined use of ANP and naloxone
was more eective for the treatment of comatose traumatic
brain injury patients than use of naloxone alone. Wang et
al. [] evaluated the eect of combining ANP with conven-
tional therapy on brain trauma-induced diuse axonal injury.
Compared with the control group that received conventional
therapy alone, the combined therapy improved conscious-
ness disorder, body temperature, and decerebrate tetanus in
patients to yield favorable prognosis. Li et al. []found
that the recovery time and disease course in patients treated
using ANP combined with biomedicine were shorter than
in patients only treated with biomedicine. In a prospective
randomized clinical trial of  craniopathy patients with
unconsciousness, the addition of ANP to routine treatment
signicantly increased the eciency (𝑃 < 0.005)ofprocesses
used to enhance the excitation processes within the cerebral
cortex of unconsciousness patients [].
2.2.2. Coma Caused by Blocked Cerebral Blood Circulation.
Li et al. [] assessed the eects of ANP on severe cerebral
vascular disease in elderly individuals. e research team
divided  patients into a control group that received regular
treatment and the second group that were administered
regular treatment plus ANP. e total rate of eectiveness,
which was dependent on the clinical neural function, was
higherinthetreatmentgroup(.%)thaninthecontrol
group (.%, 𝑃 < 0.05). e GCS scores were increased
signicantly from baseline in both groups (𝑃 < 0.05), but
the score in the treatment group was higher than that in the
control group (𝑃 < 0.05). In addition, the reduced neurolog-
ical decit scores were higher in the treatment group than in
the control group. Statistics revealed that ANP could promote
the recovery of awareness in patients with severe cerebral
vascular diseases. Shi [] evaluated the eect of the com-
bination of TCM and biomedicine in  patients with coma
caused by brainstem hemorrhage, which shows the benets of
combining Chinese and biomedicine are obvious. Zhang and
Qu [] learnt the eect of ANP combined with biomedicine
for treating hypertensive cerebral hemorrhage. e time of
coma in the treatment group (ANP plus biomedicine) was
shorter than that in the control group (biomedicine only; 𝑃<
0.05). Consistent with this, the neural disorder scores were
lower in the treatment group than in the control group (𝑃<
0.05). However, there were no signicant dierences in blood
pressure uctuation or mortality rate between the two groups.
erefore, ANP promoted recovery from coma and improved
patient prognosis. Qiu and Wu [] studied  rst-episode
patients with an altered mental status following acute cerebral
infarction. All patients received conventional treatment, but
 patients were also administered ANP nasally. e GCS
scores of all  patients improved greatly. However, there
were statistically signicant dierences in the improvement
between the therapy and control groups regarding hemat-
ocrit, brinogen, and blood viscosity (𝑃 < 0.01). erefore,
ANP signicantly inhibited platelet aggregation, prevented
blood clots, and lowered blood viscosity to facilitate the
reversal of narcosis.
2.2.3. Infantile Coma. Li treated  children with infantile
coma by using ANP combined with biomedicine []. Aer
the treatment all but two of the children became fully
conscious. ese results suggest that ANP plus biomedicine
has a huge curative eect on infantile coma and that ANP
could counteract adverse reactions to sedative drugs such as
diazepam and phenobarbital sodium.
2.2.4. Coma Caused by Infectious Diseases. Wang and Zhang
[] evaluated the eect of combining ANP with biomedicine
on infectious disease-induced coma. Based on TCM syn-
drome dierentiation, patients in the treatment group were
given dierent decoctions in addition to ANP. Patients in the
treatment group had signicantly higher GCS scores than the
control group (𝑃 < 0.05), which conrms the applicability of
the ANP toward promoting the heat-clearing and detoxifying
functions, brain activity, and regaining consciousness.
2.3. Centric Fever. Centric fever is a nonpyrogenic fever
resulting from centric damage and an increased temperature
inthecentrum.emainclinicalfeatureisaconstantfever
that is caused by the eects of cerebrovascular disease, cranial
trauma,andMalinsyndrome[]. Shi and Tang [] explored
the antipyretic eects of ANP on centric high fever in 
patients with dierent TCM syndromes including qi system
heat excess syndrome inthechannelsandcollaterals(cases)
and heat excess syndrome and fu organ constipation in the
internal organs ( cases). e data revealed that ANP exerted
denite antipyretic eects on a centric high fever because
the % eectiveness rate was observed. Zhang et al. []
randomized  cranial trauma patients into groups that
received ANP combined with biomedicine (CW; 𝑛 = 126)or
biomedicine only (W; 𝑛=80). ANP was administered nasally
by tube or orally depending on the TCM syndrome. e CW
group had a signicantly greater improvement than the W
group (𝑃 < 0.01). In an additional study, Feng []randomly
assigned conrmed centric fever patients into treatment (T;
𝑛=33) and comparison (C; 𝑛=32) groups, and using
basic physical cooling methods treated both groups, and the T
group also received ANP (orally/lavage/enema). e T group
had an eectiveness rate of .%, which was signicantly
higher than the C group (.%; 𝑃 < 0.01). Li and Bao []
assigned  patients with cranial trauma, centric fever, and
similar baseline characteristics into groups that received a
regular Western treatment for centric fever (group C; 𝑛=50)
or Western treatment plus ANP (group T; 𝑛=50). e T
group had a mean cooling time of  h, compared with  h
in the C group. A follow-up survey revealed that the T group
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survivors had a better quality of life. Zhang and Wang []
assessed the eect of ANP in patients with centric fever that
was caused by cerebral hemorrhage. e overall eectiveness
of treating centric fever by using traditional and biomedicine
(treatment group; 𝑛=36) was higher than using biomedicine
alone (control group, 𝑛=36;𝑃 < 0.01). Jiang []combined
ANP via nasal feeding with biomedicine to treat  patients
with fever that was caused by massive cerebral infarction and
treated without mild hypothermia and hibernation therapy.
e results showed that the eective rate of cooling and
recovered consciousness was .%. erefore, ANP is highly
eective at increasing the recovery of consciousness and
cooling body temperature in patients with massive cerebral
infarction and a high fever.
