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Berberine: Therapeutic potential of an alkaloid found in several medicinal plants

Authors:
  • Pinnacle Dermatology

Abstract

Berberine-containing plants are used medicinally in virtually all traditional medical systems, and have a history of usage in Ayurvedic and Chinese medicine dating back at least 3,000 years. Berberine has demonstrated significant antimicrobial activity against bacteria, fungi, protozoans, viruses, helminths and chlamydia. In addition, berberine's actions include: antagonism of the effects of cholera and E. coli heat-stable enterotoxin, inhibition of intestinal ion secretion, inhibition of smooth muscle contraction, inhibition of ventricular tachyarrhythmias, reduction of inflammation, elevation of platelet count in patients with primary and secondary thrombocytopenia, and stimulation of bile secretion and bilirubin discharge. Berberine's most common clinical uses include: bacterial diarrhea, intestinal parasites, and ocular trachoma infections. Evidence also suggests intravenous berberine administration can play a role in preventing the onset of reentrant ventricular tachyarrhythmias and sudden coronary death after myocardial ischemie damaqe.
Page 94 Alternative Medicine Review Volume 2, Number 2 1997
Berberine: Therapeutic Potential of an
Alkaloid Found in Several Medicinal Plants
Timothy C. Birdsall, N.D. and Gregory S. Kelly, N.D.
Abstract
Berberine-containing plants are used medicinally in virtually all traditional medical
systems, and have a history of usage in Ayurvedic and Chinese medicine dating back
at least 3,000 years. Berberine has demonstrated significant antimicrobial activity against
bacteria, fungi, protozoans, viruses, helminths and chlamydia. In addition, berberine’s
actions include: antagonism of the effects of cholera and E. coli heat-stable enterotoxin,
inhibition of intestinal ion secretion, inhibition of smooth muscle contraction, inhibition
of ventricular tachyarrhythmias, reduction of inflammation, elevation of platelet count in
patients with primary and secondary thrombocytopenia, and stimulation of bile secretion
and bilirubin discharge. Berberine’s most common clinical uses include: bacterial
diarrhea, intestinal parasites, and ocular trachoma infections. Evidence also suggests
intravenous berberine administration can play a role in preventing the onset of reentrant
ventricular tachyarrhythmias and sudden coronary death after myocardial ischemic
damage.
(
Alt Med Rev
1997;2(2):94-103)
Berberine is an alkaloid present in a number of clinically-important medicinal plants,
including Hydrastis canadensis (goldenseal), Coptis chinensis (coptis or goldenthread), Berb-
eris aquifolium (Oregon grape), Berberis vulgaris (barberry), and Berberis aristata (tree tur-
meric) (See Table 1 for a list of these plants and the part used medicinally). Extracts and decoc-
tions of these plants have been used in Ayurvedic and Chinese medicine for at least 3000 years.
Berberine has been shown to exhibit significant antimicrobial activity against a variety of bac-
teria,1-7 fungi,1,8, 9 protozoans,1,10-16 helminths,17 chlamydia,18-20 and viruses. 21 In addition to this
antimicrobial activity, berberine has been found to have numerous pharmacological effects.
Amin et al screened a total of 54 microorganisms for sensitivity to berberine, and found
the alkaloid possesses antimicrobial activity against gram-positive and gram-negative bacteria,
fungi, and protozoa (see Table 2). In addition to those listed, Mycobacterium tuberculosis,
Trichophyton mentagrophytes, and some strains of E. coli, Klebsiella pneumoniae, and Crypto-
coccus neoformans exhibited moderate sensitivities. Berberine has been shown to inhibit HIV-
1 reverse transcriptase.21
Bacterial Diarrhea
Much of the research on berberine has focused on its use in cases of diarrhea, including
that caused by Vibrio cholerae1-4 and Escherichia coli.2,3,5,6 Studies have demonstrated a direct
antibacterial effect of berberine against V. cholerae,1 and berberine has been shown to inhibit
the intestinal secretory response caused by E. coli heat-stable enterotoxin (ST)22 and V. cholerae
Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprints Without Written Permission
Alternative Medicine Review Volume 2, Number 2 1997 Page 95
enterotoxins.2-4 In addition to its direct anti-
microbial action, berberine has also been
shown to block the adherence of Strep.
pyogenes6 and E. coli7 to erythrocytes and epi-
thelial cells. Thus, it is possible berberine ex-
erts an antibiotic effect, even against organ-
isms that do not exhibit in vitro sensitivity to
the alkaloid.
A series of 63 adult males with
enterotoxigenic E. coli (ETEC) diarrhea of
similar clinical characteristics were serially
assigned to either an experimental
group or a control group by use of a
random number table. Thirty-three
people were given a single dose of 400
mg berberine sulfate (BS) orally. The
control group received no treatment.
Both groups received IV rehydration
therapy, and were observed for a period
of 24 hours. During the total observa-
tion period, the experimental group had
a 48% reduction in mean stool volumes
compared with the controls (p<0.05).
