Paclitaxel is a chemotherapeutic agent that causes peripheral neuropathy as its major dose-limiting side effect. However, the peripheral neuropathy is difficult to manage. A study we recently ...conducted showed that repetitive administration of aucubin as a prophylactic inhibits paclitaxel-induced mechanical allodynia. However, the mechanisms underlying the anti-allodynic activity of aucubin, which is a major component of Plantaginis Semen, was unclear. In addition to mechanical allodynia, aucubin inhibited spontaneous and mechanical stimuli-induced firing in spinal dorsal horn neurons; however, catalpol, a metabolite of aucubin, did not show these effects. Furthermore, paclitaxel induced the expression of CCAAT/enhancer-binding protein homologous protein, a marker of endoplasmic reticulum (ER) stress, in the sciatic nerve and a Schwann cell line (LY-PPB6 cells); however, this effect was inhibited by aucubin. These results suggest that aucubin inhibits paclitaxel-induced mechanical allodynia through the inhibition of ER stress in peripheral Schwann cells.
The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in 2019 has led to a global health crisis. Mutations of the SARS-CoV-2 genome have impeded the development ...of effective therapeutics and vaccines against SARS-CoV-2. Natural products are important for discovering therapeutics to treat the 2019 coronavirus disease (COVID-19). In the present study, we investigated the antiviral activity of herbal drug extracts from Polygala Root, Areca, and Quercus Bark and natural compounds derived from herbal drug such as baicalin and glabridin, with IC
50
values of 9.5 µg/ml, 1.2 µg/ml, 5.4 µg/ml, 8.8 µM, and 2.5 µM, respectively, against SARS CoV-2 infection in vitro. Certain herbal drug extracts and natural compounds were found to inhibit viral RNA levels and infectious titers of SARS-CoV-2 in a dose-dependent manner. Furthermore, viral protein analyses showed that herbal drug extracts and natural compounds effectively inhibited SARS-CoV-2 in the various entry treatments. Our study revealed that three herbal drugs are good candidates for further in vivo and clinical studies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Chemotherapy-induced peripheral neuropathy (CIPN) manifests as mechanical allodynia and hyperalgesia, and is one of the main adverse effects of chemotherapeutic agents. Currently available ...therapeutic drugs are not sufficiently effective for the management of this adverse effect in the clinic. Therefore, the development of novel therapeutic agents for treating CIPN is necessary. Our previous study suggested the potential of aucubin and pedicularis-lactone (
1
) as active compounds responsible for the anti-allodynic property of Plantaginis Semen. However, the activity of purified
1
has not been evaluated due to its low content in Plantaginis Semen. In the present study,
1
was isolated from Viticis Fructus, as well as viteoid I (
2
) and viteoid II (
3
) during the process of isolation. The purities of isolated
1
,
2
, and
3
were determined as 67.15%, 92.12%, and 86.72%, respectively, by quantitative
1
H-NMR, using DSS-
d
6
as an internal standard. Repeated daily oral administration of these three iridoids at a dose of 15 mg/kg significantly inhibited the PTX-induced mechanical allodynia in mice, suggesting the anti-allodynic activities of
1
,
2
, and
3
. This study provides confirmatory evidence for the anti-allodynic activity of purified
1
and also reveals two additional active iridoids from Viticis Fructus. These three iridoids could be potential candidates for the treatment of CIPN.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Peony root is an important herbal drug used as an antispasmodic analgesic. To evaluate peony roots with different botanical origins, producing areas, and post-harvest processing,
1
H NMR-based ...metabolomics analysis was employed. Five types of monoterpenoids, including albiflorin (
4
), paeoniflorin (
6
), and sulfonated paeoniflorin (
25
), and six other compounds, including 1,2,3,4,6-penta-
O
-galloyl-β-
d
-glucose (
18
), benzoic acid (
21
), gallic acid (
22
), and sucrose (
26
) were detected in the extracts of peony root samples. Among them, compounds
4
,
6
,
18
, and total monoterpenoids including
21
were quantified by quantitative
1
H NMR (qHNMR). Compound
25
was detected in
1
H NMR spectra of sulfur-fumigated white peony root (WPR) extracts indicating that
1
H NMR was a fast and effective method for identifying sulfur-fumigated WPR. The content of
26