2.4. Viral Encephalitis. Viral encephalitis is an acute intracra-
nial inammation that is caused by a variety of viruses and is
characterized by fever, headache, vomiting, unconsciousness,
or mental abnormalities. In mild cases full recovery is
possible without medical treatment, whereas severe cases can
result in death or complications. Meningitis is caused by
several dierent viruses and has dierent seasonal incidence
and typical clinical features.
In terms of TCM, viral encephalitis is caused by exposure
to exogenous pathogenic heat, including wind heat,summer
heat,anddryness heat.elung and stomach are the foci of
the lesions involving the heart and liver.Duringtherecovery
stage the lesion organs are the spleen,liver,andkidneys.e
disease results from the conversion of exogenous pathogenic
heat into dryness aer the heat-re attack to the human body.
Viral encephalitis is a common acute disease with a high
prevalence and complicated course; the extreme heat causes
wind and re.epathogenicconditionspreadsandchanges
according to the system of the Defense-qi-Nutrient-Blood, as
well as heat,phlegm,andwind [].
Yu [] randomly assigned  children with viral
encephalitis into treatment (T; 𝑛=13)andcomparison
(C; 𝑛=17) groups. Both groups were given conventional
Western treatments such as antiviral agents, treatment for
dehydration, procedures to decrease the intracranial pres-
sure, and anticonvulsants. e T group was also given ANP
via the mouth or nasal feeding. e clinical evaluation and
clinical course were better in the T compared with the C
group (𝑃 < 0.05). A retrospective clinical analysis by Yao et
al. [] was performed on the clinical data of  patients with
viral encephalitis. e recovery rate and CT or MRI images
indicated that the outcome of the group treated with ANP,
acyclovir, mannitol, and adrenocortical hormone was better
than that of the biomedicine group.
Wang a n d D on g [ ] measured cerebrospinal uid NO
and TNF-𝛼levels in three children groups suering from viral
encephalitis, febrile seizures, and ordinary trauma, respec-
tively. e concentrations were higher in the viral encephalitis
group than in the febrile seizures group and ordinary trauma
group, which shows NO and TNF-𝛼participate in inamma-
tion of the CNS. Zhang et al. [] evaluated the treatment of
 children with viral encephalitis using oral or nasal ANP
combined with basic Western treatment. e total rate of
eectiveness was signicantly higher (.%) in the group
11.30%
17.88%
27.94%
42.88%
Stroke
Coma
Centric fever
Viral encephalitis
F : e distribution of severe nerve disease cases treated with
ANP.
given ANP than in the comparison group (.%; 𝑃 < 0.05).
e levels of TNF-𝛼in the cerebrospinal uid, a standard
marker used to assess the eectiveness of treatment, declined
sharply in both groups. erefore, ANP could decrease TNF-
𝛼levels, improve recovery rates, and reduce the treatment
periods. Liang [] reported the clinical eect of combining
Chinese and biomedicinal therapy to treat viral encephalitis
in children. TNF-𝛼levels in the treatment group, which were
treated using ANP plus biomedicine, declined more steeply
than did those in the control group, which were treated
usingonlyWesternmedicine(𝑃 < 0.05). erefore, the
data reveal signicant advantages of combining Chinese and
biomedicine to treat viral encephalitis.
A total of  cases of severe nerve disease that were
treated using ANP were analyzed in the clinical studies
described above. Among these,  coma cases comprised
.% of the total cases, which was the highest percentage
of the conditions. Analysis of the distribution of the severe
nerve disease cases revealed that coma and viral encephalitis
were the most and least prevalent, respectively (Figure ).
3. Pharmacological Studies
3.1. Cerebral Protection
3.1.1. Reducing Brain Edema. Cephaledema oen follows
intracerebral hemorrhage. Its causes are complex and lead
to pathological changes in physiology and function such as
the formation of intracerebral hematomas, decreased cerebral
blood ow, ischemic anoxia of brain tissue, and metabolic
disorders []. Matrix metalloproteinases, particularly matrix
metalloproteinase- (MMP-), are closely related to the
formation of cephaledema and destruction of the blood-
brain barrier because they can degrade all components of
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the extracellular matrix []. Jiang et al. []foundthat
changes in serum MMP- levels were correlated with the
evolution and volume of brain edema, and that they had a
direct eect on the condition. ANP can reduce brain edema
aer cerebral hemorrhage by regulating the expression of
MMP-.Yinetal.[,] performed two animal experiments
to demonstrate that ANP can modulate the expression of
MMP- and eectively reduce brain edema in rats with
experimental cerebral hemorrhage. Zhu []usedtheFeeney
assayinaratmodelofclosedbraininjurytodemonstrate
that the administration of ANP resulted in a greater decrease
in brain water content and cerebral cortex Evans Blue dye
content compared with the model control and Nimotop
treatment groups. In the ANP-added group, an increase in
synaptic density in the lateral ventricle was observable using
electron microscopy. erefore, ANP could reduce brain
edema by decreasing capillary permeability and improving
the tolerance to ischemia or hypoxia, thereby protecting the
organization of the brain. In a rat model of middle cerebral
arterial occlusion, Zhao [] found that ANP, both with
and without the coadministration of cinnabar and realgar,
could dramatically reduce the cerebral infarction area and
brain water content, increase the levels of catalase (CAT) and
glutathione peroxidase (GPX), and lower the levels of lipid
peroxide (LPO) and lactic acid (LD). is suggests that ANP
couldprotecttheanimalsfromcerebralischemiainawaythat
might be related to its antioxidant eects.
3.1.2. Anti-Inammatory Eects. Yin []developedarat
intracerebral hemorrhage (ICH) model by injecting anti-
coagulated arterial blood into the caudate nucleus. e
inammatory cells around the hematomas were then counted
using H&E staining. In addition, RT-PCR was used to assess
the expression of TNF-𝛼mRNA, and an ELISA was used
to measure TNF-𝛼protein. ANP reduced the number of
inammatory cells around the hematomas, inhibited the
expression of TNF-𝛼mRNA and protein, and inhibited the
inammatory reaction in rats with ICH.