Also, when compared with the control
group, significantly more of those re-
ceiving BS stopped having liquid diar-
rheal stools during the observation pe-
riod (42% vs. 20%, p<0.05).2
Berberine has been shown to
inhibit the intestinal secretory response
due to cholera toxins. Using a ligated
rabbit intestinal loop model, Sack and
Froehlich3 were able to demonstrate a
significant suppression of the intestinal
secretory response following exposure to V.
cholerae crude enterotoxin. This effect was
similar whether the berberine was
administered immediately prior to the cholera
toxin, or as long as four hours after exposure
(p<0.02), and did not require direct mucosal
contact to be effective. In discussing their
results, the authors note, “...it is also of clinical
importance the berberine has not been reported
to have significant side effects at the doses used
clinically in humans (5 to 10 mg/kg per day
orally)....”3
In patients with cholera, analysis by
factorial design equations revealed a reduc-
tion in diarrheal stools by one liter and a re-
duction in cyclic adenosine monophosphate
concentrations in stools by 77% in the groups
given berberine.23 In other studies of diarrhea
due to Vibrio cholerae and ETEC, berberine
(200 mg) reduced stool volumes 30-50% in
diarrheal patients without significant side ef-
fects.24 Berberine’s effectiveness in reducing
Latin Name Common Name Part Used
Berberis aquifolium Oregon Grape Rhizome, Roots
Berberis aristata Tree Turmeric Root
Berberis vulgaris Barberry Outer Bark of Stem, Root
Coptis chinensis Coptis or Goldenthread Rhizome
Hydrastis canadensis Goldenseal Rhizome, Root
N+
O
O
OCH3
H3CO
Chemical Structure of Berberine
Berberine
Table 1. Selected Berberine-Containing Plants and Part of Plant Used Medicinally
Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprints Without Written Permission
Page 96 Alternative Medicine Review Volume 2, Number 2 1997
water and electrolyte secretions induced by ST
and cholera toxin appear to be enhanced in a
dose-dependent manner.3,5
While the precise mechanism of action
of berberine remains to be elucidated, in
addition to the direct bacteriocidal action,
several other mechanisms may account for its
ability to inhibit infectious diarrhea. Metabolic
inhibition of certain organisms,1 inhibition of
the formation of toxins, direct antagonism of
the toxins,25 inhibition of intestinal ion
secretion, 26,27 and inhibition of smooth muscle
contraction27-29 may all play a role in this plant
extract’s antidiarrheal activity.
The antidiarrheal properties of
berberine may be mediated, at least in part, by
its ability to delay small intestinal transit
time.30-32 Berberine has been shown to block
muscarinic receptors 33 and to exhibit a
noncompetitive inhibition of the contractile
response induced by acetylcholine, thus acting
to inhibit spontaneous peristalsis in the
intestine.34 In animal studies, the transit of the
small intestine was significantly delayed at 15
and 100 minutes after the highest doses of
BS.31 In humans, 1.2 grams of berberine
significantly delayed small intestine transit
time after an oral dose.32
Intestinal Parasites
Berberine sulfate has been shown to
possess growth inhibitory activity against Gia-
rdia lamblia, Trichomonas vaginalis, and En-
tamoeba histolytica in axenic culture.13 It was
observed the crude extract was more effective
than the salt. The greater inhibitory activity of
the crude extract may be due to the cumula-
tive contributions of berberine along with other
alkaloids and pharmacologically active con-
stituents.12
Subbaiah and Amin reported that BS
was effective against the protozoan Entamoeba
histolytica in a study that evaluated both in
vitro and in vivo outcomes. In vitro testing in-
dicated berberine “...is amebicidal at a con-
centration of 0.5-1.0 mg/ml, and that it acts
rapidly.” After addition of berberine, morpho-
logical changes could be observed in the tro-
phozoites, including encystation, degenera-
tion, and lysis. Preliminary results also indi-
cated berberine may be cysticidal as well.10
Golden hamsters were given either 3
or 5 mg/kg body weight of BS orally three
times at 4-hour intervals. The initial dose was
given prior to intrahepatic infection with E.
histolytica, the second at the time of infection,
and the third 4 hours later. At 5 mg/kg, 100%
of the animals showed normal livers upon
necropsy four days later with no trophozoites
found, while at 3 mg/kg, 33% showed small
hepatic abscesses. In the control group, 75%
of the animals demonstrated liver abscesses
with trophozoites. Similar results were found
in rats infected with E. histolytica via the
intestinal tract, where the control group
developed intestinal amebiasis while the
berberine group did not.10
Bacillus pumilus
B. cereus
B. subtilis
Corynebacterium diphtheriae
Shigella boydii
Staphylococcus aureus
S. albus
Streptococcus pyogenes
Vibrio cholerae
Candida utilis
C. albicans
C. tropicalis
C. glabrata
Sporotrichum schenkii
Entamoeba histolytica
Giardia lamblia
Trichomonas vaginalis
Leishmaniasis sp.