, the main factor affecting extract yield, increased significantly in peony root after low-temperature storage for one month, whereas that in WPR did not increase due to the boiling treatment after harvesting. We investigated the impact of preprocessing methods to such analysis for NMR data from commercial samples, resulting that the data matrix transformed from qHNMR spectra and normalized to internal standard were optimum for multivariate analysis. The multivariate analysis demonstrated that among commercial samples derived from
P. lactiflora
, peony root samples in Japanese market (PR) had high contents of
18
and
22
, and red peony root (RPR) samples had high content of monoterpenoids represented by
6
; and among RPR samples, those derived from
P. veitchii
showed higher contents of
18
and
22
than those from
P. lactiflora
. The
1
H NMR-based metabolomics method coupled with qHNMR was useful for evaluation of peony root and would be applicable for other crude drugs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Saposhnikoviae Radix (SR), derived from the dried root and rhizome of
Saposhnikovia divaricata
, is a popular crude drug used in traditional Chinese and Japanese medicine. To evaluate the metabolites ...of
S. divaricata
roots from Mongolia and to investigate their geographical variation, we developed the HPLC method, determined the contents of 9 chromones and 4 coumarins, and conducted multivariate statistical analysis. All Mongolian specimens contained prim-
O
-glucosylcimifugin (
1
) and 4′-
O
-β-
d
-glucosyl-5-
O
-methylvisamminol (
3
), and their total amount (5.04–25.06 mg/g) exceeded the criterion assigned in the Chinese Pharmacopoeia. Moreover, the content of
1
(3.98–20.79 mg/g) was significantly higher in the Mongolian specimens than in Chinese SR samples. The specimens from Norovlin showed the highest contents of
1
and
3
. The total levels of dihydropyranochromones were higher in the specimens from Bayan-Uul. The orthogonal partial least squares-discriminant analysis revealed that the Mongolian specimens tended to be separated into three groups based on growing regions, in which several chromones contributed to each distribution. Furthermore,
1
H NMR analysis revealed that Mongolian specimens had less amount of sucrose and a substantial amount of polyacetylenes. Thus, in this study, the chemical characteristics of Mongolian
S. divaricata
specimens were clarified and it was found that the specimens from the northeast part of Mongolia, including Norovlin, had the superior properties due to higher amounts of major chromones.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Two phenylpropanoid-conjugated iridoids, deglucosyl gaertneroside (
1
) and morindoidin (
2
), were isolated from the leaves of
Morinda morindoides
(Rubiaceae) by activity-guided fractionation using ...an anti-malarial activity assay. The known related iridoids molucidin (
3
) and prismatomerin (
4
), two lignans, abscisic acid, two megastigmanes, and two flavonol glycosides were also identified. The structures of isolated compounds were elucidated using spectroscopic analysis. The isolated compounds were evaluated for anti-malarial activity against the chloroquine/mefloquine-sensitive strains of
Plasmodium falciparum
together with cytotoxicity against adult mouse brain cells. Potent anti-malarial activity of
3
and
4
(IC
50
of 0.96 and 0.80 μM, CC
50
of 1.02 and 0.88 μM, and SI of 1.06 and 1.10, respectively) was shown, while new iridoids
1
and
2
and pinoresinol (
5
) displayed moderate activity (IC
50
of 40.9, 20.6, and 24.2 μM) without cytotoxicity (CC
50
> 50 μM). These results indicate that
1
–
5
may be promising lead compounds for anti-malarial drugs. In addition, our results imply the necessity of the quality control of the extract of
M. morindoides
leaves based on the contents of
1
–
5
in terms of the safety and efficacy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the dose-limiting side effects of cancer chemotherapy. Although the control of CIPN is important, it is difficult to manage with currently ...available therapeutic drugs. Therefore, there is a need for novel therapeutic agents for treating CIPN. Goshajinkigan (GJG) is a Kampo formula composed of ten crude drugs. While GJG has been used for the treatment of CIPN, the active constituents of GJG and their underlying mechanisms of pharmacological effects are still unknown. Our previous study revealed that repetitive oral administration of the water extract of Plantaginis Semen, a crude drug ingredient of GJG, inhibited the mechanical allodynia induced by an intraperitoneal injection of paclitaxel in mice. To elucidate the active compounds of Plantaginis Semen, activity-guided separation of the water extract of Plantaginis Semen was performed. From the active fraction, four iridoids (
1
–
4
) were identified. Repetitive oral administration of aucubin (
1
) at 100 or 30 mg/kg and 100 mg/kg of the fraction
crude 3
primarily comprised of pedicularis-lactone (
3