3.1.3. Neuroprotective Eects. Zhang et al. []usedprimary
rat midbrain neuronal-glia cultures as an in vitro model
to measure the neuroprotective eects of dierent agents.
Compared with the normal control group, the number of
dopamine (DA) neurons in the lipopolysaccharide (LPS)
model group was decreased by % (𝑃 < 0.05). LPS also
activated the microglia. e expression of TNF-𝛼and iNOS
mRNA was increased in the microglia in LPS control group
(𝑃 < 0.05). Compared with the LPS control group, LPS-
mediated DA neuronal loss was attenuated signicantly by
% and % by the administration of ANP and realgar,
respectively (𝑃 < 0.05), whereas the activation of microglia
and the expression of TNF-𝛼mRNA were decreased by
% and % (𝑃 < 0.05). ese results demonstrate that
ANP protects against LPS-induced neurotoxicity via anti-
inammatory properties and suggest that realgar might play
a key role in the neuroprotective eects of ANP. In contrast,
cinnabar did not exert any neuroprotective eects. Li et al.
[] studied heat shock protein  (HSP) expression in
rats with cerebral ischemia injury. e infarct volume was
signicantly smaller in the ANP group compared with that
in the ischemia group (𝑃 < 0.05). HSP expression was
signicantly higher in the ANP group than in the ischemia
group. ANP increased HSP expression and protected brain
cells from cerebral ischemia beginning on day .
Zhong et al. [] found that ANP could promote angio-
genesis in the cerebral cortex and striatum of ischemic rats
andalsoincreasetheamountofbloodvesselsintheinjured
area. It also increased neurogenesis in the subgranular zone
(SGZ), subventricular zone (SVZ), cortex, and striatum.
Experimental results assessing the protective eects of ANP
in a model of experimental cerebral ischemia in rats showed
that it could not only decrease the cerebral water content,
but also increase the serum levels of interleukin- (IL-)
[]. is inhibits the expression of the inammatory cell
factors IL-, IL-, and IL- and their receptors, thereby reduc-
ing inammatory reactions and tissue injury []. During
cerebral ischemia and cerebral infarction, IL- facilitates
recovery and the survival of injured neurons by alleviating
inammation and inhibiting neuronal apoptosis in areas of
cerebral hemorrhage [,]. A recent review discussed the
role of ANP in inhibiting nerve cell apoptosis by upregulating
the phosphorylation of Akt, which is the key molecule for the
survival of motor neurons following cerebral ischemia [].
3.1.4. Eects on Nitric Oxide (NO) and Nitric Oxide Synthase
(NOS). NOS participates in the release of free oxygen rad-
icals during brain ischemia-reperfusion. eNOS in vascular
endothelial cells catalyzes the release of NO via L-arginine.
In turn, NO maintains normal vascular function []. Xing
and Zhang [] randomized  patients with cerebral hemor-
rhageintogroupsthatreceivedcytidinediphosphatecholine
(observation group; 𝑛=33) or ANP (comparison group,
𝑛=35
). One week later serum asymmetric dimethylarginine
(ADMA) levels were reduced signicantly in the observation
group compared with those in the comparison group (𝑃<
0.01). However, there was a signicant increase in NO in
the serum of the observation group (𝑃 < 0.01). Liu et
al. [] used a hypertensive (hypervolemic) rat model to
demonstrate that the serum NO content was lower in animals
treated using integrated Chinese and biomedicine compared
with the other three groups (TCM group, biomedicine group,
and control group) (𝑃 < 0.05). Data revealed that ANP
combined with biomedicine could alleviate acute brain tissue
injury during the acute stage of spontaneous hypertensive
cerebral hemorrhage in rats. Yang et al. []veriedthe
protective eects of ANP in acute cerebral hemorrhage by
demonstrating that it could decrease NO levels, NOS activity,
and the cerebral monoamine neurotransmitter content.
3.2. Resuscitation and Sedation Eects. When studying the
sedative eects of ANP and its simplied prescription, Ye et al.
[] found that the administration of ., ., and .g kg−1
ANP once daily with  mg kg−1 pentobarbital sodium
(below the hypnotic threshold) had more pronounced
synergisticsedationeectsthandidthemodelcontrolgroup
(𝑃 < 0.005).
Evidence-Based Complementary and Alternative Medicine
T : Main pharmacological ingredients and the pharmacological eects of the main constituent herbs.
Herbs [] Main pharmacological ingredients [] Pharmacological eects []
Bezoar
Bilirubin
Bile acid
Deoxycholic acid
Taurine
Cholesterol
Sedation
Anticonvulsion
Antipyretic
Anti-inammatory
Antiviral
Cardiotonic
Antiplatelet
Aggregation
Rhinoceros horn
Keratin
Cholesterol
Calcium phosphate
Calcium carbonate
Sedation
Anticonvulsion
Antipyretic
Anti-inammatory
Antiviral
Cardiotonic
Antiplatelet
Aggregation
Radix scutellariae
Baicalin
Baicalein
Wogonoside
Wogonin
Neobaicalein
Anti-pathogeny microorganism
Anti-inammatory
Antiallergy
Antipyretic
Sedation
Hepatoprotective
Cholagogue
Coptidis rhizome Berberine
Anti-pathogeny microorganism
Antipyretic
Anti-inammatory
Antiallergy
Cholagogue
Sedation
Hepatoprotective
Cape jasmine
Gardenoside
Geniposide
Genipin
Anti-pathogeny microorganism
Anti-inammatory
Anti-allergy
Antipyretic
Sedation
Hepatoprotective
Cholagogue
Musk Muscone
Double-acting role in regulating the CNS,
anti-inammatory
Antiplatelet aggregation
Cardiotonic
Borneol Borneol
Double-acting role in regulating the CNS,
anti-inammatory
Postoperative analgesia
Antimicrobial
Antimyocardial ischemia
Antifertility
Curcuma
Curcumene
Curcumine
Turm e r o n e
Ar-turmerone
Anticancer
Hepatoprotective
Cholagogue
Exciting gastrointestinal smooth muscle
Immunosuppressive
3.3. Antipyretic Eects. Experiments performed by Ye con-
rmed that ANP and its simplied prescription (without
Zhusha and Xionghuang) exerted clear antipyretic and seda-
tive eects in models including rabbits with high fevers
caused by typhoid vaccine, sleeping rats caused by pento-
barbital sodium, oxygen-decient rats killed using NaNO2,
and rats with eclampsia was caused by strychnine nitrate
and PTZ []. Jin and Pan [] administered . g/kg
Evidence-Based Complementary and Alternative Medicine
ANP by intraperitoneal injection to rabbits, and the rise
in body temperature of the rabbits caused by the triple
vaccine was clearly lower than the control group aer
.–. h.