Table 2. Microorganisms Sensitive
In Vitro To Berberine1,9,10,13,14
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Alternative Medicine Review Volume 2, Number 2 1997 Page 97
Giardia lamblia, another common pro-
tozoan infecting humans, has also been found
to be sensitive to berberine. Nearly 20 years
ago, Choudhry et al reported on 40 children
(ages 1-10 years) infected with Giardia, who
received either B-vitamin syrup (which they
termed “a placebo”), berberine (5 mg/kg/day)
or metronidazole (10 mg/kg/day). The sub-
stances were administered in three divided
doses for 6 days. Following the placebo, 15%
of the subjects became symptom-free and 25%
demonstrated no Giardia in the stool. After
taking berberine, 48% became asymptomatic
and 68% were Giardia-free upon stool analy-
sis. All of those receiving metronidazole
showed no Giardia remaining, but only 33%
of them had resolution of symptoms.16
In another study, a total of 137 chil-
dren (ages 5 months to 14 yr, mean age 5 yr)
with documented Giardiasis were given either
5 mg/kg/day or 10 mg/kg/day of berberine in
divided doses, for a period of either 5 or 10
days. They were then compared with 242 sub-
jects placed on conventional therapy, includ-
ing 88 who received metronidazole (20 mg/
kg/day for 5-7 days). Ninety percent of those
receiving berberine (10 mg/kg/day for 10 days)
had negative stool specimens after 10 days,
and 83% remained negative one month later,
which compared favorably with those treated
with metronidazole (95% and 90%, respec-
tively). The author concludes by citing
berberine’s “...convenience of administration
and freedom from unpleasant side effects.”11
In visceral Leishmaniasis, berberine
has also shown significant effectiveness. One
percent BS inoculated intralesionally on four
occasions at weekly intervals was found to be
highly effective against cutaneous
leishmaniasis in domestic dogs.35 Berberine
was evaluated in golden hamsters infected with
L. donovani amastigotes in two separate trials.
In the 8-day model, berberine was
administered intraperitoneally at 50 and 100
mg/kg/day for 4 days beginning on the third
day following infection, and compared with
infected controls. On necropsy, the liver
parasite burden was determined: the 50 and
100 mg/kg/day berberine groups showed 0.86
+/- 0.09 and 0.65 +/-0.10 cells x 108
respectively, compared with infected controls
which showed 1.67 +/- 0.63 cells x 108
(p<0.05).15
In an extended 60-day model,
uninfected hamsters, infected controls, and
infected animals treated with berberine were
observed. The experimental group was
administered berberine intraperitoneally (50
mg/kg/day) for 5 days, beginning 1 month after
infection. After a five-day interval the
berberine course was repeated. Upon
evaluation, the berberine group was found to
have a reduction in both liver and spleen
parasite burden of 90% compared to infected
controls (p<0.001). In addition, leukocyte
counts were normalized: normal hamsters =
9343 +/- 1627; infected controls = 2862 +/-
534; berberine group = 7112 +/- 13.7 cells/
mm3 (p<0.001). “In vivo, berberine was found
to be as effective as pentamidine and had the
advantage of being better tolerated.”15
Ocular Trachoma Infections
Aqueous solutions of berberine have
also been employed in cases of ocular infec-
tions, especially those resulting from Chlamy-
dia trachomatis.18-20 Fifty-one people attend-
ing an out-patient eye clinic having stage I or
stage II trachoma lesions were recruited into
the study. Subjects were divided into three
groups: Group I received 0.2% berberine chlo-
ride eye drops, 2 drops per eye 3 times daily
for 3 weeks; Group II received eye drops con-
taining 0.2% berberine chloride plus 20% sul-
facetamide according to the same schedule;
Group III received eye drops containing only
20% sulfacetamide.