), showed anti-allodynic activity, suggesting
1
and
3
could be some of the active compounds responsible for the anti-allodynic property of Plantaginis Semen and GJG. Our study establishes that oral administration of
1
has potent anti-allodynic effect in addition to the activity of intraperitoneally administered
1
reported previously. Identification of active anti-allodynic compounds found in Kampo formulations will support the development of novel therapies for the management of CIPN in cancer patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Three phenylpropanoid-conjugated iridoid glucosides, acetylgaertneric acid (
1
), acetyldehydrogaertneroside (
2
), and dehydrogaertneric acid (
10
), together with nine known related iridoid ...glucosides (
3
–
9
,
11
, and
12
), two coumaroyl alkaloids, one benzenoid, and three flavonoid glucosides were isolated from leaves of
Morinda morindoides
(Rubiaceae). Structures of these isolated compounds were determined using spectroscopic analysis. Compounds
1
–
18
and previously isolated compounds (
19
–
29
) were evaluated for anti-trypanosomal activity against
Trypanosoma cruzi
Tulahuen strain (trypomastigote and amastigote) together with cytotoxicity against host cells, new-born mouse heart cells. Among them, molucidin (
21
) and prismatomerin (
22
) exhibited good anti-trypanosomal activity (IC
50
of 4.67 and 5.70 µM, respectively), together with cytotoxicity (CC
50
of 2.76 and 3.22 μM, respectively). Compounds
1
–
18
did not show anti-malarial activity against a chloroquine/mefloquine-sensitive strain of
Plasmodium falciparum
.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In traditional Japanese medicine, Rhei Rhizoma is used as a purgative, blood stasis-resolving and antipsychotic drug. The latter two properties are possibly related to anti-inflammatory effects. ...Microglia regulate inflammation in the central nervous system. M1 microglia induce inflammation, while M2 microglia inhibit inflammation and show neurotrophic effects. This study investigated the effects from water extracts of roots of cultivated
Rheum
species in Nagano Prefecture, Japan (strain C, a related strain to a Japanese cultivar, ‘Shinshu-Daio’; and strain 29, a Chinese strain) and 3 kinds of Rhei Rhizoma available in the Japanese market, and also examined their constituents on the polarization of cultured microglia. All extracts significantly decreased M1 microglia, and strains C and 29 significantly increased M2 microglia. Furthermore, the extracts of both strains significantly increased the M2/M1 ratio. Among the constituents of Rhei Rhizoma, ( +)-catechin (
2
), resveratrol 4′-
O
-β-D-(6″-
O
-galloyl) glucopyranoside (
5
), isolindleyin (
8
), and physcion (
15
) significantly increased the M2/M1 ratio. The contents of the constituents in water extract of each strain were quantified using HPLC. The extracts of strains C and 29 contained relatively large amounts of
2
and
5
; and
2
,
8
, and
15
, respectively. This study showed the water extracts of roots of cultivated
Rheum
strains in Japan had the effects of M2 polarization of microglia, suggesting that these strains become the candidate to develop anti-inflammatory Rhei Rhizoma. Moreover, the suitable chemical composition to possess anti-inflammatory activity in the brain was clarified for the future development of new type of Rhei Rhizoma.
Graphical Abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Dengue virus (DENV) is transmitted to humans by
mosquitoes and is a public health issue worldwide. No antiviral drugs specific for treating dengue infection are currently available. To identify novel ...DENV inhibitors, we analyzed a library of 95 compounds and 120 extracts derived from crude drugs (herbal medicines). In the primary screening, A549 cells infected with DENV-1 were cultured in the presence of each compound and extract at a final concentration of 10 μM (compound) and 100 μg/mL (extract), and reduction of viral focus formation was assessed. Next, we eliminated compounds and extracts which were cytotoxic using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Hirsutine, an indole alkaloid of
, was identified as a potent anti-DENV compound exhibiting high efficacy and low cytotoxicity. Hirsutine showed antiviral activity against all DENV serotypes. Time-of-drug-addition and time-of-drug-elimination assays indicated that hirsutine inhibits the viral particle assembly, budding, or release step but not the viral translation and replication steps in the DENV lifecycle. A subgenomic replicon system was used to confirm that hirsutine does not restrict viral genome RNA replication. Hirsutine is a novel DENV inhibitor and potential candidate for treating dengue fever.
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