With the development of pharmacological research, the
main drugs in Angong Niuhuang prescriptions and their
pharmacological eects have been identied, which revealed
that Angong Niuhuang is eective for the treatment of
diseases of the nervous system (Tab l e  ).
4. STDDP Applied in CNS Diseases
RegardlessofthecauseandpathogenesisofthefourCNSdis-
eases described above, their symptoms overlap. For example,
stroke patients and children with viral encephalitis can also be
in a coma or have a high fever. erefore, Chinese clinicians
consider these dierent diseases from a TCM perspective
and nd the common features that represent the same TCM
pathogenesis and then make a decision to use the same
medicine or treatment according to the “Same Treatment
for Dierent Diseases” principle (STDDP), which is a crucial
principle of TCM.
STDDP has been widely applied in TCM. In addition
to the diseases described above, ANP can also be used to
treat pulmonary cerebral disease, insolation, and eclampsia,
which can have common symptoms such as coma and high
fever []. As a result, the use of ANP for centuries has
suggested that it could be used to treat CNS diseases by both
Chinese and Western clinicians.
5. Conclusion
Although the mechanism by which ANP cures these dis-
easesandtheactiveingredientswithinANPareyettobe
elucidated, Chinese clinicians have used ANP to treat CNS
diseases for hundreds of years, which suggested that ANP is
both eective and safe.
We realize that clinical research is not an end but a way to
solve clinical problems. With the development of evidence-
based medicine, clinical research has developed from the
case level to the population level, and best evidence has
become the main principle of prescriptions. Findings have
been reported and scrutinized, and TCM research should
continue to be performed in real-world studies to ensure the
reliability of the results.
e results of the literature are persuasive; however, there
are some problems with the way the clinical conditions have
been analyzed. () e clinical observations and research
areofpoorquality.Forexample,mostofthestudieson
stroke patients, including cases of cerebral hemorrhage and
cerebral ischemia, do not report the symptoms fully. Even the
blockage syndrome”and“prostration syndrome”deviatefrom
the principle of combining disease, syndrome, and symptom.
is could be attributable to a lack of response to treatment.
() Few trials have studied the mechanism of central heat-
ing, which could be attributed to a lack of mature animal
models. () ere is small number of single case reports,
which is consistent with the development of evidence-based
medicine.
Research Highlights
() Because of its fever-reducing, detoxication, and
decongestive actions, ANP has long been used to treat
conditions such as coma, fever, and cephaledema in
China.
() Modern pharmacological studies reveal that ANP
aects the central nervous system by relieving cere-
bral edema, exerting antipyretic and anti-inamma-
tory eects, and allowing resuscitation and sedation,
as well as other related actions.
() e indication for ANP in treating CNS diseases
highlights the “Same Treatment for Dierent Diseases
principle.
Disclosure
e paper is original, has not been submitted to and is not
under consideration by another publication, has not been
previously published in any other language or form, including
electronic version, and contains no disclosure of condential
information or authorship/patent application/funding source
disputations.
Conflict of Interests
e authors declare no conict of interests.
Authors’ Contribution
Yu Guo and Shaohua Yan collected data and wrote the paper.
LipengXu,GexinZhu,andXiaotongYuprovideddataforthe
paper. Xiaolin Tong reviewed the paper. All authors approved
the nal version of the paper.
Acknowledgment
is work is supported by the National Basic Research
Program  (no. CB).
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... Here, we selected a composite formula of neuroprotection and antiinflammation agents which has been in use for 200 years till this day, its name being Angong Niuhuang pill (Angong). In this composite formula, at least half of the ingredients (herbal or animal components) had neuroprotective and antithrombic activities [6] [7] [8]. Components of three anti-inflammatory herbs in the formula have been classified as ocular protective agents and they were extracts from Gardenia jasminoides, Coptis chinensis and Scutellaria baicalensis [9] [10] [11] [12]. ...
... For Scutellaria baicalensis, the main chemical is Baicalin which is antimicrobial [19]. The chemical constituents above were documented to affect the blood brain barrier of experimental animals [6] [8]. ...
... Borneol is a highly lipid-soluble bicyclic terpene which is mainly extracted from Cinnamomum camphora (L.) and Blumea balsamifera (L.) (Zhang et al., 2017;Zheng et al., 2018). In Traditional Chinese Medicine, borneol as a messenger drug is a well-known prescription to treat strokes (Guo et al., 2014). Borneol is known as a "Courier herb" that helps to direct the herbs upward to the target organ, particularly in the brain. ...