After 3 weeks, subjects in Group III
had a slightly better clinical improvement as
judged by conjunctival congestion, number of
Berberine
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Page 98 Alternative Medicine Review Volume 2, Number 2 1997
follicles and papillary reaction. The
conjunctival scrapings of all subjects in Group
III still tested positive for C. trachomatis, and
these subjects were likely to have a relapse of
symptoms. Subjects in Groups I and II showed
a significant improvement in symptoms
compared to their initial examination, and
following the experimental period had only
very mild symptoms remaining. All subjects
in Groups I and II had conjunctival scrapings
which were negative for C. trachomatis. Those
in Groups I and II had no incidence of relapse
up to one year later.19
To further determine if these anti-tra-
choma effects were related to direct anti-
chlamydial properties of berberine or to host-
mediated factors, a series of in vitro and in
vivo experiments were carried out using chick
embryos. Three different C. trachomatis iso-
lates were incubated in vitro with 0.2% ber-
berine chloride prior to inoculation into chick
embryos. A different set of embryos was ini-
tially infected with the C. trachomatis isolates,
and then subsequently given 3 doses of 0.2%
berberine chloride. The in vitro incubation of
C. trachomatis with berberine had no effect in
reducing the lesion scores or mortality of the
organism, whereas administration of the ber-
berine to infected embryos resulted in elimi-
nation of both lesion and mortality. This sug-
gests that, with C. trachomatis, berberine’s
method of action is by “...stimulating some
protective mechanism in the host.”19
The clinical serological response to
topical treatment of trachoma with berberine
was studied in 32 microbiologically confirmed
cases. Efficacy of berberine 0.2% when com-
pared to sulfacetamide 20% was found to be
superior in both the clinical course of trachoma
and in achieving a fall in serum antibody ti-
ters against chlamydia trachomatis.36
Cardiovascular Effects
Experimental results in animals and
clinical trials in humans suggest intravenous
berberine may be effective in preventing the
onset of reentrant ventricular tachyarrhythmias
and sudden coronary death after myocardial
ischemic damage.37
In vitro, berberine increases, in a
concentration-dependent manner, the action
potential duration in canine Purkinje and
ventricular muscle fibers without effecting
other parameters of the action potential. The
authors suggest, “...berberine exerts Class III
antiarrhythmic and proarrhythmic actions in
cardiac muscle of the dog in vitro.”38
In 18 dogs with ischemic left ventricu-
lar failure, berberine was able to improve
impaired left ventricular function by its posi-
tive inotropic effect and mild systemic vasodi-
lation.39 Berberine increased coronary artery
flow of anesthetized open-chest canines and
isolated guinea pig hearts. Rabbits were pro-
tected by berberine from ischemic ECG
changes caused by posterior pituitary hor-
mones. Spasm of isolated swine coronary ar-
terial rings was prevented and treated effec-
tively by berberine.40
In humans, 12 patients with refractory
congestive heart failure were studied before
and during berberine intravenous infusion at
rates of 0.02 and 0.2 mg/kg per min for 30
minutes. The lower infusion dose produced no
significant circulatory changes, apart from a
reduction in heart rate (14%). The 0.2 mg/kg
per min dose elicited several significant
changes. A 48% decrease in systemic and a
41% decrease in pulmonary vascular resis-
tance, along with a 28% decrease in right
atrium and 32% decrease in left ventricular
end-diastolic pressures were observed. Mea-
surable increases in cardiac index (45%),
stroke index (45%), and left ventricular ejec-
tion fraction (56%) were found. Also noted
were increases in hemodynamic and
echocardiographic indices of left ventricular
performance and a decrease in arteriovenous
oxygen uptake (28%) with no changes in total
body oxygen uptake, arterial oxygen tension,
or hemoglobin dissociation properties.41
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Alternative Medicine Review Volume 2, Number 2 1997 Page 99
The effects of berberine on 100
individuals with ventricular tachyarrhythmias
observed with 24 to 48 hour ambulatory
monitoring has also been reported. The results
indicate 62% of patients had 50% or greater,
and 38% of patients had 90% or greater
suppression of ventricular premature
contractions (VPC). No severe side effects
were observed; however, mild gastro-
enterologic symptoms were reported by some
patients.42
Several mechanisms have been pro-
posed to explain the observed effects of ber-
berine. Zhou observed berberine works as a
Ca2+ channel agonist,43 while Hua and Wang
suggest the antiarrhythmic action of berberine
might be due to its potassium channel block-
ing effects.44 Experiments on the rat fundus
indicate berberine inhibits the entry of extra-
cellular calcium into the cell.45 Evidence also
suggests berberine, by reducing tyrosine hy-
droxylase activity, has an inhibitory effect on
catecholamine biosynthesis.46
Anti-inflammatory
Among berberine’s multiple
pharmacological actions is anti-inflammatory
activity. In vitro, a consistent and progressive
inhibitory influence of berberine with
increasing concentrations was identified with
all mitogens and was most pronounced with
pokeweed mitogen.47 Berberine (20 mg/kg/d)
inhibited platelet aggregation and platelet
adhesion induced by ADP, arachidonic acid,
and collagen in rats. The same dose of
berberine also inhibited thrombus formation.48
Berberine may inhibit the release of
arachidonic acid from cell membrane phos-
pholipids and exerts an effect on arachidonic
acid metabolites. Berberine dose-dependently
inhibits collagen-, ADP-, and arachidonic acid
(AA)-induced thromboxane A2 release from
platelets. Berberine given intravenously low-
ers rabbit plasma level of PGI2.49 While an
extract of the bark from Berberis aquifolium
has been shown to inhibit 5-lipoxygenase with
an IC50 value of 50 microM,50 berberine has
not been shown to exert a significant inhibi-
tory effect.50,51
In experimental animals, berberine has
been shown to reduce the purging effects of
castor oil or Cassia angustifolia leaf,
significantly inhibit drug-induced vascular
permeability, and inhibit drug-induced
swelling in a dose-dependent manner.52
Berberine has shown an inhibitory effect
against induced ear edema in experimental
animals.53
Other Effects
Berberine also has other
immunostimulatory effects. Sabir and Bhide
have reported berberine stimulates blood flow
to the spleen.29 Berberine has been shown to
activate macrophages.54 Berberine sulfate has
demonstrated antipyretic effects in experimen-
tally-induced fevers in rats. This effect has
been found to be approximately three times
greater than the antipyretic effect of sodium
salicylate.55
In vitro, experimental, and clinical re-
sults indicate that berberine is an excellent dis-
infectant for infective deciduous root canal.56
Because of its ability to block adhesion of E.
coli and to suppress synthesis and assembly
of fimbriae by uropathogenic organisms, ber-
berine may be beneficial in E. coli-induced
urinary tract infections.6
Berberine sulfate, given as
monotherapy and in combined treatment 3
times a day for 15 days in a dose of 5 mg 20
minutes before meals, increases platelet count
in patients with primary and secondary throm-
bocytopenia.57
Results indicate berberine has
antinephritic effects partly due to antiplatelet
action and improved renal hemodynamics.