Article
Introduction: A worldwide pandemic infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a deadly disease called COVID-19. Interaction of the virus and the Angiotensin converting-enzyme 2 (ACE2) receptor leads to an inflammatory-induced tissue damage. Thymus vulgaris L. (TvL) is a plant with a long history in traditional medicine that has antimicrobial, antiseptic, and antiviral properties. Thymol and Carvacrol are two important biological components in Thyme that have anti-inflammatory, antioxidant, and immunomodulatory properties. This study is a molecular review on the potential effects of TvL and its active compounds on SARS-COV2 infection. Method: This is a narrative review in which using PubMed, Scopus, ISI, Cochrane, ScienceDirect, Google scholar, and Arxiv preprint databases, the molecular mechanisms of therapeutic and protective effects of TvL and its active compounds have been discussed regarding the molecular pathogenesis in COVID-19. Results: Thyme could suppress TNF-alpha, IL-6, and other inflammatory cytokines. It also enhances the anti-inflammatory cytokines like TGF-beta and IL-10. Thyme extract acts also as an inhibitor of cytokines IL-1-beta and IL-8, at both mRNA and protein levels. Thymol may also control the progression of neuro-inflammation toward neurological disease by reducing some factors. Thyme and its active ingredients, especially Thymol and Carvacrol, have also positive effects on the renin-angiotensin system (RAS) and intestinal microbiota. Conclusions: Accordingly, TvL and its bioactive components may prevent COVID-19 complications and has a potential protective role against the deleterious consequences of the disease.
... Angong Niuhuang pill (ANP) is a famous traditional Chinese medicine which is used for the treatment of coma after stroke. In China, ANP was employed as adjuvant therapy for treating acute cerebral infarction and acute ICH [18][19][20]. ICH is often accompanied with intestinal mucosal injury and intestinal permeability increase. However, the role of the parasympathetic nervous system in the effects of ANP on ICH remains unclear and needs to be studied. ...
Article
Stroke is a devastating disease, intracerebral hemorrhage (ICH) is a devastating subtype. This study aimed to investigate whether cholinergic receptors participate in the process of Angong Niuhuang Pill (ANP) improving neurological function and relieving intestinal injury in ICH mice. The mice were treated with ANP, cholinergic receptor blockers, atropine (ATR), penehyclidine hydrochloride (PHC) or methyllycaconitine (MLA). Male CD-1 mice were randomly divided into 9 groups, Sham, ICH, ANP (0.2 g/kg), ANP plus ATR, ANP plus PHC, ANP plus MLA, ATR, PHC, MLA. ICH model is made by collagenase VII injection (0.075 U). ANP (0.2 g/kg) was administered by gavage after 30 min of ICH. MLA, ATR, PHC was given at 15 min after ICH. Neurological function was evaluated by Garcia test. Intestinal injury was observed by histological analysis. Endotoxin (ET) was measured by enzyme-linked immunosorbent assay. Compared to the Sham group, the score of Garcia test in the ICH significantly decreased. ANP increased significantly the score of ICH mice. ANP also ameliorated the intestinal injury caused by ICH. Cholinergic receptor blockers reversed partially the improvement of neurological function and intestinal injury by ANP. ANP attenuates the neurological deficits and intestinal injury in ICH mice and the protective effect of ANP may be involved in the regulation of the cholinergic system.
... Accumulating evidence highlights the central role of the microbiota-gut-brain axis in preventing and treating stroke, implying that modulation of the gut microbiota is becoming a new target for anti-stroke therapies. In this study, we validated the therapeutic effects of ANP in a mouse model of acute ischemic stroke using multiple histopathological examinations and a neurological deficit score assessment in mice, and our findings were consistent with clinical data (Guo et al., 2014;Liu FIGURE 5 LEfSe analysis for the gut microbiota alterations among the groups. (A) LEfSe analysis between the model group and the sham group. ...
Article
Full-text available
Angong Niuhuang Pill (ANP) is a famous traditional Chinese patent medicine and is used for treating ischemic or hemorrhagic stroke for centuries. However, the mechanism of action of ANP in stroke treatment has rarely been reported. With increasing evidence for a mechanistic link between acute ischemic stroke and gut microbiota alterations, this study aimed to determine the mechanism of action of ANP in treating acute ischemic stroke from the perspective of the gut microbiota. A mouse model of acute ischemic stroke by middle cerebral artery occlusion (MCAO) was established, and 16S ribosomal RNA (rRNA) gene sequencing and metabolomic analysis were performed on the cecal content samples collected from the sham, model, and ANP-treated MCAO mice. The results showed that ANP significantly ameliorated cerebral infarct volume, improved neurological deficits, and reduced histopathological injuries in the ipsilateral ischemic cortex, hippocampus, and striatum. The latter effects included inhibition of neuronal death, increased Nissl bodies, and decreased cell apoptosis. Moreover, ANP reversed gut microbiota dysbiosis by modulating the abundance of bacteria whose effects may mitigate MCAO damage, such as the phyla Bacteroidetes and Firmicutes , the families Lachnospiraceae and Prevotellaceae , and the genera Alloprevotella and Roseburia . Microbial metabolites related to inflammation and neuroprotection, such as prostaglandin I2 and uridine, were also regulated by ANP treatment. Uridine, guanosine, and inosine might be potential neuromodulators produced by the gut microbiota in the ANP-treated group. Spearman correlation analysis revealed that these metabolites were intimately related to certain genera, including Alloprevotella , Lachnoclostridium , Enterorhabdus , Roseburia , Lachnospiraceae_UCG-006 , and Colidextribacter . Our results demonstrated that alleviating gut microbiota dysbiosis is one of the mechanisms by which ANP protects against ischemic stroke and suggest that targeting Alloprevotella , Lachnoclostridium , Enterorhabdus , Roseburia , Lachnospiraceae_UCG-006 , and Colidextribacter might be a potential anti-stroke therapy.
... According to the TCM theory and clinical practice, ANP has been proved to be beneficial to the treatment of various central nervous system diseases, such as stroke coma, meningitis and intracerebral hemorrhage [1]. A recent meta-analysis of 18 trials involving 1601 patients reported that adjuvant treatment with ANP could significantly improve the total response rate and reduce the neurologic deficit score in patients with acute cerebral infarction and acute intracerebral hemorrhage [2]. ...
Article
Full-text available
Background Angong Niuhuang Pill (ANP), a renowned precious traditional Chinese medicine prescription, is extensively utilized for the clinical treatment of stroke, meningitis and encephalorrhagia in China. As a classic resuscitation-inducing aromatic prescription, ANP has been investigated for its pharmacological effects in recent years, while the volatile composition in ANP still lacks comprehensive elucidation. Method To better explore the volatile constituents in ANP, a qualitative analysis method was developed based on gas chromatography coupled with mass spectrometry. Furthermore, a validated quantitative method was established to determine 21 main compounds in 8 batches of commercially available ANP samples by gas chromatography-tandem mass spectrometry. The quantitative data were successively subjected to Pearson correlation coefficient analysis. Additionally, the absorbed volatile constituents in rat plasma after single oral administration of ANP have also been characterized. Results A total of 93 volatile constituents including 29 sesquiterpenoids, 28 monoterpenoids, 13 fatty acids and their esters, 7 alkanes, 6 ketones, 3 phenols, 3 aldehydes, 2 benzoate esters, and 2 other types, were preliminarily characterized, which primarily originated from Borneolum, Moschus, Curcumae Radix, and Gardeniae Fructus. d -Borneol, isoborneol and muscone were the top three abundant ingredients (> 600 μg/g) in 8 batches of ANP samples. Subsequently, the average Pearson correlation coefficient of the contents of 21 analytes was 0.993, inferring the high batch-to-batch similarity among 8 batches. After oral administration of ANP, d -borneol, isoborneol, muscone and camphor were the main volatile constituents absorbed in the rat plasma. Conclusion This research may be helpful for the comprehensive quality control study of ANP, and provide for guarantee the clinical efficacy of ANP.
... AGNHW was first documented in the Qing Dynasty (seventeenth century) [22], and it has been approved for acute stroke treatment by the China's State Food and Drug Administration. AGNHW has neuroprotective effects in ischemic stroke patients [23]. Previous studies indicate that AGNHW can reduce infarct volume, attenuate brain edema, and improve neurological functions in animal models of ischemic stroke [24][25][26][27]. ...
Article
Full-text available
Background Hemorrhagic transformation (HT) is a common complication of delayed tissue plasminogen activator (t-PA) treatment for ischemic stroke. Peroxynitrite plays an important role in the breakdown of blood–brain barrier (BBB) and the development of HT. We tested the hypothesis that Angong Niuhuang Wan (AGNHW), a traditional Chinese medicinal formula, could be used in conjunction with t-PA to protect the BBB, minimize HT, and improve neurological function by suppressing peroxynitrite-mediated matrix metalloproteinase-9 (MMP-9) activation. Methods We first performed quality control study and chemical identification of AGNHW by using UPLC. In animal experiments, male Sprague–Dawley rats were subjected to 5 h of middle cerebral artery occlusion (MCAO) followed by 19 h of reperfusion plus t-PA infusion (10 mg/kg) at 5 h of cerebral ischemia. AGNHW (257 mg/kg) was given orally at 2 h after MCAO. Hemorrhagic transformation was measured using hemorrhagic scores and hemoglobin levels in ischemic brains. Evans blue leakage was utilized to assess the severity of the blood–brain barrier (BBB) damage. The modified neurologic severity score (mNSS) test was used to assess neurological functions. Peroxynitrite and superoxide was detected by using fluorescent probes. MMP-9 activity and expression were examined by gelatin zymography and immunostaining. The antioxidant effects were also studied by using brain microvascular endothelial b.End3 cells exposed to 5 h of oxygen and glucose deprivation (OGD) plus 5 h of reoxygenation with t-PA treatment (20 µg/ml). Results AGNHW significantly reduced the BBB damage, brain edema, reduced hemorrhagic transformation, enhanced neurological function, and reduced mortality rate in the ischemic stroke rats with t-PA treatment. AGNHW reduced peroxynitrite and superoxide in vivo and in vitro and six active chemical compounds were identified from AGNHW with peroxynitrite scavenging activity. Furthermore, AGNHW inhibited MMP-9 activity, and preserved tight junction protein claudin-5 and collagen IV in the ischemic brains. Conclusion AGNHW could be a potential adjuvant therapy with t-PA to protect the BBB integrity, reduce HT, and improve therapeutic outcome in ischemic stroke treatment via inhibiting peroxynitrite-mediated MMP-9 activation. Graphical Abstract
... Apart from purified cinnabar, rasa chenduram also contains a minimum quantity of mercuric sulphide that would have potentiated the antioxidant and anti-inflammatory properties of CC in ischemic condition. Interestingly, a traditional Chinese medicine Angong Niu Huang Wan (AGNHW) which includes arsenic sulphide and cinnabar combination is used for acute ischemic stroke and traumatic brain injury in China for centuries (Guo et al., 2014) and it could be a useful alternative therapeutic agent for ischemic stroke patients. Also, AGNHW has attenuated the brain injury in rat model of ischemic stroke through up-regulation of Bcl-2 and down-regulation of Bax and caspase-3 (Wang et al., 2014). ...
Article
Ethnopharmacological relevance Chandamarutha Chenduram (CC), an Indian traditional Siddha preparation officially recorded in the Siddha formulary of India and its composition are widely used in the Siddha practice of neurological disorders like stroke/paralysis in India. However, the scientific validation and mechanistic evidence is lacking and yet to be elucidated. Aim of the study To establish the scientific evidences and to explore the possible neuroprotective mechanism of CC in cerebral ischemia. Materials and methods Chemical standardization of the CC was performed using atomic absorption spectroscopy and gravimetric analysis. Acute toxicity study for CC in mice was performed in accordance with OECD 423 guidelines. CC (5 mg/kg) and CC (10 mg/kg) were investigated in bilateral common carotid occlusion (BCCAo) model in mice. After, behavioral assessments, the brain samples were collected and the hippocampus region was micro-dissected for neurotransmitter, neurobiochemicals and inflammatory cytokines estimation. The excitatory amino acid transporter-2 (EAAT-2) expressions was analyzed by RT-PCR to understand the possible molecular mechanism. In addition, hematoxylin and eosin staining of CA1 hippocampal brain region was performed to support the neuroprotective effect of CC in ischemic condition. Results Chemical standardization analysis showed that CC has acceptable range of mercury (0.82 ppm) and elemental sulphur (11% w/w). Also, other heavy metal limits were found to be less or not detectable. Toxicity study also evidenced the safety profile of CC. CC has significantly reversed the behavioral dysfunctions (p < 0.001) in global ischemic mice. Treatment with CC has attenuated the excitatory neurotransmitter glutamate, lipid peroxide, nitric oxide, cytokines (IL-1β, TNF-α) (p < 0.001) and increased the antioxidant enzymes (SOD, CAT, GSH) and EAAT-2 expression level (p < 0.001) in ischemic brain. The hematoxylin and eosin staining in CA1 region of hippocampus also evidence the neuroprotective effect exhibited by CC. Conclusions Treatment with CC has exhibited dose dependent effect and CC10 has shown significant protective effect in comparison to CC5 in most of the parameters studied. CC prevented further degeneration of neurons in cerebral ischemic mice through ameliorating inflammatory cytokines and oxy-radicals mediated EAAT-2 dysfunction and subsequent excitotoxicity in neurons.