Berberine at doses of 0.5, 1.0 and 5.0 mg/kg/
day, i.p., was effective in inhibiting urinary
protein excretion, elevation of serum
Berberine
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Page 100 Alternative Medicine Review Volume 2, Number 2 1997
cholesterol and creatinine levels, and
glomerular histopathological changes. In
addition, berberine given orally at 20 mg/kg/
day inhibited urinary protein excretion
throughout the experimental periods.
Berberine inhibited platelet aggregation in
both in vitro and in vivo assays, and inhibited
the decline of renal blood flow. Berberine also
inhibited an increase in thromboxane B2
formation, and increased the formation of 6-
keto-prostaglandin F1 alpha in platelets and
isolated glomeruli.58
The excretion of bilirubin has been
found to be stimulated by the acute adminis-
tration of berberine, although the effect dimin-
ished with chronic administration.59 Berberine,
in vitro, has been shown to be a potent
displacer of bilirubin. In vivo administration
of berberine to adult rats resulted in a signifi-
cant decrease in mean bilirubin serum protein
binding, due to a displacement effect and a
persistent elevation in steady-state serum con-
centrations of unbound and total bilirubin,
possibly due to inhibition of metabolism.60
The accumulation of tyramine and its
derivatives in individuals with cirrhosis is as-
sociated with lowered peripheral resistance,
high cardiac output, reduced renal function,
and cerebral dysfunction. Berberine (600-800
mg/day) was shown to correct the
hypertyraminemia in patients with liver cir-
rhosis, thus indicating its possible use as an
adjunctive supplement.61
Experimental evidence suggests ber-
berine increases the concentration of polar
drugs in the skin when applied concurrently
as a topical preparation; it also enhances skin
permeation in a manner similar to surfactants.62
Dosage and Toxicity
Berberine is generally considered to be
nontoxic at doses used in clinical situations.
Berberine shows no genotoxic activity; is
unable to induce significant cytotoxic,
mutagenic or recombinogenic effects; and it
is not a potent mutagenic agent in dividing
cells.63 The LD50 of berberine sulfate in mice
is approximately 25 mg/kg, while intravenous
administration of berberine to dogs at doses
up to 45 mg/kg does not produce gross toxic
effects.29 High doses of berberine can result in
the following side effects: lowered blood
pressure, dyspnea, flu-like symptoms,
gastrointestinal discomfort, and cardiac
damage. Most berberine-containing plants are
considered uterine stimulants or
emmenogogues, so historically it has been
recommended they be used with care during
pregnancy. Because of these considerations
and because of berberine’s ability to displace
bilirubin, the use of berberine should be
avoided in pregnant women, as well as
jaundiced neonates.
The therapeutic dose of berberine for
conditions responsive to oral supplementation
is typically 200 mg two or three times daily.
Summary
Berberine-containing plants have been
used in traditional and folk medicine around
the world for centuries. Many of these uses
have centered around conditions caused by
various micro-organisms, including bacteria
and parasites. Current scientific research has
not only validated these historic applications,
but also provided valuable insight into the
mechanisms by which this alkaloid acts on
organisms and tissues. Because of the wide
variety of pharmacologic actions of berberine,
it is likely future research will identify other
clinical conditions which are responsive to
supplementation of berberine-containing
plants or with the alkaloid berberine.
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Berberine
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... Furthermore, the leaves and fruits have also found applications in the production of food flavorings and teas. Berberis are popular due to their nutritional importance; however, they have found most usefulness in folk and traditional medicine where various parts, including roots, bark, leaves and fruits serve as major ingredients of herbal remedies in Ayurvedic, Iranian and Chinese medicine dating back at least 3000 years [6]. Currently, this species flower is popularly used amongst Tibetan speaking population in areas, such as Litang, China [7]. ...
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The genus Berberis includes about 500 different species and commonly grown in Europe, the United States, South Asia, and some northern areas of Iran and Pakistan. Leaves and fruits can be prepared as food flavorings, juices, and teas. Phytochemical analysis of these species has reported alkaloids, tannins, phenolic compounds and oleanolic acid, among others. Moreover, p-cymene, limonene and ocimene as major compounds in essential oils were found by gas chromatography. Berberis is an important group of the plants having enormous potential in the food and pharmaceutical industry, since they possess several properties, including antioxidant, antimicrobial, anticancer activities. Here we would like to review the biological properties of the phytoconstituents of this genus. We emphasize the cultivation control in order to obtain the main bioactive compounds, the antioxidant and antimicrobial properties in order to apply them for food preservation and for treating several diseases, such as cancer, diabetes or Alzheimer. However, further study is needed to confirm the biological efficacy as well as, the toxicity.