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Corona virus disease (COVID-19) is a pandemic disease caused by SARS-COV2 that attacks primarily the respiratory system of the host. This disease was first reported in early December 2019, and the World Health Organization (WHO) classified the ongoing COVID-19 outbreak as a pandemic disease causing global public health emergency by mid-January 2020. It is the human-to-human transmission that occurs by droplets, infected hands or surfaces with an incubation time of 2-14 days. It displays signs and symptoms, and if the disease progresses it leads to death. To avoid symptomatic symptoms or increase infection severity, early diagnosis, quarantine, and supportive care can help to cure the patient infected with COVID-19. Several attempts have been projected for the development of vaccines against COVID-19. As of July 2, 2021, 600 vaccine candidates worldwide were evaluated against SARS-CoV-2, in which 300 have reached out to the preclinical stage of their development. Presently, Moderna (mRNA-1273), Shenzhen Geno-Immune Medical Institute (LV-SMENP-DC), Shenzhen Geno-Immune Medical Institute (Pathogenspecific aAPC), CanSino Biologicals (Ad5-nCoV), Inovio Pharmaceuticals (INO-4800) have plunged into the phase I/II clinical trials (Source: ClinicalTrials.gov website; WHO). Scientists are increasingly seeking a key hide behind pathogenic pathways and epidemiological features, as well as future drug goals, which will lead to the development of successful strategies for prevention and treatment. Based on the current published data, we summarize the structure, life cycle of SARS-CoV2 and the various product categories available as anti-COVID-19 agents (antiviral), with special emphasis on Chinese herbal medicines, which were licensed as anti-COVID agent by the Chinese Government. Such knowledge can be used as guidelines for COVID-19 clinical therapy. Keywords: COVID-19, coronavirus, Anti-COvid drugs, Chinese traditional medicine, Chloroquine, Herbal Medicine.
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The ancient composite formulae Angong Niuhuang pill and Pien Tze Huang that were used a few hundred years ago to treat febrile disease and inflammation respectively are found to exert effects benefiting other neurological diseases and conditions. This short review introduces the main constituents of the two formulae, looking into both the cumulative synergetic and possible individual effects of each herb or animal apcoien. In essence, the main effects of Angong Niuhuang pill include antiinflammation, antioxidation, anti-cell death, anticonvulsion, antiedema, antipyretic, antithrombotic, antimicrobial (bacteria, viruses, fungi), neuroprotective effects, and cardiovascular protection. The main effects of Pien Tze Huang include antiinflammation, antioxidation, anti-cell death, antithrombotic, antimicrobial, neuroprotective effects, and cardiovascular protection. Comparing both composites, similarities of the effects and part of the components are found, showing some pharmacological evidence. This review casts light on research on the effects of neuroprotective and cardiovascular protective mechanisms as well as treatment mechanisms for cerebral accidents in the integrative medicine perspective.
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Cerebral ischemic reperfusion injury (CI/RI) is a critical factor that leads to a poor prognosis in patients with ischemic stroke. It is an extremely complicated pathological process that is clinically characterized by high rates of disability and mortality. Current available treatments for CI/RI, including mechanical and drug therapies, are often accompanied by significant side effects. Therefore, it is necessary to discovery new strategies for treating CI/RI. Many studies confirm that Chinese herbal medicine (CHM) was used as a potential drug for treatment of CI/RI with the advantages of abundant resources, good efficacy, and few side effects. In this paper, we investigate the latest drug discoveries and advancements on CI/RI, make an overview of relevant CHM, and systematically summarize the pathophysiology of CI/RI. In addition, the protective effect and mechanism of related CHM, which includes extraction of single CHM and CHM formulation and preparation, are discussed. Moreover, an outline of the limitations of CHM and the challenges we faced are also presented. This review will be helpful for researchers further propelling the advancement of drugs and supplying more knowledge to support the application of previous discoveries in clinical drug applications against CI/RI.
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To improve the pharmacokinetics and stability of recombinant human erythropoietin (rhEPO), rhEPO was successfully formulated into poly(ethylene glycol)-poly(d,l-lactide) (PEG-PLA) di-block copolymeric micelles at diameters ranging from 60 to 200 nm with narrow polydispersity indices (PDIs; PDI < 0.3) and trace amount of protein aggregation. The zeta potential of the spherical micelles was in the range of -3.78 to 4.65 mV and the highest encapsulation efficiency of rhEPO in the PEG-PLA micelles was about 80%. In vitro release profiles indicated that the stability of rhEPO in the micelles was improved significantly and only a trace amount of aggregate was found. Pharmacokinetic studies in rats showed highly enhanced plasma retention time of the rhEPO-loaded PEG-PLA micelles in comparison with the native rhEPO group. Increased hemoglobin concentrations were also found in the rat study. Native polyacrylamide gel electrophoresis results demonstrated that rhEPO was successfully encapsulated into the micelles, which was stable in phosphate buffered saline with different pHs and concentrations of NaCl. Therefore, PEG-PLA micelles can be a potential protein drug delivery system.