... [202] Due to the broad spectrum of antimicrobial activity, the extract of berberine-containing plants or berberine was used as a folklore remedy to get rid of dysentery and infectious diarrhea in China for centuries. [203] It was also reported that berberine-containing natural medicine can be used for the treatment of food allergy. [204] Microbial biosynthesis of berberine can decrease doubling times so that it has better productivity than plant cell cultures. ...
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Plant natural products have been particularly important due to their use in food, cosmetic, and pharmaceutical industries. In particular, Traditional Chinese Medicine provides a precious potential for the discovery of bioactive natural products and development of novel modern medicines. However, the existing production methods for plant natural products such as chemical synthesis and plant extraction does not meet the current demand. Due to their environmental and economic concerns, engineered production of valuable natural products in microbial hosts has become an attractive alternative platform. This review covers the recent advances in the engineered production of plant natural products in microorganisms. A special focus was placed on the biotechnological production of plant-derived terpenoids, flavonoids, and alkaloids. Some successful examples of engineered production of plant natural products (or their precursors) such as artemisinin, paclitaxel, naringenin, quercetin, berberine, and noscapine are summarized. This clearly indicates that the engineered production method is a promising approach with various advantages over current methods.
... Barberry extracts have been used in Ayurveda and Chinese medicine for more than 3000 years. Berberine is reported to have anti-microbial properties and is active against a wide range of bacteria, fungi, protozoans, flatworms, chlamydia and viruses [24]. Berberine was also used in China to colour paper and silk and as protection from damage by insects [25]. ...
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This article has been published in the Bulletin of The International Association of Forensic Toxicologists (TIAFT Bulletin 2021, volume LI, number 2, pages 46-52). Prologue "Which molecule is shown on the cover this time?" asked KS as the latest (12th) edition of Baselt's 'Disposition of Toxic Drugs and Chemicals in Man' landed in our lab. The answer was a look of astonishment. "Haven't you noticed that there is a different structure shown on the cover of each edition?" We looked and, of course, didn't recognise the structure. The book did not reveal the identity either in the legal disclosure (Impressum) or the Foreword and so we began to search the 12th edition page by page-almost all 2343 of them! We compared the structure with that on each page and we had searched almost 75% of the entries when we found the answer: sanguinarine. We then thought: "which structures are shown on the covers of the previous editions?" and started to peruse the available volumes (8th to 11th) in our laboratory. We searched the Internet for earlier editions but it was quite clear that they would not be easy to find. We borrowed some earlier editions from colleagues and after several months of research, we acquired the 1st and 3rd editions. The series was almost complete except for the 6th edition which was unavailable apart from an Internet offer for 1200 USD!
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Polycystic ovary syndrome (PCOS) is the most frequent endocrine-metabolic disorder among women at reproductive age. The diagnosis is based on the presence of at least two out of three criteria of the Rotterdam criteria (2003). In the last decades, the dysmetabolic aspect of insulin resistance and compensatory hyperinsulinemia have been taken into account as the additional key features in the etiopathology of PCOS, and they have been widely studied. Since PCOS is a complex and multifactorial syndrome with different clinical manifestations, it is difficult to find the gold standard treatment. Therefore, a great variety of integrative treatments have been reported to counteract insulin resistance. PCOS patients need a tailored therapeutic strategy, according to the patient’s BMI, the presence or absence of familiar predisposition to diabetes, and the patient’s desire to achieve pregnancy or not. The present review analyzes and discloses the main clinical insight of such complementary substances.
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Berberine (BBR) is a pentacyclic benzylisoquinoline alkaloid that can be found in diversity of medicinal plants. BBR has a wide range of pharmacological bioactivities, in addition when administrated orally, it has a broad safety margin. It has been used as an antidiarrheal, antimicrobial, and anti-diabetic drug in Ayurvedic and Chinese medicine. Several scholars have found that BBR has promising renoprotective effects against different renal illnesses, including diabetic nephropathy, renal fibrosis, renal ischemia, renal aging, and renal stones. Also, it has renoprotective effects against nephrotoxicity induced by chemotherapy, heavy metal, aminoglycosides, NSAID, and others. These effects imply that BBR has an evolving therapeutic potential against acute renal failure and chronic renal diseases. Hence, we report herein the beneficial therapeutic renoprotective properties of BBR, as well as the highlighted molecular mechanism. In conclusion, the studies discussed throughout this review will afford a comprehensive overview about renoprotective effect of BBR and its therapeutic impact on different renal diseases.
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Berberine, a traditional Chinese medicine, was found to exhibit anticoccidial activity. However, its mechanism is unclear. Trace metals such as copper and zinc are extremely low (less than 0.01% of the total weight of the body) but play a vital role in organisms. In the present study, we investigated the effect of berberine on copper and zinc levels in chickens infected with Eimeria tenella. Firstly, our data confirmed that infected chickens with E. tenella exhibited classic impairment on the 8th day of post infection, such as weight loss and increased feed conversion. Further study showed that E. tenella infection decreased the contents of copper and zinc in the liver and serum of chickens. Berberine was similar to amprolium and significantly improved the pathogenic conditions. Berberine could restore copper and zinc imbalance caused by E. tenella in chickens to a large extent. Studies on the development of cecum lesions demonstrated that the protective effect of berberine on the intestinal cecum was similar to that of the Cu/Zn mixture. Additionally, the mRNA expression of several metal transport related genes of the chick small intestine, including zinc transporter 1, copper transporter 1 and divalent metal ion transporter 1, was elevated by the treatment with berberine. Taken together, we speculate that the anticoccidial activity of berberine may be related to the maintenance of certain metals (Cu/Zn) homeostasis by affecting mRNA expression of their transport genes. However, the mode of action of BBR on these vital metals in the chicks infected with E. tenella still needs to be further studied.
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Introduction Clostridioides difficile infection (CDI) remains a worldwide clinical problem. Increased incidence of primary infection, occurrence of hypertoxigenic ribotypes, and more frequent occurrence of drug resistant, recurrent and non-hospital CDI, emphasizes the urgent unmet medical need of discovering new therapeutic targets for drug development to quell CDI. Areas covered We searched PubMed and Web of Science databases for articles identifying novel therapeutic targets or treatments for C. difficile from 2001 to 2021. We present an updated review on current preclinical efforts on designing inhibitory compounds against these targets, which include adhesins, biofilms, p-cresol biosynthetic pathway, spores, phage, fatty acid synthesis enoyl-acyl carrier protein reductase II (FabK), and toxins, and indicate how these drug targets could become the focus of future therapeutic approaches. We also evaluate the increasing exploitability of gut microbial-derived metabolites and host-derived therapeutics targeting VEGF-A, immune targets and pathways, ion transporters, and microRNAs as anti-C. difficile therapeutics, which have yet to reach clinical trials. Our review also highlights the therapeutic potential of re-purposing currently available agents such Auranofin, Diiodohydroxyquinoline, Ronidazole, and natural products, for the management of patients with CDI. We conclude by considering translational hurdles and possible strategies to mitigate these problems. Expert opinion Considerable progress has been made in the development of new anti-CDI drug candidates. Nevertheless, a greater comprehension of CDI pathogenesis and host-microbe interactions, informed by a systems biology high-throughput interrogation of multidimensional omics and whole structural data, coupled with comparative genomics, is beginning to uncover potential novel therapeutic targets, which can be exploited to plug gaps in the CDI drug discovery pipeline.
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Phytochemicals are plant-derived bioactive compounds, which have been widely used for therapeutic purposes. Due to the poor water-solubility, low bioavailability and non-specific targeting characteristic, diverse classes of nanocarriers are utilized for encapsulation and delivery of bio-effective agents. Cell-derived nanovesicles (CDNs), known for exosomes or extracellular vesicles (EVs), are biological nanoparticles with multiple functions. Compared to the artificial counterpart, CDNs hold great potential in drug delivery given the higher stability, superior biocompatibility and the lager capability of encapsulating bioactive molecules. Here, we provide a bench-to-bedside review of CDNs-based nanoplatform, including the bio-origin, preparation, characterization and functionalization. Beyond that, the focus is laid on the therapeutic effect of CDNs-mediated drug delivery for natural products. The state-of-art development as well as some pre-clinical applications of using CDNs for disease treatment is also summarized. It is highly expected that the continuing development of CDNs-based delivery systems will further promote the clinical utilization and translation of phyto-nanomedicines.
Chapter
Berberine is commonly used in Eastern countries due to its various biological activities and low cost. However, low permeability has limited its bioavailability. This study was conducted to fabricate solid lipid nanoparticles (SLNs) containing berberine by spray-drying method to enhance its absorption in the human body. SLNs containing berberine was prepared by stearic acid as a solid lipid base and various surfactants. Then, the aqueous dispersion of SLNs was converted into powders to be stored over a long time by the spray-drying method with carbohydrate carriers. The spray-drying parameters such as the inlet and outlet temperatures, the blower speed, the atomizing pressure, the feeding rate were optimized. The nanoparticles physicochemical properties were evaluated before and after the spraying process. The lipid nanoparticles containing berberine were successfully prepared by the spray-drying method with a small particle size (around 230 nm), zeta potential (approximately −30 mV), and homogenous dispersion (polydispersity index just above 0.12). The optimized spray drying parameters were Tinlet/outlet of 110/65 °C, the blower of 0.58 m³/min, atomizing of 20 kPa, and feeding rate of 0.1 L/h. The resulted SLNs exhibited good physical stability and redispersion. The collected SLNs by spray-drying could be considered a potential drug delivery system to enhance berberine absorption into our human body.