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OBJECTIVE: To study the protective effect of IL-10 on the injury by focal cerebral ischemia in rats. METHODS: The middle cerebral artery(MCA) was occluded for different time with modified Zea Longa's MCAO model. Then IL-10(0.5 or 1 μg) was administered centrally into lateral ventricle at 0.5 or 3 h after MCAO, the controls were treated with saline. RESULTS: Compared with the group treated with saline, the infarct volume marked and the quantity of neuron necrosis decreased(P < 0.05), and the infarct volume 1 μg IL-10 was smaller than that the group treated with 0.5 μg IL-10(P < 0.05), and the infarct volume in the group treated with 0.5 h IL-10 was smaller than that in the group treated with 3 h IL-10(P < 0.05). Compared with the saline group treated with saline, the infiltration of leukocyte was significantly reduced in the group treated with 0.5 h IL-10 group(P < 0.05), and the infiltration of leukocyte in the group was smaller than that in the group treated with 0.5 μg IL-10(P < 0.05). While compared with the group treated with saline the infiltration of leukocyte in group treated with IL-10 for 3 h showed no difference (P > 0.05). CONCLUSION: IL-10 plays a protective role in focal cerebral ischemia. It may show a protective role by inhibiting apoptotic cascade and decreasing the chemotaxis and infiltration of leukocyte to ischemic area.
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OBJECTIVE: To investigate the role of cinnabar and realgar in Angong Niuhuang Wan (AGNH) - produced neuroprotection against lipopolysaccharide (LPS) - mediated neuronal damage and further explore the corresponding mechanisms. METHODS: Primary rat midbrain neuron-glia cultures were used as an in vitro model to investigate effects of AGNH on LPS-mediated degeneration of dopamine (DA) neurons. The experiment was divided into normal control group, LPS model group, LPS + cinnabar (4 and 40 mg·L -1) groups, LPS + realgar (4 and 40 mg·L -1) groups and LPS + AGNH (40 and 400 mg·L -1) group. Drugs were added 30 min before LPS treatment. After 7 d, dopaminergic neurotoxicity was assessed through the quantification of tyrosine hydroxylase (TH)-positive neurons and morphological analysis of TH-positive neurons; the activation of microglia was evaluated using OX-42 antibody; the gene expression of tumor necrosis factor-α (TNF-α) and induced nitric oxide synthase (iNOS) mRNA in microglia was performed by real-time RT-PCR analysis, and the release of TNF-α and nitric oxide (NO) in the supernatant of neuron-glia cultures was determined respectively by the ELISA and Griess reagent. RESULTS: Compared with normal control group, DA neurons in LPS model group decreased by 40% (P < 0.05), microglial activation was induced, the expression of TNF-α mRNA and iNOS mRNA in microglia increased 9 and 2 times, respectively (P < 0.05), and subsequent production of TNF-α and NO in the supernatant of neuron-glia cultures increased 20 and 30 times, respectively (P<0.05). Compared with LPS model group, AGNH 400 mg·L -1 and realgar 40 mg·L -1 significantly attenuated LPS-mediated DA neuronal loss by 40% and 30%, respectively (P <0.05) and inhibited activation of microglia and expression of TNF-α mRNA by 61% and 52% (P<0.05). iNOS mRNA was reduced by 58% and 51% (P<0.05) in microglia. The subsequent release of TNF-α was reduced by 55% and 43% (P<0.05) and NO reduced by 53% and 34% (P<0.05) in the supernatant of neuron-glia cultures. Cinnabar had no inhibitory effect on LPS-induced changes. CONCLUSION: AGNH protects LPS-induced neurotoxicity through its anti-inflammatory properties and realgar might be the key contributor to the neuroprotective action of AGNH, while cinnabar fails to show any neuroprotection.
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104 patients of craniopathy with unconsciousness were treated with Angong-Niuhuang Pills (ANP) for a prospective random study. In 104 patients of Group A, ANP seemed to be an efficient drug to 79 patients (76%). 13 of them were on the mend with degree I consciousness. 4, 23, 24, 10 and 5 of the patients with degree II, III, IV, V and VI consciousness respectively. 25 patients failed to respond to medical treatment (24%). In 104 patients of Group B without ANP treatment, only 43 patients responded to other medical treatment (41%). 8, 4, 18, 9, and 4 patients took a turn for the better and got degree I, II, III, IV and V consciousness respectively. Inefficiency was observed among 61 patients (59%). Thus, there was a significant difference between the two groups statistically (P less than 0.005).
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Based on the therapeutic claims of Angong Niuhuang pill, a series of pharmacodynamic experiments were designed, where pharmacological effects were investigated comparatively with its simplified prescription(realgar and cinnabar are removed from the original pill) as a parallel control in order to explore possible contribution of cinnabar and realgar to pharmacodynamic activities of the pill as a whole. Anti-pyretic, sedative, anti-convulsive, and mice-protected effects of the pill and its simplified prescription as a control were observed, respectively, in rabbits with fever induced by typhoid bacillus, in pentobarbital sodium-induced sleeping mice, in mice with convulsion induced by strychnine, or pentylenetetrazole, and in mice with anoxia induced by NaNO2. Both the pill and its simplified prescription were found to have Anti-pyretic action and protective effect against the mouse death induced by anoxia, and synergistic interaction with pentobarbital sodium in sedative activity, although neither of them was found to have any effects on the convulsion of mice. No significant difference between Angong Niuhuang pill and its simplified prescription was found in the above pharmacodynamic experiments.
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The conformational changes of bovine heart cytochrome c (cyt c) induced by the adsorption on gold nanoparticles with different sizes have been investigated by electronic absorption, circular dichroism (CD), and Fourier transform infrared spectra. The combination of these techniques can give complementary information about adsorption-induced conformational changes. The results show that there are different conformational changes for cyt c adsorbed on gold nanoparticles with different sizes due to the different interaction forces between cyt c and gold nanoparticles. The colloidal gold concentration-dependent conformation distribution curves of cyt c obtained by analysis of CD spectra using the singular value decomposition least-squares method show that the coverage of cyt c on the gold nanoparticles surface also affects the conformational changes of the adsorbed cyt c.