Article
Liver diseases are life‐threatening illnesses and are the major cause of mortality and morbidity worldwide. These may include liver fibrosis, liver cirrhosis, and drug‐induced liver toxicity. Liver diseases have a wide prevalence globally and the fifth most common cause of death among all gastrointestinal disorders. Several novel therapeutic approaches have emerged for the therapy of liver diseases that may provide better clinical outcomes with improved safety. The use of phytochemicals for the amelioration of liver diseases has gained considerable popularity. Berberine (BBR), an isoquinoline alkaloid of the protoberberine type, has emerged as a promising molecule for the treatment of gastrointestinal disorders. Accumulating studies have proved the hepatoprotective effects of BBR. BBR has been shown to modulate multiple signaling pathways implicated in the pathogenesis of liver diseases including Akt/FoxO2, PPAR‐γ, Nrf2, insulin, AMPK, mTOR, and epigenetic pathways. In the present review, we have emphasized the important pharmacological activities and mechanisms of BBR in liver diseases. Further, we have reviewed various pharmacokinetic and toxicological barriers of this promising phytoconstituent. Finally, formulation‐based novel approaches are also summarized to overcome the clinical hurdles for BBR.
Article
Berberine, an alkaloid from Berberis aristata Linnaeus, may be a useful drug for the treatment of visceral leishmaniasis. In both the 8-day and long-term models of Leishmania donovani infection in hamsters, it markedly diminished the parasitic load and proved to be less toxic than pentamidine. It rapidly improved the hematological picture of infected animals. Like pentamidine, it inhibited in vitro multiplication of amastigotes in macrophage culture and their transformation to promastigotes in cell free culture. Manometric studies showed that both drugs had inhibitory action on both the endogenous and the glucose-stimulated respiration of amastigotes. They inhibited incorporation of [14C]adenine, [14C]uracil, and [3H]thymidine into nucleic acids, and of [14C]leucine into the protein of amastigotes, indicating an inhibitory action on macromolecular biosynthesis. They also decreased deoxyglucose uptake. Using spectrophotometric, spectrofluorimetric, and circular dichroism techniques, berberine was found to interact in vitro with nuclear DNA from L. donovani promastigotes.
Article
Berberine-containing herbs have been used in folk medicine to relieve neonatal jaundice. In the present investigation, the acute and chronic effects of berberine on bilirubin excretion were studied in rats. Acute doses of berberine were found to increase the secretion of bilirubin in experimental hyperbilrubinemia without affecting the UDP-glucuronyltransferase activity and BSP clearance. Continuous treatment abolished this effect. This apparent tolerance could be attributed to the inhibitory action of chronic berberine treatment on UDP-glucuronyltransferase activity, but the mechanism of this inhibition was not elucidated. Liver microsomal protein concentration, ethylmorphine N-demethylation, and BSP clearance were unchanged.
Article
Subcutaneous injection of cholera toxin in the dorsum of the rat's neck produced local inflammation. Between 1 and 100 mg./kg. doses, the cholera toxin produced swelling which showed a fair dose-response relationship. It was maximal about 27 hour after injecting cholera toxin and completely subsided over 4 days. The rat neck method proposed in this paper compares well in sensitivity and temporal course of swelling with the classic rat paw model of earlier workers. Further, it is found to involve a simpler instrument, obviating the need for anaesthesia and probably less painful to the animals. In control experiments, heat-inactivated toxin, Richardson's TRY medium, cholera vaccine or staphylococcal toxin proved entirely ineffective. The proposed method seems to be one of the most sensitive, also permitting the survival of the animals, which is an added advantage for the chronic immunological study. The method may be useful for the bioassay of cholera toxin batches. Berberine was found to effectively inhibit the local inflammation induced by cholera toxin. The inhibition was dose-dependent. Berberine was more efficacious when injected at the inflammation site. Unlike berberine, hydrocortisone and cyproheptadine did not inhibit this inflammation. Indomethacin (like cycloheximide-Actidione) inhibited swelling only in toxic doses. In the present method, carrageenin or formalin produced local swelling which was inhibited by cyproheptadine and indomethacin, but not by berberine. Also, berberine was far less effective than hydrocortisone in inhibiting chronic cotton-pellet-induced granuloma. The experiments suggested that berberine cannot be considered as a classic anti-inflammatory agent. It is, therefore proposed that inhibition of cholera toxin induced inflammation by berberine is a selective antagonism.
Article
Berberine was found effective against cholera toxin in adult rats in a number of experiments. Berberine at 10 mg/kg prolonged the latent period and significantly reduced incidence and severity of diarrhea induced by 2 and 4 g/kg cholera toxin. Berberine (10 mg/kg) reduced the levels of water and electrolytes in the gastrointestinal tract of rats killed within 4 hr of the oral feeding of cholera toxin. In the ligated 30 cm long intestinal loop preparation, 30 and 100 mg cholera toxin provoked fluid accumulation over 5 hr which was significantly inhibited by 5 mg berberine. 'Raswat', a traditional crude dried preparation of Berberis aristata at 1.2 g/kg dose, inhibited cholera toxin-induced diarrhea and fluid accumulation in the gastrointestinal tract. The study thus supports the traditional use of berberine as an adjuvant in clinical cholera.